Gangguan psikiatrik dan trauma kepala

Jurnal 1
Womens Health Issues. Author manuscript; available in PMC 2012 July 1.
Published in final edited form as:
Womens Health Issues. 2011 Jul-Aug; 21(4 Suppl): S210S217.
doi: 10.1016/j.whi.2011.04.019
PMCID: PMC3132395
NIHMSID: NIHMS292608

Psychiatric Diagnoses and

Neurobehavioral Symptom Severity
Among OEF/OIF VA Patients with
Deployment-Related Traumatic Brain
Injury: A Gender Comparison
Katherine M. Iverson, PhD,1,2,3,7,10,11 Ann M. Hendricks, PhD,2,3,4 Rachel Kimerling, PhD,5
Maxine Krengel, PhD,3 Mark Meterko, PhD,2,3,4 Kelly L. Stolzmann, MS,2,3 Errol Baker,
PhD,2,3 Terri K. Pogoda, PhD,2,3,4 Jennifer J. Vasterling, PhD,6,7 and Henry L. Lew, MD,
PhD8,9
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Abstract
Background

Traumatic brain injury (TBI) has substantial negative implications for the post-
deployment adjustment of Veterans who served in Operation Enduring Freedom (OEF)
and Operation Iraqi Freedom (OIF); however, most research on Veterans has focused on
males. This study investigated gender differences in psychiatric diagnoses and
neurobehavioral symptom severity among OEF/OIF Veterans with deployment-related
TBI.

Methods

This population-based study examined psychiatric diagnoses and self-reported

neurobehavioral symptom severity from administrative records for 12,605 United States
OEF/OIF Veterans evaluated as having deployment-related TBI. Men (n = 11,951) and
women (n = 654) who were evaluated to have deployment-related TBI during a
standardized comprehensive TBI evaluation in Department of Veterans Affairs (VA)
facilities were compared on the presence of psychiatric diagnoses and severity of
neurobehavioral symptoms.

Findings

Posttraumatic stress disorder (PTSD) was the most common psychiatric condition for
both genders, although women were less likely than men to have a PTSD diagnosis. In
contrast, relative to men, women were 2 times more likely to have a depression diagnosis,
1.3 times more likely to have a non-PTSD anxiety disorder, and 1.5 times more likely to
have PTSD with comorbid depression. Multivariate analyses indicated that blast exposure
during deployment may account for some of these differences. Additionally, women
reported significantly more severe symptoms across a range of neurobehavioral domains.

Conclusions

Although PTSD was the most common condition for both men and women, it is also
critical for providers to identify and treat other conditions, especially depression and
neurobehavioral symptoms, among women Veterans with deployment-related TBI.

Keywords: traumatic brain injury, Veterans, women, gender, psychiatric conditions,

neurobehavioral symptoms, post-deployment adjustment

In recent years, concerns about the high rates of traumatic brain injury (TBI) experienced
by Veterans who served in Operation Enduring Freedom (OEF) and Operation Iraqi
Freedom (OIF) have led researchers, policy makers, and the media to pay considerable
attention to the identification and treatment of TBI and its comorbidities. The prevalence
of TBI is between 1220% for OEF/OIF Veterans, with most cases being mild in severity
(Hendricks et al., 2011; Hoge, McGurk, Thomas, Cox, Engel, & Castro, 2008;
Schneiderman, Braver, & Kang, 2008; Tanielian & Jaycox, 2008). Although women are
serving in the military at higher rates than ever before and have expanded their
occupational roles during deployments (Murdoch et al., 2006; Street, Vogt, & Duttra,
2009), the impact of deployment-related TBI on womens health is largely unknown. Yet,
12.7% of the Department of Veterans Affairs (VA) OEF/OIF women patients screen
positive for TBI or report a prior TBI diagnosis (Hendricks et al., 2011).

In Veterans, psychiatric and neurobehavioral disturbances often co-occur with TBI, which
can complicate recovery and add to the challenge of coordination of care (Sayer et al.,
2009). For example, a recent investigation of VA patients with TBI documented in their
medical charts found that nearly two-thirds (63.9%) also had a diagnosis of posttraumatic
stress disorder (PTSD), and large pluralities had diagnoses of depression (46.3%), non-
PTSD anxiety disorders (35.6%), and substance-use disorders (26.2%) documented at
least once in a VA mental health, primary care, or rehabilitation clinic since separation
from the military (Carlson et al., 2010). Despite the potential impact of these conditions,
there exists no published investigation of gender differences in the psychiatric and
neurobehavioral comorbidities of TBI among OEF/OIF Veterans.

Such research is needed in Veterans because a growing literature suggests that women
tend to fare worse than men in terms of psychiatric and neurobehavioral symptoms
following TBI (Colvin et al., 2009; Fann et al., 2004; Jensen & Nielsen, 1990; McCarthy
et al., 2006). For instance, among a health maintenance organization sample with no
history of psychiatric illness, Fann et al. (2004) found that women were at greater risk,
relative to men, for developing psychiatric problems subsequent to TBI. It is unclear,
however, whether these findings would generalize to OEF/OIF VA patients given the
large age range of the sample (i.e., 15 to 95 years old). A meta-analysis of eight studies
concluded that TBI neurobehavioral outcomes were worse in women than in men for
85% of 20 measured outcomes, including memory, headaches, dizziness, fatigue,
irritability, anxiety and depression (Farace & Alves, 2000). Moreover, the sports
concussion literature suggests there may be gender differences in postconcussive
symptom reporting among athletes (Dick, 2009). For example, in a sample of soccer
players with a history of concussion, women reported a significantly higher number of
discrete neurobehavioral symptoms than their male counterparts (Colvin et al., 2009).

Given the growing number of women Veterans seeking care within the VA (Yano et al.,
2010), as well as evidence of gender differences in psychiatric and neurobehavioral
comorbidities of TBI in non-Veteran samples, it is important to determine whether gender
differences exist among OEF/OIF VA patients with deployment-related TBI. This study
examined gender differences in the presence of psychiatric diagnoses and
neurobehavioral symptom severity among the population of OEF/OIF VA patients judged
to have deployment-related TBI. Consistent with the research described above, we
hypothesized that women Veterans would be more likely than their male counterparts to
experience more psychiatric diagnoses as well as more severe neurobehavioral
symptoms.

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Methods
Data Sources

This study used VA administrative data, extracted from the Patient Care Services patient-
level TBI screening database to identify the sub-group of OEF/OIF Veterans who were
judged to have deployment-related TBI during a Comprehensive TBI Evaluation
conducted within the VA between April 1, 2007 and August 7, 2009 (for a detailed
description of the OEF/OIF screened population, see Hendricks et al. 2011). The protocol
was approved by the VA Boston Healthcare System Institutional Review Board (IRB).
We obtained records for this study population from VAs National Patient Care Database,
which includes VA utilization data and some demographic information. Psychiatric
diagnostic information was derived from this VA data. Veterans military service
information (i.e., component, rank, and years of service) was provided by the Department
of Defenses Defense Management Data Center (DMDC) database. DMDC identifiers
were converted to scrambled social security numbers and merged to VA administrative
data. General demographics for the current study population are provided in Table 1.

Table 1
Participant Characteristics, Psychiatric Diagnoses, and Neurobehavioral Symptoms.

Measures

TBI screening and evaluation instruments

The VA is mandated to administer a national TBI screen as part of its electronic medical
records system for clinical reminders to all Veterans who report OEF/OIF deployment.
The screen consists of four sequential sets of questions concerning: 1) Exposure to events
that may increase risk of TBI (i.e., blast or explosion, vehicular or aircraft accident,
fragment or bullet wound above the shoulders, fall); 2) Symptoms that occurred
immediately following the injury (i.e., disorientation, alterations in consciousness,
memory problems); 3) New or exacerbated symptoms following the injury (i.e., memory
problems, dizziness, difficulties with balance, sensitivity to light, irritability, headaches,
sleep problems); and 4) Symptoms that have persisted through the past week. Veterans
who respond positively to one or more problems in each of the four sections are
considered to screen positive for TBI and are eligible for a referral for a Comprehensive
TBI Evaluation.

The Comprehensive TBI Evaluation is conducted by a VA clinician who uses a defined

protocol to assist in making a clinical judgment about whether a TBI occurred and in
developing a treatment plan (Department of Veterans Affairs and Department of Defense,
2009). During this evaluation, the clinician conducts a targeted physical examination and
psychiatric history. The clinician also asks a series of standardized questions about
deployment-related experiences regarding blast exposure and non-blast related head
injuries (i.e., bullet, vehicular accident, fall, or other blunt trauma), as well as pre- and
post-deployment TBIs. Blast exposure is assessed based on patients self-report of the
number of blast exposures experienced during deployment that were associated with an
injury. Response options include 1, 2, 3, 4, and 5 or more blasts. Neurobehavioral
symptoms are assessed using the 22-item Neurobehavioral Symptom Inventory (NSI;
Cicerone & Kalmar, 1995). This self-report measure asks patients to rate the severity of
common postconcussive symptoms (e.g., vision, sleep, headaches, fatigue) over the past
30 days on a 5-point scale, ranging from 0 (none) to 4 (very severe). The Comprehensive
TBI Evaluation also includes an item about the prevalence of general pain over the past
30 days. An exploratory factor analysis (EFA) on the 23 items (22 NSI items, plus pain)
yielded four distinct factors: affective (e.g., irritability, anxiety/tension, fatigue),
somatosensory (e.g., pain, headaches, nausea), cognitive (e.g., poor concentration,
forgetfulness, difficulties making decisions), and vestibular (e.g., loss of balance,
dizziness, poor coordination). The fit of the EFA-based models to the data was verified
using confirmatory factor analysis and is described elsewhere (Meterko et al., 2011).

Psychiatric Diagnoses

Patient-level data from the Comprehensive TBI Evaluation were merged to International
Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM; National
Center for Health Statistics and the Centers for Medicare & Medicaid Services, 2008)
diagnostic codes from VA administrative data. As in previous studies of psychiatric
diagnoses in OEF/OIF VA patients (e.g., Carlson et al. 2010; Kimerling et al., 2010), we
used ICD-9 codes to identify men and women who were diagnosed in VA with PTSD,
depression, non-PTSD anxiety disorders, adjustment disorders and stress reactions,
alcohol-related disorders, drug-related (non-alcohol) disorders, number of psychiatric
diagnoses, and PTSD with comorbid depression (see Note in Table 1 for a list of all ICD-
9 codes used to classify psychiatric diagnoses). Consistent with a previous examination
of psychiatric comorbidities among OEF/OIF Veterans with TBI (Carlson et al., 2010),
we confined our inclusion of psychiatric conditions to those that are most commonly
observed among OEF/OIF Veterans (Seal, Berthenthal, Miner, Sen, & Marmar, 2007).
Less common diagnoses, such as psychotic disorders, were not examined in the current
study. We included ICD-9 codes that were assigned in primary care, mental health,
womens health, rehabilitation or a combination of these outpatient clinics, as well as
those assigned from an acute or extended care inpatient stay during fiscal years (FY)
20072009. A psychiatric diagnosis was considered present when it was listed for a total
of two or more separate outpatient and/or inpatient visits during FY2007-FY2009.

Procedure

The TBI-screened population of OEF/OIF Veterans for our observational period consisted
of 327,633 Veterans. Figure 1 illustrates the screening and subsequent evaluation of
female and male patients in this population. A total of 40,448 women and 287,185 men
were screened for TBI, with rates of positive screens at 10.5% and 21.3%, respectively.
Compared to all screened patients, those with positive TBI screens were about half as
likely to be women (6.3% vs. 12.4%, p<0.01); were 2 years younger, on average (31.6 vs.
33.7; p<0.01), with significantly fewer years of military service (18% with 8 or more
years compared to 27%, p<0.01) [data not shown].

Figure 1
This figure illustrates, among the population of OEF/OIF Veterans who were screened for
TBI during the observation period, the number of female and male patients who screened
positive for TBI, completed a Comprehensive TBI Evaluation, and were judged ...

Approximately half of the women (n = 1,912) and men (n = 31,873) who screened
positive for TBI subsequently completed a Comprehensive TBI Evaluation. Of the
Veterans who completed the evaluation, nearly equivalent proportions of women (34%)
and men (37%) were judged to have deployment-related TBI. Veterans who reported that
they had a TBI prior to or following deployment to Iraq or Afghanistan (n = 6,840) were
excluded from the current analyses. There were no other exclusions based on psychiatric
or medical diagnoses. Thus, the total study sample of 12,605 Veterans was comprised of
654 women and 11,951 men judged to have deployment-related TBI. Compared to all
screened OEF/OIF VA patients, the sample of Veterans judged to have deployment-
related TBI had less than half the proportion of women (5% versus 12%), officers (4%
versus 8%) and Navy/Air Force personnel (9% versus 23%) (Hendricks et al., 2011).

Data Analysis

First, descriptive statistics were generated to determine the percentage of the sample,
stratified by gender, with psychiatric diagnoses and severe neurobehavioral symptoms.
Scores on the neurobehavioral symptom scales (22 NSI items plus pain item) were
dichotomized into none/mild/moderate (mean scale score < 3) or severe/very severe
(mean scale score 3) groups to examine clinically relevant severity of neurobehavioral
symptoms. Second, we conducted binary logistic regression analyses with the presence of
psychiatric diagnoses and severe/very severe neurobehavioral symptoms as dependent
variables and gender as the predictor variable to examine the univariate relationships for
women compared to men on those outcome variables. Third, we adjusted for the
potentially important confounder of blast exposure (i.e., experienced one or more blasts
while deployed as reported during the Comprehensive TBI Evaluation) because blast
exposure may uniquely contribute to the odds of psychiatric and neurobehavioral
outcomes (Sayer et al., 2008). Additionally, these analyses were adjusted for etiology
(blast, bullet, fall, vehicle, other blunt trauma) and all demographic variables. For all
regression analyses, odds ratios (OR) and 95% confidence intervals (CI) were calculated.
Alpha-levels were adjusted to correct for multiple tests (p < .005 was the significance
criterion for psychiatric diagnoses and p < .012 was the significance criterion for
neurobehavioral symptom severity).

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Results
As noted earlier, analyses were focused on the 12,605 OEF/OIF Veterans who were
evaluated as having deployment-related TBI during the observation period. Patient
demographic characteristics, percentages with psychiatric diagnoses and severe/very
severe neurobehavioral symptoms are presented separately for women (n = 654) and men
(n = 11,951) in Table 1. The mean scores for the neurobehavioral symptoms domains are
as follows: affective (women: m = 2.53, SD = 0.96; men: m = 2.43, SD = 0.96),
somatosensory (women: m = 1.80, SD = 0.79; men: m = 1.55, SD = 0.76), cognitive
(women: m = 2.29, SD = 1.05; men: m = 2.16, SD = 1.04), and vestibular (women: m =
1.54, SD = 0.91; men: m = 1.28, SD = 0.86).

Univariate relationships for women compared to men on psychiatric diagnoses and

severe/very severe neurobehavioral symptoms revealed gender differences in both types
of outcomes (see Table 2 for unadjusted relationship values). For psychiatric diagnoses,
women were .70 times less likely than men to have a PTSD diagnosis. Women were also
significantly less likely than men to have substance abuse diagnoses as well as only one
psychiatric diagnosis. In contrast, relative to men, women were nearly 2 times more
likely to have a depression diagnosis, 1.3 times more likely to have a non-PTSD anxiety
disorder, and over 1.5 times more likely to have PTSD with comorbid depression. In
terms of neurobehavioral symptoms, women were significantly more likely than men to
report severe somatosensory, cognitive, and vestibular symptoms, with ORs ranging from
1.3 to 1.9.

Table 2
Psychiatric Diagnoses and Severe/Very Severe Neurobehavioral Symptoms for Women
Relative to Men.

Some of the gender difference findings were no longer significant after accounting for
participants exposure to blasts while on deployment (see Table 2 for blast-adjusted
relationship values). Specifically, women were no longer less likely than men to have a
PTSD diagnosis, drug-related diagnoses, or have only one psychiatric diagnosis after
controlling for blast exposure. Additionally, women were no more likely than men to
have a diagnosis of a non-PTSD anxiety disorder after controlling for blast exposure. In
contrast, women were more likely to report severe/very severe symptoms on all four
neurobehavioral symptom domains.

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Discussion
To our knowledge, this is the first study analyzing gender differences in psychiatric
conditions and neurobehavioral symptom severity among OEF/OIF Veterans with
deployment-related TBI who are using VA care. As expected, and consistent with
previous research in the general population (e.g., Fann et al. 2004) and with athletes (e.g.,
Colvin et al., 2009), we documented gender differences in the unadjusted odds of
psychiatric diagnoses and neurobehavioral outcomes among VA patients with
deployment-related TBI. Specifically, we found that compared to men, women were
much more likely to have a depression diagnosis. Women were also more likely than men
to be diagnosed with a non-PTSD anxiety disorder as well as PTSD with comorbid
depression. In contrast, women were less likely than men to be diagnosed with PTSD
only or with substance use disorders. In terms of neurobehavioral symptoms, women
were more likely to report severe or very severe somatosensory, cognitive, and vestibular
symptoms. Some of these gender differences (i.e., PTSD differences, non-PTSD anxiety
disorders, and drug-related disorders), were not maintained after adjusting for blast
exposure.

The large gender difference in depression diagnoses among patients judged to have
deployment-related TBI (49% compared to 33%, a 16 point difference) is more than
twice that observed in the general population of OEF/OIF VA patients (23% compared to
17%, a 6 point difference; Maguen et al., 2010). The high percentages of depression
reported by women in this study is notable because greater functional disability, poorer
recovery, and higher rates of suicide attempts are all associated with depression after TBI
(Fann, Katon, Uomoto, & Esselman, 1995; Mooney, Speed, & Shepard, 1995; Rapoport,
McCullagh, Streiner, & Feinstein, 2003; Silver, Kramer, Greenwald, & Weissman, 2001).
Consistent with the VAs clinical practice guidelines for the management of mild TBI, the
current findings highlight the critical need for early detection and aggressive treatment of
depression among women Veterans with deployment-related TBI (Department of
Veterans Affairs and Department of Defense, 2009).

Regarding other gender differences in psychiatric diagnoses, consistent with the general
population of OEF/OIF VA patients (Maguen et al., 2010), univariate analyses
demonstrated women were more likely than men to have a non-PTSD anxiety disorder
(20.3% compared to 16.3%) and less likely than men to have alcohol (16.2% compared to
27.0%) and drug-related disorders (4.9% compared to 8.2%). However, the magnitude of
these gender differences are more pronounced in the current sample relative to the
general population of OEF/OIF VA patients (Maguen et al., 2010). It is noteworthy that
the gender effect for non-PTSD anxiety disorders and drug-related disorders was not
maintained once controlling for blast exposure. Despite these important gender
differences, women and men did not differ significantly in terms of adjustment disorders
or stress reactions. Additionally, contrary to our hypotheses, women were no more likely
than men to have multiple psychiatric diagnoses, with approximately half of Veterans of
either gender (53.2% of women, 48.7% of men) being diagnosed with two or more
psychiatric conditions.

The univariate associations between gender and PTSD (59.6% of the women compared to
67.8% of the men) was not maintained after controlling for blast exposure. This finding
suggests that mens greater likelihood of blast exposure (see Table 1), possibly from
greater combat exposure (Hoge, Clark, & Castro, 2007), may account for their higher
likelihood of having a PTSD diagnosis. This adjusted finding is consistent with previous
research demonstrating a lack of gender differences in terms of PTSD among Veterans,
controlling for specific deployment-related stressors (Kimerling, Ouimette, & Weitlauf,
2007). Additionally, approximately 38% of women had diagnoses of PTSD with
comorbid depression compared to 28% of the men. Thus, PTSD with comorbid
depression is a prominent womens health issue among VA patients judged to have
deployment-related TBI.

Findings did support our hypothesis that women would report more severe
neurobehavioral symptoms. Specifically, women were significantly more likely to report
severe or very severe symptoms on three of the four neurobehavioral symptom
domains in the univariate analyses (the exception being affective symptoms) and all four
of the symptom domains in the multivariate analyses adjusting for blast exposure. These
findings match results from studies examining gender differences in neurobehavioral
symptoms among athletes with TBI (Colvin et al., 2009; Dick, 2009). Although the
mechanisms associated with these worse outcomes remain unknown, these findings
suggest that in addition to the identification and treatment of psychiatric conditions, it is
critical that clinicians attend to the affective, somatosensory, cognitive, and vestibular
symptoms experienced by women Veterans with deployment-related TBI. Recognition of
these symptoms in women Veterans enables clinicians to better tailor treatment
approaches for womens specific health care needs. For example, a woman who reports
severe cognitive symptoms may benefit from cognitive remediation (French, Iverson, &
Bryant, 2011). Likewise, increased detection of neurobehavioral symptoms among
women Veterans may lead to improvements in coordination of care for women in mental
health, as well as physical and occupational rehabilitation settings. Consistent with the
literature pertaining to VA care for women (Yano, Washington, Goldzweig, Caffrey, &
Turner, 2003), the current findings also suggest the importance of interdisciplinary
treatment of women VA patients with mild TBI.

In light of the high rates of psychiatric and neurobehavioral comorbidities observed in

this study, the current findings can help guide clinicians use of specific therapy options
for their female patients with TBI and these co-occurring conditions, particularly PTSD
and depression. In particular, cognitive-behavioral therapies for PTSD are very effective
in ameliorating Veterans symptoms of both PTSD and depression (Iverson, Lester, &
Resick, 2011), and at this time, there is no evidence that these treatments need to be
significantly altered for patients with mild TBI. On the contrary, there is preliminary
evidence that Cognitive Processing Therapy (CPT; Resick, Monson, & Chard, 2009), an
empirically-supported treatment for PTSD that is widely available in the VA, is effective
for reducing PTSD and depression symptoms in Veterans with TBI with little alteration to
the protocol (Chard, Schumm, Mcllvain, Bailey & Parkinson, in press). Yet, some
clinicians understandably worry that existing cognitive-behavioral therapies, such as
CPT, are too reliant on memory and thus may be inappropriate for patients with TBI
(Sayer et al., 2009). Clinicians should keep in mind that many evidence-based therapies,
such as CPT, can be altered to meet the needs of individual patients with TBI (e.g., longer
or shorter sessions, greater repetition of materials, engagement of family members to
promote treatment adherence) while still maintaining fidelity to the treatment model.

Several limitations of this study should be noted as they point to avenues for future
research. Although the determination of TBI was established via structured clinical
interviews and is thus an asset of the study, the VA Comprehensive TBI Evaluation has
not undergone an evaluation of sensitivity and specificity in terms of accuracy of
determining TBI. Similarly, the psychiatric diagnoses were derived from ICD-9 codes.
Although this method is common in research examining psychiatric conditions among
patients of large health care systems (Carlson et al., 2010; Fann et al., 2004; Kimerling et
al., 2010), these diagnoses can be subject to false-positive and false-negative cases. Thus,
the current findings may not reflect the true rate of psychiatric disorders among this
population and findings should be replicated using validated assessments of psychiatric
conditions and more rigorous neurobehavioral symptom measures. Another limitation is
that this study measured cognitive symptoms via a self-report measure. Additional
research is needed to replicate the current findings with cognitive performance measures
because subjective cognitive complaints have been found be related to mood, such as
depressive symptoms (Marino et al., 2009).

Another study limitation is the cross-sectional nature of the research design. As such, a
causal relationship cannot be inferred between deployment-related TBI and the
psychiatric conditions and neurobehavioral symptoms. Future longitudinal research
should evaluate the nature of these relationships, as well as elucidate mediating and
moderating variables that may help to explain gender differences in health outcomes
among Veterans with deployment-related TBI. In addition to blast exposure, researchers
should investigate a broader range of deployment-related stressors that may contribute to
gender differences (and lack thereof), including sexual trauma and combat severity.
Given that only half of the Veterans who screened positive for TBI received a
Comprehensive TBI Evaluation, it is possible that the current sample is an underestimate
of the true rate of OEF/OIF Veterans with deployment-related TBI. Research is needed to
elucidate patient, provider, and facility-level factors that impact the likelihood a patient
will go on to receive a Comprehensive TBI Evaluation following a positive TBI screen.
For example, patient-level factors, such as mental health diagnoses or cognitive
disturbances, may impact a Veterans willingness or ability to arrange and attend such an
appointment. There may also be differences in how clinicians provide feedback about a
positive TBI screen and referrals for the evaluation that may influence variation in rates
of receiving a Comprehensive TBI Evaluation. Additionally, it is important to remember
that the current findings based on VA patients may not generalize to patients in other
health care settings. Future inquiries should include samples of Veterans who do not
utilize VA health care to determine if the pattern of findings presented here is maintained.
Future research is also needed to further identify and treat symptoms (e.g., pain) that are
of high clinical relevance in female patients judged to have mild TBI. Finally, it is
essential to monitor whether evidence-based treatments for conditions such as PTSD and
depression lead to improvements in neurobehavioral symptom severity for women VA
patients judged to have deployment-related TBI.

In summary, there are gender differences in the comorbidities of deployment-related TBI

among OEF/OIF VA patients. It is important to continue to understand these differences,
as well as similarities, in order to inform practices to provide the highest quality care
possible for women Veterans.
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Acknowledgments
This paper is based on work supported by the Office of Research and Development,
Health Services R&D Service, Department of Veterans Affairs, through SDR 08-405. The
study was reviewed and approved by the Institutional Review Board of the VA Boston
Healthcare System. The opinions expressed in this article are the authors and do not
reflect those of the Department of Veterans Affairs, the Veterans Health Administration,
Health Services R&D, the Defense and Veterans Brain Injury Center or the Department
of Defense.

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References
1. Carlson KF, Nelson D, Orazem RJ, Nugent S, Cifu DX, Sayer NA. Psychiatric
diagnoses among Iraq and Afghanistan war veterans screened for deployment-
related traumatic brain injury. Journal of Traumatic Stress. 2010;23:1724. doi:
10.1002/jts.20483. [PubMed] [Cross Ref]
2. Chard KM, Schumm J, McIlvain S, Bailey G, Parkinson R. Exploring the efficacy
of a CPT-Cognitive Only (CPT-C) focused residential treatment program for
veterans with PTSD and traumatic brain injury. Journal of Traumatic Stress in
press.
3. Cicerone KD, Kalmar K. Persistent postconcussion syndrome: The structure of
subjective complaints after mild traumatic brain injury. Journal of Head Trauma
Rehabilitation. 1995;10:117. doi: 10.1097/00001199-199510030-00002. [Cross
Ref]
4. Colvin AC, Mullen J, Lovell MR, West RV, Collins MW, Groh M. The role of
concussive history and gender in recovery from soccer-related concussion. The
American Journal of Sports Medicine. 2009;37:16991704. doi:
10.1177/0363546509332497. [PubMed] [Cross Ref]
5. Department of Veterans Affairs and Department of Defense, Management of
Concussion/mTBI Working Group. VA/DoD Clinical Practice Guideline for
Management of Concussion/Mild Traumatic Brain Injury. Washington, DC:
Author; 2009.
6. Fann JR, Burington BE, Leonetti A, Jaffe K, Katon WJ, Thompson RS.
Psychiatric illness following traumatic brain injury in an adult health maintenance
organization population. Archives of General Psychiatry. 2004;61:5361. doi:
10.1001/archpsyc.61.1.53. [PubMed] [Cross Ref]
7. Fann JR, Katon WJ, Uomoto JM, Esselman PC. Psychiatric disorders and
functional disability in outpatients with traumatic brain injuries. American Journal
of Psychiatry. 1995;152:14931499. [PubMed]
8. Farace E, Alves WM. Do women fare worse? A metaanalysis of gender
differences in outcome after traumatic brain injury. Neurosurgery Focus.
2000;8:18. doi: 10.3171/foc.2000.8.1.152. [PubMed] [Cross Ref]
9. Fedoroff JP, Starkstein SE, Forrester AW, Geisler FH, Jorge RE, Arndt SV,
Robinson RG. Depression in patients with acute traumatic brain injury. The
American Journal of Psychiatry. 1992;149:918923. [PubMed]
10. French LM, Iverson GL, Bryant RA. Traumatic brain injury. In: Benedek, Wynn,
editors. Clinical manual for the management of PTSD. Arlington, VA: American
Psychiatric Publishing, Inc; 2011. pp. 383414.
11. Hendricks A, Amara J, Baker E, Charns M, Gardner JA, Iverson KM, Kimerling
R, Krengel M, Meterko M, Pogoda TK, Stolzmann KL, Wolfsfeld L, Lew HL.
Screening for mild traumatic brain injury in OEF-OIF deployed military: An
empirical assessment of the VA Experience. Research paper presented at the
National HSR&D Conference; Washington, DC. Feb, 2011.
12. Hoge CW, Clark JC, Castro CA. Commentary: Women in combat and the risk of
post-traumatic stress disorder and depression. International Journal of
Epidemiology. 2007;36:327329. doi: 10.1093/ije/dym013. [PubMed] [Cross Ref]
13. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild
traumatic brain injury in U.S. soldiers returning from Iraq. New England Journal
of Medicine. 2008;358:453463. doi: 10.1056/NEJMoa072972. [PubMed] [Cross
Ref]
14. Holbrook TL, Hoyt DB, Anderson JP. The importance of gender on outcome after
major trauma: Functional and psychologic outcomes in women versus men.
Journal of Trauma. 2001;50:270273. doi: 10.1097/00005373-200102000-00012.
[PubMed] [Cross Ref]
15. Iverson KM, Lester KM, Resick PA. Psychosocial treatments. In: Benedek, Wynn,
editors. Clinical manual for the management of PTSD. Arlington, VA: American
Psychiatric Publishing, Inc; 2011. pp. 157203.
16. Jensen OK, Nielsen FF. The influence of sex and pre-traumatic headache on the
incidence and severity of headache after head injury. Celphalgia. 1990;10:285
293. doi: 10.1046/j.1468-2982.1990.1006285.x. [PubMed] [Cross Ref]
17. Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S. Major
depression following traumatic brain injury. Archives of General Psychiatry.
2004;61:4250. doi: 10.1001/archpsyc.61.1.42. [PubMed] [Cross Ref]
18. Kimerling R, Ouimette P, Weitlauf JC. Gender issues in PTSD. In: Friedman MJ,
Keane TM, Resick PM, editors. Handbook of PTSD: Science and Practice. New
York, NY: The Guilford Press; 2006. pp. 207228.
19. Maguen S, Ren L, Bosch JO, Marmar CR, Seal KH. Gender differences in mental
health diagnoses among Iraq and Afghanistan Veterans enrolled in Veterans
Affairs health care. American Journal of Public Health. 2010;100:24502456. doi:
10.2105/ajph.2009.166165. [PMC free article] [PubMed] [Cross Ref]
20. Marino SE, Meador KJ, Loring DW, Okun MS, Fernandez HH, Fessler AJ, Kustra
RP, Miller JM, Ray PG, Schoenberg MR, Vahle VJ, Werz MA. Subjective
perception of cognition is related to mood not performance. Epilepsy & Behavior.
2009;14:459464. [PMC free article] [PubMed]
21. McCarthy ML, Dickmen SS, Langlois JA, Selassie AW, Gu JK, Horner MD. Self-
reported psychosocial health among adults with traumatic brain injury. Archives
of Physical Medicine and Rehabilitation. 2006;87:953961. doi:
10.1016/j.apmr.2006.03.007. [PubMed] [Cross Ref]
22. Meterko M, Baker E, Stolzmann KL, Cicerone KD, Hendricks KM, Lew HL.
Unpublished manuscript. 2011. Psychometric assessment of the NSI-22.
23. Mooney G, Speed J, Sheppard S. Factors related to recovery after mild traumatic
brain injury. Brain Injury. 2005;19:975987. doi: 10.1080/02699050500110264.
[PubMed] [Cross Ref]
24. Murdoch M, Bradley A, Mather SH, Klein RE, Turner CL, Yano EM. Women and
war: What physicians should know. Journal of General Internal Medicine.
2006;21(Suppl 3):S5S10. doi: 10.1111/j.1525-1497.2006.00368.x. [PMC free
article] [PubMed] [Cross Ref]
25. National Center for Mental Health Statistics and the Centers for Medicare &
Medicaid Services. Revision, Clinical Modification. 9. Washington, DC: Author;
2008. The International Classification of Diseases.
26. Rapoport MJ, McCullagh S, Streiner D, Feinstein A. The clinical significance of
major depression following traumatic brain injury. Psychosomatics. 2003;44:31
37. doi: 10.1176/appi.psy.44.1.31. [PubMed] [Cross Ref]
27. Resick PA, Monson CM, Chard KM. Cognitive processing therapy:
Veteran/military version. Washington, DC: Department of Veterans Affairs; 2007.
28. Satz P, Forney DL, Zaucha K, Asarnow RR, Light R, McCleary C, Levin H, Kelly
D, Bergsneider M, Hovda D, Martin Namerow N, Becker D. Depression,
cognition, and functional correlates of recovery outcome after traumatic brain
injury. Brain Injury. 1998;12:537553. doi: 10.1080/026990598122313.
[PubMed] [Cross Ref]
29. Sayer NA, Chiros CE, Sigford B, Scott S, Clothier B, Pickett T, et al.
Characteristics and rehabilitation outcomes among patients with blast and other
injuries sustained during the Global War on Terror. Archives of Physical Medicine
and Rehabilitation. 2008;89:163170. doi: 10.1016/j.apmr.2007.05.025.
[PubMed] [Cross Ref]
30. Sayer NA, Rettmann NA, Carlson KF, Bernardy N, Sigford BJ, Hamblen JL,
Friedman MJ. Veterans with history of mild traumatic brain injury and
posttraumatic stress disorder: Challenges from provider perspective. Journal of
Rehabilitation Research & Development. 2009;46:703716. doi:
10.1682/JRRD.2009.01.0008. [PubMed] [Cross Ref]
31. Schneiderman AI, Braver ER, Kang HK. Understanding sequelae of injury
mechanisms and mild traumatic brain injury incurred during the conflicts of Iraq
and Afghanistan: Persistent postconcussive symptoms and posttraumatic stress
disorder. American Journal of Epidemiology. 2008;167:14461452. doi:
10.1093/aje/kwn068. [PubMed] [Cross Ref]
32. Seal KH, Bertenthal D, Miner CR, Sen S, Marmar C. Bringing the war back
home: Mental health disorders among 103,788 US Veterans returning from Iraq
and Afghanistan seen at Department of Veterans Affairs facilities. Archives of
Internal Medicine. 2007;167:476482. doi: 10.1001/archinte.167.5.476.
[PubMed] [Cross Ref]
 33. Silver JM, Kramer R, Greenwald S, Weissman M. The association between head
injuries and psychiatric disorders: findings from the New Haven NIMH
Epidemiologic Catchment Area Study. Brain Injury. 2001;11:935945. doi:
10.1080/02699050110065295. [PubMed] [Cross Ref]
34. Street AE, Vogt D, Dutra L. A new generation of women Veterans: Stressors faced
by women deployed to Iraq and Afghanistan. Clinical Psychology Review.
2009;29:685694. doi: 10.1016/j.cpr.2009.08.007. [PubMed] [Cross Ref]
35. Tanielian T, Jaycox LH. Invisible wounds of war: Psychological and cognitive
injuries, their consequences, and services to assist recovery. Santa Monica, CA:
RAND Corp; 2008.
36. Yano EM, Hayes P, Wright S, Schnurr PP, Lipson L, Bean-Mayberry B,
Washington DL. Integration of women Veterans into VA quality enhancement
research efforts: What researchers need to know. Journal of General Internal
Medicine. 2010;25:5661. doi: 10.1007/s11606-009-1116-4. [PMC free article]
[PubMed] [Cross Ref]
37. Yano EM, Washington DL, Goldzweig C, Caffrey C, Turner C. The organization
and delivery of womens health care in Department of Veterans Affairs Medical
Center. Womens Health Issues. 2003;13:5561. doi: 10.1016/S1049-
3867(02)00198-6. [PubMed] [Cross Ref]

Jurnal 2
Sleep. 2013 January 1; 36(1): 8390.
doi: 10.5665/sleep.2306
PMCID: PMC3524546

Do Sleep Problems Mediate the

Relationship between Traumatic Brain
Injury and Development of Mental
Health Symptoms after Deployment?
Caroline A. Macera, PhD, Hilary J. Aralis, MS, Mitchell J. Rauh, PhD, PT, MPH, and
Andrew J. MacGregor, PhD
Author information Article notes Copyright and License information
See editorial "Sound Sleep, a Crucial Component of Military Medicine's
Armamentarium?" on page 7.
This article has been cited by other articles in PMC.
Go to:

Abstract
Study Objectives:
Military members screening positive for blast-related traumatic brain injury (TBI) may
subsequently screen positive for posttraumatic stress disorder (PTSD) or depression. The
role of sleep as a mediating factor in the development of mental health symptoms was
explored.

Design:

Prospective study with symptoms evaluated at two time points.

Setting:

Postdeployment service in Iraq, Afghanistan, or Kuwait during 2008 and 2009.

Participants:

There were 29,640 US Navy and Marine Corps men (29,019 who did not screen positive
for PTSD at baseline, 27,702 who did not screen positive for depression at baseline, and
27,320 who did not screen positive at baseline for either condition).

Measurements and Results:

After controlling for sleep problems, the adjusted odds of receiving a positive PTSD
screening at follow-up decreased from 1.61 (95% confidence interval [CI] 1.212.14) to
1.32 (95% CI 0.991.77) for a subject screening positive for TBI relative to a subject
screening negative, suggesting that sleep problems mediated 26% of TBI's effect on
development of PTSD. Likewise, after controlling for sleep problems, the adjusted odds
of receiving a positive depression screening decreased from 1.41 (95% CI 1.111.80) to
1.15 (95% CI 0.901.47), suggesting that sleep problems mediated 41% of TBI's effect
on development of depression. Results were similar for those with either PTSD or
depression (37% mediated).

Conclusions:

These results suggest that sleep problems mediate the effect of a positive TBI screening
on the development of mental health disorders, and sleep problems may be an early
indicator of risk for PTSD or depression.

Citation:

Macera CA; Aralis HJ; Rauh MJ; MacGregor AJ. Do sleep problems mediate the
relationship between traumatic brain injury and development of mental health symptoms
after deployment? SLEEP 2013;36(1):8390.

Keywords: Posttraumatic stress disorder, sleep problems, traumatic brain injury

Go to:
INTRODUCTION
Traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and depression are
common occurrences for military personnel returning from deployment to Kuwait, Iraq,
or Afghanistan in support of Operation Iraqi Freedom and Operation Enduring Freedom
(OIF/OEF). These injuries are often the result of the type of combat to which these
individuals are exposed, including explosive devices. Although physical trauma
associated with combat is easy to document, diagnose, and treat, neurologic sequelae and
psychologic trauma are difficult to assess, partly because the diagnosis relies on symptom
reporting. However, symptoms may appear insignificant in contrast to the other injuries
incurred by that person, or the diagnosis may not yet be identified because some
symptoms are not immediately present and may appear gradually over subsequent weeks
or months. Because TBI, PTSD, and depression have some overlapping symptoms, it is
not clear if the presence of one condition is a precursor to another or how the symptoms
may interact with each other.

Sleep problems are common during and after deployment. A review of an Internet-based
study of more than 30,000 military men and women found that sleep problems were more
common among those with current or recent deployments than among those who were
not deployed.1 Another study, which used a 21-item Military Deployment Survey of
Sleep, found that almost 75% of active-duty Air Force members (n = 156) rated their
quality of sleep as worse while deployed than in their home environment.2 Furthermore,
there is evidence that the presence of even mild TBI, which may occur during
deployment, can affect sleep patterns and quality.35

The health of military service members who have been deployed is routinely monitored
by screening tools assessing TBI, PTSD, and depression as well as by instruments
measuring related symptoms. These screening tools are administered immediately after
deployment and again several months later to monitor long-term health effects. Studies of
these screening tools and symptoms allow tracking of sleep problems and other
symptoms over time. However, the course of these symptoms that may lead to diagnosis
of TBI, PTSD, or depression is complicated. One of the most prevalent complaints has
concerned sleep, especially in the case of mild TBI.5 Trouble falling or staying asleep is a
common symptom that occurs with TBI, PTSD, and depression, but its role in causation
is unclear. There is evidence that long-standing sleep problems (e.g., insomnia) prior to
trauma may lead to psychiatric disorders including depression and anxiety.6 It has also
been suggested that symptoms related to sleep problems may co-occur with other
cognitive and mental disorders.79

Although numerous studies have concluded that sleep problems are a frequent
consequence of TBI, few have related these sleep problems to mental health outcomes
among military service members, and no known studies have attempted to quantify
potential indirect effects.5,1013 By evaluating sleep problems and potential TBI
immediately after deployment and PTSD and depression several months later, the ability
to describe potential causal mechanisms will be further enhanced. This study tested
whether sleep problems significantly mediated the relationship between TBI and the
development of PTSD and/or depression using standardized questionnaires administered
to all service members after return from deployment.

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METHODS
Study Population and Data Sources

Male Navy and Marine Corps personnel who returned from an OIF/OEF deployment in
2008 or 2009 and completed a Post-Deployment Health Assessment (PDHA) and
associated Post-Deployment Health Reassessment (PDHRA) were selected for inclusion
in the study sample. The PDHA is a brief self-report questionnaire administered to all
military personnel at deployment end. The PDHRA is similar in format and content but is
administered approximately 3 to 6 mo after the end of deployment. Developed by the
Department of Defense, both assessments aim to characterize service members' current
health, identify possible deployment-related occupational and environmental exposures,
and provide service members with an opportunity to discuss health concerns with a
trained healthcare provider. Completed PDHA and PDHRA records were obtained from
the US Navy's Electronic Pre- and Post-Deployment Health Assessment Database. A
PDHRA was considered to be associated with a PDHA if the date of administration was
at least 30 but no more than 365 days after the date of the PDHA. Because some service
members had completed several assessments, in the event that more than one PDHRA
met the criteria, the first PDHRA was selected. Female service members were excluded
because they are believed to be at decreased risk of incurring a TBI due to combat duty
restrictions. Were female service members to be included, only 32 female service
members in the potential sample screened positive for TBI on the PDHA (1.7%), severely
limiting our ability to conduct meditation analyses among women in this population. For
the purpose of this study, OIF/OEF deployment was defined as having received
hazardous duty pay while deployed for more than 30 days in Afghanistan, Iraq, or
Kuwait. To exclude prolonged duty station changes to regions deemed hazardous,
deployments lasting longer than 18 mo were not considered for inclusion. Hazardous
duty pay and deployment start and end dates were verified using information obtained
from the Defense Manpower Data Center (Monterey, CA).

TBI on the PDHA

Beginning in January 2008, a revised version of the PDHA containing additional

questions on TBI was introduced. On the electronic assessment, service members were
asked to respond yes or no to having experienced a blast or explosion, vehicular
accident/crash, fragment wound or bullet wound above the shoulders, fall, or other event
such as a sports injury to the head during deployment. After endorsement of at least one
injury item, service members were asked whether or not they immediately lost
consciousness or got `knocked out', felt dazed, confused, or `saw stars', or didn't
remember the event. In accordance with guidance distributed to military healthcare
providers14 and established criteria,15 service members who reported having sustained a
head injury and chose at least one of the three alteration/loss of consciousness items were
considered to have screened positive for a potential TBI. The TBI screening included on
the PDHA and PDHRA is a modified version of the three-item Brief Traumatic Brain
Injury Screen (BTBIS). One study found that among those screening positive for
probable TBI on the BTBIS, 83% provided information consistent with mild TBI at a
follow-up interview conducted by a trained specialist and that this percentage did not
increase significantly when including the results of longer screening instruments in
conjunction with the BTBIS.16

Sleep on the PDHA

The PDHA asks service members to respond yes or no to experiencing each of 24

symptoms at the time of the questionnaire. These symptoms include musculoskeletal,
systemic, gastrointestinal, and mental health complaints. For the purpose of this study, a
service member response of yes to experiencing the symptom described as problems
sleeping or still feeling tired after sleeping was assumed to indicate postdeployment
sleep problems. This single item aims to capture problems related to both quantity and
quality of sleep, although distinction between the two issues is not possible given the
nature of the measure. Researchers have noted that future inclusion of a more detailed
instrument for identifying sleep problems post-deployment would have merit.17

PTSD on the PDHRA

An abbreviated screening instrument known as the four-item Primary Care PTSD screen
(PC-PTSD) is included on the PDHA and PDHRA. To increase the relevance of the four-
item PC-PTSD among a military population, the original stem was adapted to read Have
you ever had any experience that was so frightening, horrible, or upsetting that, in the
past month, you By referring to a specific traumatic experience and stipulating a 1-mo
time frame, the adapted stem is expected to have increased likelihood of identifying
current PTSD cases. For the purpose of this study, service members received a positive
PTSD screening if they answered yes to at least three of the four questions about having
experienced symptoms related to the four dimensions of PTSD (re-experiencing,
numbing, avoidance, and hyperarousal).18,19 The four-item PC-PTSD has been validated
among combat-exposed military service members, and the three-item cutoff is known to
have reasonable screening properties with a sensitivity of 0.78 and a specificity of
0.87.20,21 To focus on the development of PTSD, rather than the persistence, service
members screening positive for PTSD on the PDHA were excluded from all analyses for
which PTSD screening results on the PDHRA were the outcome of interest.

Depression on the PDHRA

Both the PDHA and the PDHRA assessments contain a two-item depression screen
derived from the validated Patient Health Questionnaire.22 Based on identified constructs
of depression, the screening instrument assesses the amount of time in the past mo a
service member was bothered by little interest or pleasure in doing things (anhedonia)
and feeling down, depressed, or hopeless (depressed mood). A response of more than
half the days or nearly every day to either item resulted in a positive screen for
potential depression. Similar to the PTSD exclusion criterion, service members who
screened positive for depression on the PDHA were not included in analyses for which
the outcome of interest was potential depression on the PDHRA.

Demographic and Deployment-Related Variables

A categoric variable for military pay grade was created with one category for all warrant
and commissioned officers and three categories representing junior, intermediate, and
senior enlisted personnel. Variables indicating service branch (Marine Corps or Navy),
service component (active duty or reserve), and deployment location (Afghanistan,
Kuwait, or Iraq) were also obtained. From the PDHA, information was collected
regarding age in years (younger than 25, 2529, 3034, 3539, or 40 and older) and
combat exposure (three items specific to the previous deployment asked service members
to respond yes or no to having (1) encountered dead bodies or seen people killed or
wounded, (2) engaged in direct combat where they discharged a weapon, or (3) felt in
great danger of being killed). Length of deployment was analyzed as a categorical
variable with the effect of exceptionally long deployments examined by comparing the
fourth quartile of deployment length for the entire sample (214 days or longer) to the
three lesser quartiles. Although it is recommended that the PDHRA be completed 36 mo
after the completion of the PDHA, there was wide variation in the actual time between
assessments. For this reason, a variable representing the categorical number of days
between questionnaires was created and used in the analyses ( 90, 91120, 121150,
151180, > 180 days).

Statistical Analysis

Sleep problems, TBI screening results, and demographic and deployment-related

variables were tested for association with mental health outcomes using chi-square tests.
In testing the mental health outcome of PTSD, all subjects who screened positive for
PTSD on the PDHA were excluded. Similarly, all subjects who screened positive for
depression on the PDHA were excluded from depression analyses. When a positive PTSD
or depression screen was the outcome of interest, all subjects who screened positive for
either PTSD or depression on the PDHA were excluded from the analyses. Additionally,
the hypothesis that sleep problems at baseline are associated with persistent mental health
complaints was examined using a chi-square test to determine whether service members
who screened positive for mental health problems on the PDHA were more likely to
screen positive for the same problems on the PDHRA if they also indicated sleep
problems at the time of the PDHA.

A mediator is defined as a variable that accounts for all or part of the relation between a
predictor and an outcome.23 Unlike a confounder, a mediator can be thought to represent
an intermediate state through which the effects of an independent variable are conferred
to a dependent variable.24 Although a confounder is frequently introduced into a model to
provide an undistorted estimate of the relationship between the independent and
dependent variables, a mediator is introduced when interest lies in both the direct and
indirect effects of the independent variable on the dependent variable. A statistically
significant mediation effect does not confirm causation, but it is frequently observed
when a predictor variable causes a mediator, which causes an outcome. In examining
mediation, we are making the assumption that sleep problems, although measured at the
same time as TBI, commonly develop after TBI. Because we are making this assumption,
throughout this article sleep problems will subsequently be considered to be an
intermediary symptom hypothesized to represent a causal mechanism through which TBI
could potentially affect development of PTSD and/or depression. The limitations of this
assumption will be further addressed in the discussion section.

To test our hypotheses that sleep problems mediate the development of PTSD,
depression, and PTSD or depression following TBI, the steps for mediation outlined by
Baron and Kenny23 were followed. In steps one and two, the associations of the predictor
with both the outcome of interest and the potential mediator are independently tested. If
both associations are significant, step three entails modeling the association between the
predictor and the outcome of interest while controlling for the potential mediator.
Mediation is said to occur when the coefficient for the predictor in the controlled model is
significantly reduced, relative to the coefficient obtained from the univariate model
excluding the mediator. The mediated or indirect effect of a predictor on an outcome can
traditionally be calculated as the product of the regression coefficient relating the
predictor to the mediator in the univariate model and the coefficient relating the mediator
to the outcome in the multivariate model.

All mental health outcomes in this study were dichotomous screening results; therefore,
logistic regression models were constructed and the appropriate procedures for mediation
with dichotomous dependent variables were followed.25 For each of the three mental
health outcomes, Models 1, 2, and 3 were constructed. Model 1 regressed mental health
outcomes onto the TBI screening result variable. The resulting coefficient (c) represents
the total effect of TBI on the outcome of interest, and a significant c suggests the
existence of an effect to be mediated. Model 2 regressed sleep problems onto the TBI
screening result variable. The resulting Model 2 coefficient (a), if significant, confirms
the existence of a relationship between the mediator and the dependent variable. Model 3
regressed mental health outcomes onto both the TBI screening result variable and sleep
problems to obtain two coefficients (c and b, respectively). If sleep problems are a
significant mediator, a decrease should be seen from c to c, and the indirect effect of TBI
screening results on mental health outcomes (ab) should be different from zero. The
Sobel test evaluates the null hypothesis that ab = 0, denoting an insignificant indirect
effect of TBI on the mental health outcome of interest.26 In logistic regression, however,
comparing coefficients across equations is problematic because independent and
dependent variables are measured on a different scale. Prior to testing for the significance
of mediation using the Sobel test, coefficients were therefore standardized by multiplying
each coefficient by the standard deviation of the independent variable and dividing by the
standard deviation of the dependent variable.27 Pay grade, service branch, service
component, age, deployment location, combat experiences, deployment length, and time
between assessments were controlled in all logistic regression models.
When the direct effect is not zero, the percentage of the total effect that is mediated (ab/
[ab + c]) and the ratio of the indirect to the direct effect (ab/c) are two measures of the
extent of mediation. Although MacKinnon et al.28 conducted simulation studies showing
the limited stability of the percentage mediated and the ratio of effects, both measures
stabilized when replications were increased and should therefore be acceptable for use in
this large sample study.

Go to:

RESULTS
A total of 55,047 Navy and Marine Corps service members completed a PDHA and an
associated PDHRA in 20082009. Of these 55,047 sailors and Marines, assessments
completed by 29,640 male service members met the inclusion criteria and 825 (2.8%)
screened positive for TBI on the PDHA. Relative to service members who screened
negative for TBI, those who screened positive were more likely to report sleep problems
on the PDHA (36.7% versus 10.3%).

Among the 29,019 service members who did not screen positive for PTSD on the PDHA,
27% of those who screened positive for PTSD on the PDHRA had reported sleep
problems on the PDHA compared with fewer than 10% of those who did not screen
positive. Similarly, service members who screened positive for TBI on the PDHA had an
increased likelihood of screening positive for PTSD on the PDHRA relative to those who
did not screen positive for TBI (6.6% and 2.3%, respectively) (Table 1). Only 4.1% of
service members screening positive for PTSD on the PDHRA were officers relative to
10.8% of those who screened negative. Additionally, reserve personnel and service
members deployed to Afghanistan were significantly more likely to screen positive for
PTSD on the PDHRA, relative to active-duty personnel and those deployed to Iraq or
Kuwait. All three combat exposures were endorsed at a significantly higher rate among
service members screening positive for PTSD on the PDHRA (Table 1). Service members
returning from long deployments ( 214 days) and those completing the PDHRA more
than 180 days after the PDHA had an increased likelihood of screening positive for PTSD
(Table 1).

Table 1
Frequencies associated with new positive PTSD screening (n = 29,019 men)
Sleep problems at baseline were determined to be associated with the persistence of
mental health problems within this sample. Among service members who screened
positive for PTSD on the PDHA, 47% of those who also reported sleep problems on the
PDHA went on to screen positive for PTSD again on the PDHRA, relative to only 33% of
those who did not report sleep problems on the PDHA (P = 0.0002). Similarly, in the
sample of service members screening positive for depression on the PDHA, depression
symptoms were shown to persist, based on PDHRA screening results, among 41% of
those reporting sleep problems relative to only 30% of those reporting no sleep problems
(P < 0.0001) (results not shown).

Excluding Navy and Marine Corps personnel who screened positive for depression on the
PDHA, a sample of 27,702 men was used to evaluate factors associated with a
subsequent positive depression screen. Subjects screening positive for depression on the
PDHRA were more likely to have reported sleep problems on the PDHA (20.8%) and to
have screened positive for TBI on the PDHA (4.5%) compared with those who did not
screen positive for depression on the PDHRA (8.2% and 2.3%, respectively). Among
those screening positive for depression, a significantly higher percentage were junior and
intermediate enlisted personnel, Marines, service members deployed to Iraq or
Afghanistan, and subjects younger than 25 years compared with senior enlisted
personnel, officers, sailors, service members deployed to Kuwait, and older individuals
(Table 2). All three combat exposures were reported at a significantly higher rate among
service members screening positive for depression.

Table 2
Frequencies associated with new positive depression screening (n = 27,702 men)

Navy and Marine Corps personnel who screened positive for either PTSD or depression
on the PDHA were excluded, leaving a sample of 27,320 male subjects to evaluate the
association of TBI and sleep problems with a subsequent positive PTSD or depression
screen on the PDHRA.

Following the Baron and Kenny23 approach, sleep problems reported on the PDHA
significantly mediated the relationship between TBI and receipt of a new positive PTSD
screen on the PDHRA (Sobel P < 0.01). After controlling for sleep problems, the adjusted
odds of receiving a positive PTSD screen for a subject screening positive for TBI
compared with a subject who did not screen positive decreased from 1.61 (95%
confidence interval [CI] 1.21-2.14) to 1.32 (95% CI 1.32: 0.99-1.77) (Figure 1). Twenty-
six percent of the effect of TBI on development of PTSD was mediated by sleep
problems. The mediated effect was 35% as large as the direct effect (Table 3).
Figure 1
Diagram depicting the role of self-reported sleep problems in mediating the association
between a positive TBI screening on the PDHA and a new positive PTSD screening on
the PDHRA (n = 29,019 men). Bolding denotes estimates obtained from the final
adjusted ...

Table 3
Tests of significant mediated effects and additional measures of mediation

Sleep problems reported on the PDHA significantly mediated the relationship between
TBI and receipt of a new positive depression screen on the PDHRA (Sobel P < 0.01). The
adjusted odds of a service member screening positive for depression were estimated to be
1.41 (95% CI 1.11-1.80) times higher for a sailor or Marine who screened positive for
TBI relative to a service member who screened negative. However, after controlling for
sleep problems, the estimated adjusted odds ratio decreased to 1.15 (95% CI 0.90-1.47)
and was no longer significant (Figure 2). Furthermore, sleep problems mediated 41% of
the effect of TBI on the development of depression. The mediated effect was 70% as
large as the direct effect (Table 3).

Figure 2
Diagram depicting the role of self-reported sleep problems in mediating the association
between a positive TBI screening on the PDHA and a new positive depression screening
on the PDHRA (n = 27,702 men). Bolding denotes estimates obtained from the final ...

Finally, sleep problems reported on the PDHA also significantly mediated the relationship
between TBI and receipt of a new positive PTSD or depression screen on the PDHRA
(Sobel P < 0.01). Thirty-seven percent of the effect of TBI on development of PTSD or
depression was mediated by sleep problems. The mediated effect was 60% as large as the
direct effect (Figure 3 and Table 3).
Figure 3
Diagram depicting the role of self-reported sleep problems in mediating the association
between a positive TBI screening on the PDHA and a new positive PTSD or depression
screening on the PDHRA (n = 27,320 men). Bolding denotes estimates obtained from ...
Go to:

DISCUSSION
This large study found that the effect of a positive TBI screenon the development of
PTSD or depression (or both) is mediated by sleep problems. The results of this study
emphasize the importance of early identification and treatment of sleep problems. Service
members with a potential TBI reported sleep problems immediately after return from
deployment but did not endorse PTSD and depression symptoms until several months
later. Sleep problems may therefore be an early indicator of risk for PTSD or depression.
Immediate treatment of self-reported sleep problems could mitigate the risk for
development of mental health disorders, although future (intervention) studies are needed
for verification. Attention to and evaluation of sleep problems (regardless of mental
health diagnosis) may be an effective strategy to reduce postdeployment morbidity. When
considering mental health outcomes, it may be advantageous to implement rehabilitation
efforts aimed at preventing and treating sleep problems during the acute postinjury phase.
Because most combat-related TBIs are mild and do not require medical evacuation to the
United States, in-theater strategies for evaluating sleep should be adopted.

The low prevalence of TBI found in this study (2.8%) compared with previous studies is
likely due to the broad inclusion of both combat- and noncombat-exposed personnel in
our study sample. Although sleep problems have been shown to mediate the relationship
between combat stressors and development of PTSD and depression,29 this study
controlled for combat exposures and still identified a strong, independent relationship
between TBI and sleep problems. Even after controlling for combat exposure, a known
predictor of PTSD and depression, a positive TBI screen remained associated with the
development of PTSD and depression both directly and indirectly through sleep
problems.

TBI may be a significant predictor of sleep problems, even after controlling for combat
exposures, because biological mechanisms independent of psychological distress are
frequently responsible for sleep disturbances among service members with TBI. This
study demonstrated that independent of reported combat exposure, sleep problems that
co-occur with a positive TBI screening are associated with PTSD development.

There are several limitations in this analysis. All presumed diagnoses of TBI, PTSD, and
depression were made on the basis of screening tools but without verification of clinical
diagnoses. Medical records prior to deployment were not evaluated, making it impossible
to determine if subjects had a history of depression, PTSD, or one or more previous TBIs.
Furthermore, we did not know the specifics of the sleep problem (e.g., insomnia) or use
of medications or stimulants, and we did not know if the sleep problem was preexisting.
We had access to one question that indicated sleep was a problem. We had no way to
quantify sleep duration and information regarding potential underlying causes for
troubled sleep, such as chronic pain or recurring nightmares, was not available. Finally,
the severity of TBI, sleep problems, and mental health symptoms was not evaluated.
Future studies on this topic would benefit by using several measures of sleep (including
objective measures) and examining the dose-response properties of the interrelationships
between these three conditions along a spectrum of severity.

Another limitation of this study is that we did not know how long the sleep problems had
existed. Bryant et al.6 determined that sleep disturbances during the weeks prior to
traumatic injury directly increased a subject's risk of developing a psychiatric disorder in
the 3 months postinjury. A study of young adults found that sleep problems (insomnia)
were comorbid rather than secondary to depression,7 whereas another study of veterans
returning from conflicts in Iraq and Afghanistan found that pain was comorbid with
insomnia.30 Although the chronology of TBI, sleep problems, PTSD, and depression was
taken into account by analyzing data from two time points, this procedure does not rule
out the existence of a single causative event that results in the development of sleep
problems, TBI, and delayed-onset PTSD/depression. Our conclusion that sleep problems
act as an intermediary between TBI and the development of mental health symptoms also
relies on the assumption that TBI precedes development of sleep problems. Such an
assumption could not be verified in the current study but is supported throughout the
literature.5,1013

Other issues that should be considered in the interpretation of this report include the
psychological motivations that may exist for military personnel completing the
postdeployment questionnaires. Warner et al. found in a validation study that Army
soldiers were less likely to report depression, PTSD symptoms, and suicidal ideation on
the PDHA than with an anonymous survey with many of the same questions.31 If service
members in our sample were in fact underreporting depression or PTSD symptoms on the
PDHA, the findings presented here regarding sleep problems as a mediator for the
development of PTSD/depression may need to be reinterpreted as sleep problems
mediating the persistence or worsening of PTSD/depression to the extent where the
service member thought it necessary to endorse symptoms on the PDHRA that were not
endorsed on the PDHA. Further, if the nonanonymous nature of the assessments resulted
in underreporting on both the PDHA and the PDHRA our findings could potentially be
underestimates of the role of mediation by sleep problems.32

Several methodological features strengthened our study. Records were obtained from a
large sample of more than 25,000 men who responded to a standardized set of questions
immediately after deployment and again several months later. Unlike other reports, we
collected information from the same men at both time points.33 This large sample used
documented deployment activity and included combat- and noncombat-exposed service
men. Well-validated screening tools were used to assess likelihood of TBI, PTSD, and
depression. Taking a new approach, our analyses modeled sleep problems as a mediator
for the association of TBI with PTSD, depression, and both conditions.

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CONCLUSION
This work extends what is known about the interrelationships of TBI and mental health
symptoms as mediated by sleep problems, and it points to further research directions that
may improve the health of service members facing similar stresses associated with
deployment. Evaluating sleep problems immediately after TBI while still in theater
should be explored as a way to reduce poor mental health outcomes.

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DISCLOSURE STATEMENT
This was not an industry-supported study. The authors have indicated no financial
conflicts of interest.

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ACKNOWLEDGMENTS
This work was supported by the U.S. Navy Bureau of Medicine and Surgery under Work
Unit No. 60818. The views expressed are those of the authors and do not reflect the
official policy or position of the Department of the Navy, Department of Defense, or the
US Government. Approved for public release; distribution is unlimited. This research was
conducted in compliance with all applicable federal regulations governing the protection
of human subjects (protocol NHRC.2009.0020).

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Footnotes
A commentary on this article appears in this issue on page 7.

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REFERENCES
1. Seelig AD, Jacobson IG, Smith B, et al. Sleep patterns before, during, and after
deployment to Iraq and Afghanistan. Sleep. 2010;33:161522. [PMC free article]
[PubMed]
2. Peterson AL, Goodie JL, Satterfield WA, Brim WL. Sleep disturbance during military
deployment. Mil Med. 2008;173:23035. [PubMed]
3. Rao V, Bergey A, Hill H, Efron D, McCann U. Sleep disturbance after mild traumatic
brain injury: indicator of injury? J Neuropsychiatry Clin Neurosci. 2011;23:2015.
[PubMed]
4. Schreiber S, Barkai G, Gur-Hartman T, et al. Long-lasting sleep patterns of adult
patients with minor traumatic brain injury (mTBI) and non-mTBI subjects. Sleep Med.
2008;9:4817. [PubMed]
5. Orff HJ, Ayalon L, Drummon SP. Traumatic brain injury and sleep disturbance: a
review of current research. J Head Trauma Rehabil. 2009;24:15565. [PubMed]
6. Bryant RA, Creamer M, O'Connell M, Silove D, McFarlane AC. Sleep disturbance
immediately prior to trauma predicts subsequent psychiatric disorder. Sleep. 2010;33:69
74. [PMC free article] [PubMed]
7. Buysse DJ, Angst J, Gamma A, Ajdacic V, Eich D, Rossler W. Prevalence, course, and
comorbidity of insomnia and depression in young adults. Sleep. 2008;31:47380. [PMC
free article] [PubMed]
8. Zeiter JM, Friedman L, O'Hara R. Insomnia in the context of traumatic brain injury. J
Rehabil Res Dev. 2009;46:82736. [PubMed]
9. Lewis V, Creamer M, Failla S. Is poor sleep in veterans a function of post-traumatic
stress disorder? Mil Med. 2009;174:94851. [PubMed]
10. Castriotta RJ, Wilde MC, Lai JM, Atanasov S, Masel BE, Kuna ST. Prevalence and
consequences of sleep disorders in traumatic brain injury. J Clin Sleep Med. 2007;3:349
56. [PMC free article] [PubMed]
11. Clinchot DM, Bogner J, Mysiw WJ, Fugate L, Corrigan J. Defining sleep disturbance
after brain injury. Am J Phys Med Rehabil. 1998;77:2915. [PubMed]
12. Ouellet M, Beaulieu-Bonneau S, Morin CM. Insomnia in patients with traumatic
brain injury: frequency, characteristics, and risk factors. J Head Trauma Rehabil.
2006;21:199212. [PubMed]
13. Parcell DL, Ponsford JL, Rajaratnam SM, Redman JR. Self-reported changes to
nighttime sleep after traumatic brain injury. Arch Phys Med Rehabil. 2006;87:27885.
[PubMed]
14. Deployment Health Clinical Center. ASD (HA) Memorandum, Implementation of
Revised DD Forms 2796 and 2900, 24 Mar 08. [Accessed March 30]. Retrieved from
http://www.pdhealth.mil/dcs/DD_form_2796.asp.
15. American Congress of Rehabilitative Medicine. Definition of mild traumatic brain
injury. J Head Trauma Rehabil. 1993;8:867. http://dx.doi.org/10.1097/00001199-
199309000-00010.
16. Schwab KA, Ivins B, Cramer G, et al. Screening for traumatic brain injury in troops
returning from deployment in Afghanistan and Iraq: initial investigation of the usefulness
of a short screening tool for traumatic brain injury. J Head Trauma Rehabil. 2007;22:377
89. [PubMed]
17. Wright KM, Adler AB, Bliese PD, Eckford RD. Structured clinical interview guide
for postdeployment psychological screening programs. Mil Med. 2008;173:41121.
[PubMed]
18. Asmundson G, Frombach I, McQuaid J, Pedrelli P, Lenox R, Stein M. Dimensionality
of posttraumatic stress symptoms: a confirmatory factor analysis of DSM-IV symptom
clusters and other symptom models. Behav Res Ther. 2000;38:20314. [PubMed]
19. King WW, Leskin GA, King LA, Weathers FW. Confirmatory factor analysis of the
Clinician-Administered PTSD Scale: evidence for the dimensionality of posttraumatic
stress disorder. Psychol Assessment. 1998;10:906.
20. Bliese PD, Wright KM, Adler AB, Cabrera O, Castro CA, Hoge CW. Validating the
Primary Care Posttraumatic Stress Disorder screen and the Posttraumatic Stress Disorder
Checklist with soldiers returning from combat. J Consult Clin Psychol. 2008;76:27281.
[PubMed]
21. Prins A, Ouimette P, Kimerling R, et al. The Primary Care PTSD screen (PC-PTSD):
development and operating characteristics. Primary Care Psychiatry. 2003;9:914.
22. Kroenke K, Spitzer RL, Williams JBW. The Patient Health Questionnaire-2: Validity
of a two-item depression screener. Med Care. 2003;41:128492. [PubMed]
23. Baron RM, Kenny DA. The moderator-mediator variable distinction in social
psychological research: conceptual, strategic, and statistical considerations. J Pers Soc
Psychol. 1986;51:117382. [PubMed]
24. MacKinnon DP, Krull JL, Lockwood CM. Equivalence of the mediation, confounding
and suppression effect. Prev Sci. 2000;1:17381. [PMC free article] [PubMed]
25. MacKinnon DP, Dwyer JH. Estimating mediated effects in prevention studies. Eval
Rev. 1993;17:14458.
26. Preacher KJ, Leonardelli GJ. Calculation for the Sobel test: an interactive calculation
tool for mediation tests. [Accessed April 2011]. Available at:
http://www.people.ku.edu/preacher/sobel/sobel.htm.
27. Herr NR. Mediation with dichotomous outcomes, spreadsheet. [Accessed April 2011].
Available at: http://nrherr.bol.ucla.edu/Mediation/logmed.html.
28. MacKinnon DP, Warsi G, Dwyer JH. A simulation study of mediated effect measures.
Multivariate Behav Res. 1995;30:41. [PMC free article] [PubMed]
29. Picchioni D, Cabrera OA, McGurk D, et al. Sleep symptoms as a partial mediator
between combat stressors and other mental health symptoms in Iraq war veterans. Mil
Psychol. 2010;22:34055.
30. Gellis LA, Gehrman PR, Mavandadi S, Oslin DW. Predictors of sleep disturbances in
Operation Iraqi Freedom/Operation Enduring Freedom veterans reporting a trauma. Mil
Med. 2010;1755:6773. [PubMed]
31. Warner CH, Appenzeller GN, Grieger T, et al. Importance of anonymity to encourage
honest reporting in mental health screening after combat deployment. Arch Gen
Psychiatry. 2011;68:106571. [PubMed]
32. Milliken C, Auchterlonie J, Hoge C. Longitudinal assessment of mental health
problems among active and reserve component soldiers returning from the Iraq war.
JAMA. 2007;298:21418. [PubMed]
33. McLay RN, Klam WP, Volkert SL. Insomnia is the most commonly reported
symptom and predicts other symptoms of post-traumatic stress disorder in U.S. service
members returning from military deployments. Mil Med. 2010;175:75962. [PubMed]

Jurnal 3
Front Neurol. 2013; 4: 91.
Published online 2013 July 22. doi: 10.3389/fneur.2013.00091
PMCID: PMC3717660

Patient Characterization Protocols for

Psychophysiological Studies of Traumatic
Brain Injury and Post-TBI Psychiatric
Disorders
Paul E. Rapp,1 Brenna M. Rosenberg,1 David O. Keyser,1,* Dominic Nathan,1 Kevin M.
Toruno,1 Christopher J. Cellucci,2 Alfonso M. Albano,3 Scott A. Wylie,4 Douglas Gibson,5
Adele M. K. Gilpin,6,7 and Theodore R. Bashore8
Author information Article notes Copyright and License information
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Abstract
Psychophysiological investigations of traumatic brain injury (TBI) are being conducted
for several reasons, including the objective of learning more about the underlying
physiological mechanisms of the pathological processes that can be initiated by a head
injury. Additional goals include the development of objective physiologically based
measures that can be used to monitor the response to treatment and to identify minimally
symptomatic individuals who are at risk of delayed-onset neuropsychiatric disorders
following injury. Research programs studying TBI search for relationships between
psychophysiological measures, particularly ERP (event-related potential) component
properties (e.g., timing, amplitude, scalp distribution), and a participants clinical
condition. Moreover, the complex relationships between brain injury and psychiatric
disorders are receiving increased research attention, and ERP technologies are making
contributions to this effort. This review has two objectives supporting such research
efforts. The first is to review evidence indicating that TBI is a significant risk factor for
post-injury neuropsychiatric disorders. The second objective is to introduce ERP
researchers who are not familiar with neuropsychiatric assessment to the instruments that
are available for characterizing TBI, post-concussion syndrome, and psychiatric
disorders. Specific recommendations within this very large literature are made. We have
proceeded on the assumption that, as is typically the case in an ERP laboratory, the
investigators are not clinically qualified and that they will not have access to participant
medical records.

Keywords: cognitive assessment, neuropsychiatric assessment, resilience, sociological

assessment
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Introduction
The assessment of mild TBI presents significant challenges. This is particularly true in
those cases where the patient is asymptomatic or minimally symptomatic in the
immediate post-injury period and subsequently presents a serious neuropsychiatric
disorder. This has motivated the search for physiological variables, including alterations
in the properties of ERPs (event-related potentials), which can identify individuals at risk
of illness while in the premorbid state.

We wish to outline the specific aims of this contribution. It is not our present purpose to
identify a comprehensive assessment procedure for traumatic brain injury (TBI). Such an
assessment would include elements of the pre-injury medical history, laboratory results
(biomarkers, genomics, neuroendocrine evaluation, markers of inflammation),
quantitative electroencephalography, evoked potentials, event-related potentials,
electromyography, eye tracking, balance assessments, a neurological examination, a
psychiatric interview, and the results of imaging studies. Our purpose is far more limited.
Hundreds, if not thousands, of standardized patient self-report instruments have been
used in TBI studies. The diversity of instruments used has made it impossible to compare
the results of different studies in a statistically meaningful way. Our object was to review
the instruments that have been used and evaluate the clinical and statistical evidence that
supported their use. Our recommendations, which are principally directed to
psychophysiologists who are not necessarily familiar with this material, are based on this
review. While this paper is primarily directed to the psychophysiological community, the
recommendations may be useful in other types of TBI research such as imaging or
biomarker studies. We explicitly recognize that no set of recommendations will be
applicable to all studies. Investigators must make choices that will be informed by the
studys objects and clinical population. It is hoped that these recommendations may be
helpful when making study-specific choices.

As part of the effort to construct psychophysiological characterization of TBI, it is

necessary to identify relations between experimentally induced factor effects on
candidate assessment measures like ERPs and clinically observable manifestations of
injury. This is particularly important in longitudinal studies where the ability of ERPs to
provide indices of the responses to treatment or the progression of disease is being
investigated. Variations in the levels of experimental factors (i.e., independent variables)
can produce different effects on two or more dependent measures. A classic example is
provided in the McCarthy and Donchin (1) matrix task in which both stimulus
discriminability and stimulus-response compatibility are varied. In the matrix task visual
stimuli are presented on a computer. A single trial has two components, a cue word
(SAME or OPPOSITE) followed by a matrix containing the word LEFT or RIGHT.
Example matrices, Noise or No-Noise, are shown in Figure Figure1.1. If the cue word is
SAME and the matrix contains the word LEFT, then a left button press is the correct
response. If the cue word is OPPOSITE and the word LEFT appears, a right button press
is the correct response. Two factors are therefore manipulated, stimulus identification and
response selection. The dependent measures were reaction time (RT) and P300 latency.
McCarthy and Donchin found that variations in both stimulus discriminability and S-R
compatibility influenced RT; RT was prolonged by the appearance of the target word in
the noise (AZ) matrix and by the need to make an incompatible response. In contrast,
P300 latency was influenced only by variations in stimulus discriminability; it was
increased when the target word appeared in a noise matrix. However, P300 latency was
not altered by variations in compatibility. Thus, the factor effects on RT and P300 latency
were dissociated; they were not the same. Dissociations of this type provide the rationale
for using a demanding technology like ERPs. They yield information not evident in RT
and allow us to fractionate the stimulus input-response output process with greater
precision than is afforded by reliance exclusively on response latency.

Figure 1
Examples of high discriminability (NO NOISE) and low discriminability (NOISE)
stimulus matrices used in the McCarthyDonchin matrix task [modified from
McCarthy and Donchin(1)].

In the ideal case, the identification of systematic relations between well-delineated

clinical symptoms and precisely controlled experimental factor effects would be
accomplished by a review of the patients clinical history in which all medical records
obtained in the post-injury period including neuroradiological studies are obtained. In
many cases, these records are not available to researchers. In the extreme case, clinical
characterization of participants published in some ERP studies of TBI is limited to the
simple statement that participants have a documented history of TBI. The objective of
this contribution is to construct a middle path between the ideal case of access to all
pertinent medical records on one hand, and the absence of any patient characterization on
the other hand. The construction proceeds with two assumptions. First, it is assumed that
medical records will not be available to investigators. The only data they will have is
what they measure themselves. Second, the assessment will be limited to standardized
clinical inventories that can be administered by ERP investigators who are not physicians
or licensed psychologists. The selection of neuropsychological tests to be incorporated
into a battery for TBI patients is not discussed in this paper. This issue has been addressed
by Bagiella et al. (2).

A head injury is an event that may lead to a disease process or processes; it is not a
disease (3). Given the lack of diagnostic precision, we propose a purely operational
response by recommending that all studies of TBI/PCS [post-concussion syndrome
(PCS)] have four participant groups: head injury negative/head injury positive crossed
against symptom negative/symptom-positive where, if possible, symptoms are assessed
on the day of the ERP study. Even this seemingly robust operationalization will introduce
sources of ambiguity because a participant is symptom-positive or asymptomatic
depending on the symptoms assessed and on the threshold criteria used to determine
symptom presence or absence. Additionally, the symptoms presented following a brain
injury are not unique to head injury patients. It is therefore essential to recognize that a
Head Injury Negative-Symptom-Positive group should be incorporated into the study. In
studies with sufficiently large participant populations, nature of injury (for example, blast
versus non-blast injury) and time after injury can also be considered in-group
partitioning.

The administration of any inventory requires time. It is impractical to administer all of

the inventories and tests that come to mind. We have constructed a prioritized list for
studies that reflect an interest in mild TBI that may progress to the presentation of a
major psychiatric disorder or clinically significant psychiatric symptoms. Studies with a
particular emphasis investigating a specific hypothesis will need to include assessment
instruments that speak most directly to the hypothesis. A structured evaluation is
therefore suggested. If a brief instrument for a given presentation meets diagnostic
threshold, it can be followed with a more detailed examination in that area if this is a
focus of the investigation. In cases where we have to make a choice between equivalent
or nearly equivalent instruments, we have chosen the assessment instrument that has the
longest application history and the largest validating population.

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Assessments Recommended for all ERP Studies of

Traumatic Brain Injury
Demographic information

It is essential that the demographic characteristics of the participant population be

described thoroughly. Demographic information should include conventional elements:
age, gender, education, ethnic/racial identification, employment status, family/household
status (marriage/partnership/living alone), number of children (in home/not in home), and
handedness since there are important relations between handedness and cerebral laterality
which may have important implications for the effects of TBI. For participants who are
present or prior serving members of the armed forces, we recommend recording duty
status (active duty/separated), years in military, service branch/component, highest
grade/rank attained, deployments (locations and dates), and duration since separation
from service. Because it is well documented that medications can affect quantitative
EEGs (4, 5), EEG topography and Loreta computations (6) and event-related potentials
(7, 8), a record of current medications (name of medication, dose, and date initiated)
should, therefore, be included in the patient characterization. Some medications used in
the past, but not currently used may have prolonged effects on cognition, affect, and
EEGs/ERPs. An effort should be made to obtain a record of past medications and the date
of medication termination.

Combat exposure
In studies with active duty military personnel and veterans, an assessment of combat
exposure can inform the interpretation of other measures. Keane et al. (9) (Table 10.1)
have identified 11 standardized measures of combat exposure. The most commonly used
is the seven item Combat Exposure Scale (10, 11). For this reason, this instrument is
recommended for use in studies where combat exposure is not a central focus of the
investigation. For studies where adverse military experiences are a critical interest, the
more detailed Deployment Risk and Resilience Inventory should be used (1215)
(additional information can be found at the Department of Veterans Affairs, National
Center for PTSD website).

The Deployment Risk and Resilience Inventory uses 104 items to construct 14 scales,
two predeployment/prewar scales, 10 deployment/Warzone scales, and two
postdeployment/postwar scales. The deployment/Warzone scales are Combat
Experiences, Concerns about Life and Family Disruption, Deployment Social Support,
Difficulty Living and Working Environment, Exposure to the Aftermath of Battle,
General Harassment, Perceived Threat, Self-Report of Nuclear/Biological/Chemical
(NBC) Exposures, Sense of Preparedness, and Sexual Harassment.

Categorization of severity at the time of injury

A categorization of severity at the time of injury can be attempted, but as noted above the
uncertainties associated with long delayed assessments indicate that these classifications
are only an approximation. A search for relations between changes in the characteristics
of EEGs/ERPs and post-concussion symptoms determined at the time of testing
(described in the next section) is more likely to be scientifically fruitful. Arlinghaus et al.
(16) presented a classification of TBI based on the clinical presentation at the time of
injury using either the Glasgow Coma Scale (GCS), or the duration of loss of
consciousness (LOC) or the duration of post-traumatic amnesia. The VA/DoD TBI
Severity Classification (17) is similar to, but not identical to, the Arlinghaus et al.
classification. The two classifications differ in the LOC criterion separating moderate and
severe injury and in the introduction of an additional criterion (alteration of
consciousness/mental state) in the DoD classification (see Table Table11).

Table 1
Classification of traumatic brain injury severity.

There is a lack of consensus in the literature. Greenwald et al. (18) and Rao and Lyketsos
(19) have the same classification based on the GCS, but have different criteria when
classification is based on LOC (see Table Table22).
Table 2
Comparison of TBI classification criteria.

This is not an exhaustive account of TBI/concussion classification systems. Cantu (20)

has summarized grading systems by Nelson et al. (21), Ommaya (22), Cantu (23, 24),
Colorado Medical Society (25), Jordan et al. (26), Torg (27), Roberts (28), and Kelly and
Rosenberg (29). Anderson et al. (30) report that there are at least 41 different guidelines
for grading mild head injury. The Mayo Classification for Traumatic Brain Injury
Severity (31) establishes criteria for the categories Symptomatic (Possible), Mild
(Probable), and Moderate-Severe. The strength of the Mayo classification lies in its use of
multiple indicators. It can be used when a specific single indicator is not available to
investigators. In their study sample (N = 1501 participants) at least one single measure
was not available for a large number of injury events. For example, GCS scores were not
available in 74% of the injury events, loss consciousness data were not available in 70%,
post-traumatic amnesia was absent in 58%, and head CT was not performed in 49% of
the incidents. Using available information, however, all injury events could be classified
using this procedure. This system of classification is therefore particularly well suited for
retrospective studies. We recommend use of the Mayo Classification for
psychophysiological research in non-clinical, civilian research environments. For
research with military populations, however, it may be important to relate
psychophysiological variables to pre-existing military medical histories. The VA/DoD
classification is warranted in these instances. We recommend using either the Mayo or the
VA/DoD classification or recording both. We again note that classifications long after the
time of injury based on patient report are potentially unreliable and that these assessments
should be the last elements in the battery.

Current post-concussion symptoms

Care should be exercised in the interpretation of symptoms identified using checklists of

PCS. For example, Gunstad and Suhr (32) investigated the non-specificity of PCS
symptom expectation and concluded that symptom checklists for PCS may not be
useful for diagnosis. Two sets of diagnostic criteria for PCS are available, the ICD-10
criteria for PCS (33), and the DSM-IV criteria for post-concussional disorder (PCD) (34).
The ICD-10 criteria require a LOC to meet diagnostic threshold, whereas the DSM-IV
criteria require significant cerebral concussion as evidenced by LOC, post-traumatic
amnesia, or post-traumatic onset of seizures. As McCrea (35) observes, given the
restrictiveness of both sets of criteria, most mild TBI patients would be excluded from
diagnosis even in the presence of significant post-traumatic symptoms. The problem of
selecting which of the two criteria should be used to determine the presence or absence of
post-concussion symptoms is revealed by Boake et al. (36). They compared agreement
observed against agreement expected by chance between the two diagnoses using the
Kappa statistic and found that it was low, a value of 0.13.
Assessment is obscured further by the fact that post-concussion symptoms are not
specific to head injury. Boake et al. (37) found that among patients presenting
extracranial trauma, 40% met the PCS diagnostic criterion and 7% met the PCD
diagnosis criterion, whereas patients with TBI had rates of 64 and 11% (see Table
Table3).3). However, Iverson (38) found that 80% of non-head injury patients reported
three or more post-concussion symptoms while Gouvier et al. (39) found no significant
differences between the brain-damaged individuals and normals on items assessing self-
reported memory problems, problems becoming interested in things, frequent loss of
temper, irritability fatigue, or impatience.

Table 3
Comparison of post-concussion symptoms following TBI and extracranial injury
Boake et al. (37).

The non-specificity of PCS/PCD symptoms has caused some investigators to question the
utility of the diagnosis (3). In a review of the studies cited here and additional work,
Smith (40) concluded: In summary, the so-called symptoms of post-concussional
syndrome are notable in that: (1) they are present in a significant number of the normal
population, and (2) they are present in very significant numbers of patients who have
suffered trauma not involving concussion or brain injury. Therefore, I conclude there is
inadequate evidence that these symptoms meet the definition of a syndrome. Professor
Smith entitled his letter Post-concussional symptoms, not a syndrome. We agree. While
the validity of the diagnosis is in doubt, the characterization of symptoms remains
important in the search for relationships between clinical presentation and CNS
electrophysiology. Precisely articulating extant symptoms at the time of testing is
important irrespective of their meeting any particular diagnostic criteria.

Our review of the literature suggests that the most viable instrument for assessing current
post-concussive symptom is the Rivermead Post-Concussion Symptom Questionnaire
[RPQ16, (41)], a 16 item questionnaire that can be self-administered or clinician
administered. It assesses the degree of symptom severity on a scale from 0 to 4 (0 = not
experienced at all; 1 = no more of a problem than before injury; 2 = a mild problem; 3 = a
moderate problem; 4 = a severe problem). The RPQ16 yields an aggregate score by
summing all scores of two or more. The King et al. (41) test-retest reliability study of self
administration of the questionnaire resulted in a Spearman correlation coefficient of 0.90.
The inter-rater (inter-clinical) scoring gave a Spearman correlation of 0.87. Their study
also indicated that some symptoms (namely, headaches, dizziness, noise sensitivity,
forgetfulness, and poor concentration) were experienced consistently. In contrast, other
symptoms were more difficult to identify and had variable expressions. These symptoms
included feeling frustrated, feeling depressed, taking longer to think, and restlessness.
The authors reasoned that the reliability of the aggregate score indicates that individual
symptoms may substitute for each other over time, but leave the general level of
subjective experience unchanged.

In addition to the test-retest reliability of the summed RPQ16, Eyres et al. (42) assessed
its internal and external construct validity. They estimated its internal construct validity
using the Rasch model (43) and its external construct validity by comparing the summed
RPQ16 score with the score on the Rivermead Head Injury Follow-Up Questionnaire
(44). Their results indicated that the original 16 item summed RPQ16 score did not meet
Rasch internal construct validity criteria, meaning that summing individual responses into
a single aggregate score could not be justified. Their analysis did reveal, however, that if
three (headache, dizziness, and nausea) of the 16 elements were summed separately, then
the two resulting scales did meet internal construct validity, the RPQ3 and the RPQ13.
Importantly, using the Spearman rank correlation, they estimated the external construct
validity of the RPQ13 to be 0.82, with individual item correlations between 0.52 and
0.71, and of the RPQ3 to be 0.62 with individual item correlations between 0.40 and
0.60. The overall test-retest reliability of the RPQ13 was 0.89 with individual item
correlations between 0.59 and 0.69. The overall test-retest reliability of the RPQ3 was
0.72 with individual item correlations between 0.59 and 0.69. This pattern of results
supported their recommendation that the RPQ16 be used as two distinct scales, the RPQ3
and the RPQ13. It is interesting to note the division into two independent scales resulting
from statistical analysis conducted by Eyres et al. is consistent with Ryan and Wardens
classification of symptom clusters based on clinical observation (45). Ryan and Warden
identified two symptom clusters, early symptoms that are present immediately after
injury and late symptoms that appear days and weeks after injury. Early symptoms
include drowsiness, headaches, dizziness, and nausea. The late symptoms in the Ryan
Warden classification include irritability, concentration difficulties, memory problems,
headaches, fatigue, dizziness, visual disturbances, noise sensitivity, judgment problems,
depression, and anxiety.

An alternative subscale structure (somatic, cognitive, emotional) using the 16 elements of

the Rivermead Post-Concussion symptom scale has been proposed by Smith-Seemiller et
al. (46) (see Table Table4).4). The utility of this set of subscores was indicated by their
results which showed that chronic pain patients and mild TBI patients were
indistinguishable when characterized using the single summed RPQ16; however,
significant between-group differences were observed when the subscales were compared.
Mild TBI patient had higher scores on the cognitive subscale than did patients with
chronic pain (at p = 0.0005), indicating greater cognitive symptoms in the mild TBI
group; whereas patients with chronic pain had higher scores on the affective subscale
than did patients with mild TBI (at p = 0.05), indicating greater affective symptoms in the
chronic pain group. In contrast, the scores on the somatic subscale for the two groups
were indistinguishable. It should be stressed that, as Smith-Seemiller et al. noted, these
between-group differences were found in two patient populations whose subscale scores
overlapped considerably. These scores cannot, therefore, accurately classify individual
chronic pain and mild TBI patients, a serious deficiency when the goal is diagnostic
specificity that guides therapeutic decisions for individual patients. Potter et al. (47)
performed a structural equation modeling analysis of the Smith-Seemiller three-factor
results. They concluded, as did Eyres et al. that PCS is not a unitary single factor
syndrome, but their analysis did support the identification of separate cognitive,
emotional, and somatic subscales.

Table 4
Rivermead subscales.

Based on the results of Eyres et al. (42), Potter et al. (47) and more recently Ettenhofer
and Barry (48), we conclude that PCS is not a unitary syndrome. This being the case, we
recommend administering the Rivermead Post-concussion Questionnaire and reporting
both the RP3/RP13 identified by Eyres et al. (42) and the RPQ (Cognitive), RPQ
(Emotional), and RPQ (Somatic) identified by Smith-Seemiller et al. (46). The
components assigned to each factor are identified in Table Table44.

Current post-concussion severity classification

It is helpful to characterize a clinical condition in broad categories of minimal, mild,

moderate, and severe. The previously described analysis of the Rivermead Post-
Concussion Questionnaire indicates that PCS is not a unitary disorder. This suggests that
when a severity classification is made by summing 16 individual scores, it must be
interpreted with care. It would, at best, be a broad indication of clinical status. Explicitly
recognizing this, Potter et al. (47) computed the cumulative frequencies of summed
RPQ16 scores from their clinical sample (168 head injury patients where post-traumatic
amnesia was less than 24 h, assessed 6 months after sustaining a closed skull head injury).
They considered taking 75, 90, 95 limits as cut-off bands to produce the following
classification.

Minimal (<75% of sample) RPQ 012

Mild (7590% of sample) RPQ 1324

Moderate (9095% of sample) RPQ 2532

Severe (95% of sample) RPQ > 33

A limited qualitative understanding of classification based on these cut scores can be

obtained by noting that the RPQ16 score for a non-clinical sample of adults in the general
population is 5.8 (49). Potter et al. state that these bands are provisional and await
further research to examine their sensitivity and specificity against general clinical
populations, as well as their correspondence to quality of life and general functioning.

Assessment of general health at the time of the ERP study

Event-related potentials are a sensitive but non-specific indication of CNS function. They
can be altered by a wide variety of medical conditions. The interpretation of ERPs
should, therefore, incorporate at least a cursory assessment of the participants state of
health at the time of recording. Health assessments fall into two general categories,
disease-specific assessments and generic assessments of health. Consideration here is
limited to generic assessments. Of the generic instruments now available, the SF36 (Short
Form Health Survey) is the most commonly used and systematically validated (50, 51)
and is recommended for ERP studies of TBI. A qualifying observation should be made.
The use of the SF36, or indeed any outcome measure, in a randomized clinical trial raises
additional issues (52). The selection of instruments used in randomized clinical trials
should follow the COSMIN standards (53). The SF36, a generic measure of perceived
health (5456), yields an eight scale profile of functional health and well-being: physical
functioning, role-physical (problems with work or daily activities as a result of physical
health), bodily pain, general health, vitality, social functioning, role-emotional (problems
with work or daily activities as a result of emotional problems), and mental health.
Estimates of internal consistency ( coefficients) range from 0.62 to 0.94, with majority
of scores equaling or exceeding 0.80. Test-retest coefficients ranged from 0.43 to 0.90 for
a 6-month interval and from 0.60 to 0.81 for a 2-week interval.

Assessment of psychiatric symptoms at time of the ERP study

The symptom checklist-90-revised (57, 58) is a psychiatric instrument which is not

specific to a single disorder. The 90 item instrument is self-administered and consists of
questions of the form How much were you disturbed by .? The participant responds
on a scale of 0 = Not at All to 4 = Extremely. The Checklist provides scores on nine
dimensions and three global indices (see Table Table55).

Table 5
Symptom checklist-90-R subscales and global indices.

An extensive literature reporting on the instruments reliability and validity is

summarized in Derogatis (59). Reliability studies resulted in Cronbach scores for the
subscales and global indices between 0.77 and 0.90. The 1 week test-retest correlations
ranged from r = 0.78 to 0.90, and the 10 week test-retest correlations ranged from 0.68 to
0.80. Validity was established by comparisons with the Minnesota Multiphasic
Personality Inventory, the Beck Depression Inventory, the Beck Anxiety Inventory, the
MontgomeryAsberg Depression Rating Scale, and the Maudsley Obessional
Compulsive inventory. Separate norms are available for adolescents as young as 13 years.
A sixth grade reading competency is required.

Estimation of premorbid intelligence

It has been argued that an estimate of premorbid intellectual functioning is critical to the
interpretation of any post-injury assessment (60, 61). This is a matter of particular interest
for ERP researchers since there is a prior literature suggesting that there are ERP
correlates with intelligence [for example (6264)]. As summarized by Franzen et al. (65)
[see also (66)] there are, broadly speaking, five approaches to estimating premorbid
intelligence: (1) historical data, (2) hold-dont hold estimates, (3) best performance
estimates, (4) demographic estimation, and (5) combined methods (demographic and
hold-dont hold or best performance). Franzen et al. noted that, Although none of
the methods reviewed in this paper are optimal in all situations, any one of them is
probably preferable to none at all.

Historical data

Historical data include information about educational and employment history obtained
in clinical interviews with the patient and family members can be used to provide an
approximate estimate of premorbid intelligence. Kareken and Williams (67) conducted
experiments comparing clinical judgment against a quantitative procedure for estimating
an IQ. Clinicians were given demographic information about hypothetical patients and
asked to estimate the corresponding IQs. The same information was used in an actuarial
equation to compute an IQ estimate. The clinicians estimates were close to the computed
estimates. Nonetheless, on reviewing systematic biases that lead to inaccurate clinician
estimates of intellectual function, Kareken (68) recommended using quantitative
methods. This is especially appropriate for ERP researchers since the clinicians
participating in the Kareken and Williams study were highly experienced
neuropsychologists.

Hold-dont hold methods

Hold-dont hold methods estimate premorbid functioning by measuring variables that

are believed to be spared by the injury or disease, that is a hold variable is a component
of intellectual functioning that is assumed to retain its premorbid value. The validity of
the procedure therefore turns on the validity of this assumption. Word reading tests are a
specific implementation a of hold estimation procedure. They estimate premorbid
intelligence by determining the participants ability to pronounce words from a
standardized reading list. The test is constructed on the assumption that reading is highly
correlated with intelligence and that reading ability is resilient against disease and injury
(a hold variable). It is further assumed that the reading of irregular words is more
robust against CNS insult than the reading of regular words (69). Evidence supporting
this assumption is summarized presently. Ciplotti and Warrington (70) have noted that the
method can be inaccurate if the patient had a specific learning disability prior to injury or
if the injury damaged areas specifically important to the process tested, for example left
temporal lobe injury. Several variants have been introduced. The National Adult Reading
Test [NART, (71)] is appropriate for British participants. The North American Adult
Reading Test [NAART, (72)] and the American National Adult Reading Test [AMNART,
(73)] were designed for use with North American participants.
Best performance methods

As typically implemented in a best performance estimation, several tests are administered

post-injury and the highest score is used as the estimate of pre-injury ability (61). Scores
on other tests are assumed to reflect post-injury deficits if they are 1.5 SD below the
highest score. This procedure assumes that there is a single performance level that
characterizes an individuals competence across many areas and that the highest score on
a given test reflects this overall level (the existence of a general ability factor). This
assumption has, however, been challenged (74). Their results indicate that the best
performance method can result in an overestimate of premorbid functioning. In
reviewing the Mortensen et al. results, Lezak et al. (61) noted that the Mortensen results
were in most instances based on the single highest score obtained by healthy control
subjects in the WAIS-A (Wechsler Adult Intelligence Scale) battery of tests. Since the
overall score is a weighted average of individual test scores, the highest single score will
be expected to give an overestimate of the overall score. Lezak et al. recommended using
a cluster of highest scores, though the criterion for selecting that score cluster is not
specified.

Demographic methods

The demographic method can be viewed as a quantitative version of the historical method
in which a regression equation uses demographic variables to compute the premorbid IQ
(75, 76). The best known example is the Barona equation (76) that predicts the WAIS-R
IQ using age, sex, race, education, occupation, urban/rural residence, and geographical
region. However, there is controversy over the accuracy of the estimate it provides. For
example, whereas, Eppinger et al. (77), using the 1984 Barona et al. equation found that
the equation overestimates the IQ of normal individuals, Ryan and Prifitera (78) found
that the equation under-estimated IQ when IQ was greater than 110, but it was generally
reliable in the 90109 range. A revised formula (79) has improved accuracy for
populations composed primarily of Caucasians and African Americans but also shows
regression to the mean [(80, 81), where Groves response to Veiel and Koopman, Grove
(82), and the counter-response, Veiel and Koopman (83), should also be noted].

Combined methods

Combined methods use both demographic and current test scores to estimate premorbid
IQ. Strictly speaking, the most commonly used implementation of AMNART in IQ
estimation is a combined method since it includes one demographic variable (years of
education) in its regression equation (73). A more systematic approach was published by
Crawford et al. (84, 85) who used NART with five demographic variables (age, sex, race,
education, occupation). They found that the combined method outperformed NART alone
in predicting IQ. Vanderploeg and Schinka (86) used WAIS-R subtests as measures of
current ability. No single subtest was specified as the hold measure. Rather, 33
regression formulas were constructed using the 11 WAIS-R subtests to estimate Full
Scale, Verbal and Performance IQs. Because Vanderploeg and Schinka anticipated using
the procedure to estimate premorbid IQ in a TBI population, they did not make a
recommendation as to which of the 33 equations should be used with a specific patient.
Rather, they indicated that the choice of WAIS-R subtest should be based on the patients
injury. For example, they suggested that the WAIS-R picture completion subtest be used
following left hemisphere damage, while the comprehension, information, and
vocabulary subtests be considered following right hemisphere damage. In the Oklahoma
Premorbid Intelligence estimation (OPIE) procedure, another combined method, Scott et
al. (87) used four demographic variables (age, race, education, and occupation). Four
predictions of Full Scale IQ were computed for each participant. Three were produced
using the WAIS-R Vocabulary score only, the Picture Completion score only, and both the
Vocabulary and Picture Completion scores along with the demographic variables. The
fourth prediction used the highest WAIS-R. The OPIE procedure was tested with several
clinical populations (dementia, TBI, cerebral vascular accident, neoplasm, epilepsy, and
chronic pain). Estimates of premorbid IQ did not show systematic under- or over-
estimation in any of these populations.

In a comparison study, Axelrod et al. (88, 89) computed predicted FSIQ (Full Scale
Intelligence Quotient) scores obtained using five methods from a population of 104
neurological patients. The five methods used were:

1. The Barona equation that uses demographic data only (76).

2. BEST-3 (90) that uses demographic information and the best age-scaled score of
the WAIS-R Information, Vocabulary, and Picture Completion subtests with the
corresponding regression equation of Vanderploeg and Schinka (86).
3. OPIE (91), that uses raw scores from the WAIS-R Vocabulary and Picture
Completion subtests and demographic information as did Vanderploeg and
Schinka (86).
4. OPIE-2 (91) a variant of the OPIE method that uses the better of the two scores on
Vocabulary or Picture Completion subtests if one is specifically impaired along
with demographic information.
5. OPIE-R ((92), as described in (88)) provides a quantitatively based criterion for
implementing OPIE-2. The Vocabulary score and demographic information are
used if the age-scaled Vocabulary score is more than four points greater than the
Picture Completion score, and if the picture Completion score is four points
greater than the Vocabulary score, it is used with demographic information. If the
point spread between the two scores is less than four, both scores and
demographic information are used in the Krull et al. (91) equation.

Results obtained with the five methods were compared to the actual FSIQ. Axelrod et al.
concluded that BEST-3, OPIE, OPIE-2, and OPIE-R are equally effective approaches for
premorbid estimation.

Riley and Simmonds (93) studied 26 patients who sustained a severe TBI. They were
given the NART within 12 months of injury and again at least 12 months later. If the
NART score is acceptable as a hold variable in this population, it should be
approximately constant with time. Eleven participants (4% of sample) showed an
improvement of more than five IQ points. Three participants showed an improvement of
20 points. This argues against accepting NART as a hold variable in the severe TBI
population.

Further evidence against a hold-dont hold procedure in a TBI population was

published by Hoofien et al. (94). They began their investigation by noting that most of
the studies used to validate predictions of premorbid intelligence are studies of concurrent
validity in which a predictor based on demographic variables and/or current performance
is used to estimate current performance in the WAIS-R. They also note that the studies
are usually performed with a healthy control population. Hoofien et al. provide a direct
test of predictive validity in which current performance and demographic information
was used to estimate a premorbid intelligence score in a TBI population. The premorbid
measure was the Israeli militarys Primary Psychometric Rating which is administered at
age 18. This score is highly correlated with WAIS and was used to compute a premorbid
IQ. The population (N = 54) had sustained a TBI subsequent to this initial testing.
Hoofien et al. used two methods to estimate premorbid IQ. The first method, denoted
BEST-10, used the best score of 10 of the 11 WAIS subtests and demographic variables
with the regression equations published by Vanderploeg and Schinka (86) (10 scales are
used because the Hebrew version of WAIS does not include a Vocabulary subtest.). The
second method, denoted BEST-2, used the best score of either the Information subtest or
the Picture Completion subtest and the same Vanderploeg and Schinka regression
equations. BEST-2 therefore differs from BEST-10 in implementing an a priori
identification of two hold variables. Both procedures used the same demographic
variables: age, gender, premorbid occupation, and premorbid education. Following
Vanderploeg and Schinka, the premorbid education and premorbid occupation scores
were combined to form a single socio-economic status score. The correlations between
the estimates of premorbid IQs were 0.583 for BEST-2 and 0.622 for BEST-10. The
difference was not statistically significant. The BEST-10 under-estimated IQ by 2.07
points (not significant) and the BEST-2 under-estimated IQ by 5.39 points (statistically
significant). In the case of BEST-2, 26% of the participants had an estimated IQ more
than 1 SD from the premorbid score. While with BEST-10, 6% of the patients had an
estimated score more than 1 SD from the premorbid score. Hoofien et al. conclude that
for this population, a best performance procedure is better than a hold-dont hold
method.

In contrast, positive evidence for using a hold-dont hold procedure to estimate

premorbid intelligence in a TBI population has been published by Green et al. (95). In the
Green et al. study, 24 participants who had experienced a severe TBI were assessed 2 and
5 months post-injury. Three tests were used to measure premorbid intelligence, the
Wechsler Adult Reading Test [WTAR, (96)], the Vocabulary subtest of WAIS-III, and the
Matrix Reasoning subtest of WAIS-III. As in the case of AMNART, the WTAR (Wide
Range Achievement Test) uses words that have an atypical grapheme to phoneme
translation. Three subtest of current ability from the WAIS-III were also administered:
symbol digit modalities, similarities, and block design. The scores obtained with tests of
current ability improved in a manner consistent with recovery from the TBI. Performance
on WTAR was stable and the WTAR-derived estimate of IQ was similar to the estimate
obtained with the 1997 Crawford and Allan demographic equation (460). Green et al.
concluded Thus, converging evidence high stability during recovery from TBI and
similar IQ estimates to those of a demographic equation suggests that the WTAR is a
valid measure of premorbid IQ for TBI. Where word pronunciation tests are indicated
(i.e., in patients for whom English is spoken and read fluently), these results endorse the
use of WTAR for patients with TBI.

This review of the literature supports the conclusion that the observation of Franzen et al.
(65) that no method for estimating premorbid intelligence is optimal in all situations is
particularly true in the case of TBI populations. The situation is further complicated by
the evolution of intelligence testing. WAIS-III was released in 1997, and WAIS-IV was
released in 2008. The scores obtained on these tests are highly correlated with each other
and with WAIS-R. This indicates that previous studies of the comparative value of
different methods for estimating premorbid intelligence are still valid, but it is necessary
to use recomputed regression equations if WAIS-III or WAIS-IV scores are to be used.

For ERP researchers premorbid intelligence estimates based on WAIS-IV and WRAT-4
raise practical difficulties. Administration of these tests requires considerable time.
Administration of the complete WAIS battery requires 75 min (range 6090 min). In a
research study where premorbid intelligence is not a critical measure, this may be an
unacceptable participant burden. The WTAR requires 10 min. However, access to the
WAIS battery and to WTAR requires clinical licensure, and most ERP researchers are not
clinically qualified. Though it is normalized for WAIS-R, AMNART with the Grober and
Sliwinski formula continues to be used (97). For ERP studies where assessment of injury-
induced cognitive decline is not a primary focus, and in the absence of collaborators with
appropriate licensure, we recommend using AMNART with the Grober and Sliwinski
formula (73) and both Barona formulas (76, 79). Caution must be exercised in the
interpretation of the results particularly when the three methods give divergent values. If
a licensed collaborator is available, the choice between WAIS and WTAR should be
based on an overall assessment of participant burden, with WTAR being the choice that
minimizes that burden.

Go to:

Additional Assessments Recommended for Studies

Investigating Traumatic Brain Injury and Specific
Neuropsychiatric Disorders
The relationships between TBI and neuropsychiatric disorders are receiving increased
attention. In those studies where these relationships are a primary focus, it is
recommended that the assessment provided by the Symptom Checklist-90-R be
confirmed by additional instruments. This concurs with the recommendation of Homaifar
et al. (98), who writing specifically about depression following TBI, recommended that
multiple means of assessment should be used when diagnosing neuropsychiatric disorders
following TBI. Here we consider eight disorders where a substantial body of evidence
indicates that a TBI is a significant risk factor for their presentation: depressive illness,
post-traumatic stress disorder (PTSD), anxiety, psychotic disorders, sleep disorders,
suicidal ideation, alcohol abuse, and substance abuse.

The recommendations presented here follow the diagnostic classifications of the DSM-
IV. At present, these diagnostic groups define the assessment criteria that must be
satisfied in studies of post-TBI psychopathology. It should be noted, however, that a
significant revision of assessment practices may soon be required. The classical discrete
disease conceptualization of psychopathology that was modeled on physical medicine is
being challenged. As summarized by Smith and Oltmanns (99), the syndromal approach
may need to be jettisoned due to lack of validity. Among others, Smith and Oltmanns
have argued for an emerging consensus in which psychopathology is described along
continuous, homogeneous dimensions of functioning instead of in discrete categories.
This type of dimensional approach has been taken, for example, by Widiger et al. (100)
who described a four-dimensional continuum for describing personality disorders and by
Brown and Barlow (101) who published a dimensional model for describing anxiety and
mood disorders. Therefore while the current classifications are observed here,
investigators who are looking for changes in the properties of ERPs that may be
associated with different types of psychopathology should recognize that the diagnostic
structure on which their investigations are based is being challenged and may be
discarded. Indeed, if it is found that different alterations in the morphology and timing of
ERP components are associated with the different functional dimensions now being
proposed (100, 101) and not with DSM-IV categories, then ERP evidence may be
important in facilitating this transition.

Further cautionary observations should be made. Association, even temporally sequenced

association, does not establish causation. The results summarized here indicating that TBI
can lead to psychiatric disorders require further development and should be considered
suggestive, certainly important, but not definitive. The identification of causal
associations between TBI and psychiatric disorders is complicated by case histories that
include multiple injury events, which is particularly true in military populations, and in
some instances by the delayed onset of psychiatric symptoms. This time delay can be
highly variable from patient to patient. Delayed-onset presentations following TBI
include depression (102106, 463), PTSD (106110), PCS (111113), and psychosis
(114116).

Assessment of depression

In addition to the general considerations concerning psychiatric diagnosis outlined above,

problems are encountered when assessing post-injury depression that are specific to
depressive illness. Differences in the etiology of post-injury depression can be a
significant complication. Depression following TBI can be a psychological response to
deficits (117) or a neurologically derived consequence of failures in CNS networks (118).
This complex multifactor etiology has resulted in large variation in the reported incidence
of depression following TBI. Some of the reasons for which have been summarized by
Kim et al. (119). Part of the variability is due to differences in the patient populations
being examined. Some studies consider only mild TBI while some include patients with
moderate and severe injuries. All too often the criteria for sub-typing the severity of a
TBI between mild, moderate and severe are not reported explicitly. Moreover, the time
interval between injury and assessment can also be a critical factor and goes unreported.
It is also important to recognize that acute, transient depression can be an appropriate
situational reaction to the injury. However, if the depression persists for several months
following the injury then the concern is that it reflects a symptomatic expression of
underlying neuropathophysiology. Between-study variability in reported incidence is also
due to differences in diagnostic criteria used to diagnose depression. For example, Seel
and Kreutzer (120) found a diagnosis of depression in 38% of their sample with the Beck
Depression Inventory and a rate of 30% in the same sample with the Neurobehavioral
Functioning Inventory Depression Scale. The concerns raised by Kim et al. (119) were
echoed by Iverson (121) who argued that PCS is often misdiagnosed as depression.

In Table Table66 we have listed the incidence of depressive illness following TBI as
reported over the past 25 years. Arguably the most interesting aspect of the numbers in
the table is their diversity. The patient inclusion criteria of the studies listed in the table
differed from study to study. For example, the highest incidences were reported by
Bombardier et al. (122) who excluded uncomplicated mild TBI (GCS score from 13 to 15
with no radiological abnormalities) and by deGuise et al. (123), whose patients all
presented with severe TBI. Hibbard (124) who found a depression incidence of 61% did
not report injury severity. The post-TBI depression population is very heterogeneous
clinically. This point in emphasized by Moldover et al. (125). These authors reviewed the
multiple etiological pathways that can result in post-injury depression and emphasized
the need for similarly diverse clinical responses. An especially instructive example of the
etiological heterogeneity of depression in TBI patients was given by Wilk et al. (126).
They compared rates observed in four groups (concussions with/without LOC crossed
against blast-induced versus non-blast injury). The following rates of major depression
were observed: concussion with LOC following blast (21.2%), concussion with LOC
following non-blast injury (15.8%), concussion without LOC following blast-induced
injury (10.2%), and concussion without LOC following non-blast injury (16.0%).

Table 6
Depressive illness following traumatic brain injury.

An alternative assessment of the relationship between TBI and depression can be

obtained from a lifetime prevalence study. Holsinger et al. (105) found that the lifetime
prevalence of major depression among men who had suffered a head injury in World War
II was 18.5% as compared to a rate of 13.4% for a matched comparison group. However,
this is probably an underestimate. Using recently developed epidemiological methods,
Kruijshaar et al. (127) controlled for the influence of recall bias when responding to
survey questions. They obtained an estimate of a lifetime prevalence of major depression
in the general population of 20% in men and 30% in women. Though the absolute values
obtained by Holsinger et al. may be underestimates, the important observation in the
present context is obtained by comparing the results from the two populations.

In summary, although the reported incidence of depressive illness after suffering a head
injury varies across a reasonably wide range, the overall pattern points clearly to an
increase in the probability of a depressive illness emerging following such an event.
Therefore, assessment of depression in the TBI-positive population is of critical
importance. Based on an assessment of diagnostic sensitivity and specificity (128),
Robinson and Jorge (129) concluded that the standard DSM-IV-TR criteria are the most
logical criteria to use for the diagnosis of major depression in the TBI population.
Several standardized self-report inventories for depression that are consistent with DSM-
IV criteria are available. We reviewed the Patient Health Questionnaire 9, the
Neurobehavioral Functioning Inventory, and the Beck Depression Inventory.

The Patient Health Questionnaire [PHQ, (130)] screens for several common mental
disorders and was originally designed for use in primary care. Included within the PHQ is
a nine item depression subscale, the PHQ-9, based directly on the diagnostic criteria for
major depressive disorder in the DSM-IV. The nine items are presented as a series of
questions. For example, over the past 2 weeks have you been bothered by any of the
following problems: little or no interest or pleasure in doing things? Items are scored by
the assignments 0 = not at all, 1 = several days, 2 = more than half the days, 3 = nearly
every day. A global score is computed by summing all individual items scores. In a
general medical practice population, the PHQ-9 was found to have a sensitivity of 88%
and a specificity of 88% for major depression when a global score of 10 was used as the
cut-off score (131). For this population, Kroenke et al. recommended cut-off scores of 5,
10, 15, and 20 for mild, moderate, moderately severe and severe depression.

Fann et al. (132) assessed the validity of the PHQ-9 for diagnosis of major depressive
disorder following TBI using the Structured Clinical Interview for Diagnosis [SCID,
(133)] as the gold standard for diagnostic comparison. The study population was limited
to patients with a GCS score less than or equal to 12 (i.e., moderate to severe injury) or
radiological evidence of acute brain abnormality. Fann et al. found that the PHQ-9 had a
diagnostic specificity of 93% and a sensitivity of 89%, a concurrence with the SCID that
was anticipated since the nine items in the PHQ-9 cover the A Criterion symptoms of
depression in the DSM-IV.

An important additional problem encountered in the assessment of depression in a post-

TBI population was addressed by Cook et al. (134) using the PHQ-9. Namely, many of
the symptoms of TBI and PCS (fatigue, poor concentration, disturbed sleep) are also
symptoms of depression. These transdiagnostic symptoms could result in an over-
estimate of depression following TBI. Stated operationally, should symptoms common to
both TBI and major depressive disorder be dropped from a depression screening
instrument or included with a correction factor when used in a post-TBI population? This
question has been addressed by Cook et al. using a Differential Item Functioning analysis
(135, 136) from Item Response Theory (137). They compared responses to PHQ-9 items
obtained from a primary care patient population (N = 3000) and from patients presenting
complicated mild to severe TBI (N = 365) and found that no PHQ-9 item demonstrated
significant Differential Item Functioning attributable to TBI. Moreover, a sensitivity
analysis did not detect an inflation of PHQ-9 scores due to the cumulative effects of
negligible Differential Item Functioning. Cook et al. therefore recommended using all
items of the PHQ-9 when assessing depression following TBI.

The Neurobehavioral Functioning Inventory [NFI, (138)] was developed for patients with
TBI. Like the PHQ, it is not specific to depression. It assesses six different sets of
symptoms: depression, somatic complaints, memory/attention, communication
difficulties, aggression, and motor dysfunction. Administration requires approximately 30
min. The depression scale is based on the DSM-IV criteria for depression. Seel and
Kreutzer (120) compared the depression scale of the NFI against the Beck Depression
Inventory [BDI (139, 140)] and the Minnesota Multiphasic Personality Inventory
[MMPI-2 (141, 142)] in participants who had suffered TBIs with mean duration of
unconsciousness of 4.0 11.5 days and mean number of days of post-traumatic amnesia
of 12 26.7 days, one third of whom experienced amnesia for more than 7 days. Thus,
most of the TBIs sustained by participants in this study would be classified as moderate
to severe. Kreutzer et al. observed a high degree of correlation in the diagnosis of
depression between the NFI and both the BDI (r = 0.765) and the MMPI-2 (r = 0.752).

Unlike the NFI and the PHQ, the BDI (139, 140) was developed specifically to assess
depression. Administration requires 510 min. The maximum possible aggregate score is
63. When validated with psychiatric populations, the BDI was found to have high test-
retest reliability [r = 0.96 (143)] and high internal consistency [ = 0.92, (144)].
Moreover, responses on items in the BDI have been found to correlate with those in the
SCID at r = 0.83 and in the Hamilton Psychiatric Rating Scale for Depression at r = 0.71
(145, 461). Importantly, the utility of the BDI in assessing depression following TBI has
been studied by several investigators. Sliwinski et al. (146) compared the diagnostic
efficacy of the 1987 version of the BDI (147) with the SCID (133) and the Institute of
Rehabilitation Research Symptom Checklist [TIRR, (148)], the latter of which covers
symptoms related to cognition, somatic complaints, communication problems, and
behavioral problems in addition to those related to depression. They found a statistically
significant but small correlation (r = 0.30) between a SCID diagnosis of depression and
the total BDI score, whereas in contrast they found a higher and significantly larger (r =
0.67) correlation between the total BDI score and non-depressive symptoms on the TIRR.
These differences, as Sliwinski et al. reasoned, suggest that transdiagnostic somatic
symptoms common to both depression and TBI influence the BDI diagnosis. A
Differential Item Functioning analysis was not performed. However, with specificities at
80 and 90%, the respective sensitivities of the BDI were 36 and 20% for this population.
This overall pattern of effects led Sliwinski et al. to conclude that In fact, current
findings call into question the validity of BDI as a tool for detecting clinical depression
after TBI.
However, this conclusion was not supported by Green et al. (149) in a study of TBI
patients discharged from an in-patient unit who completed the BDI as part of a 24 month
follow-up assessment. These investigators were specifically interested in determining the
degree to which the presence of somatic symptoms in TBI that are common to depression
contribute to inflating the diagnosis of depression among TBI patients when Beck
diagnostic criteria are used. A Principal Component Analysis identified three-factors that
accounted for most of the variance. Those related, in order of variance explained, to
negative cognition and affect, negative attitudes toward self, and somatic disturbances.
More patients were classified as depressed using the cognitive/affective score only than
using the total BDI score. This finding argues against the conclusion that somatic
disturbance items in the Beck inventory lead to an overestimate of depression in a TBI
population. Cronbachs alpha was 0.92 indicating excellent internal consistency (150).
Green et al. concluded, This study provides preliminary evidence suggesting that the
BDI (Beck Depression Inventory) may be an effective screening tool for self-report
depression in TBI.

In addition to Green et al. two other studies have implemented a factor analysis of the
BDI in a TBI population. Christensen et al. (151) used the original BDI (147) and found a
five-factor structure. Rowland et al. (152) used the BDI-II during the immediate post-
injury period. In addition to using the current version of the BDI, this study included a
mix of mild/moderate (49%) and severe injury (51%) patients. Rowland et al. identified a
three-factor model that was not identical to the Green et al. factorization described above.
The Rowland et al. factors are Negative Self Image (20% of the variance) symptoms of
Depression (18% of the variance) and Vegetative Symptoms of Depression (12% of the
variance, see Table Table7).7). The factor structure found in the TBI population was not
the same as the two-factor structure, Cognitive and Somatic-Affective, found in
psychiatric populations (140). They conclude that it seems reasonable to conclude that
these items (which includes a separate factor characterizing Vegetative Symptoms of
Depression) are measuring something unique to the TBI sample.

Table 7
Depression subscales in a TBI population based on the Beck depression inventory-II
(152).

Of fundamental interest to investigations of the influence of TBI on ERP measures of

cognitive processing is the relationship between the severity of the injury and the severity
of the concomitant depressive symptoms. Various classifications of the severity of
depressive illness based on the aggregate score obtained with different instruments have
been proposed. Beck et al. (153) have partitioned depressive disorder into the following
levels of severity: none or minimal depression (aggregate score less than 10), mild to
moderate depression (aggregate score 1018), moderate to severe depression (aggregate
score 1929), and severe depression (aggregate score 3063). The appropriateness of
applying these cut-off criteria to a post-TBI population was examined systemically by
Homaifar et al. (98). Using signal detection theory they constructed the receiver operating
characteristic (ROC) for depression following TBI with the BDI-II as the discriminating
metric and the SCID as the diagnostic standard. Optimal diagnostic efficiency (87%
sensitivity and 79% specificity) was obtained with an aggregate Beck score of at least 19
following mild TBI and at least 35 following moderate or severe TBI.

On the basis of the patterns of results reviewed here, our recommendation is that
depression following TBI be assessed using the BDI with the Homaifar et al. (98) cutoffs
of 19 following mild TBI and 35 following moderate to severe TBI. Subscales based on
the Rowland et al. factor analysis (Table (Table7)7) can be included in the report in order
to explore relationships between different depression factors and post-injury alterations of
ERPs.

Assessment of post-traumatic stress disorder

According to the DSM-IV, PTSD can occur in an individual who has been exposed to a
traumatic event in which both of the following were present: (1) The person experienced,
witnessed, or was confronted with an event or events that involve actual or threatened
death or serious injury, or a threat to the physical integrity of self or others, (2) The
persons response involved intense fear, helplessness, or horror. Symptoms vary from
patient to patient and can include recurrent and intrusive recollections of the event,
recurrent dreams of the event and avoidance of stimuli associated with the event.
Additional symptoms can include difficulty falling or staying asleep, irritability or
outbursts of anger, difficulty concentrating, hypervigilance, and an exaggerated startle
response. In the case of women the most frequent precipitating event is rape or physical
assault whereas for most men it is a combat-related event (154).

The general observations made at the beginning of Section Additional Assessments

Recommended for Studies Investigating Traumatic Brain Injury and Specific
Neuropsychiatric Disorders concerning the assessment of psychiatric disorders
following TBI apply with particular force when considering the assessment of PTSD.
After reviewing the prior research on factor analysis of PTSD symptoms, Smith et al.
(155) concluded, There is thus reason to question whether PTSD is best considered to be
a theoretically coherent psychological entity. Clearly, identical PTSD symptom counts
can refer to different symptom pictures. It may not be in patients best interests to assign
them a diagnosis that lacks clear meaning. Nonetheless, the investigation of PTSD is
now the focus of a major research effort.

The assessment recommendations presented in this paper are specifically directed to ERP
studies in a TBI-positive population. Therefore, an operational question must be
addressed: can PTSD occur as the result of a TBI? In 1996 Boake (160) wrote Yet the
preponderance of available evidence suggests that PTSD is not a major problem in the
brain injured population. The traditional view of the relationship between brain injury and
PTSD is that these disorders do not co-occur because they are incompatible. Similarly,
Bontke (156) reported that At this point I can only claim to have seen one patient out of
2000 in the last 9 years with the dual diagnosis of PTSD and a mild TBI. Sbordone and
Liter (157) examined 28 patients with PCS and 42 with PTSD. The first author
interviewed each patient individually for 23 h and asked them to describe their
symptoms. In contrast to the patients diagnosed with PTSD, none of the mild TBI
patients reported intrusive recollections of the traumatic event, nightmares.
hypervigilance, phobic reactions, exaggerated startle reactions, or distress when asked to
describe the traumatic event. Sbordone and Liter concluded that mild TBI and PTSD are
incompatible.

This conclusion was challenged, however, by Bryant (158) and more recently in Bryant
(159) who identified two critical methodological flaws in the Sbordone and Liter study:
the interviewer was not blind to the status of each patient and standardized measures of
PTSD were not used. Indeed, he directed attention to processes characteristic of PTSD
following TBI including implicit processing, biologically mediated fear conditioning
and reconstruction of trauma events, and ended his review by concluding that TBI and
PTSD can co-exist. Consistent with Bryants (158) conclusion, PTSD has been reported
in TBI populations (Table (Table8).8). Although it has been asserted that PTSD is highly
improbable if not impossible in cases of brain injury when the patient does not have a
memory of the injury event (156, 160), Joseph and Masterson (161) have argued that
PTSD and TBI can co-occur either through a subconscious (i.e., implicit) level or through
social reconstruction. Gil et al. (162) found that while explicit memory of the
traumatizing event was a strong predictor of PTSD 6 months after a mild TBI, it was not
an absolute requirement. Of the 55 participants with a memory of the traumatic event,
23% presented PTSD, while 6% of the patients who had no memory of the traumatic
event met full diagnostic criteria for PTSD.

Table 8
Incidence of PTSD in a TBI population.

The more recent literature (163165) convincingly argues that TBI and PTSD can indeed
be comorbid. The question of neurological mechanism has been addressed by Gil et al.
(162) who suggested that One possible mechanism by which these results could be
explained is that emotionally charged traumatic memories are initially processed with
brain circuits that bypass cortical structures and are mediated primarily through the
amygdale, resulting in the formation of implicit (unconscious) memories (166168). In
addition, the stress-induced secretion of glucocorticosteroids, which have been shown to
impair hippocampal functioning, may disrupt the formation of explicit memory (169).
Further understanding of the neurological basis of a relationship between PTSD and TBI
has been found by MacDonald et al. (170). Using diffusion tensor imaging to examine
blast-induced TBI patients, these investigators found abnormalities in cingulum bundles,
in right orbitofrontal white matter and in the middle cerebellar peduncles.
Asymmetrically altered integrity of the cingulum bundle is associated with PTSD (171)
and alteration in the right orbitofrontal cortex has been observed longitudinally in cancer
patients who present PTSD. Like Gil et al. Zatzick et al. (165) found that individuals who
had suffered a mild to moderate TBI were more likely to experience PTSD than were
those who experienced a severe TBI.

All participants in the TBI/PTSD incompatibility debate agree that the assessment of
PTSD in a post-TBI population presents formidable challenges, and a large number of
diagnostic instruments have been proposed to address these challenges (Table
(Table9).9). Hickling et al. (172) found that patients with PTSD could be misdiagnosed
with TBI, and McMillan (173) found that individuals with TBI could be misdiagnosed
with PTSD. These misdiagnoses could have resulted from differences in the diagnostic
procedures used. For example, Harvey et al. (174) found that the use of standardized self-
report questionnaires (seven different instruments were used in the studies reviewed)
resulted in a high incidence of PTSD diagnoses in a post-TBI population while clinical
interviews resulted in a low incidence. Similar results were reported in a study by
Sumpter and McMillan (175) of 34 patients with severe TBI (post-traumatic amnesia
greater than 1 day) whose PTSD symptoms were assessed using two self-report
questionnaires, the Post-Traumatic Diagnostic Scale (176) and the Impact of Events Scale
((177) with the (178) cut-off score of 25 as the criterion for PTSD), and a structured
clinical interview, the Clinician Administered PTSD Scale (CAPS, (179)). They found
that 59% of the participants met criterion for PTSD using the Post-Traumatic Diagnostic
Scale and 49% of the participants met criterion for PTSD using the Impact of Events
Scale. However, very different incidence rates were obtained with the Clinician
Administered PTSD Scale (179). In the with judgment variant, a symptom is scored if
it is present and the administering clinician concludes that the symptom is related to the
traumatic event. In the 2005 Sumpter and McMillan study, 18% of the participants met
the CAPS PTSD diagnostic criterion based on symptom presence. If the additional
requirement of clinical attribution of a symptom to the traumatic event was introduced,
3% (N = 1) of the sample met the diagnostic criterion. This should be compared with the
59% value obtained with the Post-Trauma Diagnostic Scale and the 49% obtained with
the Impact of Event Scale with the same patient sample.

Table 9
Instruments used in the assessment of PTSD.

In a subsequent paper, Sumpter and McMillan (180) analyzed the sources of diagnostic
discrepancy between self-report questionnaires and the clinician administered structured
interview. They cited the following possible causes. (1) Post-injury cognitive
impairments caused errors in understanding. (2) Recurrent efforts to reconstruct
memories lost during peri-trauma amnesia were scored as intrusive thoughts. (3)
Upsetting thoughts that scored on the PTSD Diagnostic Scale were due to frustrations
with post-injury physical limitations and not due to re-experiencing. (4) Detachment
which scored on the questionnaire was also due, in some instances, to disability-
dependent social isolation and not to a psychological consequence of the injury event.
Sumpter and McMillan explicitly stated that their results do not indicate that PTSD
cannot occur after severe TBI. They also noted that the observed diagnostic discrepancy
may not be replicated in a mild TBI population. The results demonstrating the limitations
of self-report questionnaires for assessing PTSD after TBI that were reported by Sumpter
and McMillan are consistent with the conclusions of Sbordone and Ruff (181) and the
recommendation of Bryant (158) who concluded: Accordingly assessment for PTSD
following TBI should not rely excessively on the clients capacity to report relevant
symptoms. In the Sumpter and McMillan study, the self-report questionnaires did not,
however, produce false negative assessments. Sumpter and McMillan therefore suggest
that these questionnaires can be used as a first screen for PTSD following brain injury
which is followed by a more demanding clinician administered instrument, for example
the CAPS.

The Clinician Administered PTSD Scale CAPS, Blake et al. (179, 182, 183) is a
structured interview containing 17 items scoring DSM criteria for PTSD. Frequency (0 =
never, 1 = once a week, 2 = once or twice a week, 3 = several times a week, 4 = daily or
almost every day) and intensity (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme)
are scored for each item. Aggregate scores are produced by adding the frequency and
intensity scores. Scores for a single item can therefore range from 0 to 8, and the
aggregate score for the entire assessment can range from 0 to 136. Using signal detection
theory Shalev et al. (184) determined that a CAPS score of 40 yielded 93% sensitivity
and 80% specificity. The total score can be re-expressed as three subscales: re-
experiencing (Items 1 to 5), Avoidance (Items 612), and Hyperarousal (Items 1317). A
factor analysis by King et al. (185) identified four correlated but distinct factors: re-
experiencing, effortful avoidance, emotional numbing, and hyperarousal. Following
Sumpter and McMillan (175), one can generate two CAPS scores, one without judgment
(the symptom is present) and one with judgment (the symptom is present and is deemed
to be a consequence of the traumatic incident). The instrument also provides five global
scales: (1) Impact on Social Functioning, (2) Impact on Occupational Function, (3)
Global Validity, (4) Global Severity, and (5) Global Improvement.

The National Center for PTSD (United States Department of Veterans Affairs) advises
that the CAPS was designed to be administered by clinicians and clinical researchers
who have a working knowledge of PTSD, but can also be administered by appropriately
trained paraprofessionals. The CAPS training CD-ROM can be ordered from the
National Technical Information Service. The International Association of Trauma
Professionals provides certification for administration, scoring, and interpretation of the
CAPS. The CAPS-CA (186) is a version of CAPS that is appropriate for children and
adolescents.

The PTSD Checklist [PCL, (187)] has three versions. The PCL-M measures responses to
stressful military experiences. The PCL-C is directed to civilians and assesses symptoms
in relation to generic stressful occurrences, and the PCL-S is used in studies of symptoms
relating to a specific stressful experience. There are minimal differences between the
three versions. They all have 17 questions scored on a scale of 1 = Not at All to 5 =
Extremely. A higher score indicates a greater symptom burden. The questions are
divided into three groups designated Group B, C, and D. Group B questions (Questions
15) assess intrusive thoughts, disturbing dreams, re-experiencing, and physical
(autonomic) responses to memory of the stressful experience. Group C questions
(Questions 612) score avoidance, memory deficits, psychological numbing, and social
isolation. Group D questions (Questions 1317) evaluate sleep, labile affect, and
concentration difficulties. Patients will meet DSM-IV diagnostic criteria for PTSD if they
have a moderate or severe response (scores 35) for at least one Group B question, three
or more Group C questions and two or more Group D questions. The National Center for
PTSD (188) proposes cut scores of 3035 for the general population (civilian primary
care, Department of Defense screening and general population screening), 3644 for
specialized medical clinics (TBI clinics, pain clinics, VA primary care) and 4550 for VA
or civilian specialty mental health clinics). Monson et al. (189) concluded that when used
longitudinally a change of 510 points is reliable (that is, it is not due to chance), and a
change of 1020 points is clinically significant.

Several investigators have examined the psychometric properties of the PCL. Blanchard
et al. (190) studied motor vehicle accident patients and sexual assault patients and used
the CAPS diagnosis as the dispositive metric. They found that a PCL cutoff of 44 had a
sensitivity of 0.94 and a specificity of 0.86. Norris and Hamblen (191) studied Viet Nam
era veterans. The internal consistency of the total score was 0.97. The internal
consistency of subscales ranged from 0.92 to 0.93. The 2-day test-retest reliability was
0.46. The correlation with the Mississippi Scale of Combat-Related PTSD was 0.93. The
correlation with the PK Scale of the MMPI (Minnesota Multiphasic Personality
Inventory) was 0.77, and the correlation with the impact of Events Scale was 0.90. In a
study in which a DSM-derived Structured Clinical Interview for Diagnosis was used as
the defining metric, the PCL has a sensitivity of 0.82 and a specificity of 0.83 when a
PCL score of 50 was used as the cut-off score.

Wilkins et al. (192) reviewed 72 studies using the PCL that were conducted between 1993
and 2010. In summary, they found that the PCL is psychometrically sound. They cite ease
of administration as one of its strengths. Two weaknesses were identified. They suggested
that the PCL may be above the reading level of some participants. Additionally, they
found that the PCL may over-estimate the prevalence of PTSD. This observation is
consistent with the results of Ruggiero et al. (193). Ruggiero et al. used both the National
Womens Study PTSD module (NWS-PTSD) and the PCL to assess 233 New York City
area residents 4 months after the 9/11 attacks. In this sample, the prevalence was 1.7% for
the NWS-PTSD and 4.1% for the PCL.

Administration of the CAPS requires 4560 min. For this reason, it is not recommended
for an initial PTSD screening in studies where PTSD is not the primary focus of the
investigation. Administration of the PTSD Checklist requires approximately 5 min. We
follow the proposal of McDonald and Calhoun (194) in recommending that the PCL be
used as a screening test to be followed with a second-tier diagnostic evaluation. We
recommend using the CAPS in this second-tier evaluation with the Shalev et al. cut-off
score of 40.

Assessment of anxiety

We consider here anxiety disorders following TBI that do not meet PTSD diagnostic
criteria. TBI is a significant risk factor for anxiety disorders. Epstein and Ursano (195)
reviewed 11 studies with a total post-TBI clinical population of 1119 and reported an
aggregate incidence of 29%. As noted, however, by Hiott and Labbate (196) some of the
studies summarized in Epstein and Ursano predate the publication of DSM-III criteria.
Interpretation is, therefore, difficult. In a more recent review, Warden and Labbate (197)
cited the following incidence of anxiety disorders following TBI: generalized anxiety
disorder 824%, panic disorder 27%, obsessive-compulsive disorder 12%, and specific
phobias (especially driving) less than 25%. For the specific diagnosis of generalized
anxiety disorder following TBI (see Table Table10),10), Hiott and Labbate reviewed four
studies and found a cumulative incidence of 10.2% (26 of 254). This should be compared
against the lifetime prevalence rate of generalized anxiety disorder in the general
population of 5.1% reported by Kessler et al. (198) and approximately 6% reported by
Ritter et al. (199). However, determination of incidence rates is complicated by symptom
overlap between disorders and by comorbidities. Jorge et al. (104) found that two-thirds
of the post-TBI patients in their sample presenting major depression also met the
diagnostic criteria for generalized anxiety disorder.

Table 10
Incidence of generalized anxiety disorder in a TBI population.

Shear et al. (200) discuss several standardized instruments for assessing anxiety
disorders. No single instrument has emerged as the preferred choice for studies of TBI-
related anxiety disorders Because it has been used in a number of studies of anxiety
following TBI (201203) we recommend the Beck Anxiety Inventory (204, 458) for a
rapid assessment of general anxiety and mixed anxiety disorders. Instruments for
assessing specific anxiety disorders, such as panic disorder, social phobia, obsessive-
compulsive disorder, and generalized anxiety disorder, are also described in Shear et al.
(200).

Assessment of psychotic disorders

Psychotic disorders can follow TBI (205207), but there is considerable uncertainty
about the frequency of post-injury psychosis. Davison and Bagley (208) [as cited by
(209)] found the 10- to 20-year incidence of psychosis following TBI to be two to three
times higher than in the general population. Achte et al. (210) reviewed cases of 3000
combat veterans who had suffered moderate to severe brain injury and found that 750
(25%) of these patients displayed psychotic symptoms. Paranoid schizophrenia and
paranoid schizophreniform psychosis developed earlier (23% within 1 year) than did
delusional psychosis (4%). Delusional psychosis lasted less than a year in 28% of the
cases and more than 5 years in 40% of the cases. Thomsen (211) followed 40 TBI patients
with severe blunt head trauma. Twenty percent (N = 8) developed psychotic disorders.
Early onset of psychotic symptoms occurred in two patients (3 and 5 months post-injury),
and six patients presented delayed-onset psychosis (16 years post-injury). For
comparison, Perl et al. (212). reported lifetime prevalence in a general population to be
0.87% for schizophrenia, 0.32% for schizoaffective disorders, 0.07% for
schizophreniform disorder, and 0.18% for delusional disorder.

The attribution of psychosis to brain injury is complicated not only by the delayed onset
of psychotic symptoms (114116), but also by the lack of uniformity in the occurrence of
TBI in the population. Malaspina et al. (213) found that the rate of TBI was significantly
higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than
for those with no mental illness. It therefore seems possible that in some instances brain
injuries that evolved to psychosis were sustained by individuals who either had
premorbid histories of psychotic disorders or were at increased risk of developing a
psychosis prior to the injury. This later speculation is consistent with the finding of
Sachdev et al. (116) who found that, along with the duration of LOC, a family history of
psychotic illness was the best predictor of psychosis following TBI. An argument for a
causative role of TBI in some instances of psychotic illness can nonetheless be made.
Wilcox and Nasrallah (214) reviewed medical histories of 200 schizophrenic patients,
203 depressed patients, 122 manic patients, and 134 surgical controls. Histories were
examined to determine if there was a history of head injury before the age of 10 (an age
well before the appearance of psychotic symptoms) severe enough to require medical
attention or a LOC due to head injury. Schizophrenics had a significantly greater
frequency of TBI than did depressives, manics or surgical controls Wilcox and Nasrallah
argued that because the head injuries occurred before the age of 10, deficits in premorbid
functioning did not predispose schizophrenics to head injuries, suggesting that head
injury may have a causative role in some presentations of schizophrenia. Arciniegas et al.
(205) noted that the age of onset of psychosis following TBI does not follow the typical
pattern of 1825 years for males and 2530 years for females [citing (115, 116, 215)].
Arciniegas et al. (205) also noted that at least in some instances, symptom types include
comorbid seizure disorders and associated cognitive impairments which are not typical in
a primary psychotic disorder. This further argues for a role of TBI in the etiology of post-
injury psychosis in some patients, support for which is provided in a meta-analysis by
Molloy et al. (216) who found a significant association between TBI and schizophrenia.
Additionally, estimates they derived from family studies were higher than those from
cohort case-control studies by a factor of almost two. Consequently Molloy et al.
concluded this meta-analysis supports an increased risk of schizophrenia following TBI
with a larger effect in those with a genetic predisposition to psychosis.

Symptom-Checklist-90-R includes paranoid ideation and psychoticism subscales. For

most ERP studies with TBI patients, this will be sufficient for studies that do not have
post-TBI psychotic disorders as a primary focus. For research studies where psychotic
disorders are a central concern, we recommend the clinician administered Scale for the
Assessment of Positive Symptoms [SAPS, (217)] and the Scale for the Assessment of
Negative Symptoms [SANS, (218)]. The SAPS has 30 items and four domains covering
(1) hallucinations, (2) delusions, (3) bizarre behavior, and (4) positive formal thought
disorders (incoherence, distractible speech, clanging). The SANS has 20 items covering
five domains: (1) affective flattening or blunting, (2) alogia, (3) avolition-apathy, (4)
anhedonia-asociality, and (5) attention. Participant burden is significant. Administration
of each scale requires approximately 30 min. It should be noted that clinician training is
required in order to achieve reliable ratings.

Sleep disorders

In part because of the social acceptability of symptoms associated with sleep disorders,
they are among the most frequently endorsed symptoms following TBI (219221).
However, evaluation of a causal role of TBI in disturbed sleep is difficult for several
reasons. First, the sleep disorder may be pre-existing. Moreover, quantitative
characterization of the epidemiology of sleep disorders in the general population, which
provides an essential comparator to the TBI population, is complicated by a lack of
uniformity in reporting criteria. For example, Hochstrasser (222) reported a prevalence of
sleep disturbance in the general population of 26% with a 13% prevalence of moderate to
severe disturbance. Ford and Kamerow (223) found that 10% of the general population
endorses symptoms of insomnia, and Rosekind (224) reported 30%. An additional factor
complicates the evaluation of sleep disturbances following TBI. As we previously
reviewed, depression is a common sequel to TBI, and as reviewed by Masoodi and Jiva
(225), sleep disturbances are a frequent element in depressive illness. This TBI-
depression-sleep disorder confound is documented in Fichtenberg et al. (226) who found
a significant correlation between insomnia and depression, as documented by the BDI, in
a TBI population. It is estimated that 5080% of patients with a psychiatric disorder
present sleep disturbances that can be attributed to the underlying psychiatric disorder.
Further, the pattern of sleep disturbances following TBI is highly varied from patient to
patient thereby complicating epidemiological study. In Table Table1111 we have listed
the incidence of sleep disorders among TBI patients as reported across several studies.
Table 11
Incidence of sleep disorders in a TBI population.

Instruments for assessing sleep disorders have been reviewed by Benca and Lichstein
(227) who began their review by observing that the definitive assessment of sleep
disorders requires a polysomnographic study. With this understanding, we recommend
the Pittsburgh Sleep Quality Index [PSQI, (228)]. It is the most comprehensive of the
available instruments, and it has been validated with TBI patients. The internal
consistency of the PSQI is good [Cronbach > 0.8; (228, 230, 231, 459)]. The test-retest
reliability, as quantified by the Pearson linear correlation coefficient is 0.85 for the global
score and 0.650.84 for the component scores. The validity of the instrument was
assessed by its ability to discriminate between different populations. In the Buysse et al.
(228) study, the two groups were good and poor sleepers. Using a global score cutoff of
five gave a sensitivity of 89.6% and a specificity of 86.5%. Backhaus et al. (230)
compared healthy controls and insomnia patients. Using the same cut-off score, they
observed a sensitivity of 98.7% and a specificity of 84.4%. Administration of the PSQI
requires 510 min. It contains 19 self-rated multiple choice questions and four write-in
questions (typical bedtime, typical wakeup time, sleep latency, sleep duration). An
additional five multiple choice questions are to be answered by a bed partner or
roommate. They are not used in scoring. The instrument generates scores for seven
component scales. A global score greater than five is deemed to indicate significant
dysfunction. There are no cut-off scores for component scales. The seven component
scales are Subjective Sleep Quality, Sleep Latency, Sleep Duration, Habitual Sleep
Efficiency, Sleep Disturbances, Use of Sleep Medications, and Daytime Dysfunction.

Fichtenberg et al. (232) conducted a validation study of the PSQI in a TBI population.
Data taken from sleep diaries and interviews were used to classify 91 consecutive
patients admitted to an outpatient neurorehabilitation program as insomnia or non-
insomnia based on DSM-IV criteria. Patients taking sleep medications were excluded
from the study. Using a PSQI global score of>8 as the cutoff, the sample was classified
with 93% sensitivity and 100% specificity. Classification was also determined using the
component scores. The criterion of sleep onset>30 min more than twice a week gave an
accurate classification for 92% of the sample. Sleep duration<6.5 h more than twice a
week had 82% accuracy, and sleep efficiency (the amount of time asleep divided by the
amount of time in bed)<85% more than twice a week gave an accurate classification in
74% of the cases. A further classification was constructed by requiring two or more of the
component score criteria described above to be satisfied. This procedure had a sensitivity
of 100% and a specificity of 91%. For purposes of ERP studies it is typically not
necessary to make a dichotomous insomnia/non-insomnia distinction. In studies where
sleep quality is a measure of interest we recommend reporting both the global score and
the seven component scores.

Assessment of suicidal ideation

Traumatic brain injury is a risk factor for suicide (233236), suicide attempts (237, 238),
and suicidal ideation (106, 239). The most exhaustive investigation to date of the
relationship between TBI and suicide was conducted by Brenner et al. (240) who studied
individuals receiving Veterans Health Administration services between 2001 and 2006.
Patients with a history of TBI (N = 49,626) were compared with no history of brain injury
(N = 389,053). Models were adjusted for demographic and psychiatric covariates.
Veterans in the TBI-positive group were 1.55 times more likely to die by suicide than
veterans in the TBI-negative group. The relationship between TBI and suicide is
particularly pressing for the military because of the high incidence of TBI and suicide in
the military population. Approximately 64% of OEF/OIF personnel wounded on active
duty are wounded by blast events (241) indicating the presence of a large at-risk
population in the military. The increased incidence of TBI in the military coincides with
an increase in Army suicide rates from 9 per 100,000 in 2001 to 22 per 100,000 in 2009
(242). This should be compared with a global incidence of 16 per 100,000 per year (243).

Several instruments for assessing suicidal behavior and suicidal ideation are available
(244). The Columbia Suicide History Form (244, 245) documents previous suicide
attempts, and the Suicide Intent Scale (246) assesses the intensity of an attempters wish
to die at the time of the attempt. Neither scale is appropriate for evaluating suicidal
ideation in individuals who do not have a history of attempted suicide. The risk of suicide
following TBI has been assessed by Lon-Carrion et al. (247) using response Rorschach
profiles evaluated with Exners (248) scoring system to assess the risk of suicide, but this
method requires expertise that is not typically available in an ERP laboratory. As an
alternative, Tsaousides et al. (249) used the suicide related questions of the Beck
Depression Inventory in their study of suicidal ideation following TBI. We suggest that
either the BDI or the SCL-90-R, which asks about thoughts of ending life, is adequate for
studies where suicide risk is not a major focus. For studies where suicidal ideation is a
matter of specific interest, we join with Dennis et al. (250) in recommending the Beck
Hopelessness Scale (251, 252) that was also used by Simpson and Tate (238) and
Simpson et al. (253) in studies of suicide prevention after TBI.

The Beck Hopelessness Scale (252) consists of 20 true/false questions and can be self-
administered or administered verbally by a clinician. A global score from 0 to 20 is
formed by summing individual items. Beck and Steer proposed the following
classification: 03 minimal, 48 mild, 914 moderate, 1520 severe. It has good internal
consistency, Pearson r = 0.820.93 for different populations and test-retest reliability at 1
week of r = 0.69, and at 6 weeks of r = 0.66 (252). Moreover, the validity of the measure
was assessed by comparing the Beck Hopelessness Scale with measures of depression
(252, 254). Nekanda-Trepka et al. (254) found that the Hopelessness Score was positively
correlated with the aggregate BDI score (r = 0.47, p = 0.001). In a prospective study of
1958 psychiatric outpatients, Beck et al. (255) found that individuals with a global score
of greater than or equal to 9 were 11 times more likely to commit suicide than those with
a lower score. This cut-off score identified 16 of the 17 individuals in the sample who
committed suicide. It should be noted, however, that because the incidence of completed
suicide is low, this criterion yields a high incidence of false positive evaluations, 59.0%.
Keller and Wolfersdorf (256) followed 61 depressed patients for 1 year. During this
period there were eight suicide attempts and two completed suicides. A cut-off score of
eight on the Hopelessness Scale successfully identified 90% of the suicidal actions. These
investigators also found a high incidence of false positives.

Assessment of alcohol abuse

The association between alcohol and TBI is a complicated one because alcohol use is
often a causative factor in civilian brain injury. Kraus et al. (257) found that 56% of adult
civilians with a brain injury had a positive blood alcohol concentration at the time of
injury, of whom 49% had a blood alcohol concentration in excess of the legal limit.
Similarly, Sparedo and Gill (258) found that 67% of TBI patients tested positive for
alcohol and 51% were intoxicated when the injury occurred. That these levels may be
associated with pre-injury alcohol abuse is suggested by Kreutzer et al. (259) who
reported a high incidence of heavy alcohol consumption both before and after injury. That
a history of alcohol use or abuse is strongly associated with a higher risk of suffering a
TBI is suggested by Hillbom and Holm (260) who found that the overall incidence of
head injury in alcoholics is two to four times the incidence in the general population.
Using the Quantity-Frequency-Variability Index (261, 262) to characterize alcohol
consumption, Horner et al. (263) found that at 1 year post-injury 15.4% of the TBI
sample were heavy drinkers and 14.3% were moderate drinkers. Bombardier et al. (264)
found that drinking decreased following injury, but approximately 25% of their sample
reported heavy drinking 1 year post-injury. Ponsford et al. (265) found that pre-injury TBI
and appropriately matched control populations showed similar alcohol consumption. In
the pre-injury TBI group, 31.4% used alcohol at a hazardous level, and 29.3% of the
controls used alcohol at a hazardous level (In this study hazardous use was defined as a
score greater or equal to eight on the Alcohol Use Disorder Identification Test. This
instrument is discussed presently.). As did Bombardier et al. Ponsford et al. found that
alcohol abuse declined post-injury, but it subsequently increased with 25.4% of the TBI
group drinking at hazardous levels 2 years post-injury. In a 30-year follow-up study using
DSM-IV criteria for alcohol dependence and alcohol abuse, Koponen et al. (266) found
that 11.7% of their sample either abused alcohol or were alcohol dependent. This sample
had a pre-injury prevalence of 8.3%.

Alcohol use following head injury is higher than in the general population. In part this is
to be expected since alcohol misuse may have been present prior to injury, but post-injury
factors are also important. Reilly et al. (267) identified four psychosocial factors that
increase the risk of alcohol abuse after TBI: (1) increased discretionary time and
boredom, (2) increased enabling from family and friends, (3) uncertainty over the ability
to return to work or to function effectively at work, and (4) physical limitations and post-
traumatic mood change. Horner et al. (263) found six risk factors for heavy drinking
following TBI: (1) gender, (2) young age, (3) history of abuse prior to TBI, (4) diagnosis
of depression since TBI, (5) fair/moderate mental health, and (6) better physical
functioning. Recidivism following completion of alcohol rehabilitation is high in the
post-TBI population. Sparedo and Gill (258) found that 54% of patients who completed
alcohol rehabilitation returned to alcohol. Of the remaining 46%, post-injury seizure
disorders or placement into long-term supervised living were significant factors in
maintaining abstinence.

Martino et al. (268) listed 14 instruments for assessing alcohol abuse and for planning
and monitoring treatment for alcohol abuse. Of these, we recommend the Alcohol Use
Disorders Identification Test [AUDIT (269)]. Martino et al. cited AUDITs slightly better
psychometric performance as quantified by internal consistency, test-retest reliability, and
validity. In a review of 13 psychometric studies of AUDIT, Reinert and Allen (270)
concluded that AUDIT is comparable and typically superior to other self-report screening
measures. AUDIT measures a continuum of alcohol use and has proven to be of value in
characterizing this continuum. It may therefore be useful in identifying clinically
significant alcohol misuse at an early stage of drinking before it has reached the level of
alcohol dependence.

AUDIT consists of 10 questions scored from 0 = never to 4 = daily or almost daily. A

global score is obtained by summing the scores of individual test items. Babor et al. (269)
indicate that for men less than 65 years old, a score greater than or equal to eight indicates
hazardous and harmful alcohol use. For men over 65 and all women, they recommend a
cut-off score for hazardous use of seven. A score greater than or equal to 20 clearly
warrants further diagnostic evaluations for alcohol consumption. The instrument has a
high internal consistency (271, 272). AUDIT is also consistent with other instruments that
assess alcohol use. Bohn et al. (273) found a correlation between AUDIT and the
Michigan Alcohol Screening Test [MAST, (274)] of=0.88. The correlation with the four
question CAGE Questionnaire (275) is r = 0.78 (272). The instrument has also been
shown to be a valid indicator of alcohol impact on global life functioning. Claussen and
Aasland (276) found that the probability of being unemployed over a 2 year period was
1.6 times higher for individuals with an AUDIT score greater than or equal to eight.
Conigrave et al. (277) found that AUDIT scores predict future occurrences of physical
disorders. The AUDIT score is not affected by question ordering or the wording of
questions (278). Several groups have investigated the test-retest reliability of AUDIT
reporting values of r = 0.92 ((279), university students, 2 week interval), r = 0.81 (280)
(primary care patients, 6 week interval), and r = 0.64 (281) (primary care patients selected
for alcohol treatment, 2 week interval). Further results of validity and reliability testing of
AUDIT are given in Reinert and Allen (270).

Substance abuse

Most of the literature examining the relationship between substance abuse and TBI limits
the discussion to alcohol. The literature that is available does, however, establish that as
in the case of alcohol, the use of illicit drugs is a risk factor for sustaining TBI, and a
history of pre-injury substance abuse is correlated with increased disability, delayed
recovery, and poor outcome [reviewed in (282285)]. Based on a review of the literature,
Graham and Cardon reported that substance abuse rates decline following TBI, including
mild TBI. Based on our non-systematic review of the literature, we concluded that the use
of illicit drugs following TBI in individuals who did not have prior history of drug use is
unusual.

We recommend the Drug Abuse Screening Test [DAST, (286)] for assessing drug abuse
or dependence on psychoactive drugs other than alcohol. The DAST can be self-
administered or administered in an interview by a clinician. It consists of a series of
yes/no questions with zero being scored for no and one being scored for yes. A global
score is constructed by summing the responses to individual items. There are two
versions, 20 question and 28 questions. A global score greater or equal to five obtained
with the 28 question version indicates that a drug disorder is probable. The instrument is
consistent having a Cronbach of 0.92 for individuals with a substance abuse disorder
and of 0.94 for general psychiatric admissions (286). Using a DSM-III-R diagnosis by a
psychiatrist as the reference standard, Gavin et al. (287) found that a cut-off score of 5
had a sensitivity of 0.96 and a specificity of 0.79.

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Cognitive Assessments
Executive function

Executive functions are broadly defined as the integrative and organizing functions of
cognition. In the Cicerone et al. (288) characterization, executive functions can be
categorized into four domains: executive cognitive functions (planning and organization),
behavioral self-regulation functions (emotional processing, understanding the
consequences of behavior), activation regulating functions (decreased initiation), and
metacognitive processes (self-awareness). All or some of these functions can be impaired
following brain injury. Malloy and Grace (289) reviewed five instruments for assessing
executive function: the Behavior Rating Inventory of Executive function [BRIEF, (290)],
the Dysexecutive Questionnaire [DEX, (291)], the Frontal Behavioral Inventory [FBI,
(292)], the Frontal Systems Behavior Scale [FrSBe (293, 294)], and the Iowa Rating
Scales of Personality Change [IRSPC, (295)]. Of these, Malloy and Grace note that the
BRIEF and the FrSBe have good reliability and large scale norms. The BRIEF, however,
is a measure for pediatric populations and normative data are only available for children
up to 18 years old. The FrSBe has normative data for 1895 years. A further argument for
using the FrSBe in studies of TBI is provided by Reid-Arndt et al. (296) who found that
while neuropsychological tests of executive function did not help predict post-injury
community integration, the FrSBe did predict important functional outcomes.
Additionally, the Apathy Subscale of the FrSBe (described below) was investigated by
Lane-Brown and Tate (297) who found that it was a reliable and valid measure of apathy
following TBI. Therefore, we recommend using the FrSBe in ERP studies of TBI where
executive function is topic of interest.
The Frontal System Behavior Scale (293) is a 46 item questionnaire with each item score
on a scale of 1, Almost Never to 5 Almost Always. A high score indicates greater
disability. It is composed of three subscales. Subscale A, 14 items, assesses apathy, and
akinesia (anterior cingulate). Subscale D contains 15 items and evaluates disinhibition
and emotional dysregulation (orbital frontal cortex). Scale E, 16 items, evaluates deficits
in executive function (dorsolateral prefrontal cortex).

Cognitive insight

Insight is a word of many meanings. We have considered two distinct capabilities,

cognitive insight (an assessment of the patients self-understanding) and (ii) the ability to
form novel insight-dependent associations. Both can be significantly impaired following
a TBI. At present there are no procedures for constructing premorbid estimates of these
measures. In the absence of pre-injury measurement, their use will be limited to post-
injury longitudinal assessments. Their utility in this regard should not, however, be under-
estimated.

Several instruments for evaluating insight [see Ref. (229)] have been published. These
are directed to evaluating insight in psychotic patients. The Beck Cognitive Insight Scale
[BCIS, (229)] serves that function but is more broadly constructed and is applicable to
other populations. It is therefore recommended for use in TBI studies. The instrument
assesses self-reflectiveness about unusual experiences, the capacity to correct erroneous
judgments and certainty about mistaken judgments. It is self-administered and contains
15 items that are scored on a four-point scale with 0 = Do Not Agree at All to 3 =
Agree Completely. There are two subscales. The self-reflectiveness scale has nine
items and evaluates objectivity, reflectiveness, and openness to feedback. The self-
certainty subscale has six items and assesses certainty about beliefs and conclusions. A
cognitive insight score is calculated by subtracting the aggregate self-certainty score from
the aggregate self-reflectiveness score. Factor analysis indicated that the two subscales
are minimally correlated. Internal consistency was indicated by scores of 0.68 (self-
reflectiveness) and 0.60 (self-certainty). Beck et al. acknowledge that these values are
less than the 0.7 value recommended by Nunnally (298) but note that the prior literature
(299, 300) indicates that these values are acceptable for research purposes. Construct
validity for inpatients diagnosed with schizophrenia or schizoaffective disorders was
indicated by comparisons with the Scale to Assess Unawareness of Mental Disorders
(301). Construct validity was further supported by a study by Granholm et al. (302) who
found that changes scores in positive and negative symptoms in response to treatment for
schizophrenia were significantly correlated with changes scores on the BCIS.

Insight formation

Typically, assessment following TBI is based on tasks that are simple, undemanding tasks
that can be accomplished in the absence of intellectual insight. Life is not simple. It is not
undemanding, and it frequently demands insight formation. It is possible that a test of
higher cognitive processes can identify significant injury-derived deficits in individuals
who present normal results in standard assessments. Tasks based on the discovery of
compound remote associates provide a means of testing the capacity for insight. Schooler
et al. (303) have published the following definition of an insight problem. It is a problem
that

(a) is well within the competence of the average subject; (b) has a high probability of
leading to an impasse, that is, a state in which the subject does not know what to do next;
and (c) has a high probability of rewarding sustained effort with an Aha experience in
which the impasse is suddenly broken and insight in to the solution is rapidly attained.

The remote associates test was introduced by Mednick (304) in studies of creativity. In
the remote associates test, words from mutually distinct associative clusters are presented
to the participant who must find a word that provides an associative mediating link
between them. For example, the stimulus words rat, blue and cottage have the associative
connection cheese. Success on this test has been shown to correlate with other tests of
insight formation (305, 306). The test has also been used in investigations of
psychopathology (307) (specifically subclinical predisposition to manic depression), in
investigations of reactions to positive affect (308), and in research on self-esteem (309).
The compound remote associate problem is a specific type of remote associate task (310).
For example, in this task, three stem words (pine, crab, sauce) are presented
simultaneously to the subject. The subjects task is to find a single-word that can be used
to form a compound word or phrase with all three test words (apple to give pineapple,
crab apple, and applesauce). The previous example from Mednicks remote associates test
(rat, blue, cottage) would not satisfy the more restrictive criterion of a compound remote
associate stimulus, but the stimulus triple board, blue, and cottage would meet the
criterion. Bowden and Jung-Beeman (310) have constructed and tested 144 compound
associate problems. Their documentation provides normative data regarding the
percentage subjects solving the problem within a given time limit (2, 7, 15, or 30 s) and
the average time-to-solution of those trials where the problem was solved.

Bowden and Jung-Beeman (310) list the following advantages that compound remote
associate problems have over what they term classical insight problems.

(1) They can be solved in a short time, so that many can be attempted in a single
experimental session of 1 h or less. (2) They are simpler than classic insight problems,
thus allowing better control of possible confounding variables. (3) They have single-
word, unambiguous solutions, making scoring of responses easier. (4) They are
physically compact, so that they can be presented in a small visual space or short time
span.

To this we would add that the test can be performed with a laptop computer. A
sophisticated laboratory infrastructure is not required.

It should be noted that it is possible to incorporate a compound remote associate task in

an experimental protocol that incorporates simultaneous neurophysiological measures
(311, 312). Bowden and Jung-Beeman (313) and Jung-Beeman and Bowden (314) have
used compound remote associates to investigate differential hemispheric contributions to
problem solving and hemispheric contributions to the experience of a moment of insight
when they are solved. The two phenomena, they argue, are distinct. In many cases, the
subject solves the problem but does not have an experience of a punctate transition to the
solution, what Bowden and Jung-Beeman refer to as the Aha! experience. In a
modification of the basic experimental procedure that includes electroencephalography
and an fMRI study, the three stem words were presented to the left or to the right visual
hemifield. Bowden and Jung-Beeman concluded that semantic activation of the right
hemisphere may help solve insight problems (313), and that the right hemisphere
maintains solution-related activation for yet to be solved problems (314). Bowden and
Jung-Beeman (315) subsequently found that the insight experience correlates with
solution activation in the right hemisphere (see Table Table1212).

Table 12
Instruments recommended for cognitive assessments.
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Sociological Assessments
Socio-economic status

As outlined in preceding sections some patients who sustain a TBI may be asymptomatic
or minimally symptomatic immediately following injury but subsequently present
neuropsychiatric disorders. The ability of ERPs to identify individuals at risk of delayed-
onset psychiatric presentations is now being investigated. Given the heterogeneity of this
clinical population, however, it is not suggested that ERPs alone will provide a uniformly
successful indicator. ERP data must be combined with other physiological measures
including serum biomarkers and imaging studies. Sociological factors, for example socio-
economic status, SES, should also be considered. Research has established a correlation
between PTSD and depression following injury or traumatic experiences with socio-
economic status (316320). Evidence indicates that both possible causal relationships can
occur, that is psychiatric disorders result in lower socio-economic status, but conversely
low socio-economic status is a risk factor for psychiatric disorders after a traumatic event.
Socio-economic status may therefore be an important complement to physiological
measures in efforts to identify individuals at risk of delayed-onset psychiatric disorders
following TBI. Additionally, it is important to control for socio-economic status when
constructing matching participant groups in clinical studies. This can be especially
relevant for ERP studies as correlations between differences in SES and differences in
ERPs have been observed (321323).

The assessment of socio-economic status is, however, exceptionally difficult, Braverman

et al. (324) summarized the situation admirably in the title of their JAMA review, Socio-
economic status in health research: one size does not fit all. While recognizing these
difficulties, we recommend the Barratt Simplified Measure of Social Status [BSMSS,
(325)] because of its simplicity and public domain availability. The aggregate score is
computed from knowledge of the education and occupation of the participant, the
participants spouse/partner, and the participants parents. Educational status is
partitioned onto a seven-element scale, and occupations are classified into nine elements.
The scale is derived from the widely used Hollingshead (326, 327) scale. Barrett made
two significant modifications. First, the list of occupations reflects research updating
occupational prestige ratings (328, 329). Second, the Barratt instrument incorporates
scoring of parental and partner education and occupation. Adjustments are made in the
scoring algorithm for participants who are not married/partnered and for participants who
grew up in a single parent family. Parental scores are used for full time students.

The estimation of the socio-economic status of active duty military personnel is

complicated. Past research which indicated that occupation is the best single indicator of
SES (330) has no discriminatory power within this population since by definition they all
have the same employer. In the case of military personnel, the procedure in Barratt for
full time students should be used; namely the SES of the family of origin should be
reported.

Social support

Social support and patient perception of social support is a significant factor in the
recovery from any illness or injury. A substantial body of literature indicates this is true of
TBI. Perceived social support can be a significant predictor of neuropsychiatric disorders
and post-injury community integration (331333) (The relationship between social
support and neuropsychiatric sequelae can, however, be complex. Leach et al. (334)
found that effective use of problem solving and behavioral coping strategies by the family
of a TBI patient correlated with reduced incidence of depressive illness, but perceived
social support was not predictive of depression.).

The Multidimensional Scale of Perceived Social Support (335) measures subjective

assessment of social support adequacy from three specific sources. Twelve items are
scored on a scale from 1 (Very Strongly Disagree) to 7 (Very Strongly Agree). The
instrument provides a total score and scores on three subscales (Significant Other, Family,
Friends). In a study with undergraduates reliability was indicated by Cronbach alphas of
0.91 (Significant Other), 0.87 (Family), 0.85 (Friends), and 0.88 (Total Score). The test-
retest reliability scores were 0.72 (Significant Other), 0.85 (Family), 0.75 (Friends), and
0.85 (Total Score). The construct validity was examined by comparisons with the
Depression and the Anxiety subscores of the Hopkins Symptom Checklist [HSCL, a
precursor of the SCL-90, (336)]. Zimet et al. hypothesized the perceived social support
should be negatively related to depression and anxiety. Perceived support from family
was inversely related to depression (r = 0.24, p < 0.01) and anxiety (r = 0.18, p < 0.01).
Support from friends was inversely related to depression (r = 0.24, p < 0.01) as was
support from significant others (r = 0.13, p < 0.05) and the aggregate score (r = 0.25, p
< 0.01). These psychometric results were subsequently confirmed with other participant
populations (337, 338).

Quality of life

Bullinger et al. (339) have correctly observed that the report of family members should
not be used as a proxy measure of the patients quality of life. When making this
assessment, a distinction should be made between an assessment of the health-related
quality of life and community integration. We consider here health-related quality of life.
Community integration is considered in the next section.

Some investigators, for example Guilfoyle et al. (340) and Beseoglu et al. (341) have
used the Short Form 36 (SF36) to assess health-related quality of life. While this measure
is not specific to TBI, it is often an acceptable measure in TBI studies. A possible
exception to this observation would be rehabilitation and treatment studies of TBI. In
these studies a TBI-specific instrument is indicated. Several instruments for assessing
health-related quality of life following TBI are available. They include the Function
Independence Measure [FIM (342, 343)], the Function Independence Measure and
Functional Assessment Measure [FIM + FAM (344, 345)], the Disability Rating Scale
[DRS, (346)] and the Quality of Life After Brain Injury instrument [QOLIBRI (347
349)]. We recommend the QOLIBRI.

The QOLIBRI has 37 items scored on a five point scale. There are four Satisfaction
subscales (Cognition, Self, Daily Life/Autonomy, and Social Relationships) and two
Bothered By subscales (Emotions, Physical Problems). The subscales have high
internal consistency (Cronbach alpha 0.75 to 0.89) and good test-retest reliability
[interclass correlations from 0.78 to 0.85 (347, 348)]. The TOTAL QOLIBRI has an
internal consistency of alpha = 0.75 and a test-retest reliability of ICC = 0.95 (347, 348).
The instrument can be clinician administered or self-administered. Administration
requires approximately 10 min (see Table Table1313).

Table 13
Instruments recommended for sociological assessments.

Community integration

The importance of community integration as an outcome measure for treatment of TBI

has been considered by several authors [reviewed in (350)]. The Community Integration
Questionnaire [CIQ, (351)] is self-administered, contains 15 items and has three
subscales (Home Integration, Social Integration, and Productive Activities which
characterizes travel, work, and training). Willer et al. (351) report good test-retest
reliability and internal consistency. A subsequent study (352) established validity and
showed good separation (p < 0.01) between TBI-positive and TBI-negative populations.
The early applications of the CIQ were reported by Dijkers (353). Sander et al. (354)
performed a factor analysis in a large population (N = 312). The three-factors identified
by these calculations suggested modifications to the original questionnaire. Items on child
care and shopping were deleted. The item Who usually looks after your personal
finances such as banking and paying bills? was moved to the Home Integration subscale.
The item How often do you travel outside the house? was moved to the Social
Integration subscale.

Using the original scoring system, Zhang et al. (355) compared the CIQ against the Craig
Handicap Assessment and Report Technique (356) and the Disability Rating Scale (346).
They concluded that the CIQ was the most appropriate of these three instruments for
characterizing post-rehabilitation community participation. Doninger et al. (357) studied
the CIQ and in contrast with earlier investigators reported low reliability, poor
measurement properties, and definitional problems. Reid-Arndt et al. (296) explicitly
addressed the issues raised by Doninger et al. They wrote: The validity of this measure
has been suggested by several studies, including one evaluating a large sample of
individuals with TBI (358) and another specifically assessing the measures reliability
and validity (352). On the other hand, the CIQ has also been the subject of some
criticism. For example, rating scale analyses have resulted in low reliabilities suggestive
of poor item coherence (357) and observations have been made that the CIQ fails to
account for non-TBI factors that may influence scores such as pre-injury activity levels
(342) and gender (359). Despite this, results from a comparison of several outcome
measures suggested that of currently available instruments, the CIQ may be the most
effective measure of rehabilitation outcomes following a TBI (355).

Dijkers (360) expanded the CIQ to produce a 47 item CIQ-2 that was used in Whiteneck
et al. (361) to produce the Participation Assessment with Recombined Tools-Objective,
PART-O, instrument. This instrument was used by Brenner et al. (362) in a study of
health and wellness interventions for individuals with moderate to severe TBI. Insofar as
we can determine, this is the only study to date to use the PART-O.

In the absence of extensive experience with the PART-O, our present recommendation is
to use the Community Integration Questionnaire. It should be administered in its original
form, but both the original scoring and the revised Sander et al. scoring should be
reported for both the total score and the three subscales. A reassessment of this
recommendation should be made after additional experience with the PART-O is
published.

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Resilience
Like all psychological constructs, resilience is difficult to define in a manner that readily
provides in a definition that can be assessed by a psychological instrument. As
emphasized by Meichenbaum (363), resilience is not the absence of symptoms, but rather
refers to a pattern of adaptation in response to stress. Castro has presented a definition
that has become standard in the US military. Resilience comprises the sum total of the
psychological processes that permit individuals to maintain or return to previous levels of
well-being and functioning in response to adversity [(364); see also (365)]. Given the
difficulty in defining resilience, it is not surprising that a very large number of
instruments have been constructed in an effort to provide a valid and reliable assessment
instrument. Several are listed in Table Table1414.

Table 14
Instruments used in the assessment of resilience and related constructs.

Windle et al. (366) reviewed 15 instruments for assessing resilience including some of
those listed in the table. Based on our review, we concur with Windle et al. that there is
no gold standard for assessing resilience. Windle et al. concluded that the Connor
Davidson Resilience Scale, the Resilience Scale for Adults and the Brief Resilience Scale
had the best psychometric properties. Of these we recommend the ConnorDavidson
Resilience Scale.

The ConnorDavidson Resilience Scale assesses 17 domains with 25 questions that are
scored on a five point scale. Not true at all is scored as zero and True nearly all the
time is scored as four. The maximum score is 100, and a higher score indicates greater
resilience. There are also 10 question and two question versions. We recommend the 25
question version. The scores in evaluation studies [reviewed in (367)] were for the US
general population 80.4(12.8), primary care patients 71.8(18.4), generalized anxiety
disorder 62.4(10.7), major depression 57.1(13.3), and two PTSD populations 47.8(19.5)
and 52.8(20.4).

Connor and Davidson (368) performed a factor analysis and found five factors
corresponding to persistence/tenacity, self-efficacy, emotional, and cognitive control
when under pressure, adaptability/ability to bounce back, and control/meaning.
Subsequent studies found that the factor structure varied with setting, and therefore
Connor and Davidson (367) do not recommend separate scoring of factor subscales. The
scale has excellent test-retest reliability [(368), r = 0.87; (369), r = 0.70]. The 10 question
version also has good test-retest properties [(370), r = 0.73; (371), r = 0.90]. An extensive
literature establishing construct validity is reviewed in Connor and Davidson (367). This
document also reviews studied reporting the Scales applications in clinical studies and in
studies with military populations.
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Summary and Additional Considerations

The assessments recommended for all ERP studies are summarized in Table Table15.15.
Each of the instruments listed in Table Table1616 is directed to a specific disorder and is
appropriate in studies where the relationship between TBI and the comorbid psychiatric
disorder is of specific interest. A number of issues should be noted. Several of the
recommended instruments are proprietary, and investigators should obtain appropriate
access before using them. It should be remembered that the psychometric validation of an
instrument is specific to the form of its presentation. If, for example, an instrument that
was validated in a paper-and-pencil form is implemented on a computer, the previous
validation studies are not, strictly speaking, applicable. Investigators will have to make a
judgment as to the importance of prior validation before using an instrument. Validation
concerns are particularly relevant to the acceptability of an outcome measure when
studies are submitted to the Food and Drug Administration as the scientific basis for
approval or clearance of an FDA regulated device or medication.

Table 15
Instruments recommended for all studies of traumatic brain injury.

Table 16
Additional instruments recommended for studies investigating traumatic brain
injury and neuropsychiatric disorders.

Some of the recommended instruments assess suicidal ideation, uncontrolled outbursts of

temper, and thoughts of injuring others. Investigators have a responsibility to respond if a
participant discloses thoughts of injury to self or others. The form of this response will
vary according to the qualifications of the investigators and the location of the study. For
example, support resources such as emergency psychiatric consultations that are available
in a teaching hospital will not be available in academic departments and schools. The
specific legal requirements placed on investigators will vary. Typically, a response plan
should be in place and approved by the investigators Institutional Review Board (Human
Subjects Protection Committee) before initiating the investigation.

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Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of interest.

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Acknowledgments
The opinions and assertions contained herein are the private opinions of the authors and
are not to be construed as official or reflecting the views of the United States Department
of Defense. Paul E. Rapp, David O. Keyser, Kevin M. Toruno, Christopher J. Cellucci,
Dominic Nathan, and Brenna M. Rosenberg would like to acknowledge support from the
Traumatic Injury Research Program of the Uniformed Services University of the Health
Sciences, from the Defense Medical Research and Development Program and from the
United States Marine Corps Systems Command.

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References
1. McCarthy G, Donchin E. A metric for thought: a comparison of P300 latency and
reaction time. Science (1981) 211:7780. doi: 10.1126/science.7444452. [PubMed]
[Cross Ref]
2. Bagiella E, Novack TA, Ansel B, Diaz-Arrastia R, Dikmen S, Hart T, et al. Measuring
outcome in traumatic brain injury trials: recommendations from the traumatic brain injury
clinical trials network. J Head Trauma Rehabil (2010) 25(5):37582. doi:
10.1097/HTR.0b013e3181d27fe3. [PMC free article] [PubMed] [Cross Ref]
3. Rapp PE, Curley KC. Is the diagnosis of mild traumatic brain injury a category
mistake? J Trauma Acute Care Surg (2012) 73(2, Suppl 1):S1323. doi:
10.1097/TA.0b013e318260604b. [PubMed] [Cross Ref]
4. Mucci A, Volpe U, Merlotti E, Bucci P, Galderisi S. Pharmaco-EEG in psychiatry. Clin
EEG Neurosci (2006) 37:8198. [PubMed]
5. John ER, Prichep LS. The relevance of qEEG to the evaluation of behavioral disorders
and pharmacological interactions. Clin EEG Neurosci (2006) 37:13543. [PubMed]
6. Saletu B, Anderer P, Saletu-Zyhlarz GM. EEG topography and tomography (LORETA)
in the classification and evaluation of the pharmacodynamics of psychotropic drugs. Clin
EEG Neurosci (2006) 37:6680. [PubMed]
7. Polich J, Criado JR. Neuropsychology and neuropharmacology of P3a and P3b. Int J
Psychophysiol (2006) 60(2):17285. doi: 10.1016/j.ijpsycho.2005.12.012. [PubMed]
[Cross Ref]
8. Pogarell O, Mulert C, Hegerl U. Event related potentials and fMRI in
neuropsychopharmacology. Clin EEG Neurosci (2006) 37:99107. [PubMed]
9. Keane TM, Street AE, Stafford J. Assessment of military related PTSD In: Wilson JP,
Keane TM. editors. Assessing Psychological Trauma and PTSD. New York, NY: Guilford
Press; (2004). p. 26288.
10. Lund M, Foy D, Sipprelle C, Strachan A. The combat exposure scale: a systematic
assessment of trauma in the Vietnam war. J Clin Psychol (1984) 40(6):13238. doi:
10.1002/1097-4679(198411)40:6<1323::AID-JCLP2270400607>3.0.CO;2-I. [PubMed]
[Cross Ref]
11. Keane TM, Fairbank JA, Caddell JM, Zimering RT, Taylor KL, Mora CA. Clinical
evaluation of a measure to assess combat exposure. Psychol Assess (1989) 1(1):535.
doi: 10.1037/1040-3590.1.1.53. [Cross Ref]
12. King DW, King LA, Vogt DS. Manual for Deployment Risk and Resilience Inventory
(DDRI). A Collection of Measure for Studying Deployment Related Experiences in
Military Veterans. Boston, MA: National Center for PTSD, Department of Veterans
Affairs; (2003).
13. King L, King D, Vogt D, Knight J, Samper R. Deployment risk and resilience
inventory: a collection of measures for studying deployment-related experiences of
military personnel and veterans. Mil Psychol (2006) 18(2):89120. doi:
10.1207/s15327876mp1802_1. [Cross Ref]
14. Fikretoglu D, Brunet A, Poundja J, Guay S, Pedlar D. Validation of the deployment
risk and resilience inventory in French-Canadian Veterans: findings on the relation
between deployment experiences and postdeployment health. Can J Psychiatry (2006)
51:75563. [PubMed]
15. Vogt DS, Proctor SP, King DW, King LA, Vasterling JJ. Validation of scales from the
deployment risk and resilience inventory in a sample of Operation Iraqi Freedom
veterans. Assessment (2008) 15:391403. doi: 10.1177/1073191108316030. [PubMed]
[Cross Ref]
16. Arlinghaus KA, Shoaib AM, Price TRP. Neuropsychiatric assessment. In: Silver JM,
McAllister TM, Yudofsky SC, editors. editors. Textbook of Traumatic Brain Injury.
Washington, DC: American Psychiatric Publishing, Inc; (2005). p. 5978.
17. Management of Concussion/mTBI Working Group VA/DoD Clinical Practice
Guideline for Management of Concussion/Mild Traumatic Brain Injury. Washington, DC:
Veterans Administration Department of Defense; (2009). Available from:
http://www.warrelatedillness.va.gov/WARRELATEDILLNESS/provider/tbi/VADoD-
CPG-concussion-mTBI.pdf.
18. Greenwald BD, Burnett DM, Miller MA. Congenital and acquired brain injury. 1.
Brain injury: epidemiology and pathophysiology. Arch Phys Med Rehabil (2003) 84(3
Suppl 1):S37. doi: 10.1053/apmr.2003.50052. [PubMed] [Cross Ref]
19. Rao V, Lyketsos C. Psychiatric aspects of traumatic brain injury. Psychiatr Clin North
Am (2002) 25(1):4369. doi: 10.1016/S0193-953X(03)00052-2. [PubMed] [Cross Ref]
20. Cantu RC. Concussion classification: ongoing controversy. In: Slobunov S,
Sabastianelli W, editors. editors. Foundations of Sports-Related Brain Injuries. New York,
NY: Springer; (2006). p. 87110.
21. Nelson WE, Jane JA, Gieck JH. Minor head injury in sports: a new system of
classification and management. Phys Sportsmed (1984) 12(3):1037.
22. Ommaya AK. Biomechanics of head injury: experimental aspects. In: Nahum AM,
Melvin J, editors. editors. Biomechanics of Trauma. Norwalk, CT: Appleton and Lange;
(1984). p. 24569.
23. Cantu RC. Guidelines for return to contact sports after a cerebral concussion. Phys
Sportsmed (1986) 14:769.
24. Cantu RC. Post traumatic (retrograde and anterograde) amnesia: pathophysiology and
implications in grading and safe return to play. J Athl Train (2001) 36(3):2448. [PMC
free article] [PubMed]
25. Colorado Medical Society Report of the Sports Medicine Committee. Guidelines for
Management of Concussion in Sports. Denver, CO: Colorado Medical Society; (1990).
26. Jordan BJ, Tsairis PT, Warren RF, editors. editors. Head Injury in Sports: Sports
Neurology (Vol. 227). Rockville, MD: Aspen Publications; (1989).
27. Torg JS. Athletic Injuries to Head, Neck and Face. St. Louis, MO: Mosby-Year Book;
(1991).
28. Roberts WO. Who plays? Who sits? Managing concussion on the sidelines. Phys
Sportsmed (1992) 20:6676.
29. Kelly JP, Rosenberg JM. The diagnosis and management of concussion in sports.
Neurology (1997) 48:57580. doi: 10.1212/WNL.48.3.575. [PubMed] [Cross Ref]
30. Anderson T, Heitger M, Macleod AD. Concussion and mild head injury. Pract Neurol
(2006) 6:34257. doi: 10.1136/jnnp.2006.106583. [Cross Ref]
31. Malec JF, Brown AW, Leibson CL, Flaada JT, Mandrekar JN, Diehl NN, et al. The
Mayo classification system for traumatic brain injury. J Neurotrauma (2007) 24:141724.
doi: 10.1089/neu.2006.0245. [PubMed] [Cross Ref]
32. Gunstad J, Suhr JA. Perception of illness: nonspecificity of postconcussion syndrome
symptom expectation. J Int Neuropsychol Soc (2002) 8(1):3747. doi:
10.1017/S1355617702811043. [PubMed] [Cross Ref]
33. World Health Organization International Statistical Classification of Diseases and
Related Health Problems. 10th ed. Geneva: World Health Organization; (1992).
34. American Psychiatric Association Diagnostic and Statistical Manual of Mental
Disorders. DSM-IV Fourth Edition. Washington, DC: American Psychiatric Association;
(1994).
35. McCrea MA. Mild Traumatic Brain Injury and Postconcussion Syndrome: The New
Evidence Base for Diagnosis and Treatment. New York: Oxford University Press; (2007).
36. Boake C, McCauley SR, Levin HS, Contant CF, Song JX, Brown SA, et al. Limited
agreement between criteria-based diagnoses of postconcussional syndrome. J
Neuropsychiatry Clin Neurosci (2004) 16:4939. doi: 10.1176/appi.neuropsych.16.4.493.
[PubMed] [Cross Ref]
37. Boake C, McCauley SR, Levin HS, Pedroza C, Contant CF, Song JX, et al.
Diagnostic criteria for postconcussional syndrome after mild to moderate traumatic brain
injury. J Neuropsychiatry Clin Neurosci (2005) 17:3506. doi:
10.1176/appi.neuropsych.17.3.350. [PubMed] [Cross Ref]
38. Iverson GL. Outcome from mild traumatic brain injury. Curr Opin Psychiatry (2005)
18(3):30117. doi: 10.1097/01.yco.0000165601.29047.ae. [PubMed] [Cross Ref]
39. Gouvier WD, Uddo-Crane M, Brown LM. Base rates of post-concussive symptoms.
Arch Clin Neuropsychol (1988) 3(2):2738. doi: 10.1016/0887-6177(88)90019-4.
[PubMed] [Cross Ref]
40. Smith DH. Postconcussional symptoms not a syndrome. Psychosomatics (2006)
47(3):2712. doi: 10.1176/appi.psy.47.3.271. [PubMed] [Cross Ref]
41. King NS, Crawford S, Wenden FJ, Moss NE, Wode DT. The Rivermead post
concussion symptoms questionnaire: a measure of symptoms commonly experienced
after head injury and its reliability. J Neurol (1995) 242:58792. doi:
10.1007/BF00868811. [PubMed] [Cross Ref]
42. Eyres S, Carey A, Gilworth G, Neumann V, Tennant A. Construct validity and
reliability of the Rivermead post concussion symptoms questionnaire. Clin Rehabil
(2005) 19:87887. doi: 10.1191/0269215505cr905oa. [PubMed] [Cross Ref]
43. Andrich D. Rasch Models for Measurement. London: Sage; (1988).
44. Crawford S, Wenden FJ, Wade DT. The Rivermead head injury follow up
questionnaire: a study of a new rating scale and other measures to evaluate outcome after
head injury. J Neurol Neurosurg Psychiatry (1996) 60:5104. doi: 10.1136/jnnp.60.5.510.
[PMC free article] [PubMed] [Cross Ref]
45. Ryan LM, Warden DL. Post concussion syndrome. Int Rev Psychiatry (2003) 15:310
6. doi: 10.1080/09540260310001606692. [PubMed] [Cross Ref]
46. Smith-Seemiller L, Fow NR, Kant R, Franzen MD. Presence of post-concussion
syndrome symptoms in patients with chronic pain vs mild traumatic brain injury. Brain
Injury (2003) 17(3):199206. doi: 10.1080/0269905021000030823. [PubMed] [Cross
Ref]
47. Potter S, Leigh E, Wade D, Fleminger S. The Rivermead post concussion symptoms
questionnaire: a confirmatory factor analysis. J Neurol (2006) 253(12):160314. doi:
10.1007/s00415-006-0275-z. [PubMed] [Cross Ref]
48. Ettenhofer ML, Barry DM. A comparison of long-term postconcussive symptoms
between university students with and without a history of mild traumatic brain injury or
orthopedic injury. J Int Neuropsychol Soc (2012):Online prepublication, doi:
10.1017/S1355617711001895. [PubMed] [Cross Ref]
49. Chan RCK. Base rate of post-concussive symptoms among normal people and its
neuropsychological correlates. Clin Rehabil (2001) 15:26673. doi:
10.1191/026921501675253420. [PubMed] [Cross Ref]
50. Garratt AM, Schmidt L, Mackintosh A, Fitzpatrick R. Quality of life measurement:
bibliographic study of patient assessed health outcome measures. Br Med J (2002)
324(7351):141721. doi: 10.1136/bmj.324.7351.1417. [PMC free article] [PubMed]
[Cross Ref]
51. Garratt A. Patient reported outcome measures in trials. Br Med J (2009) 338:11920.
doi: 10.1136/bmj.a2597. [PubMed] [Cross Ref]
52. Contopoulos-Ioannidis DG, Karvouni A, Kouri I, Ioannidis PA. SF-36 outcomes in
randomized trials: a systematic review. Br Med J (2008) 337:a3006.
53. Mokkind LB, Terwee CB, Knol DL, Stratford PW, Alonso J, Patrick DL, et al.
Protocol of the COSMIN study: consensus-based standards for the selection of health
measurement instruments. BMC Med Res Methodol (2006) 6:2. doi: 10.1186/1471-2288-
6-2. [PMC free article] [PubMed] [Cross Ref]
54. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36 ): I.
Conceptual framework and item selection. Med Care (1992) 30(6):47383. doi:
10.1097/00005650-199206000-00002. [PubMed] [Cross Ref]
55. McHorney CA, Ware JE, Raczek AE. The MOS 36-item short-form health survey
(SF-36 ): II. Psychometric and clinical tests of validity in measuring physical and mental
health constructs. Med Care (1993) 31(3):24763. doi: 10.1097/00005650-199303000-
00006. [PubMed] [Cross Ref]
56. Turner-Bowker DM, Bartley PJ, Ware JE. SF-36 Health Survey & SF
Bibliography: Third Edition (1988-2000). Lincoln, RI: QualityMetric Incorporation;
(2002).
57. Derogatis LR, Lipman RS, Covi L. The SCL-90: an outpatient psychiatric rating
scale. Psychopharmacol Bull (1973) 9:1328. [PubMed]
58. Derogatis LR. SCL-90-R Administration, Scoring and Procedures Manual. 3rd ed.
Minneapolis: NSC Peason, Inc; (1994).
59. Derogatis LR. Symptom checklist-90-revised (SCL-90-R). Brief symptom inventory
(BSI). 2nd ed. In: Rush AJ, First MB, Blacker D, editors. editors. Handbook of
Psychiatric Measures. Washington, DC: American Psychiatric Press; (2008). p. 736.
60. Matarazzo JD. Psychological assessment versus psychological testing: validation
from Binet to the school, clinic and courtroom. Am Psychol (1990) 45(9):9991017. doi:
10.1037/0003-066X.45.9.999. [PubMed] [Cross Ref]
61. Lezak D, Howieson DB, Loring DW, Hannay HJ, Fischer JS. Neuropsychological
Assessment. 4th ed. Oxford: Oxford University Press; (2004).
62. Bazana PG, Stelmack M. Intelligence and information processing during an auditory
discrimination task with backward masking: an event related potential analysis. J Pers
Soc Psychol (2002) 83(4):9981008. doi: 10.1037/0022-3514.83.4.998. [PubMed] [Cross
Ref]
63. Zhang Q, Shi J, Luo Y, Zhao D, Yang J. Intelligence and information processing
during a visual search task in children: an event related potential study. Neuroreport
(2006) 17:74752. doi: 10.1097/01.wnr.0000215774.46108.60. [PubMed] [Cross Ref]
64. DePascalis V, Varriale V, Matteoli A. Intelligence and P3 components of the event
related potential elicited during an auditory discrimination task with masking.
Intelligence (2008) 36(1):3547. doi: 10.1016/j.intell.2007.01.002. [Cross Ref]
65. Franzen MD, Burgess EJ, Smith-Seemiller L. Methods of estimating premorbid
intelligence. Arch Clin Neuropsychol (1997) 12(8):71138. doi: 10.1016/S0887-
6177(97)00046-2. [PubMed] [Cross Ref]
66. Lanham RA, Misukanis T. Estimating premorbid intelligence. determining change in
cognition following brain injury. Brain Injury Source (1999) 3(3):423.
67. Kareken DA, Williams JM. Human judgment and estimation of premorbid intellectual
function. Psychol Assess (1994) 6(2):8391. doi: 10.1037/1040-3590.6.2.83. [Cross Ref]
68. Kareken DA. Judgment pitfalls in estimating premorbid intellectual function. Arch
Clin Neuropsychol (1997) 12(8):7019. doi: 10.1093/arclin/12.8.701. [PubMed] [Cross
Ref]
69. Willshire D, Kinsella G, Prior M. Estimating WAIR-R IQ from the national adult
reading test: a cross-validation. J Clin Exp Neuropsychol (1991) 13:20416. doi:
10.1080/01688639108401038. [PubMed] [Cross Ref]
70. Ciplotti L, Warrington E. Neuropsychological assessment. J Neurol Neurosurg
Psychiatry (1995) 58:65564. doi: 10.1136/jnnp.58.6.655. [PMC free article] [PubMed]
[Cross Ref]
71. Nelson HE, McKenna P. The use of current reading ability in the assessment of
dementia. Br J Soc Clin Psychol (1975) 14:25967. doi: 10.1111/j.2044-
8260.1975.tb00178.x. [PubMed] [Cross Ref]
72. Spreen O, Strauss E. A compendium of Neuropsychological Tests: Administration,
Norms and Commentary. New York: Oxford University Press; (1991).
73. Grober E, Sliwinski M. Development and validation of a model for estimating
premorbid verbal intelligence in the elderly. J Clin Exp Neuropsychol (1991) 13:93349.
doi: 10.1080/01688639108405109. [PubMed] [Cross Ref]
74. Mortensen EL, Gade A, Reinisch JM. A critical note on Lezaks best performance
method in clinical neuropsychology. J Clin Exp Neuropsychol (1991) 13:36171. doi:
10.1080/01688639108401050. [PubMed] [Cross Ref]
75. Wilson RS, Rosenbaum G, Brown G, Rourke D, Whitman D, Grisell J. An index of
premorbid intelligence. J Consult Clin Psychol (1978) 46(6):15545. doi: 10.1037/0022-
006X.46.6.1554. [PubMed] [Cross Ref]
76. Barona A, Reynolds CR, Chastain R. A demographically based index of premorbid
intelligence for the WAIS-R. J Consult Clin Psychol (1984) 52(5):8857. doi:
10.1037/0022-006X.52.5.885. [Cross Ref]
77. Eppinger MG, Craig PL, Adams RL, Parsons O. The WAIS-R index for estimating
premorbid intelligence: cross validation and clinical utility. J Consult Clin Psychol (1987)
55(1):8690. doi: 10.1037/0022-006X.55.1.86. [PubMed] [Cross Ref]
78. Ryan JJ, Prifitera A. The WAIS-R index for estimating premorbid intelligence:
accuracy of predicting short IQ. Int J Neuropsychol (1990) 12:203.
79. Barona A, Chastain RL. An improved estimate of premorbid IQ for blacks and whites
on the WAIS-R. Int J Neuropsychol (1986) 8:16773.
80. Basso MR, Bornstein RA, Roper BL, McCoy VL. Limited utility of premorbid
intelligence estimators. A demonstration of regression to the mean. Clin Psychol (2000)
14:32540. [PubMed]
81. Veiel HOF, Koopman RF. The bias in regression-based indices of premorbid IQ.
Psychol Assess (2001) 13:35668. doi: 10.1037/1040-3590.13.3.356. [PubMed] [Cross
Ref]
82. Grove WM. Bias and error rates for premorbid IQ estimators: comment on Veiel and
Koopman (2001). Psychol Assess (2001) 13(3):3968. doi: 10.1037/1040-3590.13.3.396.
[PubMed] [Cross Ref]
83. Veiel HOF, Koopman RF. Biased estimators, biased experts and the Ivory Tower: a
reply to Grove. Psychol Assess (2001) 13(3):399402. doi: 10.1037/1040-3590.13.3.399.
[PubMed] [Cross Ref]
84. Crawford JR, Stewart LE, Parker DM, Besson JAO, Cochrane RHB. Estimation of
premorbid intelligence: combining psychometric and demographic approaches improves
predictive accuracy. Pers Individ Dif (1989) 10(7):7936. doi: 10.1016/0191-
8869(89)90126-8. [Cross Ref]
85. Crawford JR, Cochrane RHB, Besson JAO, Parker DM, Stewart LE. Premorbid IQ
estimates obtained by combining NART and demographic variables: construct validity.
Pers Individ Dif (1990) 11(2):20910. doi: 10.1016/0191-8869(90)90018-M. [Cross Ref]
86. Vanderploeg RD, Schinka JA. Predicting WAIS-R IQ premorbid ability: combining
subtest performance and demographic variable predictors. Arch Clin Neuropsychol
(1995) 10(3):22539. doi: 10.1093/arclin/10.3.225. [PubMed] [Cross Ref]
87. Scott JG, Krull K, Williamson DJG, Adams RL, Iverson GL. Oklahoma premorbid
intelligence estimation (OPIE) utilization in clinical samples. Clin Neuropsychol (1997)
11(2):14654. doi: 10.1080/13854049708407043. [Cross Ref]
88. Axelrod BN, Vanderploeg RD, Schinka JA. Comparing methods for estimating
premorbid intellectual functioning. Arch Clin Neuropsychol (1999) 14(4):3416. doi:
10.1093/arclin/14.4.341. [PubMed] [Cross Ref]
89. Axelrod BN, Vanderploeg RD, Rawlings DB, Dingell JD. WAIS-R prediction
estimates in patients with traumatic brain injury. J Clin Exp Neuropsychol (1999)
21(3):36874. doi: 10.1076/jcen.21.3.368.916. [PubMed] [Cross Ref]
90. Vanderploeg RD, Schinka JA, Axelrod BN. Estimation of WAIS-R premorbid
intelligence: current ability and demographic data used in a best performance fashion.
Psychol Assess (1996) 8:40411. doi: 10.1037/1040-3590.8.4.404. [Cross Ref]
91. Krull K, Scott JG, Sherer M. Estimation of premorbid intelligence from combined
performance and demographic variables. Clin Neuropsychol (1995) 9:837. doi:
10.1080/13854049508402063. [Cross Ref]
92. Williamson D, Krull KR, Scott JG. Revision and further validation of the Oklahoma
premorbid intelligence estimate. Poster Session at the Sixteenth Annual Meeting of the
National Academy of Neuropsychology Orlando, FL (1996).
93. Riley GA, Simmonds LV. How robust is performance on the National adult reading
test following traumatic brain injury? Br J Clin Psychol (2003) 42:31928. doi:
10.1348/01446650360703410. [PubMed] [Cross Ref]
94. Hoofien D, Vakil E, Gilboa A. Criterion validation of premorbid intelligence
estimation in persons with traumatic brain injury: Hold/Dont Hold versus best
performance procedures. J Clin Exp Neuropsychol (2000) 22(3):30515. doi:
10.1076/1380-3395(200006)22:3;1-V;FT305. [PubMed] [Cross Ref]
95. Green RE, Melo B, Christensen B, Ngo LA, Monette G, Bradbury C. Measuring
premorbid IQ in traumatic brain injury: an examination of the validity of the Weshsler
Test of Adult Reading (WTAR). J Clin Exp Neuropsychol (2008) 30(2):16372. doi:
10.1080/13803390701300524. [PubMed] [Cross Ref]
96. Wechsler D. Wechsler Test of Adult Reading (WTAR). San Antonio, TX: The
Psychological Corporation; (2001).
97. Lowe DA, Rogers SA. Estimating premorbid intelligence among older adults: the
utility of AMNART. J Aging Res (2011) 2011: 428132. doi: 10.4061/2011/428132. [PMC
free article] [PubMed] [Cross Ref]
98. Homaifar BY, Brenner LA, Gutierrez PM, Harwood JF, Thompson C, Filey CM, et al.
Sensitivity and specificity of the Beck depression inventory-II in persons with traumatic
brain injury. Arch Phys Med Rehabil (2009) 90(4):6526. doi:
10.1016/j.apmr.2008.10.028. [PubMed] [Cross Ref]
99. Smith CT, Oltmanns TF. Scientific advances in the diagnosis of psychopathology:
introduction to the special section. Psychol Assess (2009) 21(3):2412. doi:
10.1037/a0016919. [PMC free article] [PubMed] [Cross Ref]
100. Widiger TA, Livesley WJ, Clark LA. An integrative dimensional classification of
personality disorder. Psychol Assess (2009) 21:24353. doi: 10.1037/a0016606.
[PubMed] [Cross Ref]
101. Brown TA, Barlow DH. A proposal for a dimensional system based on the shared
features of the DSM-IV anxiety and mood disorders. Implications for assessment and
treatment. Psychol Assess (2009) 21:25671. doi: 10.1037/a0016608. [PMC free article]
[PubMed] [Cross Ref]
102. Jorge RE, Robinson RG, Arndt SV, Forrester AW, Geisler F, Starkstein SE.
Comparison between acute and delayed-onset depression following traumatic brain
injury. J Neuropsychiatr Clin Neurosci (1993) 5:439. [PubMed]
103. Jorge RE, Robinson RG, Starkstein SE, Arndt SV. Depression and anxiety following
traumatic brain injury. J Neuropsychiatr Clin Neurosci (1993) 5:36974. [PubMed]
104. Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S. Major
depression following traumatic brain injury. Arch Gen Psychiatry (2004) 61:4250. doi:
10.1001/archpsyc.61.1.42. [PubMed] [Cross Ref]
105. Holsinger T, Steffens DC, Phillips C, Helms MJ, Harlik RJ, Breitner JC, et al. Head
injury in early adulthood and the lifetime risk of depression. Arch Gen Psyciatry (2002)
59:1722. doi: 10.1001/archpsyc.59.1.17. [PubMed] [Cross Ref]
106. Brenner LA, Homaifar BY, Adler LE, Wolfman JH, Kemp J. Suicidality and
veterans with a history of traumatic brain injury: precipitating events, protective factors
and prevention strategies. Rehabil Psychol (2009) 54(4):3907. doi: 10.1037/a0017802.
[PubMed] [Cross Ref]
107. Gray MJ, Bolton EE, Litz BT. A longitudinal analysis of PTSD symptom course:
delayed-onset PTSD in Somalia peacekeepers. J Consult Clin Psychol (2004) 72(5):909
13. doi: 10.1037/0022-006X.72.5.909. [PubMed] [Cross Ref]
108. Grieger TA, Cozza SJ, Ursano RJ, Hoge C, Martinez PE, Engel CC, et al.
Posttraumatic stress disorder and depression in battle-injured soldiers. Am J Psychiatry
(2006) 163:177783. doi: 10.1176/appi.ajp.163.10.1777. [PubMed] [Cross Ref]
109. Andrews B, Brewin CR, Philpott R, Stewart L. Delayed-onset posttraumatic stress
disorder: a systematic review of the evidence. Am J Psychiatry (2007) 164:131926. doi:
10.1176/appi.ajp.2007.06091491. [PubMed] [Cross Ref]
110. Milliken CS, Auchterlonie JL, Hoge CW. Longitudinal assessment of mental health
problems among active and reserve component soldiers returning from the Iraq war.
JAMA (2007) 298(18):21418. doi: 10.1001/jama.298.18.2141. [PubMed] [Cross Ref]
111. Gerber DJ, Schraa JC. Mild traumatic brain injury: searching for the syndrome. J
Head Trauma Rehabil (1995) 10(4):2840. doi: 10.1097/00001199-199508000-00004.
[Cross Ref]
112. Bruce JM, Echemendia RJ. Delayed-onset deficits in verbal encoding strategies
among patients with mild traumatic brain injury. Neuropsychyology (2003) 17:6229.
doi: 10.1037/0894-4105.17.4.622. [PubMed] [Cross Ref]
113. Lew HL, Poole JH, Alvarez S, Moore W. Soldiers with occult traumatic brain injury.
Am J Phys Med Rehabil (2005) 84:3938. doi: 10.1097/01.phm.0000163703.91647.a7.
[PubMed] [Cross Ref]
114. Fujii D, Ahmed I. Psychosis secondary to traumatic brain injury. Neuropsychiatr
Neuropsychol Behav Neurol (1996) 9:1338.
115. Fujii D, Ahmed I. Risk factors in psychosis secondary to traumatic brain injury. J
Neuropsychiatr Clin Neurosci (2001) 13:619. doi: 10.1176/appi.neuropsych.13.1.61.
[PubMed] [Cross Ref]
116. Sachdev P, Smith PS, Cathcart S. Schizophrenia-like psychosis following traumatic
brain injury: a chart-based descriptive and case-control study. Psychol Med (2001)
31:2319. doi: 10.1017/S0033291701003336. [PubMed] [Cross Ref]
117. Lezak MD. The walking wounded of head injury: when subtle deficits can be
disabling. Trends Rehabil (1988) 3(3):49.
118. Castrn E. Is mood chemistry? Nat Rev Neurosci (2005) 6:2416. doi:
10.1038/nrn1629. [PubMed] [Cross Ref]
119. Kim E, Lauterbach EC, Reeve A, Arciniegas DB, Coburn KL, Mendez MF, et al.
Neuropsychiatric complications of traumatic brain injury: a critical review of the
literature (a report by the ANPA committee on research). J Neuropsychiatry Clin
Neurosci (2007) 19(2):10627. doi: 10.1176/appi.neuropsych.19.2.106. [PubMed] [Cross
Ref]
120. Seel RT, Kreutzer JS. Depression assessment after traumatic brain injury: an
empirically based classification method. Arch Phys Med Rehabil (2003) 84(11):16218.
doi: 10.1053/S0003-9993(03)00270-3. [PubMed] [Cross Ref]
121. Iverson GL. Misdiagnosis of persistent postconcussion syndrome in patients with
depression. Arch Clin Neuropsychyol (2006) 21:30310. doi: 10.1016/j.acn.2005.12.008.
[PubMed] [Cross Ref]
122. Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of
major depressive disorder and clinical outcomes following traumatic brain injury. J Am
Med Assoc (2010) 303(19):193845. doi: 10.1001/jama.2010.599. [PMC free article]
[PubMed] [Cross Ref]
123. deGuise E, leBlanc J, Feyz M, Meyer K, Duplantie J, Thomas H, et al. Long-term
outcome after severe traumatic brain injury: the McGill interdisciplinary prospective
study. J Head Trauma Rehabil (2008) 23(5):294303. doi:
10.1097/01.HTR.0000336842.53338.f4. [PubMed] [Cross Ref]
124. Hibbard MR, Uysal S, Kepler K, Bogdany J, Silver J. Axis I psychopathology in
individuals with traumatic brain injury. J Head Trauma Rehabil (1998) 13(4):2439. doi:
10.1097/00001199-199808000-00005. [PubMed] [Cross Ref]
125. Moldover JE, Goldberg KB, Prout MJ. Depression after traumatic brain injury: a
review of evidence for clinical heterogeneity. Neuropsychol Rev (2004) 14:14354. doi:
10.1023/B:NERV.0000048181.46159.61. [PubMed] [Cross Ref]
126. Wilk JE, Thomas JL, McGurk DM, Riviere LA, Castro CA, Hoge CW. Mild
traumatic brain injury (concussion) during combat: lack of association of blast
mechanism with persistent postconcussive symptoms. J Head Trauma Rehabil (2010)
25(1):16. doi: 10.1097/HTR.0b013e3181bd090f. [PubMed] [Cross Ref]
127. Kruijshaar ME, Barendregt J, Vos T, de Graaf R, Spiker J, Andrews G. Lifetime
prevalence estimates of major depression: an indirect estimation and a quantification of
recall bias. Eur J Epidemiol (2005) 20(1):10311. doi: 10.1007/s10654-004-1009-0.
[PubMed] [Cross Ref]
128. Jorge RE, Robinson RG, Arndt WV. Are depressive symptoms specific for a
depressed mood in traumatic brain injury? J Nerv Ment Dis (1993) 181:919. doi:
10.1097/00005053-199302000-00004. [PubMed] [Cross Ref]
129. Robinson RG, Jorge R. Mood disorders. In: Silver JM, McAllister TW, Yudofsky
SC, editors. editors. Textbook of Traumatic Brain Injury. Washington, DC: American
Psychiatric Publishing; (2005). p. 20112.
130. Spitzer RL, Kroenke D, Williams JBW, The Patient Health Questionnaire Primary
Care Study Group Validation and utility of a self-report version of PRIME-MD: the PHQ
primary care study. J Am Med Assoc (1999) 282(18):173744. doi:
10.1001/jama.282.18.1737. [PubMed] [Cross Ref]
131. Kroenke K, Spitzer R, Williams JBW. The PHQ-9, validity of a brief depression
severity measure. J Gen Intern Med (2001) 16:60616. doi: 10.1046/j.1525-
1497.2001.016009606.x. [PMC free article] [PubMed] [Cross Ref]
132. Fann JR, Bombardier CH, Dikmen S, Esselman P, Warms CA, Pelzer E, et al.
Validity of the patient health questionnaire-9 in assessing depression following traumatic
brain injury. J Head Trauma Rehabil (2005) 20(6):50111. doi: 10.1097/00001199-
200511000-00003. [PubMed] [Cross Ref]
133. First MB, Spitzer RL, Williams JB. Users Guide for the Structured Clinical
Interview for DSM-IV Axis I Disorders (SCID-I): Clinical Version. Washington:
American Psychiatric Publishing; (1996).
134. Cook KF, Bombardier CH, Bamer AM, Choi SW, Kroenke K, Fann JR. Do somatic
and cognitive symptoms of traumatic brain injury confound depression screening? Arch
Phys Med Rehabil (2011) 92:81823. doi: 10.1016/j.apmr.2010.12.008. [PMC free
article] [PubMed] [Cross Ref]
135. Jodoin MG, Gierl MJ. Evaluating type 1 error and power rates using an effect size
measure with the logistic regression procedure for DIF detection. Appl Measurement
Educ (2001) 14:32949. doi: 10.1207/S15324818AME1404_2. [Cross Ref]
136. Zumbo BD. Three generations of differential item functioning (DIF) analyses:
considering where it has been, where it is now, and where it is going. Lang Assess Q
(2007) 4:22333.
137. Lord FM. Applications of Item Response Theory to Practical Testing Problems.
Mahwah, NJ: Erlbaum; (1980).
138. Kreutzer JS, Marwitz JH, Seel R, Serio CD. Validation of a neurobehavioral
functioning inventory for adults with traumatic brain injury. Arch Phys Med Rehabil
(1996) 77(2):11624. doi: 10.1016/S0003-9993(96)90155-0. [PubMed] [Cross Ref]
139. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory of measuring
depression. Arch Gen Psychiatry (1961) 4:5363. doi:
10.1001/archpsyc.1961.01710120031004. [Cross Ref]
140. Beck AT, Steer RA, Brown GK. Beck Depression Inventory. II. Manual. San
Antonio, TX: Psychological Corporation; (1996).
141. Butcher JN, Dahlstrom WG, Graham JR, Tellegen A, Kaemmer B. Minnesota
Multiphasic Personality Inventory-2 (MMPI-2). Manual for Administration and Scoring.
Minneapolis, MN: University of Minnesota Press; (1989).
142. Butcher JN, Graham JR, Ben-Porath YS, Tellegen A, Dahlstrom WG, Kaemmer B.
Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Manual for Administration
and Scoring. Revised Edition. Minneapolis, MN: University of Minnesota Press; (2001).
143. Sprinkle SD, Lurie D, Insko SL, Atkinson G, Jones JL, Logan AR, et al. Criterion
validity, severity cut scores and test-retest reliability of the Beck depression inventory-II
in a university counseling center sample. J Couns Psychol (2002) 49:3815. doi:
10.1037/0022-0167.49.3.381. [Cross Ref]
144. Steer RA, Kumar G, Ranieri WF, Beck AT. Use of the Beck depression inventory
with adolescent psychiatric outpatients. J Psychopathol Behav Assess (1998) 20:12737.
doi: 10.1023/A:1023091529735. [Cross Ref]
145. Rosenthal M, Christensen BK, Ross TP. Depression following traumatic brain
injury. Arch Phys Med Rehabil (1998) 79:90103. doi: 10.1016/S0003-9993(98)90215-5.
[PubMed] [Cross Ref]
146. Sliwinski M, Gordon WA, Bogdany J. The Beck depression inventory: is it a
suitable measure of depression for individuals with traumatic brain injury? J Head
Trauma Rehabil (1998) 13(4):406. doi: 10.1097/00001199-199808000-00004.
[PubMed] [Cross Ref]
147. Beck AT. Beck Depression Inventory Manual. San Antonio, TX: Psychological
Corporation; (1987).
148. Lehmkuhl D. The TIRR Symptom Checklist. Houston, TX: The Institute for
Rehabilitation Research; (1988).
149. Green A, Felmingham K, Baguley IJ, Slewa-Younan S, Simpson S. The clinical
utility of the Beck depression inventory after traumatic brain injury. Brain Injury (2001)
15(12):10218. doi: 10.1080/02699050110074187. [PubMed] [Cross Ref]
150. Howell CD. Statistical Methods for Psychology. Florence, KY: Wadsworth
Publishing Company; (1997).
151. Christensen BK, Ross TP, Kotesek RS. Factor structure for the Beck Depression
Inventory in a sample of persons with traumatic brain injury. (Abstract). J Int
Neuropsychol Soc (1995) 1:12186.
152. Rowland SM, Lam CS, Leahy B. Use of the Beck depression inventory-II (BDI-II)
with persons with traumatic brain injury: analysis of factorial structure. Brain Injury
(2005) 19(2):7783. doi: 10.1080/02699050410001719988. [PubMed] [Cross Ref]
153. Beck AT, Steer RA, Garbin MC. Psychometric Properties of the Beck depression
inventory: twenty-five years of evaluation. Clin Psychol Rev (1988) 8(1):77100. doi:
10.1016/0272-7358(88)90050-5. [Cross Ref]
154. Andreasen NC, Black DW. Introductory Textbook of Psychiatry. 2nd ed.
Washington, DC: American Psychiatric Press; (1995).
155. Smith GT, McCarthy DM, Zapolski TCB. On the value of homogeneous constructs
for construct validation, theory testing and the description of psychopathology. Psychol
Assess (2009) 21(3):27284. doi: 10.1037/a0016699. [PMC free article] [PubMed]
[Cross Ref]
156. Bontke CF. Do patients with mild brain injuries have posttraumatic stress disorder
too? J Head Trauma Rehabil (1996) 11(1):95102. doi: 10.1097/00001199-199602000-
00011. [Cross Ref]
157. Sbordone RJ, Liter JC. Mild traumatic brain injury does not produce post-traumatic
stress disorder. Brain Injury (1995) 9:40512. doi: 10.3109/02699059509005780.
[PubMed] [Cross Ref]
158. Bryant RA. Posttraumatic stress disorder and traumatic brain injury: can they
coexist? Clin Psychol Rev (2001) 21(6):93148. doi: 10.1016/S0272-7358(00)00074-X.
[PubMed] [Cross Ref]
159. Bryant R. Post-traumatic stress disorder vs traumatic brain injury. Dialogues Clin
Neurosci (2011) 13(3):25162. [PMC free article] [PubMed]
160. Boake C. Do patients with mild brain injuries have post-traumatic stress disorder
too? J Head Trauma Rehabil (1996) 11(1):98100.
161. Joseph S, Masterson J. Posttraumatic stress disorder and traumatic brain injury: are
they mutually exclusive? J Trauma Stress (1999) 12(3):43753. doi:
10.1023/A:1024762919372. [PubMed] [Cross Ref]
162. Gil S, Caspi Y, Ben-Ari LZ, Koren D, Klein E. Does memory of a traumatic event
increase the risk for posttraumatic stress disorder in patients with traumatic brain injury?
A prospective study. Am J Psychiatry (2005) 162(5):9639. doi:
10.1176/appi.ajp.162.5.963. [PubMed] [Cross Ref]
163. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic
brain injury in U.S. soldiers returning from Iraq. N Engl J Med (2008) 358(5):45363.
doi: 10.1056/NEJMoa072972. [PubMed] [Cross Ref]
164. Vanderploeg RD, Belanger HG, Curtiss G. Mild traumatic brain injury and
posttraumatic stress disorder and their associations with health symptoms. Arch Phys
Med Rehabil (2009) 90(7):108493. doi: 10.1016/j.apmr.2009.01.023. [PubMed] [Cross
Ref]
165. Zatzick DF, Rivara FP, Jurkovich GJ, Hoge CW, Wang J, Fan MY, et al. Multiside
investigation of traumatic brain injuries, posttraumatic stress disorder and self-reported
health and cognitive impairments. Arch Gen Psychiatry (2010) 67(12):1291300. doi:
10.1001/archgenpsychiatry.2010.158. [PMC free article] [PubMed] [Cross Ref]
166. LeDoux JE. Emotion, memory and the brain. Sci Am (1994) 270:507. doi:
10.1038/scientificamerican0694-50. [PubMed] [Cross Ref]
167. LeDoux JE. Fear and the brain. Where we have been and where are we going? Biol
Psychiatry (1998) 44:122938. doi: 10.1016/S0006-3223(98)00282-0. [PubMed] [Cross
Ref]
168. LeDoux JE, Cicchetti P, Xagoraris A, Romanski L. The lateral amygdaloid nucleus:
sensory interface of the amygdala in fear conditioning. J Neurosci (1990) 10:10629.
[PubMed]
169. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage associated with
prolonged glucocorticoid exposure in primates. J Neurosci (1990) 10:2897902.
[PubMed]
170. MacDonald CL, Johnson AM, Cooper D, Nelson EC, Werner NJ, Shimony JS, et al.
Detection of blast-related traumatic brain injury in US military personnel. N Engl J Med
(2011) 364:2091100. doi: 10.1056/NEJMoa1008069. [PMC free article] [PubMed]
[Cross Ref]
171. Kim SJ, Heong DU, Sim ME, Bae SC, Chung A, Kim MJ, et al. Asymmetrically
altered integrity of cingulum bundle in posttraumatic stress disorder. Neuropsychobiology
(2006) 54:1205. doi: 10.1159/000098262. [PubMed] [Cross Ref]
172. Hickling EJ, Gillen R, Blanchard EB, Buckley T, Taylor A. Traumatic brain injury
and post traumatic stress disorder: a preliminary investigation of neuropsychological test
results in PTSD secondary to motor vehicle accidents. Brain Injury (1998) 12:26574.
doi: 10.1080/026990598122566. [PubMed] [Cross Ref]
173. McMillan TM. Post-traumatic stress disorder following minor and severe closed
head injury: 10 single cases. Brain Injury (1996) 40:74958. doi:
10.1080/026990596124016. [PubMed] [Cross Ref]
174. Harvey AG, Brewin CR, Jones C, Kopelman MD. Coexistence of posttraumatic
stress disorder and traumatic brain injury: towards a resolution of the paradox. J Int
Neuropsychol Soc (2003) 9:66376. doi: 10.1017/S1355617703940069. [PubMed]
[Cross Ref]
175. Sumpter RE, McMillan TM. Misdiagnosis of post traumatic stress disorder
following severe traumatic brain injury. Br J Psyhciatry (2005) 186:4236. doi:
10.1192/bjp.186.5.423. [PubMed] [Cross Ref]
176. Foa EB, Cashman L, Jaycox L, Perry K. The validation of a self-report measure of
posttraumatic stress disorder: the posttraumatic diagnostic scale. Psychol Assess (1997)
9(4):44551. doi: 10.1016/j.psychres.2007.09.005. [Cross Ref]
177. Horowitz M, Wilner M, Alvarez W. Impact of event scale: a measure of subjective
stress. Psychosom Med (1979) 41:20918. [PubMed]
178. Corneil W, Beaton R, Murphy S, Johnson C, Pike K. Exposure to traumatic incidents
and prevalence of post-traumatic stress symptomatology in urban firefighters in two
countries. J Occup Health Psychol (1999) 4:13141. doi: 10.1037/1076-8998.4.2.131.
[PubMed] [Cross Ref]
179. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, et al.
The development of a clinician administered PTSD scale. J Trauma Stress (1995)
8(1):7590. doi: 10.1002/jts.2490080106. [PubMed] [Cross Ref]
180. Sumpter RE, McMillan TM. Errors in self-report of post-traumatic stress disorder
and severe brain injury. Brain Injury (2006) 20(1):939. doi:
10.1080/02699050500394090. [PubMed] [Cross Ref]
181. Sbordone RJ, Ruff RM. Re-examination of the controversial coexistence of
traumatic brain injury and posttraumatic stress disorder: misdiagnosis and self-report
measures. Psychol Inj Law (2010) 3(1):6376. doi: 10.1007/s12207-010-9066-z. [PMC
free article] [PubMed] [Cross Ref]
182. Blake DD, Weathers FW, Nagy LN, Kaloupek DG, Klauminzer G, Charney DS, et
al. A clinician rating scale for assessing current and lifetime PTSD: the CAPS-1. Behav
Ther (1990) 13:1878.
183. Blake D, Weathers F, Nagy L, Kaloupek D, Klauminzer G, Charney D, et al.
Clinician-Administered PTSD Scale (CAPS) Form 1. Current and Lifetime Diagnosis
Version. West Haven, CT: National Center for Posttraumatic Stress Disorder; (1990).
184. Shalev AY, Freedman S, Peri T, Brandes D, Sahar T. Predicting PTSD in trauma
survivors: perspective evaluation of self-report and clinician-administered instruments.
Br J Psychiatry (1997) 170:55864. doi: 10.1192/bjp.170.6.558. [PubMed] [Cross Ref]
185. King NS, Crawford S, Wenden FJ, Caldwell FE, Wade DT. Early prediction of
persiting post-concussion symptoms following mild and moderate head injuries. British J
Clin Psychol (1999) 38(1):1525. doi: 10.1348/014466599162638. [PubMed] [Cross
Ref]
186. Newman E, Ribbe D. Psychometric review of the clinician administered PTSD scale
for children. In: Stamm BH, editor. editor. Measurement of Stress, Trauma and
Adaptation. Lutherville, MD: Sidran Press; (1996). p. 10614.
187. Weathers F, Litz B, Huska JA, Keane TM. PCL-C for DSM-IV (PTSD Checklist).
National Center for PTSD. Boston: Behavioral Science Division; (1994).
188. National Center for PTSD Using the PTSD Checklist (PCL). Washington, DC: U.S.
Department of Veteran Affairs; (2012).
189. Monson CM, Gradus JL, Young-Xu Y, Schurr PP, Price JL, Schumm JA. Change in
posttraumatic stress disorder symptoms: do clinicians and patients agree? Psychol Assess
(2008) 20(2):1318. doi: 10.1037/1040-3590.20.2.131. [PubMed] [Cross Ref]
190. Blanchard EB, Jones-Alexander J, Buckley TC, Forneris CA. Psychometric
properties of the PTSD checklist. Behav Res Ther (1996) 34(8):699673. doi:
10.1016/0005-7967(96)00033-2. [PubMed] [Cross Ref]
191. Norris FH, Hamblen JL. Standardized self-report measures of civilian trauma and
PTSD. 2nd ed. In: Wilson J, Keane T. editors. Assessing Psychological Trauma of PTSD:
A Practitioners Handbook. New York, NY: Guildford Press; (2003). p. 63192.
192. Wilkins KC, Lang AJ, Norman SB. Synthesis and psychometric properties of PTSD
checklist (PCL) military, civilian and specific versions. Depress Anxiety (2011)
28(7):596606. doi: 10.1002/da.20837. [PMC free article] [PubMed] [Cross Ref]
193. Ruggiero KJ, Rheingold AA, Resnick HS, Kilpatrick DG, Galea S. Comparison of
two widely used PTSD screening instruments: implications for public mental health
planning. J Trauma Stress (2006) 19(5):699707. doi: 10.1002/jts.20141. [PubMed]
[Cross Ref]
194. McDonald SD, Calhoun PS. The diagnostic accuracy of the PTSD checklist: a
critical review. Clin Psychol Rev (2010) 30:97687. doi: 10.1016/j.cpr.2010.06.012.
[PubMed] [Cross Ref]
195. Epstein RS, Ursano RJ. Anxiety disorders. In: Silver JM, Yudofsky SC, Hales RE,
editors. editors. Neuropsychiatry of Traumatic Brain Injury. Washington, DC: American
Psychiatric Press; (1994). p. 285311.
196. Hiott DW, Labbate L. Anxiety disorders associated with traumatic brain injury.
NeuroRehabilitation (2002) 17:34555. [PubMed]
197. Warden DL, Labbate LA. Posttraumatic stress disorder and other anxiety disorders.
In: Silver JM, McAllister TW, Yudofsky SC, editors. editors. Textbook of Traumatic
Brain Injury. Washington, DC: American Psychiatric Press; (2005). p. 23143.
198. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al.
Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United
States. Results from the National Comorbidity Survey. Arch Gen Psychiatry (1994) 51:8
19. doi: 10.1001/archpsyc.1994.03950010008002. [PubMed] [Cross Ref]
199. Ritter MR, Balckmore MA, Heimberg RG. Generalized anxiety disorder. In: McKay
D, Abramowitz JS, Taylor S, editors. editors. Cognitive-Behavior Therapy for Refractory
Cases: Turning Failure into Success. Washington, DC: American Psychological
Association; (2010). p. 11137.
200. Shear MK, Brown C, Clark DB. Anxiety disorder measures. Second ed. In: Rush AJ,
First MB, Blacker D, editors. editors. Handbook of Psychiatric Measures. Washington,
DC: American Psychiatric Publishing; (2008). p. 52958.
201. Bryant RA, Moulds MM, Guthrie R, Nixon RDV. Treating acute stress disorder
following mild traumatic brain injury. Am J Psychiatry (2003) 160(3):5857. doi:
10.1176/appi.ajp.160.3.585. [PubMed] [Cross Ref]
202. Cantor JB, Ashman TA, Schwartz ME, Gordon WA, Hibbard MR, Brown M, et al.
The role of self-discrepancy theory in understanding post-traumatic brain injury affective
disorders: a pilot study. J Head Trauma Rehabil (2005) 20(6):52743. doi:
10.1097/00001199-200511000-00005. [PubMed] [Cross Ref]
203. Kit KA, Mateer CA, Graves RE. The influence of memory beliefs in individuals
with traumatic brain injury. Rehabil Psychol (2007) 52(1):2532. doi: 10.1037/0090-
5550.52.1.25. [Cross Ref]
204. Leyfer OT, Ruberg JL, Woodruff-Borden J. Examination of the utility of the Beck
anxiety inventory and its factors as a screener for anxiety disorders. Anxiety Disorders
(2006) 20:44458. doi: 10.1016/j.janxdis.2005.05.004. [PubMed] [Cross Ref]
205. Arciniegas DB, Harris SN, Brousseau KM. Psychosis following traumatic brain
injury. Int Rev Psychiatry (2003) 15(4):32840. doi: 10.1080/09540260310001606719.
[PubMed] [Cross Ref]
206. Zhang Q, Sachdev PS. Psychotic disorders and traumatic brain injury. Curr
Psychiatry Rep (2003) 5(3):197201. doi: 10.1007/s11920-003-0042-0. [PubMed] [Cross
Ref]
207. Guerreiro DF, Navarro R, Silva M, Carhalho MJ, Gois C. Psychosis secondary to
traumatic brain injury. Brain Injury (2009) 23(4):35861. doi:
10.1080/02699050902800918. [PubMed] [Cross Ref]
208. Davison K, Bagley CR. Schizophrenia-like psychoses associated with organic
disorders of the central nervous system: a review of the literature. In: Harrington RN.
editor. Current Problems in Neuropsychiatry, Schizophrenia, Epilepsy, and the Temporal
Lobe. London: British Journal of Psychiatry; (1969). p. 11384.
209. Arciniegas DB, Beresford TP. Neuropsychiatry an Introductory Approach.
Cambridge: Cambridge University Press; (2001).
210. Achte K, Jarho L, Kyykka T, Vesterinen E. Paranoid disorders following war brain
damage. Preliminary report. Psychopathology (1991) 24:30915. doi:
10.1159/000284731. [PubMed] [Cross Ref]
211. Thomsen IV. Late outcome of very severe blunt head trauma: a 10-15 year second
follow-up. J Neurol Neurosurg Psychiatry (1984) 47(3):2608. doi:
10.1136/jnnp.47.3.260. [PMC free article] [PubMed] [Cross Ref]
212. Perl J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isomets E, Pirkola S, et al.
Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch
Gen Psychiatry (2007) 64(1):1928. doi: 10.1001/archpsyc.64.1.19. [PubMed] [Cross
Ref]
213. Malaspina D, Goetz RR, Friedman JH, Kaufman CA, Faraone SV, Tsuang M, et al.
Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar
disorder pedigrees. Am J Psychiatry (2001) 158:4406. doi: 10.1176/appi.ajp.158.3.440.
[PubMed] [Cross Ref]
214. Wilcox JH, Nasrallah HA. Childhood head trauma and psychosis. Psychiatry Res
(1987) 21(4):3036. doi: 10.1016/0165-1781(87)90013-8. [PubMed] [Cross Ref]
215. Fujii D, Ahmed I. Characteristics of psychotic disorder due to traumatic brain injury:
an analysis of case studies in the literature. J Neuropsychiatr Clin Neurosci (2002)
14:13040. doi: 10.1176/appi.neuropsych.14.2.130. [PubMed] [Cross Ref]
216. Molloy C, Conroy RM, Cotter DR, Cannon M. Is traumatic brain injury a risk factor
for schizophrenia: a meta-analysis of case-controlled population-based studies. Schizophr
Bull (2011) 37(6):110410. doi: 10.1093/schbul/sbr091. [PMC free article] [PubMed]
[Cross Ref]
217. Andreasen NC. Scale for the Assessment of Positive Symptoms. Iowa City, IA:
University of Iowa; (1984).
218. Andreasen NC. Scale for the Assessment of Negative Symptoms. Iowa City, IA:
University of Iowa; (1983).
219. Ouellet MC, Savard J, Morin CN. Insomnia following traumatic brain injury: a
review. Neurorehabil Neural Repair (2004) 18(4):18798. doi:
10.1177/1545968304271405. [PubMed] [Cross Ref]
220. Orff HJ, Ayalon L, Drummond SPA. Traumatic brain injury and sleep disturbance: a
review of current research. J Head Trauma Rehabil (2009) 24(3):15565. doi:
10.1097/HTR.0b013e3181a0b281. [PubMed] [Cross Ref]
221. Zeitzer JM, Friedman L, OHara R. Insomnia in the context of traumatic brain
injury. J Rehabil Res Dev (2009) 46(6):82736. doi: 10.1682/JRRD.2008.08.0099.
[PubMed] [Cross Ref]
222. Hochstrasser B. Epidemiology of sleep disorders. Therapeutische Umschau (1993)
50(10):67983. [PubMed]
223. Ford DE, Kamerow DB. Epidemiologic study on sleep disturbances and psychiatric
disorders. An opportunity for prevention. J Am Med Assoc (1989) 262:147984. doi:
10.1001/jama.262.11.1479. [PubMed] [Cross Ref]
224. Rosekind MR. The epidemiology and occurrence of insomnia. J Clin Psychiatry
(1992) 53:S46. [PubMed]
225. Masoodi N, Jiva TM. Sleep disturbances associated with depression. Sleep Rev
(2004) 2004:1723.
226. Fichtenberg NL, Mills SR, Mann RN, Zafonte RD, Millard AE. Factors associated
with insomnia among post-acute traumatic brain injury survivors. Brain Injury (2000)
14(7):65967. doi: 10.1080/02699050050044015. [PubMed] [Cross Ref]
227. Benca R, Lichstein KL. Sleep disorders. Second ed. In: Rush AJ, First MB, Blacker
D, editors. editors. Handbook of Psychiatric Measures. Washington, DC: American
Psychiatric Press (2008). p. 64966.
228. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep
quality index: a new instrument for psychiatric practice and research. Psychiatry Res
(1989) 28:193213. doi: 10.1016/0165-1781(89)90047-4. [PubMed] [Cross Ref]
229. Beck AT, Baruch E, Balter JM, Steer AS, Warman DM. A new instrument for
measuring insight: the Beck cognitive insight scale. Schizophr Res (2004) 68:31929.
doi: 10.1016/S0920-9964(03)00189-0. [PubMed] [Cross Ref]
230. Backhaus J, Junghanns K, Broocks A, Riemann D, Hohagen F. Test-retest reliability
and validity of the Pittsburgh sleep quality index in primary insomnia. J Psychosom Res
(2002) 53(3):73740. doi: 10.1016/S0022-3999(02)00330-6. [PubMed] [Cross Ref]
231. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh sleep
quality index. J Psychosom Res (1998) 45:513. doi: 10.1016/S0022-3999(97)00298-5.
[PubMed] [Cross Ref]
232. Fichtenberg NL, Putnam SH, Mann RN, Zafonte RD, Millard AE. Insomnia
screening in postacute traumatic brain injury: utility and validity of the Pittsburgh sleep
quality index. Am J Phys Med Rehabil (2001) 80(5):33945. doi: 10.1097/00002060-
200105000-00003. [PubMed] [Cross Ref]
233. Teasdale TW, Engberg AW. Suicide after traumatic brain injury: a population study.
J Neurol Neurosurg Psychiatry (2001) 71(4):43640. doi: 10.1136/jnnp.71.4.436. [PMC
free article] [PubMed] [Cross Ref]
234. Harrison-Felix CL, Whiteneck GG, Jha A, DeVivo MJ, Hammond FM, Hart DM.
Mortality over four decades after traumatic brain injury rehabilitation: a retrospective
cohort study. Arch Phys Med Rehabil (2009) 90(9):150613. doi:
10.1016/j.apmr.2009.03.015. [PubMed] [Cross Ref]
235. Mainio A, Kyllnen T, Viilo K, Hakko H, Srkioja T, Rsnen P. Traumatic brain
injury, psychiatric disorders and suicide: a population-based study of suicide victims
during the years 1988-2004 in Northern Finland. Brain Injury (2007) 21(8):8515. doi:
10.1080/02699050701504265. [PubMed] [Cross Ref]
236. Martin J, Ghahramanlou-Holloway M, Lou K, Tucciarone P. A comparative review
of US military and civilian suicide behavior: implications for OEF/OIF suicide
prevention efforts. J Mental Health Counseling (2009) 31(2):10118.
237. Silver JM, Kramer R, Greenwald S, Weissman M. The association between head
injuries and psychiatric disorders: findings from the New Haven NIMH Epidemiological
Catchment area study. Brain Injury (2001) 15:93545. doi:
10.1080/02699050110065295. [PubMed] [Cross Ref]
238. Simpson G, Tate R. Suicidality after traumatic brain injury: demographic, injury and
clinical correlates. Psychol Med (2002) 32(4):68797. doi:
10.1017/S0033291702005561. [PubMed] [Cross Ref]
239. Anstey K, Butterworth P, Jorm AF, Christensen H, Rodgers B, Windsor TD. A
population survey found an association between self-reports of traumatic brain injury and
increased psychiatric symptoms. J Clin Epidemiol (2004) 57(11):12029. doi:
10.1016/j.jclinepi.2003.11.011. [PubMed] [Cross Ref]
240. Brenner LA, Ignacio RV, Blow FC. Suicide and traumatic brain injury among
individuals seeking Veterans Health administration services. J Head Trauma Rehabil
(2011) 26(4):25764. doi: 10.1097/HTR.0b013e31821fdb6e. [PubMed] [Cross Ref]
241. Martin JS. A Cluster Analysis Typology of Suicide in the United States Air Force
[Dissertation]. Bethesda, MD: Uniformed Services University of the Health Sciences;
(2011).
242. Black SA, Gallaway MS, Bell MR, Ritchie EC. Prevalence and risk factors
associated with suicides of Army soldiers, 20012009. Mil Psychol (2011) 23(4):43351.
doi: 10.1037/h0094766. [Cross Ref]
243. World Health Organization Suicide prevention (SUPRE). Geneva: Available from:
http://www.who.int/mental_health/prevention/suicide/suicideprevent/en.index.html
(2011).
244. Oquendo MA, Giner L, Harkavy Friedman J, Tardiff KJ, Leon AC, Marzuk P.
Suicide risk measures. Second ed. In: Rush AJ, First MB, Blacker D, editors. editors.
Handbook of Psychiatric Measures. Washington, DC: American Psychiatric Press;
(2008). p. 23748.
245. Oquendo MA, Friend JM, Halberstam B, Brodsky BS, Burke AK, Grunebaum MF,
et al. Association of comorbid posttraumatic stress disorder and major depression with
greater risk for suicidal behavior. Am J Psychiatry (2003) 160(3):5802. doi:
10.1176/appi.ajp.160.3.580. [PubMed] [Cross Ref]
246. Beck AT, Schuyler D, Herman I. Development of suicidal intent scales. In: Beck AT,
Resnik HD, Lettieri DJ, editors. editors. Prediction of Suicide. Philadelphia, PA: Charles
Press; (1974). p. 4553.
247. Lon-Carrion J, Serdio-Arias ML, Cabezas FM, Dominguez-Roldan JM,
Dominguez-Morales R, Barroso-y-Martin JM, et al. Neurobehavioral and cognitive
profile of traumatic brain injury patients at risk for depression and suicide. Brain Injury
(2001) 15(2):17581. doi: 10.1080/026990501458407. [PubMed] [Cross Ref]
248. Exner JE. The Rorschach: A Comprehensive System. Volume 1. Basic Foundations.
2nd ed. New York: John Wiley and Sons; (1986).
249. Tsaousides T, Cantor JB, Gordon WA. Suicidal ideation following traumatic brain
injury: prevalence rates and the correlates in adults living in the community. J Head
Trauma Rehabil (2011) 26(4):26575. doi: 10.1097/HTR.0b013e3182225271. [PubMed]
[Cross Ref]
250. Dennis JP, Ghahramanlou-Holloway M, Cox DW, Brown GK. A guide for the
assessment and treatment of suicidal patients with traumatic brain injuries. J Head
Trauma Rehabil (2011) 26(4):24456. doi: 10.1097/HTR.0b013e3182225528. [PubMed]
[Cross Ref]
251. Beck AT, Weissman A, Lester D, Trexler L. Measurement of pessimism: the
hopelessness case. J Consult Clin Psychol (1974) 42(6):8615. doi: 10.1037/h0037562.
[PubMed] [Cross Ref]
252. Beck AT, Steer RA. Beck Hopelessness Scale Manual. San Antonio, TX: Harcourt
Brace; (1993).
253. Simpson GK, Tate RL, Whiting DL, Cotter RE. Suicide prevention after traumatic
brain injury: a randomized controlled trial of a program for the psychological treatment
of helplessness. J Head Trauma Rehabil (2011) 26(4):290300. doi:
10.1097/HTR.0b013e3182225250. [PubMed] [Cross Ref]
254. Nekanda-Trepka CJS, Bishop S, Blackburn IM. Hopelessness and depression. Br J
Clin Psychol (1983) 22:4960. doi: 10.1111/j.2044-8260.1983.tb00578.x. [PubMed]
[Cross Ref]
255. Beck AT, Brown G, Berchick RJ, Stewart BL, Steer RA. Relationship between
hopelessness and ultimate suicide: a replication with psychiatric outpatients. NULL
(2006) 4(2):2916. [PubMed]
256. Keller F, Wolfersdorf M. Hopelessness and the tendency to commit suicide in the
course of depressive disorder. Crisis (1993) 14:1737. [PubMed]
257. Kraus JF, Morgenstern H, Fife D, Conroy C, Nourjah P. Blood alcohol tests,
prevalence of involvement and outcomes following brain injury. Am J Public Health
(1989) 79:2949. doi: 10.2105/AJPH.79.3.294. [PMC free article] [PubMed] [Cross Ref]
258. Sparedo F, Gill D. Effects of prior alcohol use on head injury recovery. J Head
Trauma Rehabil (1989) 4:7582. doi: 10.1097/00001199-198903000-00010. [Cross Ref]
259. Kreutzer JS, Marwitz JH, Witol AD. Interrelationships between crime, substance
abuse and aggressive behaviors among persons with traumatic brain injury. Brain Injury
(1995) 9:75768. doi: 10.3109/02699059509008232. [PubMed] [Cross Ref]
260. Hillbom M, Holm L. Contribution of traumatic head injury to neuropsychological
deficits in alcoholics. J Neurol Neurosurg Psychiatry (1986) 49:134853. doi:
10.1136/jnnp.49.12.1348. [PMC free article] [PubMed] [Cross Ref]
261. Cahalan D, Cisin I. American drinking practices: summary of findings from a
national probability sample. I. Extent of drinking by population subgroups. Q J Stud
Alcohol (1968) 29:13051. [PubMed]
262. Cahalan D, Cisin I. American drinking practices: summary of findings from a
national probability sample. II. Measurement of massed versus spaced drinking. Q J Stud
Alcohol (1968) 29:64256. [PubMed]
263. Horner MD, Ferguson P, Selassie AW, Labbate LA, Kniele K, Corrigan JD. Patterns
of alcohol use 1 year after traumatic brain injury: a population-based epidemiological
study. J Int Neuropsychol Soc (2005) 11(3):32230. doi: 10.1017/S135561770505037X.
[PubMed] [Cross Ref]
264. Bombardier CH, Temkin NR, Machamer J, Dikmen SS. The natural history of
drinking and alcohol-related problems after traumatic brain injury. Arch Phys Med
Rehabil (2003) 84(2):18591. doi: 10.1053/apmr.2003.50002. [PubMed] [Cross Ref]
265. Ponsford J, Whelan-Goodinson R, Bahar-Fuchs A. Alcohol and drug use following
traumatic brain injury: a prospective study. Brain Injury (2007) 21(13-14):138592. doi:
10.1080/02699050701796960. [PubMed] [Cross Ref]
266. Koponen S, Taiminen T, Portin R, Himanen L, Isoniemi H, Heinonen H, et al. Axis I
and II psychiatric disorders after traumatic brain injury: a 30 year follow-up study. Am J
Psychiatry (2002) 159:131521. doi: 10.1176/appi.ajp.159.8.1315. [PubMed] [Cross Ref]
267. Reilly EL, Kelly JT, Faillace LA. Role of alcohol use and abuse in trauma. Adv
Psychosom Med (1986) 16:1730. [PubMed]
268. Martino S, Poling J, Rounsaville BJ. Substance use disorders measures. In: Rush AJ,
First MB, Blacker D, editors. editors. Handbook of Psychiatric Measures. Washington,
DC: American Psychiatric Press; (2008). p. 43770.
269. Babor TF, Higgins-Biddle JC, Saunders JB, Monterio MG. AUDIT. The Alcohol
Use Disorders Identification Test. Guidelines for Use in Primary Care. 2nd Editon ed.
Geneva: World Health Organization; (2001). WHO Publication Number PSA/92.4.
270. Reinert DF, Allen JP. The alcohol use disorders identification test (AUDIT): a
review of recent research. Alcohol Clin Exp Res (2002) 26:2729. doi: 10.1111/j.1530-
0277.2002.tb02534.x. [PubMed] [Cross Ref]
271. Fleming MF, Barry KL, MacDonald R. The alcohol use disorders identification test
(AUDIT) in a college sample. Int J Addict (1991) 26:117385. [PubMed]
272. Hays RD, Merz JF, Nichols R. Response burden, reliability, and validity of the
CAGE. Short MAST, and AUDIT alcohol screening measures. Behav Res Methods
Instrum Comput (1995) 27:27780. doi: 10.3758/BF03204745. [Cross Ref]
273. Bohn MJ, Babor TF, Kranzler HR. The alcohol use disorders identification test
(AUDIT): validation of a screening instrument for use in medical settings. J Stud Alcohol
(1995) 56:42332. [PubMed]
274. Selzer ML. The Michigan alcoholism screening test (MAST): the quest for a new
diagnostic instrument. Am J Psychiatry (1971) 127:16538. [PubMed]
275. Ewing JA. Detecting alcoholism: the CAGE questionnaire. J Am Med Assoc (1984)
252:19057. doi: 10.1001/jama.252.14.1905. [PubMed] [Cross Ref]
276. Claussen B, Aasland OG. The alcohol use disorders identification test (AUDIT) in a
routine health examination of long-term unemployed. Addiction (1993) 88:3638. doi:
10.1111/j.1360-0443.1993.tb00823.x. [PubMed] [Cross Ref]
277. Conigrave KM, Saunders JB, Reznik RB. Predictive capacity of the AUDIT
questionnaire for alcohol-related harm. Addiction (1995) 90:147985. doi:
10.1111/j.1360-0443.1995.tb02810.x. [PubMed] [Cross Ref]
278. Ivis FJ, Adlaf EM, Rehm J. Incorporating the AUDIT into a general population
telephone survey: a methodological experiment. Drug Alcohol Depend (2000) 60:97
104. doi: 10.1016/S0376-8716(00)80012-5. [PubMed] [Cross Ref]
279. Lennings CJ. Evaluation of the Leeds dependence questionnaire. J Child Adoles
Subst Abuse (1999) 8(3):7387. doi: 10.1300/J029v08n03_05. [Cross Ref]
280. Daeppen J, Yersin B, Landry U, Pecoud A, Decrey H. Reliability and validity of the
alcohol use disorders identification test (AUDIT) imbedded within a general health risk
screening questionnaire: results of a survey in 332 primary care patients. Alcohol Clin
Exp Res (2000) 24:65965. doi: 10.1111/j.1530-0277.2000.tb02037.x. [PubMed] [Cross
Ref]
281. Maisto SA, Conigliaro J, McNeil M, Kraemer K, Kelley ME. An empirical
investigation of the factor structure of the AUDIT. Psychol Assess (2000) 12(3):34653.
doi: 10.1037/1040-3590.12.3.346. [PubMed] [Cross Ref]
282. Corrigan JD. Substance abuse as a mediating factor in outcome from traumatic brain
injury. Arch Phys Med Rehabil (1995) 76(4):3029. doi: 10.1016/S0003-9993(95)80654-
7. [PubMed] [Cross Ref]
283. Taylor LA, Kreutzer JS, Demm SR, Meade MA. Traumatic brain injury and
substance abuse: a review and analysis of the literature. Neuropsychol Rehabil (2003)
12(1/2):16588. doi: 10.1080/09602010244000336. [PubMed] [Cross Ref]
284. Parry-Jones BL, Vaughan FL, Cox WM. Traumatic brain injury and substance
misuse: a systematic review of prevalence and outcomes research (1994-2004).
Neuropsychol Rehabil (2006) 16(5):53760. doi: 10.1080/09602010500231875.
[PubMed] [Cross Ref]
285. Graham DP, Cardon AL. An update on substance use and treatment following
traumatic brain injury. Ann N Y Acad Sci (2008) 1141(1):14862. doi:
10.1196/annals.1441.029. [PubMed] [Cross Ref]
286. Skinner HA. The drug abuse screening test. Addict Behav (1982) 7(4):36371. doi:
10.1016/0306-4603(82)90005-3. [PubMed] [Cross Ref]
287. Gavin DR, Ross HE, Skinner HA. Diagnostic validity of the drug abuse screening
test in the assessment of DSM-III drug disorders. Br J Addict (1989) 84:3017. doi:
10.1111/j.1360-0443.1989.tb03463.x. [PubMed] [Cross Ref]
288. Cicerone K, Levin J, Malec J, Stuss D, Whyte J. Cognitive rehabilitation
interventions for executive function: moving from bench to bedside in patients with
traumatic brain injury. J Cogn Neurosci (2006) 18:121222. doi:
10.1162/jocn.2006.18.7.1212. [PubMed] [Cross Ref]
289. Malloy P, Grace J. A review of rating scales for measuring behavior changes due to
frontal system damage. Cogn Behav Neurol (2005) 18:1827. doi:
10.1097/01.wnn.0000152232.47901.88. [PubMed] [Cross Ref]
290. Gioia GA, Isquith PK, Guy SC, Kenworthy L. Behavior rating inventory of
executive function. Child Neuropsychol (2000) 6(3):2358. doi:
10.1076/chin.6.3.235.3152. [PubMed] [Cross Ref]
291. Burgess PW, Alderman N, Evans J, Emslie H, Wilson BA. The ecological validity of
tests of executive function. J Int Neuropsychol Soc (1998) 4:54758. doi:
10.1017/S1355617798466037. [PubMed] [Cross Ref]
292. Kertesz A, Davidson W, Fox H. Frontal behavioral inventory: diagnostic criteria for
frontal lobe dementia. Can J Neurol Sci (1997) 24:2936. [PubMed]
293. Grace J, Malloy PF. Frontal Systems Behavior Scale (FrSBe): Professional Manual.
Lutz, FL: Psychological Assessment Resources; (2001).
294. Stout JC, Ready RE, Grace J, Malloy PF, Paulsen JS. Factor analysis of the frontal
systems behavior scale (FrSBe). Assessment (2003) 10:7985. doi:
10.1177/1073191102250339. [PubMed] [Cross Ref]
295. Barrash J, Tranel D, Anderson SW. Acquired personality disturbances associated
with bilateral damage to the ventromedial prefrontal region. Dev Neuropsychol (2000)
18:35581. doi: 10.1207/S1532694205Barrash. [PubMed] [Cross Ref]
296. Reid-Arndt SA, Nehl C, Hinkebein J. The frontal systems behaviour scale (FrSBe)
as a predictor of community integration following brain injury. Brain Injury (2007)
21(13-14):13619. doi: 10.1080/02699050701785062. [PubMed] [Cross Ref]
297. Lane-Brown AT, Tate RL. Measuring apathy after traumatic brain injury:
psychometric properties of the apathy evaluation scale and the frontal systems behavior
scale. Brain Injury (2009) 23(13-14):9991007. doi: 10.3109/02699050903379347.
[PubMed] [Cross Ref]
298. Nunnally JC. Psychometric Theory. Second ed. New York, NY: McGraw Hill;
(1978).
299. Cortina JM. What is coefficient alpha? An examination of theory and applications. J
Appl Psychol (1993) 78:98104.
300. Holden RR, Fekken GC, Cotton DHG. Assessing psychopathology using structured
test-item response latencies. Psychol Assess (1991) 3:1118. doi: 10.1037/1040-
3590.3.1.111. [Cross Ref]
301. Amador XF, Flaum M, Andreasen NC, Strauss DH, Yale SA, Clark SC, et al.
Awareness of illness in schizophrenia and schizoaffective and mood disorders. Arch Gen
Psychiatry (1994) 51(10):82636. doi: 10.1001/archpsyc.1994.03950100074007.
[PubMed] [Cross Ref]
302. Granholm E, McQuaid JR, McClure FS, Pedrelli P, Beck AT. A randomized
controlled trial of cognitive behavioral therapy for older patients with schizophrenia:
improved insight is associated with symptom change. 17th Annual Society for Research
in Psychopathology Convention San Francisco, CA: (2002) (as cited in Beck 2004).
303. Schooler JW, Ohlsson S, Brooks K. Thoughts beyond words: when language
overshadows insight. J Exp Psychol Gen (1993) 122:16683. doi: 10.1037/0096-
3445.122.2.166. [Cross Ref]
304. Mednick SA. The associative basis of the creative process. Psychol Rev (1962)
69:22032. doi: 10.1037/h0048850. [PubMed] [Cross Ref]
305. Dominowski RL, Dallob P. Insight and problem solving. In: Sternberg RJ, Davidson
JE, editors. editors. The Nature of Insight. Cambridge, MA: MIT Press; (1995). p. 3362.
306. Schooler JW, Melcher J. The ineffability of insight. In: Smith SM, Ward TB, Finke
RA, editors. editors. The Creative Cognition Approach. Cambridge, MA: MIT Press;
(1995). p. 24968.
307. Fodor EM. Subclinical inclination toward manic-depression and creative
performance on the remote associates test. Pers Individ Dif (1999) 27:127383. doi:
10.1016/S0191-8869(99)00076-8. [Cross Ref]
308. Mikulincer M, Shetti E. Adult attachment style and cognitive reactions to positive
affect: a test of mental categorization and creative problem solving. Motiv Emot (2000)
24:14974. doi: 10.1023/A:1005606611412. [Cross Ref]
309. Vohs KD, Heatherton TF. Self-esteem and threats to self: implications for self-
construals and interpersonal perceptions. J Pers Soc Psychol (2001) 81:110318. doi:
10.1037/0022-3514.81.6.1103. [PubMed] [Cross Ref]
310. Bowden EM, Jung-Beeman M. Normative data for 144 compound remote associate
problems. Behav Res Methods Instrum Comput (2003) 35:6349. doi:
10.3758/BF03195543. [PubMed] [Cross Ref]
311. Kounios J, Frymaire JL, Bowden EM, Fleck JI, Subramaniam K, Parrish TB, et al.
The prepared mind. Neural activity prior to problem presentation predicts subsequent
solution by sudden insight. Psychol Sci (2006) 17(10):88290. doi: 10.1111/j.1467-
9280.2006.01798.x. [PubMed] [Cross Ref]
312. Kounios J, Beeman M. The Aha! moment: the cognitive neuroscience of insight.
Curr Dir Psychol Sci (2009) 18(4):2106. doi: 10.1111/j.1467-8721.2009.01638.x. [Cross
Ref]
313. Bowden EM, Jung-Beeman M. Getting the right idea: semantic activation in the
right hemisphere may help solve insight problems. Psychol Sci (1998) 9:43540. doi:
10.1111/1467-9280.00082. [Cross Ref]
314. Jung-Beeman MJ, Bowden EM. The right hemisphere maintains solution-related
activation for yet-to-be-solved problems. Mem Cogn (2000) 28:123141. doi:
10.3758/BF03211823. [PubMed] [Cross Ref]
315. Bowden EM, Jung-Beeman M. Aha! Insight experience correlates with solution
activation in the right hemisphere. Psychon Bull Rev (2003) 10(3):7307. doi:
10.3758/BF03196539. [PubMed] [Cross Ref]
316. Epstein RS, Fullerton CS, Ursano RJ. Posttraumatic stress disorder following an air
disaster: a prospective study. Am J Psychiatry (1998) 155:9348. [PubMed]
317. Beckham JC, Moore SD, Feldman ME, Hertzberg MA, Kirby AC, Firbank JS.
Health status, somatization and severity of posttraumatic stress disorder in Vietnam
combat veterans with posttraumatic stress disorder. Am J Psychiatry (1998)
155(11):15659. [PubMed]
318. Cardenas J, Williasm K, Wilson JP. PTSD, major depressive symptoms and
substance abuse following September 11, 2001 in a Midwestern university population. Int
J Emerg Ment Health (2003) 5:1528. [PubMed]
319. Johnson SD, North CS, Smith EM. Psychiatric disorders among victims of a
courthouse shooting spree: a three-year follow-up study. Community Ment Health J
(2002) 38:18197. doi: 10.1023/A:1015269521969. [PubMed] [Cross Ref]
320. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress disorder
after disasters. Epidemiol Rev (2005) 27(1):7891. doi: 10.1093/epirev/mxi003.
[PubMed] [Cross Ref]
321. DAngiulli A, Herdman A, Stapells D, Hertzman C. Childrens event-related
potentials of auditory selective attention vary with their socioeconomic status.
Neuropsychology (2008) 22(3):293300. doi: 10.1037/0894-4105.22.3.293. [PubMed]
[Cross Ref]
322. DAngiulli A, Weinberg J, Grunau R, Hertzman C, Grebenkov P. Towards a
cognitive science of social inequality: childrens attention-related ERPs and salivary
cortisol vary with their socioeconomic status. Proceedings of the 30th Cognitive Science
Society Annual Meeting Wheat Ridge, CO: Cognitive Science Society, Inc (2008). p.
2116.
323. Hackman DA, Farah MJ. Socioeconomic status and the developing brain. Trends
Cogn Sci (2008) 13(2):6573. doi: 10.5363/tits.13.65. [PMC free article] [PubMed]
[Cross Ref]
324. Braverman PA, Cubbin C, Egerter S, Chideya S, Marchi KS, Metzler M, et al.
Socioeconomic status in health research: one size does not fit all. JAMA (2005)
294:287988. doi: 10.1001/jama.294.22.2879. [PubMed] [Cross Ref]
325. Barratt W. The Barratt Simplified Measure of Social Status (BSMSS) measuring
SES. Indiana State University; (2009).
326. Hollingshead AB. Two Factor Model of Social Position. New Haven, CT: Yale
University; (1957).
327. Hollingshead AB. Four Factor Index of Social Status. New Haven, CT: Yale
University; (1975).
328. Davis J, Smith T, Hodge R, Nakao K, Treas J. Occupational Prestige Ratings from
the 1989 General Social Survey. Ann Arbor, MI: Inter-University consortium for Political
and Social research; (1991).
329. Nakao K, Treas J. Updating occupational prestige and socioeconomic scores: how
the new measures measure up. Sociol Methodol (1994) 24:172. doi: 10.2307/270978.
[Cross Ref]
330. Powers MG. Measures of socioeconomic status: an introduction. In: Powers MG,
editor. editor. Measures of Socioeconomic Status. Boulder, CO: Westview; (1981). p. 1
28.
331. Rapp DL. Brain Injury Casebook: Methods for Re-Integration to Home, School and
Community. Springfield, IL: Thomas; (1987).
332. Tomberg T, Toomela T, Enok M, Tikk A. Changes in coping strategies, social
support, optimism and health-related quality of life following traumatic brain injury: a
longitudinal study. Brain Injury (2007) 21(5):47988. doi: 10.1080/02699050701311737.
[PubMed] [Cross Ref]
333. Izaute M, Durozard C, Aldigier E, Teissedre F, Perreve A, Gerbaud L. Perceived
social support and locus of control after a traumatic brain injury (TBI). Brain Injury
(2008) 22(10):75864. doi: 10.1080/02699050802366002. [PubMed] [Cross Ref]
334. Leach LR, Frank RG, Bouman DE, Farmer J. Family functioning social support and
depression after traumatic brain injury. Brain Injury (1994) 8(7):599606. doi:
10.3109/02699059409151012. [PubMed] [Cross Ref]
335. Zimet GD, Dahlem NW, Zimet SG, Farley GK. The Multidimensional scale of
perceived social support. J Pers Assess (1988) 52:3041. doi:
10.1207/s15327752jpa5201_2. [Cross Ref]
336. Derogatis LR, Lipman RS, Rickel K, Uhlenhuth EH, Covi L. The Hopkins symptom
checklist (HSCL): a self-report symptom inventory. Behav Sci (1974) 19:115. doi:
10.1002/bs.3830190102. [PubMed] [Cross Ref]
337. Zimet GD, Powell SS, Farley GK, Werkman S, Berkoff KA. Psychometric
characteristics of the multidimensional scale of perceived social support. J Pers Assess
(1990) 55:6107. doi: 10.1207/s15327752jpa5503&4_17. [PubMed] [Cross Ref]
338. Cantry-Mitchell J, Zimet GD. Psychometric properties of the multidimensional scale
of perceived social support in urban adolescents. Am J Community Psychol (2000)
28:391400. [PubMed]
339. Bullinger M, Azouvi P, Brooks N, Basso A, Christensen AL, Gobiet W, et al. Quality
of life in patients with traumatic brain injury basic issues, assessment and
recommendations. Restor Neurol Neurosci (2002) 20(3-4):11124. [PubMed]
340. Guilfoyle MR, Seeley HM, Corteen E, Harkin C, Richards H, Menon DK, et al.
Assessing quality of life after traumatic brain injury: examination of the short form 36
health survey. J Neurotrauma (2010) 27(12):217381. doi: 10.1089/neu.2010.1353.
[PubMed] [Cross Ref]
341. Beseoglu K, Roussaint N, Steiger H-J, Hnggi D. Quality of life and socio-
professional reintegration after mild traumatic brain injury. Br J Neurosurg (2012)
27(2):2026. doi: 10.3109/02688697.2012.717984. [PubMed] [Cross Ref]
342. Hall KM, Johnston MV. Outcomes evaluation in TBI rehabilitation: part II.
measurement tools for a nationwide data system. Arch Phys Med Rehabil (1994)
75(Suppl):SCI108. [PubMed]
343. Hall KM, Mann N, High WM, Wright J, Kreutzer JS, Wood D. Functional measures
after traumatic brain injury: ceiling effects of FIM FIM+FAM and CIQ. J Head Trauma
Rehabil (1996) 11(5):2739. doi: 10.1097/00001199-199610000-00004. [Cross Ref]
344. Dahmer ER, Shilling MA, Hamilton B, Bontke C, Englander J, Kreutzer JS, et al. A
model systems database for traumatic brain injury. J Head Trauma Rehabil (1993)
8(2):1225. doi: 10.1097/00001199-199308020-00004. [Cross Ref]
345. Wright J. The functional assessment measure. The Center for Outcome Assessment
in Brain Injury. (2000). Bethesda, MD: Available from:
http://www.tbims.org/combi/FAM(accessed 26 December 2012).
346. Rappaport M, Hall KM, Hopkins HK, Belleza T, Cope DN. Disability rating scale
for severe head traumas: coma to community. Arch Phys Med Rehabil (1982) 63:11823.
[PubMed]
347. von Steinbchel N, Wilson L, Gibbons H, Hawthrone G, Hfer S, Schmidt S, et al.
Quality of life after brain injury (QOLIBRI): scale validity and correlates of quality of
life. J Neurotrauma (2010) 27:115765. doi: 10.1089/neu.2009.1077. [PubMed] [Cross
Ref]
348. von Steinbchel N, Wilson L, Gibbons H, Hawthrone G, Hfer S, Schmidt S, et al.
Quality of life after brain injury (QOLIBRI): scale development and metric properties. J
Neurotrauma (2010) 27(7):116785. doi: 10.1089/neu.2009.1076. [PubMed] [Cross Ref]
349. Truelle JL, Koskinen S, Hawthorne G, Sarajuuri J, Formisano R, von Wild K, et al.
Quality of life after traumatic brain injury: the clinical use of the QOLIBRI a novel
disease-specific instrument. Brain Injury (2010) 24(11):127291. doi:
10.3109/02699052.2010.506865. [PubMed] [Cross Ref]
350. Cicerone KD. Participation as an outcome of traumatic brain injury rehabilitation. J
Head Trauma Rehabil (2004) 19(6):494501. doi: 10.1097/00001199-200411000-00006.
[PubMed] [Cross Ref]
351. Willer B, Rosenthal M, Kreutzer JS, Gordon WA, Rempel R. Assessment of
community integration following rehabilitation for traumatic brain injury. J Head Trauma
Rehabil (1993) 8(2):7587. doi: 10.1097/00001199-199308020-00009. [Cross Ref]
352. Willer B, Ottenbacher KJ, Coad ML. The community integration questionnaire: a
comparative examination. Am J Phys Med Rehabil (1994) 73:10311. doi:
10.1097/00002060-199404000-00006. [PubMed] [Cross Ref]
353. Dijkers M. Measuring long-term outcomes of traumatic brain injury: a review of
community integration questionnaire studies. J Head Trauma Rehabil (1997) 12(6):74
91. doi: 10.1097/00001199-199712000-00007. [Cross Ref]
354. Sander AM, Seel RT, Kreutzer JS, Hall KM, High WM, Rosenthal M. Agreement
between persons with traumatic brain injury and their relatives regarding psychosocial
outcome using the community integration questionnaire. Arch Phys Med Rehabil (1997)
78(4):3537. doi: 10.1016/S0003-9993(97)90225-2. [PubMed] [Cross Ref]
355. Zhang L, Abren BC, Gonzales V, Scale G, Masel B, Ottenbacher KJ. Comparison of
the community integration questionnaire, the Craig handicap assessment and reporting
technique and the disability rating scale in traumatic brain injury. J Head Trauma Rehabil
(2002) 17:497509. doi: 10.1097/00001199-200212000-00002. [PubMed] [Cross Ref]
356. Whiteneck GG, Charlifue SW, Gerhart KA, Overholser JD, Richardson GN.
Quantifying handicap: a new measure of long-term rehabilitation outcomes. Arch Phys
Med Rehabil (1992) 73:51926. [PubMed]
357. Doninger NA, Heinemann AW, Bode RK, Sokol K, Corrigan JD, Moore D.
Predicting community integration following traumatic brain injury with health and
cognitive status issues. Rehabil Psychol (2003) 48:6776. doi: 10.1037/0090-
5550.48.2.67. [Cross Ref]
358. Sander AM, Fuchs KL, High WM, Hall KM, Kreutzer JS, Rosenthal M. The
community integration questionnaire revisited: an assessment of factor structure and
validity. Arch Phys Med Rehabil (1999) 80(10):13038. doi: 10.1016/S0003-
9993(99)90034-5. [PubMed] [Cross Ref]
359. Nabors NA, Freymouth A. Renorming the community integration questionnaire:
influence of gender. Poster Presented at the Annual Meeting of the International
Neuropsychological Society Denver, CO (2000).
360. Johnston MV, Goverover Y, Dijkers M. Community activities and individuals
satisfaction with them: quality of life in the first year after traumatic brain injury. Arch
Phys Med Rehabil (2005) 86:73545. doi: 10.1016/j.apmr.2004.10.031. [PubMed] [Cross
Ref]
361. Whiteneck GG, Dijkers MP, Heinemann AW, Bogner JA, Bushnik T, Cicerone KD,
et al. Development of the participation assessment with recombined tools for use after
traumatic brain injury. Arch Phys Med Rehabil (2011) 92(4):54251. doi:
10.1016/j.apmr.2010.08.002. [PubMed] [Cross Ref]
362. Brenner LA, Braden CA, Bates M, Chase T, Hancock C, Harrison-Felix C, et al. A
health and wellness intervention for those with moderate to severe traumatic brain injury:
a randomized controlled trial. J Head Trauma Rehabil (2012) 27(6):E5768. doi:
10.1097/HTR.0b013e318273414c. [PubMed] [Cross Ref]
363. Meichenbaum D. Resiliency building as a means to prevent PTSD and related
adjustment problems in military personnel. In: Moore B, Penk W, editors. editors.
Treating PTSD in Military Personnel: A Clinical Handbook. New York, NY: Guilford
Press; (2011). p. 32544.
364. Castro CA. Technical Panel 13. Symposium of the Annual Meeting of the
International Military Testing Association on Military Resiliency Perspectives from an
International Technical Panel. Amsterdam (2008).
365. Castro CA, Adler AB. Military mental health training: building resilience. In:
Southwick SM, Litz BT, Charney D, Friedman MJ, editors. editors. Resilience and
Mental Health. Cambridge: Cambridge University Press; (2011). p. 32339.
366. Windle G, Bennett KM, Noyes J. A methodological review of resilience
measurement scales. Health Qual Life Outcomes (2011) 9:8. doi: 10.1186/1477-7525-9-8.
[PMC free article] [PubMed] [Cross Ref]
367. Connor KM, Davidson JRT. Overview: Connor-Davidson Resilience Scale.
Available from: www.cd-risc.com (2012).
368. Connor KM, Davidson JRT. Development of a new resilience scale: the Connor-
Davidson resilience scale (CD-RISC). Depress Anxiety (2003) 18:7682. doi:
10.1002/da.10113. [PubMed] [Cross Ref]
369. Baek HS, Lee KU, Joo EJ, Lee MY, Choi KS. Reliability and validity of the Korean
version of the Connor-Davidson Resilience Scale (K-CD-RISC). Psychiatric
Investigation (2010) 7:10915. doi: 10.4306/pi.2010.7.2.109. [PMC free article]
[PubMed] [Cross Ref]
370. Notario-Pacheco B, Solera-Martinez M, Serrano-Parra MD, Bartolome-Gutierrez R,
Garcia-Campayo J, Martinez-Vizcaino V. Reliability and validity of the Spanish version
of the 10-itemConnor-Davidson Resilience Scale (10-item CD-RISC) in young adults.
Health Qual Life Outcomes (2011) 9:63. doi: 10.1186/1477-7525-9-63. [PMC free
article] [PubMed] [Cross Ref]
371. Wang L, Shi Z, Zhang Y, Zhang Z. Psychometric porpoerties of the 10-item Connor-
Davidson Resilience Scale in Chinese earthquake victims. Psychiatry Clin Neurosci
(2010) 64:499504. doi: 10.1111/j.1440-1819.2010.02130.x. [PubMed] [Cross Ref]
372. Brooks N, Campsie L, Symington C, Beattie A, McKinlay W. The five year outcome
of severe blunt head injury: a relatives view. J Neurol Neurosurg Psychiatry (1986)
49(7):76470. doi: 10.1136/jnnp.49.7.764. [PMC free article] [PubMed] [Cross Ref]
373. Varney M, Martzke J, Roberts R. Major depression in patients with closed head
injury. Neuropsychology (1987) 1:79. doi: 10.1037/h0091773. [Cross Ref]
374. Schoenhuber R, Gentilini M. Anxiety and depression after mild head injury: a case
control study. J Neurol Neurosurg Psychiatry (1988) 51(5):7224. doi:
10.1136/jnnp.51.5.722. [PMC free article] [PubMed] [Cross Ref]
375. Alexander MP. Neuropsychiatric correlates of persistent postconcussive syndrome. J
Head Trauma Rehabil (1992) 7(2):609. doi: 10.1097/00001199-199206000-00009.
[Cross Ref]
376. Ettlin TM, Kischka U, Reichmann S, Radii EW, Heim S, Wengen D, et al. Cerebral
symptoms after whiplash injury of the neck: a prospective clinical and
neuropsychological study of whiplash injury. J Neurol Neurosurg Psychiatry (1992)
55:9438. doi: 10.1136/jnnp.55.10.943. [PMC free article] [PubMed] [Cross Ref]
377. Fann JR, Katon WJ, Uomoto JM, Esselman PC. Psychiatric disorders and functional
disability in out-patients with traumatic brain injuries. Am J Psychiatry (1995)
152(10):14939. [PubMed]
378. Parker RS, Rosenblum A. IQ loss and emotional dysfunctions after mild head injury
incurred in a motor vehicle accident. J Clin Psychol (1996) 52:3243. doi: 10.1002/
(SICI)1097-4679(199601)52:1<32::AID-JCLP5>3.0.CO;2-Y. [PubMed] [Cross Ref]
379. Salazar AM, Warden DL, Schwab K, Spector J, Braverman S, Walter J, et al.
Cognitive rehabilitation for traumatic brain injury. A randomized trial. JAMA (2000)
283(23):307581. doi: 10.1001/jama.283.23.3075. [PubMed] [Cross Ref]
380. Kreutzer JS, Seel RT, Gourley E. The prevalence and symptom rates of depression
after traumatic brain injury: a comprehensive examination. Brain Inj (2001) 15(7):563
76. doi: 10.1080/02699050116884. [PubMed] [Cross Ref]
381. Jorge R, Robinson RG. Mood disorders following traumatic brain injury. Int Rev
Psychiatry (2003) 15:31727. doi: 10.1080/09540260310001606700. [PubMed] [Cross
Ref]
382. Seel RT, Kreutzer JS, Rosenthal M, Hammond FM, Corrigan JD, Black K.
Depression after traumatic brain injury: a National Institute on disability and
rehabilitation research model systems multicenter investigation. Arch Phys Med Rehabil
(2003) 84(2):17784. doi: 10.1053/apmr.2003.50106. [PubMed] [Cross Ref]
383. Rapoport MJ, McCullagh S, Streiner D, Feinstein A. The clinical significance of
major depression following mild traumatic brain injury. Psychosomatics (2003) 44:317.
doi: 10.1176/appi.psy.44.1.31. [PubMed] [Cross Ref]
384. Ashman TA, Spielman SA, Hibbard MR, Silver JM, Chandna T, Gordon WA.
Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential
analyses of Axis I disorders. Arch Phys Med Rehabil (2004) 85(Supplement 2):S3642.
doi: 10.1016/j.apmr.2003.08.117. [PubMed] [Cross Ref]
385. Dikmen SS, Bombardier CH, Machamer JE, Fann JR, Temkin NR. Natural history
of depression in traumatic brain injury. Arch Phys Med Rehabil (2004) 85(9):145764.
doi: 10.1016/j.apmr.2003.12.041. [PubMed] [Cross Ref]
386. ODonnell ML, Creamer M, Pattison P, Atkin C. Psychiatric morbidity following
injury. Am J Psychiatry (2004) 161(3):50714. doi: 10.1176/appi.ajp.161.3.507.
[PubMed] [Cross Ref]
387. Rapoport MJ, McCullagh S, Shammi P, Feinstein A. Cognitive impairment
associated with major depression following mild and moderate traumatic brain injury. J
Neuropsychiatry Clin Neurosci (2005) 17:615. doi: 10.1176/appi.neuropsych.17.1.61.
[PubMed] [Cross Ref]
388. Grigsby J, Kaye K. Incidence and correlates of depersonalization following head
trauma. Brain Injury (1993) 7:50713. doi: 10.3109/02699059309008178. [PubMed]
[Cross Ref]
389. Rattok J, Ross B. Cognitive rehabilitation. In: Silver JM, Yudofsky SC, Hales RE,
editors. editors. Neuropsychiatry of Traumatic Brain Injury. Washington, DC: American
Psychiatric Press; (1994). p. 70329.
390. Ohry A, Rattok J, Solomon Z. Post-traumatic stress disorder in brain injury patients.
Brain Injury (1996) 10(9):68795. doi: 10.1080/026990596124106. [PubMed] [Cross
Ref]
391. Max JE, Castillo CS, Robin DA, Lindgren SD, Smith WL, Sato Y, et al.
Posttraumatic stress symptomatology after childhood traumatic brain injury. J Nerv Ment
Dis (1998) 186:58996. doi: 10.1097/00005053-199810000-00001. [PubMed] [Cross
Ref]
392. Harvey AG, Bryant RA. Predictors of acute stress following mild traumatic brain
injury. Brain Injury (1998) 12(2):14754. doi: 10.1080/026990598122773. [PubMed]
[Cross Ref]
393. Bryant RA, Marosszeky JE, Crooks J, Gurka JA. Posttraumatic stress disorder after
severe traumatic brain injury. Am J Psychiatry (2000) 157(4):62931. doi:
10.1176/appi.ajp.157.4.629. [PubMed] [Cross Ref]
394. Mayou R, Black J, Bryant B. Unconsciousness, amnesia and psychiatric symptoms
following road traffic accident injury. Br J Psychiatry (2000) 177:5405. doi:
10.1192/bjp.177.6.540. [PubMed] [Cross Ref]
395. Glaesser J, Neuner F, Ltgehetmann R, Schmidt R, Elbert T. Posttraumatic stress
disorder in patients with traumatic brain injury. BMC Psychiatry (2004) 4:5. doi:
10.1186/1471-244X-4-5. [PMC free article] [PubMed] [Cross Ref]
396. Bryant RA, ODonnell ML, Creamer M, McFarlane AC, Clark CR, Silove D. The
psychiatric sequelae of traumatic injury. Am J Psychiatry (2010) 167(3):31220. doi:
10.1176/appi.ajp.2009.09050617. [PubMed] [Cross Ref]
397. Wall PL. Posttraumatic stress disorder and traumatic brain injury in current military
populations: a critical analysis. J Am Psychiatr Nurses Assoc (2012) 18(5):27898. doi:
10.1177/1078390312460578. [PubMed] [Cross Ref]
398. Taylor BC, Hagel EM, Carlson KF, Cifu DX, Cutting A, Bidelspach DE, et al.
Prevalence and costs of co-occurring traumatic brain injury with and without psychiatric
disturbance and pain among Afghanistan and Iraq war veteran VA users. Med Care
(2012) 50(4):3426. doi: 10.1097/MLR.0b013e318245a558. [PubMed] [Cross Ref]
399. Bryan CJ, Clemans TA, Hernandez AM, Rudd MD. Loss of consciousness,
depression, posttraumatic stress disorder, and suicide risk among deployed military
personnel with mild traumatic brain injury. J Head Trauma Rehabil (2013) 28(1):1320.
doi: 10.1097/HTR.0b013e31826c73cc. [PubMed] [Cross Ref]
400. MacGregor AJ, Dougherty AL, Tang JJ, Galarneau MR. Postconcussive symptom
reporting among US combat veterans with mild traumatic brain injury from Operation
Iraqi Freedom. J Head Trauma Rehabil (2013) 28(1):5967. doi:
10.1097/HTR.0b013e3182596382. [PubMed] [Cross Ref]
401. Bazarian JJ, Donnelly K, Peterson DR, Warner GC, Zhu T, Zhong J. The relation
between posttraumatic stress disorder and mild traumatic brain injury acquired during
Operations Enduring Freedom and Iraqi Freedom. J Head Trauma Rehabil (2013)
28(1):112. doi: 10.1097/HTR.0b013e318256d3d3. [PubMed] [Cross Ref]
402. Davidson JRT, Book SW, Colket JT, Tupler LA, Roth S, David D, et al. Assessment
of a new self-rating scale for post-traumatic stress disorder. Psychol Med (1997) 27:153
60. doi: 10.1017/S0033291796004229. [PubMed] [Cross Ref]
403. Davidson JR, Tharwani HM, Connor KM. Davidson trauma scale (DTS): normative
scores in the general population and effect sizes in placebo-controlled SSRI trials.
Depress Anxiety (2002) 15:758. doi: 10.1002/da.10021. [PubMed] [Cross Ref]
404. Weiss D, Marmar C. The impact of event scale revised. In: Wilson J, Keane T,
editors. editors. Assessing Psychological Trauma and PTSD. New York: Guildford;
(1997).
405. Gaynes BN, DeVeaugh-Geiss J, Weir S, Gu H, MacPherson C, Schulberg HC, et al.
Feasibility and diagnostic validity of the M-3 checklist: a brief, self-rated screen for
depressive, bipolar, anxiety and post-traumatic stress disorders in primary care. Ann Fam
Med (2010) 8:1609. doi: 10.1370/afm.1092. [PMC free article] [PubMed] [Cross Ref]
406. Hammarberg M. Penn inventory for post-traumatic stress disorder: psychometric
properties. Psychol Assess (1993) 4(1):6776. doi: 10.1037/1040-3590.4.1.67. [Cross
Ref]
407. Watson CG, Juba MP, Manifold V, Kucala T, Anderson PED. The PTSD interview:
rationale, description, reliability and concurrent validity of a DSM-III technique. J Clin
Psychol (1991) 47:17988. doi: 10.1002/1097-4679(199103)47:2<179::AID-
JCLP2270470202>3.0.CO;2-P. [PubMed] [Cross Ref]
408. Foa EB, Riggs DS, Dancu CV, Rothbaum BO. Reliability and validity of a brief
instrument for assessing post-traumatic stress disorder. J Trauma Stress (1993) 6:45973.
doi: 10.1002/jts.2490060405. [Cross Ref]
409. Foa EB. Posttraumatic Stress Diagnostic Scale Manual. Minneapolis, MN: NCS
Pearson; (1995).
410. Prins A, Ouimette P, Kimerling R, Cameron RP, Hugelshofer DS, Shaw-Hegwer J, et
al. The primary care PTSD screen (PC-PTSD): development and operating
characteristics. Primary Care Psychiatry (2003) 9:914(Corrigendum 9, 151). doi:
10.1185/135525703125002360. [Cross Ref]
411. Bliese PD, Wright KM, Adler AB, Cabrera O, Castrol CA, Hoge CW. Validating the
primary care posttraumatic stress disorder screen and the posttraumatic stress disorder
checklist with soldiers returning from combat. J Consult Clin Psychol (2008) 7:27281.
doi: 10.1037/0022-006X.76.2.272. [PubMed] [Cross Ref]
412. Solomon Z, Bebenishty R, Neria Y, Abramowitz M, Ginzburg K, Ohry A.
Assessment of PTSD: validation of the revised PTSD inventory. Isr J Psychiatry (1993)
30:1105. [PubMed]
413. Peters L, Andrews G, Cottler LB, Chatterji S, Janca A, Smeets R. The composite
international diagnostic interview post-traumatic stress disorder module: preliminary
data. Int J Methods Psychiatr Res (1996) 6:16774. doi: 10.1002/(SICI)1234-
988X(199610)6:3<167::AID-MPR159>3.3.CO;2-Z. [Cross Ref]
414. Cardena EC, Koopman C, Classen C, Waeide LC, Spiegel D. Psychometric
properties of the Stanford acute stress reaction questionnaire. (SASRQ): a valid and
reliable measure of acute stress. J Trauma Stress (2000) 13(4):71934. doi:
10.1023/A:1007822603186. [PubMed] [Cross Ref]
415. Brewin CR, Rose S, Andrews B, Green J, Tata P, McEvedy C, et al. Brief screening
instrument for posttraumatic stress disorder. Br J Psychiatry (2002) 181:15862.
[PubMed]
416. Briere J. Psychological Assessment of Adult Posttraumatic States. Washington, DC:
American Psychological Press; (2004).
417. Berah E. Test review: the trauma symptom inventory. Psychiatr Psychol Law (1997)
4:934. doi: 10.1080/13218719709524901. [Cross Ref]
418. van Reekum R, Bolago I, Finlayson MA, Garner S, Links PS. Psychiatric disorders
after traumatic brain injury. Brain Injury (1996) 10:31927. doi:
10.1080/026990596124340. [PubMed] [Cross Ref]
419. Deb S, Lyons I, Koutzoukis C, Ali I, McCarthy G. Rate of psychiatric illness one
year after traumatic brain injury. Am J Psychiatry (1999) 156:3748. [PubMed]
420. Dikmen S, McLean A, Temkin N. Neuropsychological and psychosocial
consequences of minor head injury. J Neurol Neurosurg Psychiatry (1986) 49:122732.
doi: 10.1136/jnnp.49.11.1227. [PMC free article] [PubMed] [Cross Ref]
421. Cohen M, Oksenberg A, Snir D, Stern MJ, Grosswasser Z. Temporally related
changes of sleep complaints in traumatic brain injury patients. J Neurol Neurosurg
Psychiatry (1992) 55:3135. doi: 10.1136/jnnp.55.4.313. [PMC free article] [PubMed]
[Cross Ref]
422. Beetar JR, Guilmette TJ, Sparadeo FR. Sleep and pain complaints in symptomatic
traumatic brain injury and neurologic populations. Arch Phys Med Rehabil (1996)
77(12):1298302. doi: 10.1016/S0003-9993(96)90196-3. [PubMed] [Cross Ref]
423. Perlis ML, Artiola L, Giles DE. Sleep complaints in chronic postconcussion
syndrome. Percept Mot Skills (1997) 84:5959. doi: 10.2466/pms.1997.84.2.595.
[PubMed] [Cross Ref]
424. Clinchot DM, Bogner J, Mysiw WJ, Fugate L, Corrigan J. Defining sleep
disturbances after brain injury. Am J Phys Med Rehabil (1998) 77(4):2915. doi:
10.1097/00002060-199807000-00006. [PubMed] [Cross Ref]
425. Fichtenberg N, Zafonte RD, Putnam S, Mann NR, Millard AE. Insomnia in a post-
acute brain injury sample. Brain Injury (2002) 16(3):197206. doi:
10.1080/02699050110103940. [PubMed] [Cross Ref]
426. Ouellet MC, Beauleu-Bonneau S, Morin CM. Insomnia in patients with traumatic
brain injury: frequency, characteristics and risk factors. J Head Trauma Rehabil (2006)
21(3):199212. doi: 10.1097/00001199-200605000-00001. [PubMed] [Cross Ref]
427. Korinthenberg R, Schreck J, Weser J, Lehmkuhl G. Post-traumatic syndrome after
minor head injury cannot be predicted by neurological investigations. Brain Dev (2004)
26:1137. doi: 10.1016/S0387-7604(03)00110-4. [PubMed] [Cross Ref]
428. Parcell DL, Ponsford JL, Rajaratnam SM, Redman JR. Self-reported changes to
night time sleep after traumatic brain injury. Arch Phys Med Rehabil (2006) 87(2):278
85. doi: 10.1016/j.apmr.2005.10.024. [PubMed] [Cross Ref]
429. Lundin A, de Bussard C, Edman G, Borg J. Symptoms and disability until three
months after mild TBI. Brain Injury (2006) 20(8):799806. doi:
10.1080/02699050600744327. [PubMed] [Cross Ref]
430. Castriotta RJ, Wilde MC, Lai JM, Atanasov S, Masel BE, Kuna ST. Prevalence and
consequences of sleep disorders in traumatic brain injury. J Clin Sleep Med (2007)
3(4):34956. [PMC free article] [PubMed]
431. Makley MJ, English JB, Drubach DA, Kreuz AJ, Celnick PA, Tarwater PM.
Prevalence of sleep disturbance in closed head injury patients on a rehabilitation unit.
Neurorehabil Neural Repair (2008) 22(4):3417. doi: 10.1177/1545968308315598.
[PubMed] [Cross Ref]
432. Oshio A, Kaneko H, Nagamine S, Nakaya M. Construct validity of the adolescent
resilience scale. Psychol Rep (2003) 93:121722. doi: 10.2466/pr0.2003.93.3f.1217.
[PubMed] [Cross Ref]
433. Antonovsky A. The structure and properties of the sense of coherence scale. Soc Sci
Med (1993) 36(6):72533. doi: 10.1016/0277-9536(93)90033-Z. [PubMed] [Cross Ref]
434. Smith BW, Dalen J, Wiggins K, Tooley E, Christopher P, Bernard J. The brief
resilience scale assessing the ability to bounce back. Int J Behav Med (2008) 15:194200.
doi: 10.1080/10705500802222972. [PubMed] [Cross Ref]
435. Sun J, Stewart D. Development of population-based resilience measures in the
primary school setting. Health Educ (2007) 7(6):57599. doi:
10.1108/09654280710827957. [Cross Ref]
436. Ungar M, Liebenberg K, Boothroyd R, Kwong WM, Lee TY, Leblanc J, et al. The
study of youth resiliency across cultures: lessons from a pilot study of measurement
development. Res Hum Dev (2008) 5(3):16680. doi: 10.1080/15427600802274019.
[Cross Ref]
437. Bartone PK. Test-retest reliability of the dispositional resilience scale-15, a brief
hardiness scale. Psychol Rep (2007) 101:9434. doi: 10.2466/pr0.101.3.943-944.
[PubMed] [Cross Ref]
438. Block J, Kremen AM. IQ and ego resiliency: conceptual and empirical connections
and separateness. J Pers Soc Psychol (1996) 70:34961. doi: 10.1037/0022-
3514.70.2.349. [PubMed] [Cross Ref]
439. Klohnen EC. Conceptual analysis and measurement of the construct of ego-
resiliency. J Personal Soc Psychiatry (1996) 70(5):106779. doi: 10.1037/0022-
3514.70.5.1067. [PubMed] [Cross Ref]
440. Kobasa SC, Maddi SR, Kahn S. Hardiness and health: a prospective study. J Pers
Soc Psychol (1982) 42:16877. doi: 10.1037/0022-3514.42.1.168. [PubMed] [Cross Ref]
441. Scheier MF, Carver CS. Optimism, coping and health: assessment and implications
of generalized outcome expectancies. Health Psychol (1985) 4:21947. doi:
10.1037/0278-6133.4.3.219. [PubMed] [Cross Ref]
442. Scheier MF, Carver CS, Bridges MW. Distinguishing optimism from neuroticism
(and trait anxiety, self-mastery and self-esteem): a re-evaluation of the life orientation
test. J Pers Soc Psychol (1994) 67:106378. doi: 10.1037/0022-3514.67.6.1063.
[PubMed] [Cross Ref]
443. Neugarten BL, Havighurst RJ, Tobin S. The measurement of life satisfaction. J
Gerontol (1961) 16:13443. doi: 10.1093/geronj/16.2.134. [PubMed] [Cross Ref]
444. Cohen S, Williamson G. Perceived stress in a probability sample of the United
States. In: Spacapan S, Oskamp S, editors. editors. The Social Psychology of Health. The
Claremont Symposium on Applied Social Psychology. Newbury Park, CA: Sage; (1988).
p. 3167.
445. Windle G, Markland DA, Woods B. Examination of a theoretical model of
psychological resilience in older age. Aging Mental health (2008) 12(3):28592. doi:
10.1080/13607860802120763. [PubMed] [Cross Ref]
446. Hurtes KP, Allen LR. Measuring resiliency in youth: the resiliency attitudes and
skills profile. Ther Recreation J (2001) 35(4):33347.
447. Wagnild GM, Young HM. Development and psychometric evaluation of the
resilience scale. J Nurs Meas (1993) 1(2):16578. [PubMed]
448. Friborg O, Hjemdal O, Rosenvinge JH, Marinussen M. A new rating scale of adult
resilience: what are the central protective resources behind healthy adjustment? Int J
Methods Psychiatr Res (2003) 12:6576. doi: 10.1002/mpr.143. [PubMed] [Cross Ref]
449. Friborg O, Barlaug D, Martinussen M, Rosenvinge JH, Hjemdal O. Resilience in
relation to personality and intelligence. Int J Methods Psychiatr Res (2005) 14(1):2942.
doi: 10.1002/mpr.15. [PubMed] [Cross Ref]
450. Rosenberg M. Society and the Adolescent Self-Image. Princeton, NJ: Princeton
University Press; (1965).
451. Schutte NS, Malouff JM, Hall LE, Haggerty DJ, Cooper JT, Golden CJ, et al.
Development and validation of a measure of emotional intelligence. Pers Individ Dif
(1998) 25:16777. doi: 10.1016/S0191-8869(98)00001-4. [Cross Ref]
452. Connor KM, Vaishnavi S, Davidson JRT, Sheehan DV, Sheehan KH. Perceived
stress in anxiety disorders and the general population: a study of the Sheehan stress
vulnerability scale. Psychiatry Res (2007) 151(3):24954. doi:
10.1016/j.psychres.2006.11.008. [PubMed] [Cross Ref]
453. Ryff CD. Psychological well-being in adult life. Curr Dir Psychol Sci (1995) 4:99
104. doi: 10.1111/1467-8721.ep10772395. [Cross Ref]
454. Donnon T, Hammond W, Charles G. Youth resiliency: assessing students capacity
for success at school. Teach Learn (2003) 1(2):238.
455. Donnon T, Hammond W. A psychometric assessment of the self reported youth
resiliency assessing developmental strengths questionnaire. Psychol Rep (2007) 100:963
78. doi: 10.2466/pr0.100.3.963-978. [PubMed] [Cross Ref]
456. Beck AT, Weissman A, Lester D, Trexler L. Measurement of pessimism: the
hopelessness case. J Cons Clin Psychol (1974b) 42(6):8615. [PubMed]
457. Beck AT, Steer RA. Manual for beck hopelessness scale. San Antonio, TX:
Psychological Corporation; (1988).
458. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical
anxiety: psychometric properties. J Consult Clin Psychol (1988) 56:8937. doi:
10.1037/0022-006X.56.6.893. [PubMed] [Cross Ref]
459. Beck SL, Schwartz AL, Dudley W, Barsevick A. Psychometric evaluation of the
Pittsburgh sleep quality index in cancer patients. J Pain Symptom Manage (2004)
27:1408. doi: 10.1016/j.jpainsymman.2003.12.002. [PubMed] [Cross Ref]
460. Crawford JR, Allan KM. Estimating premorbid IQ with demographic variables:
regression equation derived from a UK sample. Clin Neuropsychol (1997) 11:1927. doi:
10.1080/13854049708407050. [Cross Ref]
461. Hamilton MA. A rating scale for depression. J Neurol Neurosurg Psychiatry (1960)
23:5662. doi: 10.1136/jnnp.23.1.56. [PMC free article] [PubMed] [Cross Ref]
462. Harvey AG, Bryant RA. Acute stress disorder following mild traumatic brain injury.
J Nerv Ment Dis (1998) 186:3337. doi: 10.1097/00005053-199806000-00002.
[PubMed] [Cross Ref]
463. Jorge RE, Robinson RG, Arndt SV, Starkstein SE, Forrester AW, Geisler F.
Depression following traumatic brain injury: a 1 year longitudinal study. J Affect Disord
(1993) 27:23343. doi: 10.1016/0165-0327(93)90047-N. [PubMed] [Cross Ref]
Jurnal 4
BMC Psychiatry. 2013; 13: 130.
Published online 2013 May 7. doi: 10.1186/1471-244X-13-130
PMCID: PMC3651311
Predictors of psychiatric disorders in
combat veterans
Stephanie Booth-Kewley, 1 Emily A Schmied,1 Robyn M Highfill-McRoy,1 Gerald E
Larson,1 Cedric F Garland,1,2 and Lauretta A Ziajko3
Author information Article notes Copyright and License information
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Abstract
Background

Most previous research that has examined mental health among Operation Enduring
Freedom and Operation Iraqi Freedom (OEF/OIF) combatants has relied on self-report
measures to assess mental health outcomes; few studies have examined predictors of
actual mental health diagnoses. The objective of this longitudinal investigation was to
identify predictors of psychiatric disorders among Marines who deployed to combat in
Iraq and Afghanistan.

Methods

The study sample consisted of 1113 Marines who had deployed to Iraq or Afghanistan.
Demographic and psychosocial predictor variables from a survey that all Marines in the
sample had completed were studied in relation to subsequent psychiatric diagnoses.
Univariate and multivariate logistic regression were used to determine the influence of
the predictors on the occurrence of psychiatric disorders.

Results

In a sample of Marines with no previous psychiatric disorder diagnoses, 18% were

diagnosed with a new-onset psychiatric disorder. Adjusting for other variables, the
strongest predictors of overall psychiatric disorders were female gender, mild traumatic
brain injury symptoms, and satisfaction with leadership. Service members who expressed
greater satisfaction with leadership were about half as likely to develop a mental disorder
as those who were not satisfied. Unique predictors of specific types of mental disorders
were also identified.

Conclusions

Overall, the studys most relevant result was that two potentially modifiable factors, low
satisfaction with leadership and low organizational commitment, predicted mental
disorder diagnoses in a military sample. Additional research should aim to clarify the
nature and impact of these factors on combatant mental health.
Keywords: Psychiatric disorders, Military populations, Marines, Iraq/Afghanistan wars,
Veterans, Combat
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Background
Deployment to combat zones may result in a variety of mental health problems, including
posttraumatic stress disorder (PTSD), anxiety, and depression [1,2]. Despite substantial
research, factors that increase susceptibility of military members to post-combat mental
disorders are not fully understood. Factors suspected to play a role in risk of combat-
related mental health disorders include degree of combat exposure, deployment stressors,
gender, traumatic brain injury (TBI) symptoms, degree of satisfaction with leadership,
unit cohesion, organizational commitment, and positive deployment experiences [1,3-9].

Combat exposure is the factor most consistently associated with mental disorders and
symptomatology. Research with Vietnam veterans demonstrated substantial associations
between combat exposure and PTSD [10,11]. Similar findings have emerged from studies
of Gulf War veterans [12-14] and studies of contemporary combatants in Iraq and
Afghanistan [1,6,15].

Another potentially important predictor of mental health problems in military personnel

is noncombat deployment stressors [7,16-18]. Examples of these deployment stressors
include concerns or problems with family members back home, problems with
supervisors, lack of privacy, and boredom. A link between deployment stressors and
mental disorders has been demonstrated in Vietnam veterans [11,17,18], Gulf War
veterans [18], and in combatants of Operation Enduring Freedom and Operation Iraqi
Freedom (OEF/OIF) [5].

Another possible risk factor for mental disorders in combatants is TBI symptoms.
Although the nature of the relationship between mild TBI symptoms and mental disorders
is unclear, there is substantial overlap between symptoms of mild TBI and symptoms of
PTSD [19,20]. A study of OEF/OIF veterans [3] found that those with TBI symptoms had
higher rates of PTSD, depression, anxiety, and other disorders. In veterans from prior
conflicts (e.g., Vietnam, Gulf War), self-reported head injury has been associated with
greater risk of depression [21].

Other factors that may have an impact on mental health in military combatants include
leadership and unit cohesion. Little research has examined the effects of military
leadership on mental health; however, there is some evidence that positive attitudes
toward leadership have a beneficial effect on the mental health of combat-deployed
military personnel. Perceptions that leadership is supportive are associated with greater
satisfaction with the military, higher morale, and other positive outcomes [22]. A study of
deployed U.S. soldiers reported that positive attitudes toward leadership were associated
with greater perceived well-being [23]. Castro and McGurk [4] found that combat-
deployed personnel who rated their leaders favorably were less likely to screen positive
for a mental health problem than those who rated them unfavorably. Positive leadership
may buffer the negative effects of stress experienced by deployed military personnel [24].

Unit cohesion may also play an important role in military mental health. Some experts
consider unit cohesion to be the most important factor in preventing mental health
problems among combatants [25]. Military research [26] clearly demonstrates the
importance of cohesion for performance, readiness, well-being, and satisfaction with the
military. Unit cohesion may be important for combatants because it may mitigate the
effects of stress [27] and reduce the risk of PTSD [6,28].

Organizational commitment may also play a role in service members risk for developing
mental health problems. Organizational commitment is predictive of reenlistment, job
satisfaction, morale, and adjustment to the military [29,30]. Service members with a
strong sense of commitment may have a higher level of motivation, leading to greater
resilience in the face of setbacks. On theoretical and empirical grounds, it seems plausible
that organizational commitment could have a protective effect on mental health.

Positive deployment experiences may have a protective effect on mental health. A study
of U.S. military peacekeepers deployed to Kosovo found that positive military
experiences (such as feeling that ones mission is successful) were predictive of
postdeployment morale [31]. Another study of U.S. peacekeepers found that positive
experiences while on deployment were protective against PTSD [7]. It is also known that
the experience of positive emotions can buffer the deleterious effects of stress in civilian
populations [32,33]. Thus, it seems plausible that positive experiences during deployment
could have a protective effect on mental health.

Although women make up about 14% of military service members deployed in support of
OEF/OIF, few studies have examined predictors of psychological health outcomes of
women serving in these conflicts. Evidence for gender differences among deployers has
been mixed [18,34,35] and many studies have relied on data from previous conflicts (e.g.,
Vietnam, Gulf War). In addition, little is known about the differential factors affecting the
incidence of mental disorders in male and female combatants deployed to OEF/OIF [36].
We examined gender differences in psychological outcomes in the present study.

Most previous research that has examined mental health among OEF/OIF combatants has
relied on self-report measures to assess mental health outcomes; few investigations have
studied predictors of actual mental health diagnoses. The purpose of this study was to use
a prospective design to identify demographic and psychosocial predictors of mental
health diagnoses in a sample of Marines who deployed to OEF/OIF. The inclusion of
these predictors was based on past theory and research, and it was predicted that all of
them would be associated with mental health outcomes. Because few studies have sought
to determine if different demographic and psychosocial factors are linked with different
mental health disorders, an additional objective was to determine whether different
factors predict different types of mental health diagnoses (e.g., mood disorders, PTSD) in
a combat-deployed sample.
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Methods
Overview

The present study was a longitudinal investigation of Marines who participated in a

previous study, called the Warfighter Status Survey [37]. The original sample of study
participants consisted of 1576 Marines, who were surveyed in 2007 and 2008. To be
included as a participant in this earlier study (Warfighter Status Survey), individuals had
to be active duty or reservist Marines with at least one prior combat deployment to Iraq or
Afghanistan. The study sample for the present, longitudinal study (presented in this
paper) consisted of 1113 of the original Warfighter Status Survey participants. The
sample for the longitudinal study is smaller than the original Warfighter Status Survey
sample (N = 1576), because the longitudinal study excluded Marines who had a previous
psychiatric diagnosis on record at the time of survey completion, and also excluded
Marines for whom follow-up medical or deployment data could not be obtained.

Almost all of the predictor variables for the present study were based on Marines
responses to the Warfighter Status Survey (all except for number of combat
deployments). The Warfighter Status Survey was completed only once by each
participant. Participants in the Warfighter Status Survey were asked for identifying
information and for permission to be followed up later in military personnel and medical
electronic databases. The primary outcome variables for the study (mental disorder
diagnoses) were obtained from an electronic database known as the Career History
Archival Medical and Personnel System (CHAMPS). Deployment data were obtained
from the Defense Manpower Data Center (DMDC) deployment file. Predictor variables
(primarily from the Warfighter Status Survey) were examined in relation to outcome
variables obtained from CHAMPS. The deployment data (from DMDC) provided one of
the predictors (number of combat deployments).

Participants and procedure

The longitudinal database for this study was created using three sources: (1) Warfighter
Status Survey data; (2) medical data from CHAMPS (data regarding mental disorder
diagnoses); and (3) deployment data from the DMDC deployment file. Participants in the
Warfighter Status Survey [37] were active duty and reservist Marines with at least one
prior deployment to a combat area (N = 1576).

Participants were recruited from U.S. Marine Corps bases in Southern California and
Okinawa, Japan, and completed self-report surveys in group settings between June 2007
and January 2008. Surveys were not administered immediately after Marines returned
from deployment; participants simply had to have participated in at least one prior
combat deployment to Iraq or Afghanistan to be eligible for the Warfighter Status Survey.
In the announcement inviting Marines to participate in the study, they were assured that
confidentiality of their data would be maintained. The overall response rate was 78%. To
ensure confidentiality, participants data were stored separately from identifiers, and after
matching, identifiers were stripped from the data. The participants chain of command
never had access to any part of their data.

To allow for follow-up, the Warfighter Status Survey requested identifying information
(name and social security number) from participants. A more complete description of
procedures is provided in Booth-Kewley et al. [37]. All research procedures were
approved by the Naval Health Research Center Institutional Review Board (protocol
NHRC.2007.0003).

Participants were included in the present study if (1) they were active-duty Marines (not
reservists) who completed the Warfighter Status Survey; (2) they provided identifying
information; and (3) we were able to find matching data for them in CHAMPS and
DMDC data files. These three inclusion criteria resulted in a sample of 1291 participants.
Because having a previous psychiatric diagnosis would make an individual more likely to
develop another diagnosis after exposure to combat, we excluded an additional n = 178
participants who had a pre-existing psychiatric diagnoses on record at the time of
Warfighter Status Survey completion. This resulted in a final study sample of 1113 for the
current analyses.

Predictor measures

Most of the predictor measures were obtained from the Warfighter Status Survey by
Booth-Kewley et al. [37]. Participants completing the Warfighter Status Survey were
asked to answer all survey questions with regard to their most recent combat deployment.
The only predictor that was not obtained from the Warfighter Status Survey was total
number of career combat deployments, which was extracted from the DMDC deployment
file.

Although this survey contained a large number of potential predictors of mental health,
only the factors for which there were theoretical reasons to expect an association with
mental disorders were selected for this study; these factors are described below.

Combat exposure

A combat exposure scale was adapted from one used by the Army Mental Health
Advisory Team [23]. The scale consisted of 16 items assessing experiences, such as
receiving incoming artillery, rocket or mortar fire and knowing someone seriously
injured or killed ( = .92). Participants indicated how often they experienced each
combat exposure using a five-point scale (1 = never to 5 = 10 or more times) during their
most recent deployment. An overall combat exposure score was created by summing
across all scale items. Level of combat exposure was classified into three groups (low,
medium, high) based on the tertile distribution of the combat exposure scale scores.

Deployment stressors
Deployment stressors were assessed using an 11-item scale; it was adapted from a similar
instrument used by Army researchers [23]. This scale consists of questions about
deployment stressors, such as concerns or problems back home, problems with
supervisor(s) or chain of command, and lack of time off ( = .89). With their most
recent deployment in mind, participants were asked to rate each stressor on a five-point
scale (1 = very low to 5 = very high). An overall deployment stressor score was created by
summing across all scale items. Deployment stressor level was classified into three
groups (low, medium, high) based on the tertile distribution of the scale scores.

Unit cohesion

Unit cohesion was measured using a four-item scale previously used in other military
research [38]. The items were: The members of my unit had trust in each other, The
members of my unit cared about each other, The members of my unit supported each
other as a team, and The members of my unit worked well together to get the job done
( = .93). Participants rated each item on a five-point scale (1 = not at all true to 5 =
completely true). An overall score was created by summing across all items. Unit
cohesion was classified into three groups (low, medium, high) based on the tertile
distribution of the scale scores.

Satisfaction with leadership

Satisfaction with leadership was measured using an eight-item scale that was adapted
from a leadership scale developed by Army researchers [23]. The scale assesses various
facets of leadership, such as showed clear thinking and reasonable actions, and told
Marines when they had done a good job ( = .94). Participants rated each item on a five-
point scale (1 = never to 5 = always). A leadership satisfaction scale score was created by
summing across all items. Leadership satisfaction was classified into four groups (low,
medium, high, very high) based on the quartile distribution of the scores.

Organizational commitment

A four-item organizational commitment scale was developed specifically for this study.
The items were adapted from other organizational commitment scales [30,39]. The items
were: I feel emotionally attached to the Marine Corps, I feel a strong sense of
belonging to the Marine Corps, I believe the Marine Corps takes good care of its
people, and I will always think of myself as a Marine ( = .87). Participants rated each
item on a five-point scale (1 = strongly disagree to 5 = strongly agree). A scale score was
created by summing across all items. Organizational commitment was classified into
three groups (low, medium, high) based on the tertile distribution of the scores.

Mild TBI symptoms

Mild TBI symptoms were assessed using a set of yes/no questions that asked participants
whether, during their most recent deployment, they had received an injury to the head
that involved (1) being dazed, confused, or seeing stars, (2) not remembering the
injury, or (3) losing consciousness (knocked out). A participant was considered to have a
positive mild TBI screen if any of these three questions elicited a positive response. Hoge
et al. [19] used this procedure in their study of mild TBI among soldiers returning from
Iraq.

Positive deployment experiences

Positive deployment experiences were measured using two items: Overall, my recent
deployment had a positive effect on my life, and I feel pride from my accomplishments
during my most recent deployment ( = .72). These items were rated on a five-point
scale (1 = strongly disagree to 5 = strongly agree). Positive deployment experiences was
classified into three groups (low, medium, high) based on the tertile distribution of the
scale scores.

Total number of career combat deployments

Total number of career combat deployments was extracted from the DMDC deployment
file. These data were dichotomized into two categories: single deployment or multiple
deployments.

Demographic and military background variables

The questionnaire asked for the following demographic and military information: gender,
age, marital status, rank/paygrade, military occupation, education level, race/ethnic
background, and whether the participant had deployed with his or her unit or as an
individual augmentee on the most recent deployment. Respondents were also asked to
provide the dates and locations of their combat deployments.

Outcome measures

Outcome measures (e.g., psychiatric diagnoses) were obtained from CHAMPS.

CHAMPS is an electronic database maintained by Naval Health Research Center in San
Diego, California. CHAMPS contains demographic, personnel, and medical information
(including psychiatric data) on all active-duty military personnel [40]. The medical
records in CHAMPS originate from Standard Inpatient Data Record, Standard
Ambulatory Data Record, and Health Care Service Record files via TRICARE
Management Activity. These records are generated for military personnel at every
inpatient and outpatient medical encounter, except for those that occur within a combat
zone, and those that occur outside the military health care system (i.e., visits at civilian
facilities).

Psychiatric diagnoses were the primary outcome in this study. Participants were defined
as having a psychiatric disorder if they had an outpatient or hospitalization record during
the follow-up period that included an International Classification of Diseases, Ninth
Revision, Clinical Modification diagnostic code (ICD-9-CM) ranging from 290 to 316
(mental disorders), excluding 305.1 (nondependent tobacco use disorder); 307.81 (tension
headache); and 310.20 (postconcussive disorder). The observation period was from the
time the participant completed the survey (June 2007January 2008) until December
2010, when CHAMPS records were extracted for this study. The average follow-up time
was 30.2 months (standard deviation = 11.5).

Statistical analysis

Univariate and multivariate logistic regression were used to determine the influence of
the predictors on the occurrence of psychiatric disorders. Odds ratios (ORs) and 95%
confidence intervals were calculated for each variable. To facilitate ease of interpretation
of results, continuous predictor variables (e.g., combat exposure and unit cohesion) were
made into categories.

For the multivariate analysis, all variables that were significant in the univariate analysis
(p < .10) were entered as candidates into the models. Variables were entered into the
logistic regression models using a backward stepwise procedure (criteria p < .05 for entry
and p < .10 for removal). Separate models were developed to identify predictors of
receiving (1) a psychiatric diagnoses of any kind, (2) a PTSD diagnosis, (2) an anxiety
disorder diagnosis, (3) a mood disorder diagnosis, (4) an adjustment disorder diagnosis,
or (5) a substance disorder diagnosis. These were the most common diagnoses in the
sample.

Pairwise correlations and variance inflation factors did not reveal any substantial
collinearity among model variables. Specifically, none of the covariates used in the
models correlated with another covariate with a correlation .48. Statistical analyses
were performed using SPSS software, version 18 (SPSS Inc., Chicago, IL).

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Results
The demographic characteristics of the sample are shown in Table 1. The participants
were mostly men (96%). The most common ethnic groups were white (59%) and
Hispanic (19%). About half the sample had a high school diploma or equivalency degree
or a lower level of education (53%). About half of the participants were married (47%).
Slightly more than half had experienced one combat deployment during their career
(57%); 43% had deployed twice or more. The sample was generally similar to the Marine
Corps population on demographics, except that Hispanics were overrepresented in the
study sample, and individuals in the lowest paygrades (E1E3) were somewhat
underrepresented in the study sample.
Table 1
Demographic characteristics of study participants, Marines deployed to combat (N
= 1113), 20072010

Predictors of overall psychiatric disorders

Of Marines with no previous psychiatric diagnoses at the time of survey completion (N =

1113), a total of 18% (n = 199) received a psychiatric diagnosis during the observation
period. Of the participants who received a postsurvey psychiatric diagnosis, 52% had a
single diagnosis (n = 103). Comorbid diagnoses were fairly common; 25% of the sample
had two diagnoses (n = 50), 13% had three diagnoses (n = 26), and 10% had four or more
diagnoses (n = 20). In this sample of 1113, the most common psychiatric diagnoses
received during the observation period were anxiety disorders (n = 81), mood disorders (n
= 62), substance use disorders (n = 58), adjustment disorders (n = 55), and PTSD (n = 53).

Logistic regression was used to determine predictors of receiving any psychiatric

diagnosis (Table 2). Overall, 12 of the 15 potential predictors of psychiatric diagnosis
were statistically significant in the univariate analysis (p < .05), and one additional
predictor was of borderline significance (p < .10). Gender had the strongest univariate
association with psychiatric diagnosis (OR = 3.07 for women, p < .01). Other variables
that had substantial univariate associations with overall psychiatric disorders included
satisfaction with leadership, marital status (divorced), mild TBI, combat exposure, and
positive deployment experiences.

Table 2
Logistic regression analysis of demographic and psychosocial variables in relation to
all psychiatric disorders among Marines deployed to combat (N = 1,113), 20072010

In the multivariate model, the variables with the strongest associations with any
psychiatric diagnosis were female gender, satisfaction with leadership, and mild TBI
(Table 2). Women were nearly three times as likely as men to receive a psychiatric
diagnosis during the observation period (OR = 2.87, p < .01). There was a strong inverse
association between satisfaction with leadership and psychiatric diagnosis. Participants in
the highest quartile of satisfaction with leadership were about half as likely to develop a
mental disorder as those in the lowest quartile (OR = 0.52, p < .05). Participants who
reported any mild TBI symptoms were nearly twice as likely to develop a psychiatric
disorder as those who reported no TBI symptoms (OR = 1.85, p < .01).

Other significant predictors of mental disorder diagnosis included education level (more
education was protective), marital status (being divorced was associated with the highest
risk), total number of career combat deployments (multiple deployments was associated
with the highest risk), combat exposure (moderate exposure was associated with the
highest risk), and positive deployment experiences (a moderate level was the most
protective).

Predictors of specific psychiatric disorders

Analyses were performed to identify predictors of the more common mental disorder
diagnoses in the sample (Table 3). As stated previously, the most common diagnoses were
anxiety disorders, mood disorders, substance use disorders, adjustment disorders, and
PTSD. Because of heightened interest in PTSD and anxiety disorders in general in
military samples, separate analyses were performed to identify predictors of PTSD
specifically, and the broader anxiety disorder category (which subsumes PTSD). These
two categories are not mutually exclusive; of the 81 participants with an anxiety disorder
diagnosis, 53 participants had PTSD. It should also be noted that mood disorder
diagnoses in this sample consisted mainly of major depression, dysthmia, and other
depression (only 3% had a bipolar disorder).

Table 3
Multivariate logistic regression analysis of demographic and psychosocial variables
in relation to specific mental disorder diagnosis among Marines deployed to combat
(N = 1113), 20072010

Three variables were significant predictors of PTSD in the multivariate model: combat
exposure, age, and marital status (Table 3). Marines who experienced a high level of
combat exposure in their most recent deployment were two and a half times as likely to
develop PTSD as those who experienced a low level of exposure (OR = 2.50 comparing
highest and lowest tertiles, p < .05). Older Marines (27 years or older) were much less
likely to be diagnosed with PTSD than Marines aged 1921 years (OR = 0.37, p < .05).
Marines who had never been married were at reduced risk for PTSD (OR = 0.40
comparing never married and married Marines, p < .01). Four additional variables had
marginally significant (p < .10) associations with PTSD: education, unit cohesion,
positive deployment experiences, and total number of career combat deployments.
Marines with more education were less likely to be diagnosed with PTSD, as were
Marines who reported a high level of unit cohesion and a high level of positive
deployment experiences. Marines who had been on multiple deployments were more
likely to develop PTSD than those who had deployed only once.

The strongest predictor of anxiety disorders was dissatisfaction with leadership (Table 3).
Participants in the highest quartile of satisfaction with leadership had less than half the
risk of developing an anxiety disorder as those in the lowest quartile (OR = 0.45, p < .05).
Other predictors of anxiety disorders (p < .05) included female gender, education, number
of combat deployments, and deployment stressors. Female participants, those with less
education, and those with multiple combat deployments were at increased risk for anxiety
disorders. Deployment stressors was also significantly linked with anxiety disorders, but
the trend was not linear.

The strongest predictor of mood disorders was gender (Table 3). Female Marines were
over five and half times as likely as males to receive a mood disorder diagnosis (OR =
5.68, p < .01). Number of combat deployments and low organizational commitment were
also significant predictors of mood disorders. Marines who had been on multiple combat
deployments in their career were about twice as likely to develop a mood disorder as
those who had deployed only once (OR = 1.99, p < .05). Marines who reported a high
level of organizational commitment were at reduced risk for a mood disorder compared
with Marines who reported a low level of organizational commitment (OR = .42
comparing highest and lowest tertiles, p < .01).

There were three significant predictors of adjustment disorders: gender, education, and
organizational commitment. Female Marines were over three times as likely as male
Marines to receive an adjustment disorder diagnosis (OR = 3.09, p < .05). Education was
protective; Marines who had some college or a college degree were about half as likely to
develop an adjustment disorder as those with less education (OR = 0.54, p < .05).
Organizational commitment was also inversely associated with adjustment disorders (OR
= 0.37 comparing highest and lowest tertiles, p < .05).

Age was the only significant predictor of substance use disorders in the multivariate
logistic model (results not shown). Marines who were 27 years or older were less likely
to receive a substance use diagnosis than young Marines (1821 years old; OR = 0.25; p <
.01).

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Discussion
This study examined potential predictors of new-onset psychiatric disorders among
Marines who deployed to combat in support of OEF/OIF. In a sample of 1113 active-duty
Marines with no known previous psychiatric disorders, 18% (n = 199) were diagnosed
with a new-onset psychiatric disorder during the observation period. Adjusting for other
variables, the strongest predictors of overall psychiatric disorders were female gender and
mild TBI symptoms, while there was a strong inverse association with satisfaction with
leadership.

This studys finding that female gender was associated with an increased risk of
psychiatric disorders is consistent with other military research [41-43]. Goodman et al.
[41] found that female gender was an important risk factor for becoming a psychiatric
casualty in a sample of U.S. soldiers deployed to Iraq. Similarly, Rundells investigation
of U.S. military personnel engaged in OEF/OIF [9] found a higher rate of psychiatric
evacuation for women than for men. Kehle et al. [43] and Riddle et al. [8] found higher
rates of common mental disorders (depression, anxiety, PTSD) among female than male
military personnel. Civilian studies have also identified female gender as a risk factor for
common mental disorders, such as anxiety and depression [44,45].

Women who deploy to combat zones may be particularly susceptible to psychiatric

disorders. These data may be a reflection of the expanding roles of female military
members in the current conflicts (OEF/OIF). However, reasons for the elevated levels of
mental disorders among female military members are still not well understood. While it is
possible that combat exposure has a different effect on women than men, it may be that
factors such as sexual harassment, sexual assault, lack of social support, marginalization,
and preservice psychosocial history play a role in the gender difference [18,36,46]. In
addition, it is possible that military women have a greater propensity than their male
counterparts to seek professional help for mental health problems; this is an issue that
will need to be addressed in future studies. However, there is evidence that female
veterans generally exhibit higher internalizing symptoms (e.g., anxiety and depression) in
response to combat, whereas male veterans exhibit greater externalizing symptoms, such
as substance use and antisocial behavior [8,47].

We found that veterans who reported at least one symptom of mild TBI were at increased
risk for psychiatric disorders. Although this finding is consistent with other military
studies [3,19,21], this topic deserves additional attention. Carlson and colleagues [3]
found that nearly half of the OEF/OIF war veterans screened for TBI in their sample had
at least one psychiatric diagnosis, with PTSD and depression being the most common.
Elevated rates of psychiatric disorders have also been found in civilians with a history of
TBI [48]. The nature of our data does not allow us to draw conclusions regarding
causality with regard to mild TBI symptoms and mental disorders. Prospective,
longitudinal research involving precise assessment of head injury events, TBI symptoms,
psychiatric symptoms, preexisting psychiatric conditions and outcomes will be needed to
determine the nature of this association.

A unique finding of this study was the association between satisfaction with leadership
and mental disorders. Adjusting for other variables, service members who expressed a
high level of satisfaction with leadership were about half as likely to develop a mental
disorder as those who were not satisfied. This finding suggests that for military personnel
who deploy to combat, good leadership may be a key protective factor against psychiatric
problems. This finding is consistent with research showing that positive leadership has a
beneficial effect on the mental health of combatants [4,22,23]. To our knowledge, the
present study is the first prospective military study to link leadership dissatisfaction with
diagnosed mental disorders. An implication of these findings is the need for the military
to continue to develop programs to improve leadership.

Consistent with previous research [6,42], Marines who experienced a higher level of
combat exposure, and younger Marines were at increased risk for PTSD. Also, Marines
who had never been married were at reduced risk for PTSD. Marital status findings in
past military research have not been consistent. Some studies have found that divorced
individuals are at higher risk for PTSD [49,50]; others have found minimal or no
associations between marital status and PTSD [51,52].

Similar to its inverse relationship with general mental disorders, satisfaction with
leadership had a strong inverse association with anxiety disorders. Service members who
expressed a high level of satisfaction with leadership were less than half as likely to
develop an anxiety disorder as those who were not satisfied. Our finding that lower
education was a risk factor for anxiety disorders is consistent with both military research
[53,54] and civilian research [55] linking low education with PTSD and other psychiatric
problems.

Results for mood disorders and adjustment disorders were similar. The key factors
associated with mood disorders were female gender, number of combat deployments, and
organizational commitment. The key factors associated with adjustment disorders were
female gender, lower education level, and organizational commitment. Service members
who expressed a high level of organizational commitment were less than half as likely to
develop a mood disorder or an adjustment disorder as those with low organizational
commitment. These results are consistent with research demonstrating that organizational
commitment is associated with reenlistment, job satisfaction, morale, and adjustment to
the military [29,30]. Having a strong sense of belonging to the military organization and
strongly internalized military values may help to foster psychological resilience in the
face of deployment stress.

Partial support was found for the hypothesis that deployment stressors would predict
overall psychiatric diagnoses. Deployment stressors had a significant univariate
association with psychiatric outcomes (nonsignificant in the multivariate model), and was
predictive of anxiety disorders in the multivariate model. These findings are consistent
with previous research finding relationships between deployment stressors and PTSD
symptom scales [5,11]. To our knowledge, this is the first study to find an association
between deployment stressors and diagnosed anxiety disorders.

The present study had limitations. One limitation is that our sample included only a small
number of women, and these women may not be representative of the female Marine
Corps population. Most of the predictor variables used in the study were based on self-
report, with its associated limitations (e.g., response bias and socially desirable
responding). Another limitation relates to the fact that the surveys asked for identifying
information. Although confidentiality was assured, it is likely that some degree of
underreporting occurred. Also, the military database from which mental disorder
diagnoses were drawn did not contain information about diagnoses assigned within the
theater of operations or diagnoses assigned outside the military health care system.

One other limitation of the study is that the number of psychiatric diagnoses in the
sample was relatively small, making it likely that we lacked sufficient power to detect
small effects. Another notable limitation relates to our use of military medical records for
the mental disorder outcome data. Combat veterans in our sample who had a mental
disorder but who never sought help would have been counted as not having a psychiatric
diagnosis, thus adding error to the data. It is likely that this underreporting of common
mental disorders (e.g., anxiety, mood disorders) would have lead to a reduction in the
effect sizes found in this study, compared with true effects sizes that would have been
found if all cases of mental disorders were known. In other words, the results reported in
the present study are probably an underestimation of the true effect sizes.

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Conclusions
In terms of translating research into practice, this studys most relevant results were that
two potentially modifiable factors, dissatisfaction with leadership and low organizational
commitment, were predictive of psychiatric diagnoses in a military combatant sample. To
our knowledge, this is the first study to find predictive associations between these two
organizational factors and psychiatric outcomes. This study adds to the research literature
because few prospective studies have examined predictors of psychiatric diagnoses in
contemporary combat-deployed samples. Another unique feature of this study was the
availability of a wide range of predictor variables for a cohort of military members who
were initially free of a diagnosis of a mental disorder while in the military. The available
data allowed us to evaluate a broad range of potential predictors of mental health
problems. Additional research should aim to clarify the nature and impact of these factors
on combatant mental health. It is also recommended that the military continue to develop
programs to strengthen leadership and to foster greater organizational commitment
among its members, since both factors may lead to improved psychological health.

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Abbreviations
CHAMPS: Career History Archival Medical and Personnel System; DMDC: Defense
Manpower Data Center; ICD-9-CM: International Classification of Diseases Ninth
Revision, Clinical Modification; MHAT: Mental Health Advisory Team; OEF/OIF:
Operation Enduring Freedom and Operation Iraqi Freedom; OR: Odds Ratio; PTSD:
Posttraumatic stress disorder; SPSS: Statistical Package for the Social Sciences; TBI:
Traumatic brain injury.

Go to:

Competing interests
The authors declare that they have no competing interests.

Go to:

Authors contributions
SBK conceived of the study, developed the study design, performed statistical analysis,
and drafted the manuscript. ES assisted with study design, performed data management
and statistical analysis, and assisted in drafting the manuscript. RMH assisted with study
design and statistical analysis, and made revisions to the manuscript. GEL assisted with
study design and interpretation of results, and made revisions to the manuscript. CFG
consulted on the study methodology and statistical approach, and assisted in drafting the
manuscript. LAZ assisted with study design and interpretation of results, and assisted in
drafting the manuscript. All authors read and approved the final manuscript.

Go to:

Pre-publication history
The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-244X/13/130/prepub

Go to:

Acknowledgements
The authors gratefully acknowledge CAPT Todd Sander, CAPT Steve Blivin, Suzanne
Hurtado, Susan Hilton, CAPT David Service, Dr. Thomas Gaskin, Dr. William P. Nash,
and Thierry Nedellec for help with project planning, logistics, data extraction, and data
collection.

This research was supported by the U.S. Navy Bureau of Medicine and Surgery,
Washington, DC, under Work Unit No. 61111. The views and opinions expressed herein
are those of the authors and do not necessarily reflect the official policy or position of the
Department of the Navy, Department of Defense, or the U.S. Government. Approved for
public release; distribution is unlimited. This research has been conducted in compliance
with all applicable federal regulations governing the protection of human subjects in
research (protocol NHRC.2007.0003).

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References
1. Hoge CW, Castro CA, Messer SC, McGurk DM, Cotting DI, Koffman RL.
Combat duty in Iraq and Afghanistan, mental health problems, and barriers to
care. N Engl J Med. 2004;13(1):1322. doi: 10.1056/NEJMoa040603. [PubMed]
[Cross Ref]
2. Koenen KC, Stellman JM, Stellman SD, Sommer JF. Risk factors for course of
posttraumatic stress disorder among Vietnam veterans: a 14-year follow-up of
American Legionnaires. J Consult Clin Psychol. 2003;13(6):980986. [PubMed]
3. Carlson KF, Nelson D, Orazem RJ, Nugent S, Cifu DX, Sayer NA. Psychiatric
diagnoses among Iraq and Afghanistan war veterans screened for deployment-
related traumatic brain injury. J Trauma Stress. 2010;13(1):1724. [PubMed]
4. Castro CA, McGurk D. The intensity of combat and behavioral health status.
Traumatology. 2007;13(4):623. doi: 10.1177/1534765607309950. [Cross Ref]
5. Engelhard IM, van den Hout MA. Preexisting neuroticism, subjective stressor
severity, and posttraumatic stress in soldiers deployed to Iraq. Can J Psychiatry.
2007;13(8):505509. [PubMed]
6. Iversen AC, Fear NT, Ehlers A, Hughes JH, Hull L, Earnshaw M, Greenberg N,
Rona R, Wessely S, Hotopf M. Risk factors for post-traumatic stress disorder
among UK Armed Forces personnel. Psychol Med. 2008;13(4):511522.
[PubMed]
7. Litz BT, King LA, King DQ, Orsillo SM, Friedman MJ. Warriors as
peacekeepers: features of the Somalia experiences and PTSD. J Consult Clin
Psychol. 1997;13(6):10011010. [PubMed]
8. Riddle JR, Smith TC, Smith BS, Corbeil TE, Engel CC, Wells TS, Hoge CW,
Adkins J, Zamorski M, Blazer D. Millennium Cohort Study Team. Millennium
cohort: the 20012003 baseline prevalence of mental disorders in the U.S.
military. J Clin Epidemiol. 2007;13(2):192201. doi:
10.1016/j.jclinepi.2006.04.008. [PubMed] [Cross Ref]
9. Rundell JR. Demographics of and diagnoses in Operation Enduring Freedom and
Operation Iraqi Freedom personnel who were psychiatrically evacuated from the
theater of operations. Gen Hosp Psychiatry. 2006;13(4):352356. doi:
10.1016/j.genhosppsych.2006.04.006. [PubMed] [Cross Ref]
10. Dohrenwend BP, Turner JB, Turse NA, Adams BG, Koenen KC, Marshall R.
Continuing controversy over the psychological risks of Vietnam for U.S. veterans.
J Trauma Stress. 2007;13(4):449465. doi: 10.1002/jts.20296. [PubMed] [Cross
Ref]
11. Fontana A, Rosenheck R. A model of war zone stressors and posttraumatic stress
disorder. J Trauma Stress. 1999;13(1):111126. doi: 10.1023/A:1024750417154.
[PubMed] [Cross Ref]
12. Adler AB, Vaitkus MA, Martin JA. Combat exposure and posttraumatic stress
symptomatology among U.S. soldiers deployed to the Gulf War. Mil Psychol.
1996;13(1):114.
13. Southwick SM, Morgan CA, Darnell A, Bremner D, Nicolaou AL, Nagy LM,
Charney DS. Trauma-related symptoms in veterans of Operation Desert Storm: a
2-year follow-up. Am J Psychiatry. 1995;13(8):11501155. [PubMed]
14. Wolfe J, Brown P, Kelly JM. Reassessing war stress: exposure and the Persian
Gulf War. J Soc Issues. 1993;13(4):1531. doi: 10.1111/j.1540-
4560.1993.tb01179.x. [Cross Ref]
15. Smith TC, Ryan MAK, Wingard DL, Slymen DJ, Sallis JF, Kritz-Silverstein D.
New onset and persistent symptoms of post-traumatic stress disorder self reported
after deployment and combat exposures: prospective population based U.S.
military cohort study. BMJ. 2008;13(7640):366376. doi:
10.1136/bmj.39430.638241.AE. [PMC free article] [PubMed] [Cross Ref]
16. Bartone PT, Vaitkus MA, Adler AB. Dimensions of psychological stress in
peacekeeping operations. Mil Med. 1998;13(9):587593. [PubMed]
17. King DW, King LA, Gudanowski DM, Vreven DL. Alternative representations of
war zone stressors: relationships to posttraumatic stress disorder in male and
female Vietnam veterans. J Abnorm Psychol. 1995;13(1):184195. [PubMed]
18. Vogt DS, Pless AP, King LA, King DW. Deployment stressors, gender, and mental
health outcomes among Gulf War I veterans. J Trauma Stress. 2005;13(3):115
127. [PubMed]
19. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild
traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med.
2008;13(5):453527. [PubMed]
20. Schneiderman A, Braver ER, Kang HK. Understanding sequelae of injury
mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq
and Afghanistan: persistent postconcussive symptoms and posttraumatic stress
disorder. Am J Epidemiol. 2008;13(12):14461452. doi: 10.1093/aje/kwn068.
[PubMed] [Cross Ref]
21. Vasterling JJ, Constans JI, Hanna-Pladdy B. Head injury as a predictor of
psychological outcome in combat veterans. J Trauma Stress. 2000;13(3):441451.
doi: 10.1023/A:1007781107513. [PubMed] [Cross Ref]
22. Griffith J. Measurement of group cohesion in U.S. Army units. Basic Appl Soc
Psych. 1988;13(2):149171. doi: 10.1207/s15324834basp0902_6. [Cross Ref]
23. Mental Health Advisory Team (MHAT) Mental Health Advisory Team (MHAT)
VI: Operation Iraqi Freedom (0709) 2009. [
http://www.armymedicine.army.mil/reports/mhat/mhat_vi/mhat-vi.cfm]
24. Britt TW, Davison J, Bliese PD, Castro CA. How leaders can influence the impact
that stressors have on soldiers. Mil Med. 2004;13:541545. [PubMed]
25. Helmus HT, Glenn R. Steeling the mind: combat stress reactions and their
implications for urban welfare. Santa Monica: RAND Corporation; 2005.
26. Oliver LW, Harman J, Hoover E, Hayes SM, Pandhi NA. A quantitative
integration of the military cohesion literature. Mil Psychol. 1999;13(1):5783.
27. Brailey K, Vasterling JJ, Proctor SP, Constans JI, Friedman MJ. PTSD symptoms,
life events, and unit cohesion in U.S. soldiers: baseline findings from the
 Neurocognition Deployment Health Study. J Trauma Stress. 2007;13(4):495503.
doi: 10.1002/jts.20234. [PubMed] [Cross Ref]
28. Rona RJ, Hooper R, Jones M, Iversen A, Hull L, Murphy D, Hotopf M, Wessely
S. The contribution of prior psychological symptoms and combat exposure to post
Iraq deployment mental health in the UK military. J Trauma Stress.
2009;13(1):1119. doi: 10.1002/jts.20383. [PubMed] [Cross Ref]
29. Allen NJ. Organizational commitment in the military: a discussion of research and
practice. Mil Psychol. 2003;13(3):237253.
30. Gade PA, Tiggle RB, Schumm WR. The measurement and consequences of
military organizational commitment in soldiers and spouses. Mil Psychol.
2003;13(3):191207.
31. Maguen S, Litz BT. Predictors of morale in U.S. peacekeepers. J Appl Soc
Psychol. 2006;13(4):820836. doi: 10.1111/j.0021-9029.2006.00045.x. [Cross
Ref]
32. Fredrickson BL. The role of positive emotions in positive psychology: the
broaden-and-build theory of positive emotions. Am Psychol. 2001;13(3):218226.
[PMC free article] [PubMed]
33. Lyubormirsky S, King L, Diener E. The benefits of frequent positive affect: Does
happiness lead to success? Psychol Bull. 2005;13(6):803855. [PubMed]
34. Rona RJ, Fear NT, Hull L, Wessely S. Women in novel occupational roles: Mental
health trends in the UK armed forces. Int J Epidemiology. 2007;13(2):319326.
doi: 10.1093/ije/dyl273. [PubMed] [Cross Ref]
35. Turner JB, Turse NA, Dohrenwend BP. Circumstances of service and gender
differences in war-related PTSD: Findings from the National Vietnam Veteran
Readjustment Study. J Trauma Stress. 2007;13(4):643649. doi:
10.1002/jts.20245. [PubMed] [Cross Ref]
36. Street A, Vogt D, Dutra L. A new generation of women veterans: stressors faced
by women deployed to Iraq and Afghanistan. Clinical Psychology Review.
2009;13(8):685694. doi: 10.1016/j.cpr.2009.08.007. [PubMed] [Cross Ref]
37. Booth-Kewley S, Larson GE, Highfill-McRoy RM, Garland CF, Gaskin TA.
Correlates of posttraumatic stress disorder symptoms in Marines back from war. J
Trauma Stress. 2010;13(1):6977. [PubMed]
38. Bartone PT, Johnsen BH, Eid J, Brun W, Laberg JC. Factors influencing small-
unit cohesion in Norwegian Navy officer cadets. Mil Psychol. 2002;13(1):122.
39. Allen NJ, Meyer JP. The measurement and antecedents of affective, continuance
and normative commitment to the organization. J Occup Psychol. 1990;13(1):1
18. doi: 10.1111/j.2044-8325.1990.tb00506.x. [Cross Ref]
40. Gunderson EK, Garland CF, Miller MR, Gorham ED. Career History Archival
Medical and Personnel System. Mil Med. 2005;13(2):172175. [PubMed]
41. Goodman GP, DeZee KJ, Burks R, Waterman BR, Belmont PJ. Epidemiology of
psychiatric disorders sustained by a U.S. Army brigade team during the Iraq war.
Gen Hosp Psychiatry. 2011;13(1):5157. doi:
10.1016/j.genhosppsych.2010.10.007. [PubMed] [Cross Ref]
42. Hoge CW, Auchterlonie JL, Milliken CS. Mental health problems, use of mental
health services and attrition from military service after returning from deployment
 to Iraq or Afghanistan. JAMA. 2006;13(9):10231032. doi:
10.1001/jama.295.9.1023. [PubMed] [Cross Ref]
43. Kehle SM, Reddy MK, Ferrier-Auerbach AG, Erbes CR, Arbisi PA, Polusny MA.
Psychiatric diagnoses, comorbidity, and functioning in National Guard troops
deployed to Iraq. J Psychiatr Res. 2011;13(1):126132. doi:
10.1016/j.jpsychires.2010.05.013. [PubMed] [Cross Ref]
44. Cwikel J, Zilber N, Feinson M, Lerner Y. Prevalence and risk factors of threshold
and sub-threshold psychiatric disorders in primary care. Soc Psychiatry Psychiatr
Epidemiol. 2008;13(3):184191. doi: 10.1007/s00127-007-0286-9. [PubMed]
[Cross Ref]
45. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S,
Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R
psychiatric disorders in the United States: results from the National Comorbidity
Survey. Arch Gen Psychiatry. 1994;13(1):819. doi:
10.1001/archpsyc.1994.03950010008002. [PubMed] [Cross Ref]
46. Zinzow HM, Grubaugh AL, Frueh BC, Magruder KM. Sexual assault, mental
health, and service use among male and female veterans seen in Veterans Affairs
primary care clinics: a multi-site study. Psychiatry Research. 2008;13(12):26
236. [PubMed]
47. Seal KH, Metzler TJ, Gima KS, Bertenthal D, Maguen S, Marmar CR. Trends and
risk factors for mental health diagnoses among Iraq and Afghanistan veterans
using Department of Veterans Affairs health care, 20022008. Am J Public
Health. 2009;13(9):16511658. doi: 10.2105/AJPH.2008.150284. [PMC free
article] [PubMed] [Cross Ref]
48. Silver JM, Kramer R, Greenwald S, Weissman M. The association between head
injuries and psychiatric disorders: findings from the New Haven Epidemiologic
Catchment Area Study. Brain Inj. 2001;13(11):935945. doi:
10.1080/02699050110065295. [PubMed] [Cross Ref]
49. Jordan BK, Marmar CR, Fairbank JA, Schlenger WE, Kulka RA, Hough RL,
Weiss DS. Problems in families of male Vietnam veterans with posttraumatic
stress disorder. J Consult Clin Psychol. 1992;13(6):916926. [PubMed]
50. Lapierre CB, Schwegler AF, LaBauve BJ. Posttraumatic stress and depression
symptoms in soldiers returning from combat operations in Iraq and Afghanistan. J
Trauma Stress. 2007;13(6):933943. doi: 10.1002/jts.20278. [PubMed] [Cross
Ref]
51. Maguen S, Ren L, Bosch JO, Marmar CR, Seal KH. Gender differences in mental
health diagnoses among Iraq and Afghanistan veterans enrolled in veterans affairs
health care. Am J Public Health. 2010;13(12):24502456. doi:
10.2105/AJPH.2009.166165. [PMC free article] [PubMed] [Cross Ref]
52. Richardson JD, Naifeh JA, Elhai JD. Posttraumatic stress disorder and associated
risk factors in Canadian peacekeeping veterans with health-related disabilities.
Can J Psychiatry. 2007;13(8):510518. [PubMed]
53. Booth-Kewley S, Larson GE. Predictors of psychiatric hospitalization in the
Navy. Mil Med. 2005;13(1):8793. [PubMed]
 54. Macklin ML, Metzger LJ, Litz BT, McNally RJ, Lasko NB, Orr SP, Pitman RK.
Lower precombat intelligence is a risk factor for posttraumatic stress disorder. J
Consult Clin Psychol. 1998;13(2):323326. [PubMed]
55. Kessler RC, Foster CL, Saunders WB, Stang PE. The social consequences of
psychiatric disorders. I: Educational attainment. Am J Psychiatry.
1995;13(7):10261032. [PubMed]

Jurnal 5
Arch Gen Psychiatry. Author manuscript; available in PMC 2011 May 26.
Published in final edited form as:
Arch Gen Psychiatry. 2010 December; 67(12): 12911300.
doi: 10.1001/archgenpsychiatry.2010.158
PMCID: PMC3102494
NIHMSID: NIHMS297973

Multisite Investigation of Traumatic

Brain Injuries, Posttraumatic Stress
Disorder, and Self-reported Health and
Cognitive Impairments
Douglas F. Zatzick, MD, Frederick P. Rivara, MD, MPH, Gregory J. Jurkovich, MD,
Charles W. Hoge, MD, Jin Wang, MS, PhD, Ming-Yu Fan, PhD, Joan Russo, PhD, Sarah
Geiss Trusz, BA, Avery Nathens, MD, PhD, MPH, and Ellen J. Mackenzie, PhD
Author information Copyright and License information
The publisher's final edited version of this article is available at Arch Gen Psychiatry
See other articles in PMC that cite the published article.
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Abstract
Context

Few large-scale, multisite investigations have assessed the development of posttraumatic

stress disorder (PTSD) symptoms and health outcomes across the spectrum of patients
with mild, moderate, and severe traumatic brain injury (TBI).

Objectives

To understand the risk of developing PTSD symptoms and to assess the impact of PTSD
on the development of health and cognitive impairments across the full spectrum of TBI
severity.
Design

Multisite US prospective cohort study.

Setting

Eighteen level I trauma centers and 51 nontrauma center hospitals.

Patients

A total of 3047 (weighted n=10 372) survivors of multiple traumatic injuries between the
ages of 18 and 84 years.

Main Outcome Measures

Severity of TBI was categorized from chart-abstracted International Classification of

Diseases, Ninth Revision, Clinical Modification codes. Symptoms consistent with a
DSM-IV diagnosis of PTSD were assessed with the PTSD Checklist 12 months after
injury. Self-reported outcome assessment included the 8 Medical Outcomes Study 36-
Item Short Form Health Survey health status domains and a 4-item assessment of
cognitive function at telephone interviews 3 and 12 months after injury.

Results

At the time of injury hospitalization, 20.5% of patients had severe TBI, 11.7% moderate
TBI, 12.9% mild TBI, and 54.9% no TBI. Patients with severe (relative risk, 0.72; 95%
confidence interval, 0.58-0.90) and moderate (0.63; 0.44-0.89) TBI, but not mild TBI
(0.83; 0.61-1.13), demonstrated a significantly diminished risk of PTSD symptoms
relative to patients without TBI. Across TBI categories, in adjusted analyses patients with
PTSD demonstrated an increased risk of health status and cognitive impairments when
compared with patients without PTSD.

Conclusions

More severe TBI was associated with a diminished risk of PTSD. Regardless of TBI
severity, injured patients with PTSD demonstrated the greatest impairments in self-
reported health and cognitive function. Treatment programs for patients with the full
spectrum of TBI severity should integrate intervention approaches targeting PTSD.

Traumatic brain injury (TBI) constitutes a major public health problem for both veteran
and civilian trauma-exposed patient populations.1-7 The US involvement in the current
Iraq and Afghanistan conflicts has brought the interrelationship between TBI and
posttraumatic stress disorder (PTSD) to the forefront of medical research, commentary,
and practice.8-19 Many earlier studies of TBI and PTSD focused on injured civilians
presenting with a full spectrum of mild, moderate, and severe TBI.20-33 More recent
published investigations have focused on returning soldiers with mild TBI1,34,35 and the
substantial number of wounded combat veterans who incur varying degrees of TBI in
conjunction with multiple injuries to other body regions.36-40

This growing body of literature documents that PTSD symptoms can develop after mild,
moderate, and severe TBI.1,20,21,23,30,31,34,41 Although it has frequently been suggested that
the impaired memory of an event characteristic of increasingly severe brain injury could
be associated with a diminished risk of PTSD,19,21,26,27,42,43 literature review revealed few
investigations that have directly compared the development of PTSD across TBI severity
subgroups.28 Most previous investigations have not included large enough samples of
patients with mild, moderate, severe, and no TBI to allow for comparisons of PTSD rates
across the full spectrum of TBI severity. In studies that have included examination of
other associated injuries, the composite injury severity score (ISS) has been used36,44; the
ISS does not facilitate assessments of the occurrence of injuries to specific body regions,
such as disfiguring facial injuries, that may be associated with both head injury and the
development of PTSD.38,45-47

Investigations in veterans and civilians now document that PTSD and other comorbid
psychiatric disorders make an independent contribution to a broad profile of health and
cognitive impairments after mild TBI.1,34,35 Bryant and colleagues48 reported that, in a
large sample of civilian injury survivors, functional impairment was related to the
development of a spectrum of anxiety and depressive disorders rather than mild TBI.

An unanswered question is whether observations linking PTSD to adverse health

outcomes extend to other patients experiencing more severe head injuries. Previous
investigation in patients with multiple trauma suggests that longitudinal changes in
cognition may be the outcome most clearly linked to baseline TBI severity after an injury
hospitalization.49 Investigation in noninjured veterans suggests that PTSD is
independently associated with cognitive impairments as documented by
neuropsychological assessment.50 These combined observations raise questions regarding
the nature and strength of the association between PTSD and cognitive impairments
across the full spectrum of TBI severity.

The National Study on the Costs and Outcomes of Trauma (NSCOT) is the only multisite
US investigation to date to observe PTSD symptom occurrence in a large cohort of
patients who had sustained the full spectrum of mild, moderate, severe, and no TBI
injuries.51 The present analysis of the NSCOT data capitalizes on the large numbers of
patients with mild, moderate, severe, and no TBI. The analysis also provides the ability to
assess severity of injury to other body regions and to prospectively evaluate the impact of
TBI severity on the occurrence of symptoms consistent with a screening diagnosis of
PTSD 12 months after injury. As with most PTSD studies in injured cohorts to date,33,40,52-
62
previous NSCOT PTSD analyses used a composite ISS rather than breaking down
injury severity into discrete body regions or head injury subtypes.63,64 Further analyses of
the large NSCOT sample afforded the opportunity to assess the associations between TBI
severity, PTSD, and self-reported health and cognitive outcomes while adjusting for
relevant demographic and clinical characteristics.
The investigators hypothesized that greater TBI severity would be associated with a
diminished risk of symptoms consistent with a screening diagnosis of PTSD, even after
adjustments for relevant demographic and clinical characteristics. The study also
hypothesized that a screening diagnosis of PTSD would be associated with a broad
spectrum of self-reported functional impairments across mild, moderate, severe, and no
TBI severity subgroups. Finally, the investigation sought to perform an in-depth
exploration of the interrelationships between TBI severity, PTSD, and acute neurologic
deficits and long-term impairments in self-reported cognitive function.

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METHODS
OVERVIEW OF THE NSCOT STUDY

The NSCOT was a multisite prospective cohort study designed to assess physical and
mental health outcomes after hospitalization for traumatic injury.51,63-65 All level I trauma
centers and large nontrauma center hospitals were identified within US metropolitan
statistical areas; states included were California, Florida, Illinois, Indiana, Maryland,
Massachusetts, Michigan, New Jersey, New York, North Carolina, Pennsylvania, and
Washington. Patients were enrolled from 69 hospitals. Eighteen of 27 (66.7%) level I
trauma centers and 51 of 124 (41.1%) nontrauma center hospitals agreed to participate.
The study was approved by the institutional review board of each of the participating
hospitals. Informed consent was obtained from all participants before the conduct of
patient assessments.

English- and Spanish-speaking patients aged 18 to 84 years were eligible for the study if
they arrived alive at participating hospitals and were treated for moderate to severe
injuries as defined by at least 1 injury with an Abbreviated Injury Scale (AIS) score of 3
or greater.66 Patients were not eligible for enrollment if they were incarcerated at the time
of injury, were 65 years or older, had treatment delays in excess of 24 hours, or had a first
listed diagnosis of hip fracture or major burn.

Data regarding the episode of acute care was obtained by medical record review by
trained nurse abstractors. Research nurses were trained in the chart abstraction procedure
by the study investigators (F.P.R. and A.N.) and in the AIS coding procedure by the
developers of the scale.51,63-65

Telephone assessments were conducted at 3 and 12 months after hospital discharge.

Interviewers were experienced with telephone surveys and subsequently received
additional specific training on the administration of the NSCOT assessment instruments
(see also Mackenzie et al51). Telephone interview by proxy was allowed if the study
participant was unable to be interviewed because of postinjury limitations, including
severe brain injury.51,67,68 At 3 months, 11.3% of interviews and, at 12 months, 10.0% of
interviews were completed by proxies.
STUDY ASSESSMENT AND MEASURES

AIS and Maximum AIS

Severity of injury by body region was coded by means of the AIS to determine the
Maximum AIS (MAXAIS) injury score.66 The AIS was designed 30 years ago and is the
most widely accepted anatomic measure of injury severity.69 The MAXAIS has been
shown to be highly correlated with threat to life as well as postinjury disability and
quality of life.70 Calculated as the highest AIS score for a single injury received, the
MAXAIS performs well as a single measure of injury severity with an area under the
receiver operating characteristic curve of 0.88 for mortality in a national database of more
than 75 000 patients.71

Traumatic Brain Injury

The NSCOT used a quota sampling strategy to ensure that one-third of the patients had a
head injury with an AIS score of 3 or higher and that the remainder had either a
moderate-severe extremity injury or a moderate-severe injury to the chest or abdomen.
Patients in these other 2 groups may have had a head injury, but it could not have an AIS
score greater than 2. This strategy ensured that there was adequate representation of
patients across the full spectrum of mild, moderate, severe, and no TBI severity
subgroups.

In the NSCOT prospective cohort design, TBI was identified and categorized from
hospital chartabstracted International Classification of Diseases, 9th Revision, Clinical
Modification (ICD-9-CM) codes indicative of traumatic injury. Specific ICD-9-CM codes
used to prospectively identify TBIs included 800.0 to 801.9, 803.0 to 804.9, 850.0 to
854.1, and 959.01.72,73 Severity of TBI was coded on the basis of a previously validated
algorithm for hospitalized inpatients that assigned MAXAIS head injury scores of 1 to 2
to mild TBI severity, 3 to moderate TBI severity, and 4 or higher to severe TBI.2,49

Glasgow Coma Scale

The Glasgow Coma Scale (GCS) is a widely used scale for assessing level of
consciousness after TBI.74 The GCS score is based on the evaluation of 3 categories of
neurologic function: eye opening, best verbal response, and best motor response. The
GCS score ranges from 3 (most severely impaired) to 15 (no neurologic impairment).
Lower GCS score has been shown to be highly correlated with greater duration of coma
and increased posttraumatic amnesia.75,76 In the NSCOT, GCS was assessed on initial
admission to the hospital emergency department.

Self-reported Health and Functional Outcomes

The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) was
administered during the 3- and 12-month postinjury telephone interviews.77 In the present
investigation, the 12-month SF-36 scores were used in the outcome assessment. The SF-
36 has been used extensively to assess self-reported health and functional outcomes in
injured patients.49,64 The SF-36 contains 8 subscales that assess a broad profile of
outcomes; subscales are scored from 0 to 100, with 100 equal to the best possible health
state. Previous investigation using both internal consistency and test-retest methods have
established reliability estimates for the 8 subscales of greater than 0.80.77 Cronbach for
the 8 SF-36 subscales was 0.90 or greater at the 12-month assessments. Previous reports
suggest that a single chronic medical condition, such as hypertension, diabetes, or
depression, is associated with a 10-point or greater reduction in SF-36 subscale scores.77

Self-reported Cognitive Symptoms

A 4-item self-reported cognitive symptom scale was used to assess cognitive function at 3
and 12 months after the injury.49 The items assessed 4 specific aspects of self-reported
cognitive functioning, including reasoning and problem solving, memory, attention, and
concentration and thinking. In a previous investigation, the scale demonstrated excellent
internal consistency and construct validity.49 In the present investigation, Cronbach for
the 4 items was 0.87 at the 3-month assessment and 0.90 at the 12-month assessment. The
scale is scored from 0 to 100, with 100 equal to the best possible self-reported cognitive
functioning.49

PTSD Symptoms

Symptoms of PTSD were assessed at the 12-month postinjury telephone interview with
the civilian version of the PTSD Checklist (PCL).78 The PCL is a 17-item self-report
Likert response (1-5) questionnaire that assesses the intrusive, avoidant, and arousal
PTSD symptom clusters. The measure has established reliability and validity across
trauma-exposed populations.79-82 In a study of motor vehicle crash survivors, Blanchard et
al83 reported that a PCL cutoff of 45 or greater has excellent sensitivity and specificity
when compared with the criterion standard Clinician-Administered PTSD Scale. The
PCL can be used to create an algorithm consistent with a diagnosis of PTSD by rating 1
intrusive, 3 avoidant, and 2 arousal symptoms with a score of 3 or greater as symptoms
consistent with the DSM-IV diagnostic criteria. This algorithm was used to derive
symptoms consistent with a diagnosis of PTSD at the 12-month postinjury time point.

STATISTICAL ANALYSIS

As in previously published NSCOT reports, we used sampling weights for all statistical
analyses.65 It was necessary to weight data on eligible participants because not all patients
selected for inclusion in the study were enrolled in the NSCOT investigation. The
sampling weights used in the NSCOT investigation consisted of the reciprocal product of
2 probabilities: the probability of being selected and the probability of being enrolled and
having data abstracted from the medical record, given selection into the study. The
reference population to which weighted inferences were made consisted of 15 440
patients who met or were projected to meet the inclusion criteria.
Multiple imputation techniques were used to account for missing covariates. Data were
missing for less than 5% of patients for most NSCOT variables. Ten imputed data sets
were created. To account for clustering within hospitals, robust standard errors were
computed for each data set. All analyses were first performed on each imputed data set,
and results from these 10 analyses were combined according to Rubins rule to yield the
final results.84

In the analyses, we first compared the demographic and clinical characteristics of patients
who did and did not complete the 12-month telephone interview. The 2 and 2-tailed t test
statistics were used for categorical and continuous variables, respectively, to assess for
significant differences.

We next assessed the frequencies of patients incurring mild, moderate, and severe ICD-9-
CMdocumented head injury, as well as the frequency of patients incurring injuries with
a MAXAIS score of 3 or higher to other body regions (ie, face, neck, thorax, abdomen,
upper extremity, lower extremity, spine, and integument). Because we were interested in
estimating the relative risks (RRs) and 95% confidence intervals (CIs) for developing
PTSD, we used unadjusted Poisson regression with robust error variance to ascertain
these univariate associations.85,86 To obtain adjusted RRs and 95% CIs, we entered into a
single Poisson regression model a dummy-coded variable for mild, moderate, and severe
TBI (with the no-TBI group used as the reference), as well as variables for each body
region with a MAXAIS score of 3 or higher (yes/no) that were significant at the P<.05
level in univariate analyses. Demographic and clinical characteristics previously shown
to be associated with PTSD in hospitalized injured patients were also entered into the
Poisson regression model as covariates.63,64 Covariates included were GCS score; age;
sex; ISS; race/ethnicity; injury type (intentional vs unintentional); marital status;
insurance status; education; preinjury cigarette smoking; benzodiazepine use before the
injury admission; hospital record documenting history of depressive, anxiety, alcohol,
drug, or other mental health diagnosis; intensive care unit admission (yes/no); mechanical
ventilation (yes/no); intubation (yes/no); emergency department heart rate; medical
comorbidities; and SF-36 bodily pain, and mental health symptom subscales at the 3-
month postinjury time point. Symptoms consistent with a screening diagnosis of PTSD
on the PCL at the 12-month postinjury assessment were the dependent variable.

We next assessed 12-month SF-36 scale scores for patients with and without PTSD,
stratified by mild, moderate, severe, and no TBI groups. We first conducted univariate
analyses and used 2-tailed t tests to compare SF-36 scale scores for patients with and
without PTSD. These were followed by linear regression analyses that assessed for the
association between PTSD and SF-36 scale scores across TBI subgroups while adjusting
for demographic and clinical characteristics.63,64

Next, 3- and 12-month cognitive scale scores were compared for patients across the 4
TBI subgroups. An adjusted, mixed-model regression was used to assess the association
between TBI severity and self-reported cognitive impairments over time.63,64 We next
assessed differences in 12-month postinjury cognitive scale scores for patients with and
without PTSD stratified by TBI status (ie, none, mild, moderate, or severe). Four linear
regressions were used to assess for an association between PTSD and self-reported
cognitive impairment while adjusting for covariates (as listed earlier63).

Finally, we performed sensitivity analyses for the multivariate regressions by means of

both a continuous PCL score and an alternative PCL dichotomous cutoff of 45 or greater83
instead of PTSD diagnostic screening criteria. To assess the impact of proxy interviews,
all analyses were conducted with and without proxy interview data. Analyses were
conducted with the SAS 9.2 (SAS Institute Inc, Cary, North Carolina) and STATA 10
(StataCorp, College Station, Texas) data analytic software.

Go to:

RESULTS
A total of 5043 (weighted N=14 477) patients were eligible for the study. Of these, 1245
patients (weighted n=1381) either died in the hospital or died in the days and weeks after
hospitalization. A total of 3798 patients (weighted n=13 096) were included in the 3-
month assessment; 90 died after the 3-month interview (weighted n=204), and 661 were
lost to follow-up (weighted n=2520). A total of 3047 patients (weighted n=10 372), or
82.2% of 3708 eligible injury survivors, completed the 12-month follow-up interview.
Patients lost to follow-up were significantly more likely to be younger (mean age, 38.4
years for those lost to follow-up vs 43.0 years for those who completed the interview;

t1=3.7, P<.001) and intentionally injured (32.2% vs 16.4%; , P=.001).

Relative to white patients, African American (26.2% vs 15.3%; , P=.001) and

Latino (28.7% vs 15.3%; , P=.02) patients were more likely to be lost to

follow-up. There were no significant differences in rates of loss to 12-month follow-up
for patients in the severe (17.2%), moderate (13.3%), mild (17.5%), and no (22.0%) TBI

subgroups ( , P=.14).

At the time of injury hospitalization, 20.5% of patients (2123 of 10 372) had experienced
severe TBI, 11.7% (1216) moderate TBI, 12.9% (1342) mild TBI, and 54.9% (5691) no
TBI. Patients with severe and moderate TBI were more likely to also incur severe facial
injuries (Table 1). In contrast, patients with mild and no TBI were more likely to incur
extremity, thoracic, and abdominal injuries (Table 1). Patients in the no-TBI group had
significantly lower injury severity (mean [SD] ISS, 13.5[14.4]) relative to patients with
severe (26.6 [19.2]), moderate (17.2 [14.4]), and mild (17.9 [15.9]) TBIs (F3,68=188.2,
P<.001).
Table 1
Associations Between Traumatic Brain Injury Subtype and Location of Severe Bodily
Injuriesa

At the 12-month postinjury time point, 21.8% of patients (2228 of 10 203) endorsed
symptoms consistent with a diagnosis of PTSD on the PCL. In univariate analyses,
increasing severity of TBI was associated with a diminished risk of PTSD symptoms
(Table 2). In the adjusted Poisson regression analysis, severe and moderate TBI remained
associated with a diminished risk of PTSD symptoms relative to the no-TBI comparison
group (Table 2). Severe facial and spinal cord injuries were also associated with an
increased risk of PTSD symptoms (Table 2). In this adjusted analysis, ISS was not
associated with the development of PTSD (RR, 1.00; 95% CI, 0.99-1.01).

Table 2
Associations Between TBI Subtype, Other Bodily Injury, and PTSD Symptoms 12
Months After Hospital Admissiona,b

The mean (SD) initial admission GCS score was 10.3 (9.6) for patients with severe TBI,
12.7 (7.3) for patients with moderate TBI, 13.6 (5.9) for patients with mild TBI, and 14.3
(4.6) for patients with no TBI. In analyses that adjusted for demographic and clinical
characteristics, these comparisons achieved statistical significance (F3,68=57.0, P<.001).
In univariate (RR, 0.99; 95% CI, 0.95-1.01) and multivariate (0.99; 0.97-1.01) analyses,
lower GCS score was not associated with a diminished risk of PTSD.

Across TBI subgroups, in univariate analyses patients with symptoms consistent with a
diagnosis of PTSD demonstrated clinically and statistically significant reductions in SF-
36 subscale scores relative to patients with no PTSD (Table 3). Most of these associations
remained significant in regression models that adjusted for relevant demographic and
clinical characteristics (Table 3).
Table 3
PTSD and Health and Cognitive Function Across Categories of TBI Severity Among
2993 Injured Patientsa

Patients with the most severe head injuries demonstrated the lowest cognitive scale scores
as well as more gradual cognitive improvements during the year after injury (Figure 1).
Repeated-measures mixed-model regression analyses with 3- and 12-month cognitive
scale scores as the dependent variable demonstrated a significant main effect for severe
(=8.34, SE=1.11, P<.001), moderate (=5.69, SE=1.15, P<.001), and mild (=2.06,
SE=1.09, P=.06) head injuries relative to the no-TBI comparison group.

Figure 1
Cognitive scale score by traumatic brain injury (TBI) category at 3 and 12 months after
injury.

At the 12-month postinjury time point, regardless of TBI severity, patients with PTSD
consistently demonstrated significantly lower cognitive scale scores (all P<.001) relative
to patients without PTSD (Figure 2). Adjusted regression analysis identified a significant
association between PTSD and lower cognitive scale scores in the severe TBI (=24.20,
SE=5.50, P<.001), moderate TBI (=16.25, SE=5.68, P=.01), mild TBI (=15.34,
SE=4.70, P=.002), and no TBI (=22.09, SE=1.52, P<.001) subgroups.

Figure 2
Twelve-month posttraumatic stress disorder (PTSD) and cognitive scale scores across
categories of traumatic brain injury (TBI).

Sensitivity analyses that used a continuous PCL score and an alternative PCL
dichotomous cutoff of 45 or greater83 instead of PTSD diagnostic screening criteria did
not substantially alter the magnitude, pattern, or significance of the associations between
TBI subgroup, PTSD, and functional outcomes (ie, the results presented in Table 2, Table
3, and Figure 2). Also, analyses that excluded all interview data obtained by proxy did not
substantially alter the magnitude, pattern, or significance of the observed associations
between TBI subgroup, PTSD, and functional outcomes.

Go to:

COMMENT
Recent commentary and investigation have focused extensively on the associations
between TBI, PTSD, and health status among returning veterans of the current Central
Asian conflicts.* A key criterion for the progression of epidemiologic knowledge is
consistency of observations across exposed populations.87 The prospective design and
large civilian sample of patients with head and other bodily injuries afforded by the
present NSCOT analyses allow for a unique contribution to this evolving literature on
TBI and PTSD.

The present investigation demonstrates in a large prospectively observed cohort that

patients with more severe TBI have a diminished risk of developing symptoms consistent
with a diagnosis of PTSD. Although lower GCS score was significantly associated with
TBI severity, the investigation did not find a direct association between immediate
postinjury neurologic deficits as measured by the GCS and the later development of
diminished PTSD symptoms. Although duration of coma and posttraumatic amnesia were
not directly measured in the NSCOT, previous investigations have established that lower
GCS score is associated with lengthier coma and amnesia.75,76 The diminished risk of
PTSD by TBI severity is consistent with the possibility that the mechanism involves
impaired consolidation of traumatic memories19,20,27,43; however, the immediate level of
consciousness at the time of injury does not appear to be the most important factor in this
process. Future investigations could explore alternative etiologic mechanisms including
temporal variations in the generation of posttraumatic affective responses, implicit coding
of sensory perceptual experiences, and neurobiological factors that may influence
physiologic, behavioral, and emotional responses after TBI.13,19,20,27,43

To our knowledge, this is the first investigation to document that severe facial and spinal
cord injuries are independently associated with an increased risk of symptoms consistent
with a diagnosis of PTSD. In these analyses, which included detailed assessments of
injury to specific body regions, the composite ISS was not associated with the
development of PTSD symptoms.19,36 Co-occurring head and facial injuries have been
commonly described among wounded Central Asian veteran survivors of blast
injuries/multiple trauma.37,38 A previous smaller-scale investigation suggests that
disfiguring injuries may amplify posttraumatic symptoms by increasing concerns about
body image and social acceptance,45 and other studies have described PTSD symptoms in
the aftermath of spinal cord injury.88,89

The investigation corroborates and extends previous studies by demonstrating a strong

independent association between PTSD and a broad profile of self-reported health and
cognitive functioning impairments in patients with the full spectrum of mild, moderate,
and severe TBI.52,61,90-95 Other recent investigations have focused on PTSD-related health
and cognitive limitations among returning veterans with and without mild TBI.1,34,35,50

There are a number of important limitations to this investigation. One such limitation is
the restriction of psychiatric outcomes to PTSD; recent investigation by Bryant et al48
suggests that multiple psychiatric diagnoses, including but extending beyond PTSD, may
be associated with TBI. Thus, limitations in health-related and cognitive-related
functioning observed in the present investigation could be partly explained by other
mental health symptoms. The analyses conducted at the 12-month time point assessing
the associations between PTSD symptoms, health outcomes, and self-reported cognitive
impairments are cross-sectional. The investigation cannot rule out the possibility that
self-reported health and cognitive impairments could be contributing to the worsening of
PTSD symptoms. Of note, previous prospective longitudinal investigations in injured
youth and adults suggest that early high levels of PTSD symptoms may influence the
later development of poorer health outcomes.61,92,93,95 Another limitation is that new cases
of PTSD could not be determined because the design of the investigation did not allow
for the assessment of preexisting PTSD.48 The present investigation used MAXAIS to
classify TBI severity; although there are a number of methods for classifying TBI
severity, the use of the MAXAIS classification framework allowed for head injury
severity to be assessed prospectively and did not require retrospective recall of the
physical injury trauma. An additional limitation is the exclusive reliance on self-reported
health and cognitive functional outcomes; it cannot be ruled out, for example, that what is
being described as self-reported cognitive function throughout this article is really patient
cognitive complaints. The investigation is further limited by the use of proxy interviews
in a subsample of injured trauma survivors. Finally, the present investigation did not
include indepth assessments of duration of coma, posttraumatic amnesia, memory of the
traumatic event, neuropsychological evaluation of cognitive impairments, or
neuroradiologic findings.19,27,43,96,97

Go to:

CONCLUSIONS
Traumatic brain injury represents a dynamic spectrum of physiologic and cognitive
dysfunction that exerts effects at the level of the individual neuron, neural networks, and
ultimately more global cognition and health.7 The present investigation adds to a growing
body of research that suggests that psychological factors play a substantial role in TBI-
related impairments in self-reported health and cognition function. A key assumption in
the TBI literature has been that health and cognitive impairments in more severely injured
patients with TBI would be less affected by the presence of PTSD. For example, it has
been suggested that, in moderate and severe TBI, the meticulous assessment of
neurocognitive deficits underlying functional impairments may be an essential and
valuable component of ongoing clinical care; in contrast, for mild TBI, the assessment of
neurocognitive deficits has been suggested to be less conclusive, presumably because of
the predominating influence of PTSD and other psychological factors.11 The
misattribution of health- and cognitive-related functional impairments to brain injury
alone has the potentially detrimental implication that recovery from TBI depends
predominantly on neurologic factors.10 The results of the present investigation suggest
that treatment programs for the full spectrum of injured patients with mild, moderate, and
severe TBI could productively integrate multifaceted interventions targeting PTSD.98-102

Go to:

Acknowledgments
Funding/Support: This work was funded by grant R49/CCR316840 from the National
Center for Injury Prevention and Control and the Centers for Disease Control and
Prevention, grant R01/AG20361 from the National Institute on Aging, and grants
R01/MH073613 and K24/MH086814 from the National Institute of Mental Health.

Go to:

Footnotes
*
References 1, 8, 10-12, 14, 15, 17, 19, 34-40.

Financial Disclosure: None reported.

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REFERENCES
1. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic
brain injury in U.S. soldiers returning from Iraq. N Engl J Med. 2008;358(5):453463.
[PubMed]
2. Thurman D, Guerrero J. Trends in hospitalization associated with traumatic brain
injury. JAMA. 1999;282(10):954957. [PubMed]
3. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic
brain injury: a brief overview. J Head Trauma Rehabil. 2006;21(5):375378. [PubMed]
4. Cassidy JD, Carroll LJ, Peloso PM, Borg J, von Holst H, Holm L, Kraus J, Coronado
VG, WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury Incidence,
risk factors and prevention of mild traumatic brain injury: results of the WHO
Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004
February;36(suppl 43):2860. [PubMed]
5. Presidents Commission on Care for Americas Returning Wounded Warriors Serve,
Support, Simplify: Report of the Presidents Commission on Care for Americas
Returning Wounded Warriors. Presidents Commission on Care for Americas Returning
Wounded Warriors; Washington, DC: 2007.
6. National Institute of Neurological Disorders and Stroke [Accessed April 8,
2010];Traumatic brain injury: hope through research. Published February 2002. NIH
publication 02-2478. http://www.ninds.nih.gov/disorders/tbi/detail_tbi.htm.
7. NIH Consensus Development Panel on Rehabilitation of Persons With Traumatic Brain
Injury Consensus conference: rehabilitation of persons with traumatic brain injury.
JAMA. 1999;282(10):974983. [PubMed]
8. Corrigan JD, Cole TB. Substance use disorders and clinical management of traumatic
brain injury and posttraumatic stress disorder. JAMA. 2008;300(6):720721. [PubMed]
9. Nampiaparampil DE. Prevalence of chronic pain after traumatic brain injury: a
systematic review. JAMA. 2008;300(6):711719. [PubMed]
10. Bryant RA. Disentangling mild traumatic brain injury and stress reactions. N Engl
JMed. 2008;358(5):525527. [PubMed]
11. Hoge CW, Goldberg HM, Castro CA. Care of war veterans with mild traumatic brain
injuryflawed perspectives. N Engl J Med. 2009;360(16):15881591. [PubMed]
12. Okie S. Traumatic brain injury in the war zone. N Engl J Med. 2005;352(20):2043
2047. [PubMed]
13. Stein MB, McAllister TW. Exploring the convergence of posttraumatic stress disorder
and mild traumatic brain injury. Am J Psychiatry. 2009;166(7):768776. [PubMed]
14. Kennedy JE, Jaffee MS, Leskin GA, Stokes JW, Leal FO, Fitzpatrick PJ.
Posttraumatic stress disorder and posttraumatic stress disorderlike symptoms and mild
traumatic brain injury. J Rehabil Res Dev. 2007;44(7):895920. [PubMed]
15. Warden D. Military TBI during the Iraq and Afghanistan wars. J Head Trauma
Rehabil. 2006;21(5):398402. [PubMed]
16. Friedman MJ. Acknowledging the psychiatric cost of war. N Engl J Med.
2004;351(1):7577. [PubMed]
17. Taber KH, Hurley RA. PTSD and combat-related injuries: functional neuroanatomy. J
Neuropsychiatry Clin Neurosci. 2009;21(1):14. [PubMed]
18. Tanielian T, Jaycox LH. Invisible Wounds of War: Psychological and Cognitive
Injuries, Their Consequences, and Services to Assist Recovery. Rand Corp; Santa
Monica, CA: 2008.
19. Vasterling JJ, Verfaellie M, Sullivan KD. Mild traumatic brain injury and
posttraumatic stress disorder in returning veterans: perspectives from cognitive
neuroscience. Clin Psychol Rev. 2009;29(8):674684. [PubMed]
20. Harvey AG, Brewin CR, Jones C, Kopelman MD. Coexistence of posttraumatic stress
disorder and traumatic brain injury: towards a resolution of the paradox. J Int
Neuropsychol Soc. 2003;9(4):663676. [PubMed]
21. Bryant RA, Creamer M, ODonnell M, Silove D, Clark CR, McFarlane AC.
Posttraumatic amnesia and the nature of post-traumatic stress disorder after mild
traumatic brain injury. J Int Neuropsychol Soc. 2009;15(6):862867. [PubMed]
22. Bryant RA, Harvey AG. The influence of traumatic brain injury on acute stress
disorder and post-traumatic stress disorder following motor vehicle accidents. Brain Inj.
1999;13(1):1522. [PubMed]
23. Bryant RA, Marosszeky JE, Crooks J, Gurka JA. Posttraumatic stress disorder after
severe traumatic brain injury. Am J Psychiatry. 2000;157(4):629631. [PubMed]
24. Bryant RA, Harvey AG. Acute stress response: a comparison of head injured and non-
head injured patients. Psychol Med. 1995;25(4):869873. [PubMed]
25. Hickling EJ, Gillen R, Blanchard EB, Buckley T, Taylor A. Traumatic brain injury
and posttraumatic stress disorder: a preliminary investigation of neuropsychological test
results in PTSD secondary to motor vehicle accidents. Brain Inj. 1998;12(4):265274.
[PubMed]
26. Joseph S, Masterson J. Posttraumatic stress disorder and traumatic brain injury: are
they mutually exclusive? J Trauma Stress. 1999;12(3):437453. [PubMed]
27. Gil S, Caspi Y, Ben-Ari IZ, Koren D, Klein E. Does memory of a traumatic event
increase the risk for posttraumatic stress disorder in patients with traumatic brain injury?
a prospective study. Am J Psychiatry. 2005;162(5):963969. [PubMed]
28. Glaesser J, Neuner F, Ltgehetmann R, Schmidt R, Elbert T. Posttraumatic stress
disorder in patients with traumatic brain injury. BMC Psychiatry. 2004;4:5. [PMC free
article] [PubMed]
29. Williams WH, Evans JJ, Needham P, Wilson BA. Neurological, cognitive and
attributional predictors of posttraumatic stress symptoms after traumatic brain injury. J
Trauma Stress. 2002;15(5):397400. [PubMed]
30. Bombardier CH, Fann JR, Temkin N, Esselman PC, Pelzer E, Keough M, Dikmen S.
Posttraumatic stress disorder symptoms during the first six months after traumatic brain
injury. J Neuropsychiatry Clin Neurosci. 2006;18(4):501508. [PubMed]
31. Levin HS, Brown SA, Song JX, McCauley SR, Boake C, Contant CF, Goodman H,
Kotrla KJ. Depression and posttraumatic stress disorder at three months after mild to
moderate traumatic brain injury. J Clin Exp Neuropsychol. 2001;23(6):754769.
[PubMed]
32. Sbordone RJ, Liter JC. Mild traumatic brain injury does not produce posttraumatic
stress disorder. Brain Inj. 1995;9(4):405412. [PubMed]
33. Koren D, Hemel D, Klein E. Injury increases the risk for PTSD: an examination of
potential neurobiological and psychological mediators. CNS Spectr. 2006;11(8):616624.
[PubMed]
34. Schneiderman AI, Braver ER, Kang HK. Understanding sequelae of injury
mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and
Afghanistan: persistent postconcussive symptoms and posttraumatic stress disorder. Am J
Epidemiol. 2008;167(12):14461452. [PubMed]
35. Vanderploeg RD, Belanger HG, Curtiss G. Mild traumatic brain injury and
posttraumatic stress disorder and their associations with health symptoms. Arch Phys
Med Rehabil. 2009;90(7):10841093. [PubMed]
36. MacGregor AJ, Corson KS, Larson GE, Shaffer RA, Dougherty AL, Galarneau MR,
Raman R, Baker DG, Lindsay SP, Golomb BA. Injury-specific predictors of
posttraumatic stress disorder. Injury. 2009;40(9):10041010. [PubMed]
37. Sayer NA, Chiros CE, Sigford B, Scott S, Clothier B, Pickett T, Lew HL.
Characteristics and rehabilitation outcomes among patients with blast and other injuries
sustained during the Global War on Terror. Arch Phys Med Rehabil. 2008;89(1):163170.
[PubMed]
38. Wade AL, Dye JL, Mohrle CR, Galarneau MR. Head, face, and neck injuries during
Operation Iraqi Freedom II: results from the US NavyMarine Corps Combat Trauma
Registry. J Trauma. 2007;63(4):836840. [PubMed]
39. Mora A, Ritenour A, Wade C, Holcomb J, Blackbourne L, Gaylord K. Posttraumatic
stress disorder in combat casualties with burns sustaining primary blast and concussive
injuries. J Trauma. 2009;66((4)(suppl)):S178S185. [PubMed]
40. Grieger TA, Cozza SJ, Ursano RJ, Hoge C, Martinez PE, Engel CC, Wain HJ.
Posttraumatic stress disorder and depression in battle-injured soldiers. Am J Psychiatry.
2006;163(10):17771783. [PubMed]
41. Bryant RA, Marosszeky JE, Crooks J, Baguley IJ, Gurka JA. Posttraumatic stress
disorder and psychosocial functioning after severe traumatic brain injury. J Nerv Ment
Dis. 2001;189(2):109113. [PubMed]
42. Hiott DW, Labbate L. Anxiety disorders associated with traumatic brain injuries.
NeuroRehabilitation. 2002;17(4):345355. [PubMed]
43. Bryant RA. Posttraumatic stress disorder and traumatic brain injury: can they co-
exist? Clin Psychol Rev. 2001;21(6):931948. [PubMed]
44. ODonnell ML, Creamer M, Bryant RA, Schnyder U, Shalev AY. Posttraumatic
disorders following injury: an empirical and methodological review. Clin Psychol Rev.
2003;23(4):587603. [PubMed]
45. Rusch MD, Grunert BK, Sanger JR, Dzwierzynski WW, Matloub HS. Psychological
adjustment in children after traumatic disfiguring injuries: a 12-month follow-up. Plast
Reconstr Surg. 2000;106(7):14511458. [PubMed]
46. Love B, Byrne CM, Roberts J, Browne G, Brown B. Adult psychosocial adjustment
following childhood injury: the effect of disfigurement. J Burn Care Rehabil.
1987;8(4):280285. [PubMed]
47. Glynn SM, Shetty V, Elliot-Brown K, Leathers R, Belin TR, Wang J. Chronic
posttraumatic stress disorder after facial injury: a 1-year prospective cohort study. J
Trauma. 2007;62(2):410418. [PubMed]
48. Bryant RA, ODonnell ML, Creamer M, McFarlane AC, Clark CR, Silove D. The
psychiatric sequelae of traumatic injury. Am J Psychiatry. 2010;167(3):312320.
[PubMed]
49. MacKenzie EJ, McCarthy ML, Ditunno JF, Forrester-Staz C, Gruen GS, Marion DW,
Schwab WC, Pennsylvania Study Group on Functional Outcomes Following Trauma
Using the SF-36 for characterizing outcome after multiple trauma involving head injury. J
Trauma. 2002;52(3):527534. [PubMed]
50. Marx BP, Brailey K, Proctor SP, Macdonald HZ, Graefe AC, Amoroso P, Heeren T,
Vasterling JJ. Association of time since deployment, combat intensity, and posttraumatic
stress symptoms with neuropsychological outcomes following Iraq war deployment. Arch
Gen Psychiatry. 2009;66(9):9961004. [PubMed]
51. Mackenzie EJ, Rivara FP, Jurkovich GJ, Nathens AB, Frey KP, Egleston BL, Salkever
DS, Weir S, Scharfstein DO. The national study on costs and outcomes of trauma. J
Trauma. 2007;63((6)(suppl)):S54S67. [PubMed]
52. ODonnell ML, Creamer M, Elliott P, Atkin C, Kossmann T. Determinants of quality
of life and role-related disability after injury: impact of acute psychological responses. J
Trauma. 2005;59(6):13281334. [PubMed]
53. ODonnell ML, Creamer MC, Parslow R, Elliott P, Holmes AC, Ellen S, Judson R,
McFarlane AC, Silove D, Bryant RA. A predictive screening index for posttraumatic
stress disorder and depression following traumatic injury. J Consult Clin Psychol.
2008;76(6):923932. [PubMed]
54. Shalev AY, Peri T, Canetti L, Schreiber S. Predictors of PTSD in injured trauma
survivors: a prospective study. Am J Psychiatry. 1996;153(2):219225. [PubMed]
55. Winston FK, Kassam-Adams N, Garcia-Espaa F, Ittenbach R, Cnaan A. Screening
for risk of persistent posttraumatic stress in injured children and their parents. JAMA.
2003;290(5):643649. [PubMed]
56. Schnyder U, Moergeli H, Klaghofer R, Buddeberg C. Incidence and prediction of
posttraumatic stress disorder symptoms in severely injured accident victims. Am J
Psychiatry. 2001;158(4):594599. [PubMed]
57. Saxe GN, Stoddard F, Hall E, Chawla N, Lopez C, Sheridan R, King D, King L,
Yehuda R. Pathways to PTSD, part I: children with burns. Am J Psychiatry.
2005;162(7):12991304. [PubMed]
58. Stoddard FJ, Saxe G. Ten-year research review of physical injuries. J Am Acad Child
Adolesc Psychiatry. 2001;40(10):11281145. [PubMed]
59. Stoddard FJ, Saxe G, Ronfeldt H, Drake JE, Burns J, Edgren C, Sheridan R. Acute
stress symptoms in young children with burns. J Am Acad Child Adolesc Psychiatry.
2006;45(1):8793. [PubMed]
60. Michaels AJ, Michaels CE, Moon CH, Smith JS, Zimmerman MA, Taheri PA,
Peterson C. Posttraumatic stress disorder after injury: impact on general health outcome
and early risk assessment. J Trauma. 1999;47(3):460466. [PubMed]
61. Holbrook TL, Anderson JP, Sieber WJ, Browner D, Hoyt DB. Outcome after major
trauma: 12-month and 18-month follow-up results from the Trauma Recovery Project. J
Trauma. 1999;46(5):765771. [PubMed]
62. Holbrook TL, Hoyt DB, Coimbra R, Potenza B, Sise M, Anderson JP. High rates of
acute stress disorder impact quality-of-life outcomes in injured adolescents: mechanism
and gender predict acute stress disorder risk. J Trauma. 2005;59(5):11261130. [PubMed]
63. Zatzick D, Jurkovich GJ, Rivara FP, Wang J, Fan MY, Joesch J, Mackenzie E. A
national US study of posttraumatic stress disorder, depression, and work and functional
outcomes after hospitalization for traumatic injury. Ann Surg. 2008;248(3):429437.
[PubMed]
64. Zatzick DF, Rivara FP, Nathens AB, Jurkovich GJ, Wang J, Fan MY, Russo J,
Salkever DS, Mackenzie EJ. A nationwide US study of post-traumatic stress after
hospitalization for physical injury. Psychol Med. 2007;37(10):14691480. [PubMed]
65. MacKenzie EJ, Rivara FP, Jurkovich GJ, Nathens AB, Frey KP, Egleston BL,
Salkever DS, Scharfstein DO. A national evaluation of the effect of trauma-center care on
mortality. N Engl J Med. 2006;354(4):366378. [PubMed]
66. Civil ID, Schwab CW. The Abbreviated Injury Scale: 1985 Revision. Committee on
Injury Scaling, American Association for the Advancement of Automotive Medicine;
Morton Grove, IL: 1985.
67. Sneeuw KC, Aaronson NK, Osoba D, Muller MJ, Hsu MA, Yung WK, Brada M,
Newlands ES. The use of significant others as proxy raters of the quality of life of
patients with brain cancer. Med Care. 1997;35(5):490506. [PubMed]
68. Magaziner J, Zimmerman SI, Gruber-Baldini AL, Hebel JR, Fox KM. Proxy
reporting in five areas of functional status: comparison with self-reports and observations
of performance. Am J Epidemiol. 1997;146(5):418428. [PubMed]
69. Association for the Advancement of Automotive Medicine, Committee on Injury
Scaling The Abbreviated Injury Scale1990 Revision (AIS-90) Association for the
Advancement of Automotive Medicine; Des Plaines, IL: 1990.
70. Association for the Advancement of Automotive Medicine, Committee on Injury
Scaling The Abbreviated Injury Scale 2005: Update 2008. Association for the
Advancement of Automotive Medicine; Des Plaines, IL: 2008.
71. Meredith JW, Evans G, Kilgo PD, MacKenzie E, Osler T, McGwin G, Cohn S,
Esposito T, Gennarelli T, Hawkins M, Lucas C, Mock C, Rotondo M, Rue L, Champion
HR. A comparison of the abilities of nine scoring algorithms in predicting mortality. J
Trauma. 2002;53(4):621628. [PubMed]
72. Thurman D, Sniezek J, Johnson D, Greenspan A, Smith SM. Guidelines for
Surveillance of Central Nervous System Injury. US Dept of Health and Human Services,
Centers for Disease Control and Prevention; Atlanta, GA: 1995.
73. Butler J, Langlois J. Central Nervous System Injury Surveillance Annual Data of
Submission Standards2000. US Dept of Health and Human Services, Centers for
Disease Control and Prevention, National Center for Injury Prevention and Control;
Atlanta, GA: 2001.
74. McNett M. A review of the predictive ability of Glasgow Coma Scale scores in head-
injured patients. J Neurosci Nurs. 2007;39(2):6875. [PubMed]
75. Sherer M, Struchen MA, Yablon SA, Wang Y, Nick TG. Comparison of indices of
traumatic brain injury severity: Glasgow Coma Scale, length of coma and posttraumatic
amnesia. J Neurol Neurosurg Psychiatry. 2008;79(6):678685. [PubMed]
76. Zheng WB, Liu GR, Kong KM, Wu RH. Coma duration prediction in diffuse axonal
injury: analyses of apparent diffusion coefficient and clinical prognostic factors. Conf
Proc IEEE Eng Med Biol Soc. 2006;1:10521055. [PubMed]
77. Ware JE, Snow KK, Kosinski M. SF-36 Health Survey: Manual and Interpretation
Guide. Health Institute, New England Medical Center; Boston, MA: 1993.
78. Weathers FW, Huska JA, Keane TM. The PTSD ChecklistCivilian Version.
National Center for PTSD, Boston VA Medical Center; Boston, MA: 1991.
79. Forbes D, Creamer M, Biddle D. The validity of the PTSD checklist as a measure of
symptomatic change in combat-related PTSD. Behav Res Ther. 2001;39(8):977986.
[PubMed]
80. Ruggiero KJ, Del Ben K, Scotti JR, Rabalais AE. Psychometric properties of the
PTSD ChecklistCivilian Version. J Trauma Stress. 2003;16(5):495502. [PubMed]
81. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat
duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl JMed.
2004;351(1):1322. [PubMed]
82. Ruggiero KJ, Rheingold AA, Resnick HS, Kilpatrick DG, Galea S. Comparison of
two widely used PTSD-screening instruments: implications for public mental health
planning. J Trauma Stress. 2006;19(5):699707. [PubMed]
83. Blanchard EB, Jones-Alexander J, Buckley TC, Forneris CA. Psychometric properties
of the PTSD Checklist (PCL) Behav Res Ther. 1996;34(8):669673. [PubMed]
84. Rubin DB. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons Inc;
New York, NY: 1987.
85. Zhang J, Yu KF. Whats the relative risk? a method of correcting the odds ratio in
cohort studies of common outcomes. JAMA. 1998;280(19):16901691. [PubMed]
86. Zou G. A modified Poisson regression approach to prospective studies with binary
data. Am J Epidemiol. 2004;159(7):702706. [PubMed]
87. Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed Lippincott Williams &
Wilkins; Philadelphia, PA: 1998.
88. Hatcher MB, Whitaker C, Karl A. What predicts post-traumatic stress following
spinal cord injury? Br J Health Psychol. 2009;14(pt 3):541561. [PubMed]
89. Lude P, Kennedy P, Evans M, Lude Y, Beedie A. Post traumatic distress symptoms
following spinal cord injury: a comparative review of European samples. Spinal Cord.
2005;43(2):102108. [PubMed]
90. Zatzick DF, Marmar CR, Weiss DS, Browner WS, Metzler TJ, Golding JM, Stewart
A, Schlenger WE, Wells KB. Posttraumatic stress disorder and functioning and quality of
life outcomes in a nationally representative sample of male Vietnam veterans. Am J
Psychiatry. 1997;154(12):16901695. [PubMed]
91. Schnurr PP, Lunney CA, Bovin MJ, Marx BP. Posttraumatic stress disorder and
quality of life: extension of findings to veterans of the wars in Iraq and Afghanistan. Clin
Psychol Rev. 2009;29(8):727735. [PubMed]
92. Ramchand R, Marshall GN, Schell TL, Jaycox LH. Posttraumatic distress and
physical functioning: a longitudinal study of injured survivors of community violence. J
Consult Clin Psychol. 2008;76(4):668676. [PMC free article] [PubMed]
93. Zatzick DF, Jurkovich GJ, Fan MY, Grossman D, Russo J, Katon W, Rivara FP.
Association between posttraumatic stress and depressive symptoms and functional
outcomes in adolescents followed up longitudinally after injury hospitalization. Arch
Pediatr Adolesc Med. 2008;162(7):642648. [PubMed]
94. Zatzick DF, Jurkovich GJ, Gentilello LM, Wisner DH, Rivara FP. Posttraumatic
stress, problem drinking, and functional outcomes after injury. Arch Surg.
2002;137(2):200205. [PubMed]
95. Holbrook TL, Hoyt DB, Coimbra R, Potenza B, Sise MJ, Sack DI, Anderson JP.
Trauma in adolescents causes long-term marked deficits in quality of life: adolescent
children do not recover preinjury quality of life or function up to two years postinjury
compared to national norms. J Trauma. 2007;62(3):577583. [PubMed]
96. Vasa RA, Grados M, Slomine B, Herskovits EH, Thompson RE, Salorio C,
Christensen J, Wursta C, Riddle MA, Gerring JP. Neuroimaging correlates of anxiety
after pediatric traumatic brain injury. Biol Psychiatry. 2004;55(3):208216. [PubMed]
97. Vasterling JJ, Proctor SP, Amoroso P, Kane R, Heeren T, White RF.
Neuropsychological outcomes of army personnel following deployment to the Iraq war.
JAMA. 2006;296(5):519529. [PubMed]
98. Ursano RJ, Bell C, Eth S, Friedman M, Norwood A, Pfefferbaum B, Pynous RS,
Zatzick DF, Benedek DM. Practice Guideline for the Treatment of Patients With Acute
Stress Disorder and Posttraumatic Stress Disorder. American Psychiatric Association;
Arlington, VA: 2004.
99. Engel CC, Katon W. Population and need-based prevention of unexplained physical
symptoms in the community. In: Joellenbeck LM, Russell PK, Guze SB, editors. Institute
of Medicine, Strategies to Protect the Health of Deployed U.S. Forces: Medical
Surveillance, Record Taking and Risk Reduction. National Academy Press; Washington,
DC: 1999. pp. 173212.
100. Bryant RA, Moulds M, Guthrie R, Nixon RD. Treating acute stress disorder
following mild traumatic brain injury. Am J Psychiatry. 2003;160(3):585587. [PubMed]
101. Zatzick D, Roy-Byrne P, Russo J, Rivara F, Droesch R, Wagner A, Dunn C,
Jurkovich G, Uehara E, Katon W. A randomized effectiveness trial of stepped
collaborative care for acutely injured trauma survivors. Arch Gen Psychiatry.
2004;61(5):498506. [PubMed]
102. Schnurr PP, Friedman MJ, Engel CC, Foa EB, Shea MT, Chow BK, Resick PA,
Thurston V, Orsillo SM, Haug R, Turner C, Bernardy N. Cognitive behavioral therapy for
posttraumatic stress disorder in women: a randomized controlled trial. JAMA.
2007;297(8):820830. [PubMed]

Jurnal 6
Psychiatr Serv. Author manuscript; available in PMC 2011 June 23.
Published in final edited form as:
Psychiatr Serv. 2011 March; 62(3): 264271.
doi: 10.1176/appi.ps.62.3.264
PMCID: PMC3121256
NIHMSID: NIHMS297964

Association Between Traumatic Injury

and Psychiatric Disorders and Medication
Prescription to Youths Aged 1019
Douglas F. Zatzick, M.D. and David C. Grossman, M.D., M.P.H.
Author information Copyright and License information
The publisher's final edited version of this article is available at Psychiatr Serv
See other articles in PMC that cite the published article.
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Abstract
Objective

Few clinical epidemiologic investigations have assessed whether youths exposed to a

traumatic injury demonstrate elevations in the full spectrum of provider-recognized
psychiatric disorders compared with unexposed, noninjured youths.

Methods

In a population-based prospective cohort study, data for children and adolescents aged ten
to 19 who were enrolled in the Group Health Cooperative health plan were screened for
injury visits in the index year of 2001 (N = 20,507). Psychiatric diagnoses, including
anxiety and acute stress, depressive, substance use, and disruptive behavior disorders,
given to these youths over the next three years (20022004) were documented, as were
psychotropic medication prescriptions. Regression analyses assessed for an independent
association between injury and psychiatric disorders and prescription of psychotropic
medication.

Results

In adjusted regression analyses, injury in the index year was independently associated
with significantly increased odds of receiving a diagnosis of anxiety or acute stress (odds
ratio [OR] = 1.21, 95% confidence interval [CI] = 1.021.44), depression (OR = 1.30, CI
= 1.101.53), and a substance use disorder (OR = 1.56, CI = 1.212.00) and of receiving
a psychotropic medication prescription (OR = 1.37, CI = 1.201.57). Youths with
traumatic brain injuries also were significantly more likely to receive psychotropic
medication prescriptions.

Conclusions

Traumatic injury was independently associated with an increased risk of receiving a full
spectrum of anxiety, depressive, and substance use diagnoses among youths aged ten to
19. Population-based surveillance procedures that incorporate screening and stepped-care
interventions targeting the spectrum of postinjury emotional disturbances have the
potential to improve the quality of mental health care for youths treated in general
medical settings.

Recent epidemiologic investigations have documented that more than two-thirds of

American children and adolescents are exposed to at least one traumatic life event by the
age of 16 (1). Traumatic physical injury is a leading cause of death, disability, medical
costs, and health service utilization among youths in the United States (27). Each year
more than nine million children and adolescents visit emergency departments and other
general medical settings after incurring traumatic physical injuries (8).

A series of investigations has established that exposure of children and adolescents to

traumatic injury is associated with the development of posttraumatic stress disorder
(PTSD) symptoms (926). One recent large-scale epidemiologic investigation found that
beyond its association with PTSD, exposure to trauma is associated with the development
of other anxiety, depressive, substance use, and disruptive behavior disorders among
children and adolescents (1). Smaller-scale investigations in subgroups of injured youths
have also suggested that the symptoms of other anxiety, depressive, substance-related,
and behavioral disturbances can occur in the wake of traumatic physical injury (2734).

A review of the literature also indicates that it is unclear whether children and adolescents
who incur traumatic brain injury (TBI) are particularly vulnerable to developing
postinjury psychiatric disorders (32,3440). A better understanding of the full spectrum
of psychiatric disorders that may develop in the wake of childhood injury is important
given that studies focusing on postinjury functional limitations suggest that higher initial
emotional distress is associated with enduring functional impairments (41,42). Also,
recent commentary and investigation suggest that late childhood and early adolescence
may be an optimal window in which to focus preventive interventions for many anxiety,
mood, substance use, and disruptive behavior disorders (43,44).

In reviewing the literature, we found few population-based clinical epidemiologic

investigations that have examined the full spectrum of provider-recognized psychiatric
disorders that have affected children and adolescents exposed to a traumatic injury; prior
investigation has predominantly focused on PTSD. Also, few population-based
investigations have assessed the postinjury prescription of psychotropic medication to
children. Therefore, in this investigation we aimed to compare rates of provider-
diagnosed psychiatric disorders and psychotropic medication prescription in a
population-based sample of injured and noninjured children and adolescents aged ten to
19. We hypothesized that compared with noninjured youths, those exposed to traumatic
injury would demonstrate clinically and statistically significant elevations in a full
spectrum of provider-diagnosed anxiety, depressive, substance-related, and behavioral
disorders and in frequency of receipt of prescriptions for psychotropic medication. In this
investigation we also hypothesized that any elevations in disorders or prescriptions
observed among injured youths would persist even after adjustments for relevant
demographic and clinical characteristics. The investigation also aimed to explore
variations in the diagnosis of postinjury psychiatric disorders and psychotropic
medication prescriptions for youths exposed to TBI.

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Methods
Overview

The investigation was a population-based prospective cohort study of youths enrolled in

the Group Health Cooperative, a large integrated delivery system and health plan in the
Pacific Northwest. All youths aged ten to 19 in 2001 who were continuously enrolled in
the health plan for a seven-year period from 1998 to 2004 were included in the
investigation. Their automated, deidentified medical records documented inpatient,
emergency department, and outpatient visits; pharmacy prescription records; and
demographic characteristics. The Group Health Cooperative and University of
Washington institutional review boards approved all study procedures; a waiver of
informed consent was obtained in this secondary data-analytic investigation of
deidentified medical records.

Injury visits and severity

All adolescent inpatient, emergency department, and outpatient visits between 1998 and
2004 were reviewed for ICD-9-CM codes indicative of traumatic injury. Injuries included
in the investigation were fractures (codes 800829); dislocations (codes 830839);
sprains and strains of joints and adjacent muscles (codes 840848); intracranial injury
(codes 850854); internal injury of the chest, abdomen, and pelvis (codes 860869); open
wound of the head, neck, and trunk (codes 870879); open wound of the upper and lower
limbs (codes 880897); injury to the blood vessels (900904); late injury effects (codes
905909); superficial injury (codes 910919); contusions (codes 920924); crushing
injury (925929); foreign-body injuries (codes 930939); burns (codes 940949); injury
to nerves and spinal cord (950957); and other injury complications (codes 958959).
Specific ICD-9-CM codes used to identify TBI included 800.0801.9, 803.0804.9,
850.0854.1, and 959.01 (45,46).

Injury severity and maximum Abbreviated Injury Scale score

Severity of injury by body region was coded with the Abbreviated Injury Scale (AIS) in
order to determine each persons maximum AIS score (MAXAIS) (47,48). The AIS was
designed 30 years ago and is the most accepted anatomic measure of injury severity. It
has been shown to be highly correlated with threat to life as well as postinjury disability
and quality of life (47,48). The MAXAIS, calculated as the highest AIS score for a single
injury received, performs well as a single measure of injury severity; it has an area under
the receiver operating characteristic curve of .88 for mortality in a national database of
over 75,000 patients (49).

Psychiatric diagnoses

For all youths aged ten to 19 in the index year (2001), we reviewed the automated records
to identify one or more ICD-9-CM psychiatric diagnoses made by a Group Health
Cooperative provider over the seven-year study period. On the basis of a recent
epidemiologic investigation (1) as well as prior studies of traumatically injured children
and adolescents (2931,50), we derived the following combined categories of psychiatric
disorders from ICD-9-CM codes: anxiety and acute stress (including PTSD, 309.81; acute
stress disorders, 308.0308.9; adjustment disorders, 309.0309.9; panic disorder, 300.01,
300.21, and 300.22; phobia, 300.29; social anxiety, 300.23; obsessive-compulsive
disorder, 300.3; generalized anxiety disorder, 300.02; other anxiety, 293.84, 300.00,
300.09, and 300.2; and other childhood anxiety, 313.0), depressive disorders (including
major depressive disorder, 296.2296.99; dysthymia, 300.4; and other depressive
disorders, 309.1 and 311.0), substance use disorders (including alcohol use disorders,
291.0291.3, 291.5, 291.8, 291.9, 303.0, 303.9, and 305.0 and drug use disorders, 292.0,
304.0, and 305.2305.9), and disruptive behavior disorders (including attention-deficit
hyperactivity disorder [ADHD], 314.0 314.9; conduct disorder, 312.0312.4, 312.8, and
312.9; and oppositional defiant disorder, 313.81).

Psychotropic medication prescription

Group Health Cooperative pharmacy records were reviewed to identify psychotropic

medication prescriptions. Psychotropic medication prescriptions from the following
classes of medication were included: antidepressants (bupropion, citalopram,
desipramine, doxepin, escitalopram, fluoxetine, fluvoxamine, imipramine, mirtazapine,
nefazadone, nortriptyline, paroxetine, sertraline, trazodone, and venlafaxine), anxiolytics
(alprazolam, buspirone, chlordiazepoxide, clonazepam, diazepam, oxazepam, and
triazolam), antipsychotics (aripiprazole, fluphenazine, haloperidol, molindone,
olanzapine, perphenazine, pimozide, quetiapine, risperidone, thioridazine, and
ziprasidone), and mood stabilizers (lithium). Stimulant medications were unavailable
from pharmacy records and therefore were not included in the investigation.

Data analyses

We first described the demographic, clinical, and injury characteristics of the cohort and
divided the cohort into two groups, youths with and without any ICD-9-CMdocumented
injury visits in 2001. Next, the frequencies of documented anxiety or acute stress,
depressive, substance use, and disruptive behavior disorders as well as psychotropic
medication prescription were ascertained for members of the two groups over the course
of the three subsequent years (20022004).

The unadjusted associations between injury in 2001 (yes or no) and the four categories of
psychiatric disorders (yes or no) and psychotropic medication prescription (yes or no)
were assessed for the 20022004 period. We constructed longitudinal regression models
for 2002 to 2004 to ascertain the association between youth injury in 2001 and any
psychiatric diagnosis or psychotropic medication prescription alone or in combination.
While adjusting for other clinical and demographic characteristics, five models using
generalized estimating equations longitudinally assessed for an independent association
between injury in 2001 and anxiety and acute stress, depressive, substance use, and
disruptive behavior disorders as well as psychotropic prescriptions. Repeated
measurements of the four categories of psychiatric disorders or psychotropic medication
prescription in 2002, 2003, and 2004 were the dependent variables. The primary
independent variable included in each model was injury visit in 2001 (yes or no).
Covariates included in each of the five models were age, gender, one or more psychiatric
diagnoses in 19982000, one or more psychotropic medication prescriptions in 1998
2000, the presence of one or more TBIs or any other injury in 19982000, and injury
severity (MAXAIS) for injuries incurred in 19982000 and in the index year of 2001.
Exploratory analyses assessed whether youths who incurred a TBI in 2001 had increased
odds of receiving psychiatric diagnoses or a psychotropic medication prescription relative
to both noninjured youths and youths who had incurred any other type of injury (non-
TBI) in 2001.

Outcomes for all unadjusted and adjusted associations were expressed as odds ratios
(ORs) and 95% confidence intervals (CIs) (5153). Odds ratios are commonly used in
cohort studies because they allow for a quantitative comparison of the outcome of interest
in the exposed versus unexposed groups (in this investigation, youths exposed to an
injury in 2001 compared with youths not exposed to an injury in 2001).

Finally we performed sensitivity analyses for the multivariate regressions using, first,
individual preinjury psychiatric diagnoses (including anxiety and acute stress, depressive,
substance use, and disruptive behavior disorders in 19982000) in place of a combined
category of one or more psychiatric diagnoses in 19982000, and second, the MAXAIS
for each of seven body regions (head, thorax, abdomen, spine, upper extremity, lower
extremity, and integument) in addition to the overall injury severity score (the MAXAIS
from multiple regions). Analyses were conducted with SAS, version 9.2, data-analytic
software.

Go to:

Results
In 2001 there were 20,507 youths aged ten to 19 who were continuously enrolled in the
Group Health Cooperative (Table 1). The meanSD age of youths in the cohort was
14.12.6, and 49.4% were female. Approximately 30% of these youths had one or more
injury visits in 2001. Two hundred fifty-two individuals (1.2%) had an injury visit
secondary to a TBI. Among the 6,116 adolescents with an injury visit in 2001, 142 (2.3%)
required hospitalization, 738 (12.1%) had one or more emergency department visits, and
5,949 (97.3%) had one or more ambulatory care or outpatient visits. With regard to injury
severity, 3,794 adolescent injury visits were associated with a MAXAIS of 1, 1,674 visits
were associated with a MAXAIS of 2, and 63 visits were associated with a MAXAIS 3.
Children and adolescents injured in 2001 were more likely to be male; injured youths also
were more likely than those not injured to have one or more prior psychiatric diagnoses,
prescriptions for psychotropics, or injuries in 19982000 (Table 1).

Table 1
Demographic and clinical characteristics of injured and noninjured youths aged ten to 19
in 2001a

Youths with one or more psychiatric diagnoses constituted 13.0% of the cohort in 2002,
14.2% in 2003, and 14.5% in 2004. Between 10.8% and 11.7% of youths received one or
more psychotropic medication prescriptions in the 20022004 period. Over the course of
the three years after the index injury, a pattern of elevated odds for individual ICD-9-CM
diagnoses was observed. In unadjusted analyses, youths exposed to injury had
significantly greater odds of having a diagnosis of acute stress disorder, PTSD, an
adjustment disorder, anxiety disorder, major depressive disorder, dysthymia, an alcohol or
drug use disorder, ADHD, conduct disorder, and oppositional defiant disorder compared
with youths unexposed to injury. As an example, .3% of all youths had a diagnosis of
PTSD in 2002, 2003, and 2004. In unadjusted analyses, youths injured in 2001
demonstrated significantly elevated odds of receiving a PTSD diagnosis over the course
of the three years after injury (2002, OR = 2.78, CI = 1.684.61; 2003, OR = 1.90, CI =
1.163.10; 2004, OR = 2.43, CI = 1.513.93).
Youths injured in 2001 were more likely than noninjured youths to receive one or more
diagnoses of anxiety or acute stress, depressive, substance use, and disruptive behavior
disorders in the subsequent three-year period (Table 2). Youths injured in 2001 were also
more likely to have received prescriptions for one or more psychotropic medications in
20022004 (Table 2).

Table 2
Unadjusted associations between injury among youths in 2001 and psychiatric disorders
and psychotropic medication prescription in 20022004

In regression models that adjusted for clinical and demographic characteristics,

adolescents injured in 2001 had significantly elevated odds of receiving diagnoses of
anxiety or acute stress, depressive, and substance use disorders over the three years after
injury (Table 3). Adjusted regression models also revealed a significant association
between injury in 2001 and the prescription of psychotropic medication in 20022004
(Table 3).

Table 3
Adjusted associations between injuries among youths in 2001 and psychiatric diagnoses
and psychotropic medication prescription in 20022004a

Compared with noninjured youths, those who incurred a TBI had significantly higher
odds of receiving depressive and substance use diagnoses as well as psychotropic
medication prescriptions (Table 3). Youths with TBI also had significantly elevated odds
of receiving psychotropic medication prescriptions compared with injured youths without
TBIs (OR = 1.58, CI = 1.192.08). Compared with youths with non-TBI injuries, youths
with a TBI did not show significantly higher odds of having a diagnosis from any
combined category of psychiatric disorder.

One or more preinjury psychiatric disorders in 19982000 demonstrated the strongest

independent associations with psychiatric disorders and psychotropic medication
prescription from 2002 to 2004 (OR range 2.9615.13). Psychotropic medication
prescriptions for the period 19982000 also demonstrated strong independent
associations with 20022004 psychiatric disorders and prescriptions (OR range 1.21
3.01). Female gender was associated with increased odds of receiving a diagnosis of
anxiety or acute stress disorder (OR = 1.37, CI = 1.311.43) or a depressive disorder (OR
= 1.50, CI = 1.441.58) and receiving a prescription for psychotropic medications (OR =
1.36, CI = 1.321.41). However, being female was associated with diminished odds of
receiving a diagnosis of a substance use disorder (OR = .76, CI = .71.82) or a disruptive
behavior disorder (OR = .71, CI = .67.75). Having one or more non-TBI injuries
between 1998 and 2000 was significantly associated with increased odds of having a
diagnosis of any psychiatric disorder and a psychotropic prescription within 20022004
(OR range 1.161.32). In contrast, receiving one or more TBIs between 1998 and 2000
was associated only with significantly increased odds of a diagnosis of a substance use
disorder (OR = 1.63, CI = 1.112.41) and psychotropic medication prescription (OR =
1.44, CI = 1.161.81) in 20022004.

Sensitivity analyses that incorporated individual preinjury psychiatric diagnoses and

MAXAIS for individual body regions did not substantially alter the magnitude, pattern,
or significance of the vast majority of associations between an injury in 2001 and
diagnosis of psychiatric disorders in 20022004 (Table 3).

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Discussion
This population-based, prospective investigation identified an increased risk of receiving
a broad spectrum of psychiatric diagnoses, including anxiety or acute stress, depressive,
and substance use disorders, among youths aged ten to 19 who were exposed to a single
traumatic injury. Consistent with prior reports, 30% of youths aged ten to 19 had at least
one injury visit in the index year (5,54). Prior study of more severely injured youths who
required hospitalization also suggests that a full spectrum of anxiety, depressive, and
substance use symptoms may be prominent in the months after exposure to traumatic
injury (29). In this study, the observed independent association between exposure to a
single injury and the subsequent increased risk of receiving psychiatric diagnoses is
particularly relevant given that the vast majority of injuries were relatively minor
(MAXAIS of 1 or 2). In contrast to prior reports, this investigation did not find a
significantly elevated risk of disruptive behavior disorder diagnoses for youths exposed
to traumatic injury after analyses adjusted for demographic and preinjury clinical
characteristics (1,30).

PTSD was infrequently diagnosed among youths over the course of the three years after
injury exposure; however, youths incurring injuries frequently received other anxiety,
depressive, and substance-related diagnoses. The investigation also observed that injury-
exposed children and adolescents were more likely to receive psychotropic medication
prescriptions. These findings corroborate and extend observations from previous child
and adolescent epidemiologic studies (1,44) and suggest that postinjury mental health
services may need to address the full spectrum of psychiatric presentations among injured
children and adolescents.

Preinjury psychiatric history was strongly associated with receiving postinjury

psychiatric diagnoses and psychotropic medication prescription. Also of note, traumatic
injuries incurred before 2001 were independently associated with an increased risk of
postinjury psychiatric diagnoses and psychotropic medication prescription. Prior reports
suggest that pre-event psychopathology and recurrent trauma among youths and their
family members are associated with an increased risk of developing PTSD and related
psychiatric disorders (1,21,22,30,55). These collective findings suggest that postinjury
screening and intervention protocols in acute care and pediatric practice settings may
need to target high-risk children and adolescents who have been exposed to multiple
injury events or who have a history of psychiatric disturbances.

Consistent with prior reports, approximately 1% of youths in the cohort had sustained a
TBI in 2001 (56). Youths with a TBI had a significantly increased risk of receiving
psychotropic medication prescriptions but not of having psychiatric disorders compared
with youths incurring non-TBI injuries. However, the relatively small number of youths
with a TBI may have limited the investigations ability to detect significant associations.
Some (57,58) but not all (34) prior investigations have found equivalent rates of
psychiatric symptoms among children with TBI and other kinds of injury. Anatomic
differences in TBI symptom presentations may explain some of the observed variations in
findings across investigations (59).

This investigation has a number of limitations predominantly related to the use of large
administrative databases to ascertain psychiatric diagnoses (60,61). Assignment of
diagnoses relied on diagnostic codes that frequently derived from assessments by general
medical providers rather than mental health specialty providers. This may have affected
the accuracy of specific ICD-9-CM diagnostic categories in the investigation.

Diagnostic inaccuracies could in part explain the low observed rates of postinjury PTSD
in the cohort. Also, the increased rate of diagnoses observed after the index injury could
be explained in part by the increased likelihood of detecting a disorder related to an
injury visit. Thus an alternative explanation for the observed increased rates of diagnoses
and medication prescription could be that preexisting psychiatric disorders were detected
when youths were injured and happened to visit their provider.

The investigation was also limited by the arbitrary annual categorization of injury visits;
it is quite possible that visits for a single injury extended across years (for example, an
initial injury in December of 2000 would likely have had a follow-up in January 2001).
Furthermore, because of the diversity of postinjury visit types (including visits to the
emergency department, physical therapy, and primary care), it was difficult to directly
control for number of these visits in multivariate analyses. Also, several demographic and
clinical characteristics, such as ethnicity, family income, and social support, were not
assessed. Thus we cannot rule out the possibility that other unmeasured characteristics
related to both the occurrence of childhood injury and psychiatric disorders partially
explain the observed association between injury and increased risk of psychiatric
disorders.

An important limitation of the investigation is that no information is provided on children

with undiagnosed disorders. An additional limitation is the lack of automated data from
the Group Health Cooperative regarding the stimulant class of psychotropic medication
prescriptions. Finally, the current investigation did not fully explore the effects of
individual preinjury psychiatric diagnoses or injuries to specific body regions on the
development of postinjury psychiatric disorders; these issues could be productively
addressed in subsequent investigations.

Go to:

Conclusions
Beyond these considerations this investigation has important implications for the
detection and treatment of child and adolescent emotional disturbances in general
medical settings (62). Prior investigations suggest that there are deficits in the quality of
postinjury psychiatric care such that even when adolescent posttraumatic psychiatric
symptoms are detected by primary care providers, difficulties may arise in service
coordination and initiation of evidence-based mental health treatment (29,63). Our
investigation suggests at a population level that injury is associated with an increased risk
of having a broad spectrum of psychiatric disturbances. Future research should
corroborate and extend the finding of an association between childhood injury and the
development of psychiatric disorders before population-based screening efforts are
implemented. Although psychiatric disorders appear to be detected by general medical
providers at postinjury visits, it is unclear whether high-quality evidence-based mental
health treatments are being initiated.

Future stepped-care investigations could test relatively simple screening algorithms and
computerized intervention strategies that link primary care providers detection of
postinjury psychiatric disturbances with collaborative care consultation (64).
Computerized notification linking pediatric primary care with stepped-up mental health
consultation within integrated health plan populations, such as the Group Health
Cooperative, may be a key method of enhancing the quality of mental health care for
injured youths. Ultimately, population-based surveillance procedures that integrate
screening, detection, and stepped-care interventions targeting the full spectrum of
postinjury psychiatric disorders could be developed and tested (64). Future research
efforts could be linked to changes in policy surrounding the delivery of high-quality,
sustainable mental health care for injured children and adolescents treated in general
medical settings (65,66).

Go to:

Acknowledgments
This work was supported by grants R01-MH073613 and K24-MH086914 from the
National Institute of Mental Health and by grant R49-CCR316840 from the National
Center for Injury Prevention and Control and the Centers for Disease Control and
Prevention.

Go to:

Footnotes
disclosures

The authors report no competing interests.

Go to:

Contributor Information
Douglas F. Zatzick, Department of Psychiatry and Behavioral Sciences, University of
Washington Harborview Medical Center, 325 9th Ave., Seattle, WA 98104-2499.

David C. Grossman, Group Health Research Institute and with the Department of Health
Sciences, University of Washington School of Medicine, Seattle, WA 98104-2499.

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References
1. Copeland WE, Keeler G, Angold A, et al. Traumatic events and posttraumatic stress in
childhood. Archives of General Psychiatry. 2007;64:577584. [PubMed]
2. Rivara FP, Grossman DC, Cummings P. Injury prevention. New England Journal of
Medicine. 1997;337:543548. [PubMed]
3. Bonnie RJ, Fulco CE, Liverman CT. Reducing the Burden of Injury: Advancing
Prevention and Treatment. Washington, DC: National Academy Press; 1999.
4. Emergency Care for Children: Growing Pains in Future of Emergency Care Series.
Washington, DC: Institute of Medicine, Committee on the Future of Emergency Care in
the US Health System; 2006.
5. Grossman DC. The history of injury control and the epidemiology of child and
adolescence injuries. Future of Children. 2000;10:2352. [PubMed]
6. CDC Injury Fact Book. Atlanta, Ga: Centers for Disease Control and Prevention,
National Center for Injury Prevention; 2006.
7. Owens PL, Zodet MW, Berdahl T, et al. Annual report on health care for children and
youth in the United States: focus on injury-related emergency department utilization and
expenditures. Ambulatory Pediatrics. 2008;8:219240. e17. [PubMed]
8. Borse N, Gilchrist J, Dellinger A, et al. Patterns of unintentional injuries among 019
year olds in the United States, 20002006; in CDC Childhood Injury Report. Atlanta, Ga:
Centers for Disease Control and Prevention; 2008.
9. De Vries AP, Kassam-Adams N, Cnaan A, et al. Looking beyond the physical injury:
posttraumatic stress disorder in children and parents after pediatric traffic injury.
Pediatrics. 1999;104:12931299. [PubMed]
10. Stallard P, Velleman R, Baldwin S. Prospective study of post-traumatic stress disorder
in children involved in road traffic accidents. British Medical Journal. 1998;317:1619
1623. [PMC free article] [PubMed]
11. Aaron J, Zaglul H, Emery RE. Posttraumatic stress in children following acute
physical injury. Journal of Pediatric Psychology. 1999;24:335343. [PubMed]
12. Zatzick D, Grossman D, Russo J, et al. Predicting posttraumatic stress symptoms
longitudinally in a representative sample of hospitalized injured adolescents. Journal of
the American Academy of Child and Adolescent Psychiatry. 2006;45:11881195.
[PubMed]
13. Kassam-Adams N, Winston FK. Predicting child PTSD: the relationship between
acute stress disorder and PTSD in injured children. Journal of the American Academy of
Child and Adolescent Psychiatry. 2004;43:403411. [PubMed]
14. Ehlers A, Mayou RA, Bryant B. Cognitive predictors of posttraumatic stress disorder
in children: results of a prospective longitudinal study. Behaviour Research and Therapy.
2003;41:110. [PubMed]
15. Daviss WB, Mooney D, Racusin R, et al. Predicting posttraumatic stress after
hospitalization for pediatric injury. Journal of the American Academy of Child and
Adolescent Psychiatry. 2000;39:576583. [PubMed]
16. Shemesh E, Keshavarz R, Leichtling NK, et al. Pediatric emergency department
assessment of psychological trauma and posttraumatic stress. Psychiatric Services.
2003;54:12771281. [PubMed]
17. Saxe G, Stoddard F, Hall E, et al. Pathways to PTSD, part I: children with burns.
American Journal of Psychiatry. 2005;162:12991304. [PubMed]
18. Stoddard FJ, Saxe G, Ronfeldt H, et al. Acute stress symptoms in young children with
burns. Journal of the American Academy of Child and Adolescent Psychiatry.
2006;45:8793. [PubMed]
19. Winston FK, Kassam-Adams N, Vivarelli-ONeill C, et al. Acute stress disorder
symptoms in children and their parents after pediatric traffic injury. Pediatrics.
2002;109(6):e90. [PubMed]
20. Zink KA, McCain GC. Post-traumatic stress disorder in children and adolescents with
motor vehiclerelated injuries. Journal for Specialists in Pediatric Nursing. 2003;8:99
106. [PubMed]
21. Cox CM, Kenardy JA, Hendrikz JK. A meta-analysis of risk factors that predict
psychopathology following accidental trauma. Journal for Specialists in Pediatric
Nursing. 2008;13:98110. [PubMed]
22. Langeland W, Olff M. Psychobiology of posttraumatic stress disorder in pediatric
injury patients: a review of the literature. Neuroscience and Biobehavioral Reviews.
2008;32:161174. [PubMed]
23. Mirza KAH, Bhadrinath BR, Goodyer IM, et al. Post-traumatic stress disorder in
children and adolescents following road traffic accidents. British Journal of Psychiatry.
1998;172:443447. [PubMed]
24. Kenardy JA, Spence S, MacLeod A. Screening for posttraumatic stress disorder in
children after accidental injury. Pediatrics. 2006;118:10021009. [PubMed]
25. Sturms LM, van der Sluis CK, Stewart RE, et al. A prospective study on paediatric
traffic injuries: health-related quality of life and post-traumatic stress. Clinical
Rehabilitation. 2005;19:312322. [PubMed]
26. Max JE, Castillo CS, Robin DA, et al. Posttraumatic stress symptomatology after
childhood traumatic brain injury. Journal of Nervous and Mental Disease. 1998;186:446
452. [PubMed]
27. Gerring JP, Slomine B, Vasa RA, et al. Clinical predictors of posttraumatic stress
disorder after closed head injury in children. Journal of the American Academy of Child
and Adolescent Psychiatry. 2002;41:157165. [PubMed]
28. Dunn C, Rivara FP, Donovan D, et al. Predicting adolescent alcohol drinking patterns
after major injury. Journal of Trauma. 2008;65:736740. [PubMed]
29. Sabin JA, Zatzick D, Jurkovich G, et al. Primary care utilization and detection of
emotional distress after adolescent traumatic injury: identifying an unmet need.
Pediatrics. 2006;117:130138. [PubMed]
30. Massagli TL, Fann JR, Burington BE, et al. Psychiatric illness after mild traumatic
brain injury in children. Archives of Physical Medicine and Rehabilitation.
2004;85:14281434. [PubMed]
31. Stoddard FJ, Saxe G. Ten-year research review of physical injuries. Journal of the
American Academy of Child and Adolescent Psychiatry. 2001;40:11281145. [PubMed]
32. Schwartz L, Taylor H, Drotar D, et al. Long-term behavior problems following
pediatric traumatic brain injury: prevalence, predictors, and correlates. Journal of
Pediatric Psychology. 2003;28:251263. [PubMed]
33. Grados M, Vasa R, Riddle M, et al. New onset obsessive-compulsive symptoms in
children and adolescents with severe traumatic brain injury. Depression and Anxiety.
2008;25:398407. [PubMed]
34. Schachar R, Levin H, Max JE, et al. Attention deficit hyperactivity disorder
symptoms and response inhibition after closed head injury in children: do preinjury
behavior and injury severity predict outcome? Developmental Neuropsychology.
2004;25:179198. [PubMed]
35. Levi RB, Drotar D, Yeates KO, et al. Posttraumatic stress symptoms in children
following orthopedic or traumatic brain injury. Journal of Clinical Child Psychology.
1999;28:232243. [PubMed]
36. Babikian T, Asarnow R. Neurocognitive outcomes and recovery after pediatric TBI:
meta-analytic review of the literature. Neuropsychology. 2009;23:283296. [PubMed]
37. Jaffe K, Fay G, Polissar N, et al. Severity of pediatric traumatic brain injury and
neurobehavioral recovery at one year: a cohort study. Archives of Physical Medicine and
Rehabilitation. 1993;74:587595. [PubMed]
38. Bryant RA. Disentangling mild traumatic brain injury and stress reactions. New
England Journal of Medicine. 2008;358:525527. [PubMed]
39. Levin H, Hanten G, Max J, et al. Symptoms of attention-deficit/hyperactivity disorder
following traumatic brain injury in children. Journal of Developmental and Behavioral
Pediatrics. 2007;28:108118. [PubMed]
40. Yeates K, Armstrong K, Janusz J, et al. Long-term attention problems in children with
traumatic brain injury. Journal of the American Academy of Child and Adolescent
Psychiatry. 2005;44:574584. [PubMed]
41. Zatzick D, Jurkovich G, Fan M, et al. The association between posttraumatic stress
and depressive symptoms, and functional outcomes in adolescents followed
longitudinally after injury hospitalization. Archives of Pediatrics and Adolescent
Medicine. 2008;162:642648. [PubMed]
42. Holbrook TL, Hoyt DB, Coimbra R, et al. Trauma in adolescents causes long-term
marked deficits in quality of life: adolescent children do not recover preinjury quality of
life or function up to two years postinjury compared to national norms. Journal of
Trauma. 2007;62:577583. [PubMed]
43. Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental
disorders in the United States. Annual Review of Public Health. 2008;29:115129.
[PubMed]
44. Koenen KC, Moffitt TE, Caspi A, et al. The developmental mental-disorder histories
of adults with posttraumatic stress disorder: a prospective longitudinal birth cohort study.
Journal of Abnormal Psychology. 2008;117:460466. [PMC free article] [PubMed]
45. Thurman D, Sniezek J, Johnson D, et al. Guidelines for Surveillance of Central
Nervous System Injury. Atlanta, Ga: Centers for Disease Control and Prevention; 1995.
46. Butler J, Langlois J. Central Nervous System Injury Surveillance Annual Data of
Submission Standards2000. Atlanta, Ga: Centers for Disease Control and Prevention,
National Center for Injury Prevention and Control; 2001.
47. Civil ID, Schwab CW. The Abbreviated Injury Scale: 1985 Revision. Morton Grove,
Ill: American Association for the Advancement of Automotive Medicine, Committee on
Injury Scaling; 1985.
48. The Abbreviated Injury Scale1990 Revision (AIS-90) Des Plaines, Ill: Association
for the Advancement of Automotive Medicine, Committee on Injury Scaling; 1990.
49. Meredith JW, Evans G, Kilgo PD, et al. A comparison of the abilities of nine scoring
algorithms in predicting mortality. Journal of Trauma. 2002;53:621629. [PubMed]
50. Fann JR, Burington B, Leonetti A, et al. Psychiatric illness following traumatic brain
injury in an adult health maintenance organization population. Archives of General
Psychiatry. 2004;61:5361. [PubMed]
51. Koepsell T, Weiss N. Epidemiologic Methods. New York: Oxford University Press;
2003. Studying the occurrence of illness.
52. Hosmer DW, Lemeshow S. Applied Logistic Regression. New York: Wiley; 1989.
53. Zhang J, Yu KF. Whats the relative risk? A method of correcting the odds ratio in
cohort studies of common outcomes. JAMA. 1998;280:16901691. [PubMed]
54. Rivara FP, Calonge N, Thompson RS. Population-based study of unintentional injury
incidence and impact during childhood. American Journal of Public Health.
1989;79:990994. [PMC free article] [PubMed]
55. Mueser KT, Taub J. Trauma and PTSD among adolescents with severe emotional
disorders involved in multiple service systems. Psychiatric Services. 2008;59:627634.
[PubMed]
56. Bjiur PE, Haslum M, Golding J. Cognitive and behavioral sequelae of mild head
injury in children. Pediatrics. 1990;86:337344. [PubMed]
57. Mather FJ, Tate RL, Hannan TJ. Posttraumatic stress disorder in children following
road traffic accidents: a comparison of those with and without mild traumatic brain
injury. Brain Injury. 2003;17:10771087. [PubMed]
58. Keenan HT, Hall GC, Marshall SW. Early head injury and attention deficit
hyperactivity disorder: retrospective cohort study. British Medical Journal.
2008;7680:12081210. [PMC free article] [PubMed]
59. Vasa R, Grados M, Slomine B, et al. Neuroimaging correlates of anxiety after
pediatric traumatic brain injury. Biological Psychiatry. 2003;55:208216. [PubMed]
60. Stein BD, Kogan JN, Sorbero MJ, et al. Predictors of timely follow-up care among
Medicaid-enrolled adults after psychiatric hospitalization. Psychiatric Services.
2007;58:15631569. [PubMed]
61. Stein MB, Cantrell CR, Sokol MC, et al. Antidepressant adherence and medical
resource use among managed care patients with anxiety disorders. Psychiatric Services.
2006;57:673680. [PubMed]
62. Cohen JA, Kelleher KJ, Mannarino AP. Identifying, treating, and referring
traumatized children: the role of pediatric providers. Archives of Pediatric and Adolescent
Medicine. 2008;162:447452. [PubMed]
63. Grupp-Phelan J, Delgado SV, Kelleher KJ. Failure of psychiatric referrals from the
pediatric emergency department. BMC Emergency Medicine. 2007;7:1219. [PMC free
article] [PubMed]
64. Zatzick D, Roy-Byrne P, Russo J, et al. A randomized effectiveness trial of stepped
collaborative care for acutely injured trauma survivors. Archives of General Psychiatry.
2004;61:498506. [PubMed]
65. Resources for the Optimal Care of the Injured Patient: 2006. Chicago: American
College of Surgeons, Committee on Trauma; 2006.
66. Terrell F, Zatzick DF, Jurkovich GJ, et al. A nationwide survey of alcohol screening
and brief intervention practices at US level I trauma centers. Journal of the American
College of Surgeons. 2008;207:630638. [PMC free article] [PubMed]

Jurnal 7
Dialogues Clin Neurosci. 2011 September; 13(3): 325345.
PMCID: PMC3182011

Addressing neuropsychiatric disturbances

during rehabilitation after traumatic
brain injury: current and future
methods
Go to:
Evaluation des troubles neuropsychiatriques pendant la
radaptation aprs lsion crbrale traumatique:
mthodes actuelles et futures
David B. Arciniegas, MD*
Author informaton Copyright and License informaton
This artcle has been cited by other artcles in PMC.
Go to:

Abstract
Cognitive, emotional, behavioral, and sensorimotor disturbances are the principal clinical
manifestations of traumatic brain injury (TBI) throughout the early postinjury period.
These post-traumatic neuropsychiatric disturbances present substantial challenges to
patients, their families, and clinicians providing their rehabilitative care, the optimal
approaches to which remain incompletely developed. In this article, a
neuropsychiairically informed, neurobiologically anchored approach to understanding
and meeting challenges is described. The foundation for thai approach is laid, with a
review of clinical case definitions of TBI and clarification of their intended referents. The
differential diagnosis of event-related neuropsychiatric disturbances is considered next,
after which the clinical and neurobiological heterogeneity within the diagnostic category
of TBI are discussed. The clinical manifestations of biomechanical force-induced brain
dysfunction are described as a state of post-traumatic encephalopathy (PTE) comprising
several phenomenologically distinct stages, PTE is then used as a framework for
understanding and clinically evaluating the neuropsychiatric sequelae of TBI encountered
commonly during the early post-injury rehabilitation period, and for considering the types
and timings of neurorehabilitative interventions. Finally, directions for future research
that may address productively the challenges to TBI rehabilitation presented by
neuropsychiatric disturbances are considered.

Keywords: Traumatc brain injury, encephalopathy, cogniton, neuropsychiatric assesment,

rehabilitaton, differental diagnosis
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Rsum
Les troubles cognitifs, motionnels, comportementaux et sensorimoteurs sont les
principales manifestations cliniques des lsions crbrales traumatiques (LCT) au cours
de la priode posttraumatique prcoce. Ces troubles neuropsychiatriques post-
traumatiques reprsentent un vritable dfi pour les patients, leur famille et les mdecins
qui prodiguent leurs soins de radaptation, et dont les mthodes restent imparfaites. Nous
dcrivons dans cet article une approche neuropsychiatrique, sous-tendue par la
neurobiologie, permettant la comprhension et la ralisation d'objectifs. Les fondements
de cette approche reposent sur une revue des dfinitions des cas cliniques des LCT et sur
une clarification de leur origine. Nous examinons ensuite le diagnostic diffrentiel des
troubles neuropsychiatriques lis ces vnements, puis nous analysons l'htrognit
clinique et neurobiologique de la catgorie diagnostique des LCT, Les manifestations
cliniques des troubles crbraux induits par la force biomcanique sont dcrites comme
un tat d'encphalopathie post-iraumaiique (EPT) comprenant plusieurs stades distincts
sur le plan phnomnologique, L'EPT est alors utilise comme cadre de comprhension et
d'valuation clinique des squelles neuropsychiatriques des LCT rencontres
habituellement pendant la priode de radaptation post-traumatique prcoce, renseignant
sur les types et la chronologie des interventions de radaptation neurologiques adapter.
Les directions prendre pour la recherche future sont envisages, afin d'aborder de faon
productive les dfis de la radaptation aux LCT lis aux troubles neuropsychiairiques.

Traumatic brain injury (TBI) produces clinical problems and care needs that are
intrinsically and unavoidably neuropsychiatric during both the early and late post-injury
periods. In the acute injury period, cognitive impairments are nearly universal,1-5 and are
frequently accompanied by disturbances of emotion, behavior, and/or sensorimotor
function.1-10 Neurotraumainduced neuropsychiatric disturbances are especially prominent,
among individuals who are hospitalized after TBI7-11 and, in this subpopulation, often
become chronic conditions.12,17 The neuropsychiatric consequences of TBI contribute
substantially to post-injury disability,16-18 and diminish the quality of life experienced by
persons with TBI and their families.17,19-21

We suggested elsewhere6,22 that, adverse short- and long-term TBI outcomes might be
mitigated most effectively by initiating neuropsychiatric evaluation and management, of
persons with TBI during the early post-injury (ie, the neurocritical care and inpatient
rehabilitation) periods. Although the hypotheses borne of this suggestion remain
incompletely tested, a complementary literature supports the potential benefits of early
neuropsychiatric intervention provided to patients engaged in acute neurorehabilitation
after TBI.8,23-25 Accordingly, developing further the neuropsychiatric expertise of
physicians and other specialists providing care to persons with TBI in such settings is an
important, objective.

Toward that end, this article addresses the evaluation and management of
neuropsychiatric disturbances among persons receiving rehabilitation after TBI. Clinical
case definitions of TBI are described first. The differential diagnoses of event-related
disturbances of neuropsychiatric function arc considered, after which the clinical and
neurobiological heterogeneity of TBI are discussed. A neurobiologically anchored,
neuropsychiatrically informed framework for understanding and clinically evaluating the
neuropsychiatric sequelae of TBI during the post-injury rehabilitation period is offered.
Consideration then is given to the types and timings of neuropharmacologic and
rehabilitative treatments that, follow from that framework. Finally, directions for future
research that may address productively the challenges to TBI rehabilitation presented by
neuropsychiatric disturbances are considered.

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Clinical case definition of TBI
TBI denotes a disruption of brain function and/or structure resulting from the application
of an external physical force (including biomechanical force, acceleration/deceleration
forces, and/or blast-related forces).1-5 Establishing with a reasonable certainty that, a TBI
occurred is a prerequisite to framing neuropsychiatric disturbances as post-traumatic.
This necessitates being familiar with and applying well-accepted clinical case definitions
of TBI.1-5,26 Among these, the American Congress of Rehabilitation Medicine (ACRM)
clinical case definition2 is the most widely used in clinical and research settings; it, also
serves as the foundation for more recently developed clinical case definitions.1,3,4,26 An
important shared feature of all of these clinical case definitions is that no single symptom
or sign is regarded as pathognomonic of TBI. Instead, any one (or more) of several
clinical features suffices as evidence of brain dysfunction that, in the context of
biomechanical force application, allows assignment of a TBI diagnosis. Several of the
most commonly used clinical case definitions of TBI are presented in Table I, along with
comments on their nonshared features.

Table I.
Commonly used clinical case definitions of traumatic brain injury. Notes: Traumatically induced
refers to injuries that result from the head being struck, the head striking an object, and/or the
brain undergoing an acceleration/deceleration movement without ...

Among those nonshared features, it is important, to note that the use of skull fracture as a
proxy marker for in the TBI Centers for Disease Control and Prevention5 clinical case
definition reflects its intended application: public health-oriented surveillance for central
nervous system injury in which diagnosis is based solely on the medical records of
persons hospitalized immediately following TBI. The association between skull fracture
and TBI is well described but this association is not invariant.27 Accordingly, predicating
a clinical TBI diagnosis solely on skull facture - ie, head injury in the absence of other
evidence of brain injury - presents an unacceptably high risk of misdiagnosis.

All TBI clinical case definitions also exclude brain injuries resulting from birth trauma,
hypoxic-ischemic (anoxic), inflammatory, toxic, or metabolic encephalopathies, primary
ischemic or hemorrhagic strokes, seizure disorders, intracranial surgery, and cerebral
neoplasms. While such injuries may be traumatic in a colloquial sense and/or
psychologically traumatizing, they do not constitute TBI.

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The differential diagnosis of TBI
The differential diagnosis of event-related neuropsychiatric disturbances is broad (Table
II), and their consideration is necessary before attributing these phenomena
unequivocally to TBI. As noted in Kay et al2 and Menon et al,1 conditions other than TBI
may contribute to or, in some cases, be responsible for, alterations in mental state,
emotional and behavioral changes, and sensorimotor function at the time of injury.
However, the presence of such conditions, including those with clinical features that
mimic the acute (ie, event-related) or late neuropsychiatric manifestations of TBI, does
not preclude a TBI diagnosis. In some cases, the occurrence of other conditions may
explain how a TBI occurred - for example, syncope resulting in fall-related TBI, or
alcohol intoxication while driving resulting in a road-traffic accident-related TBI.
Additionally, pre-injury developpemental, medical, neurological, psychiatric, and
substance use problems are common among persons with TBI28 and may interact with
TBI and/or each other to alter early and late post-injury neuropsychiatric
presentations.29,30 Rendering a TBI diagnosis is therefore a matter of clinical judgement
31,32
that requires interpretation of an individual clinical history not only with respect, to
well-accepted TBI clinical case definitions but also in context of a comprehensive
differential diagnosis of event-related neuropsychiatric disturbances.

Table II.
The differential diagnosis of event-related neuropsychiatric disturbances.
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Differential diagnosis within the category of TBI

Clinical case definitions usefully limit the range of problems that fall under the heading
of TBI. Nonetheless, there remains significant, phcnomcnological and pathophysiological
heterogeneity within this diagnostic category. TBI denotes a broad range of injury types
and severities as well as a host of potentially injurious biological processes,33-37 the rates
and extents of recovery from which vary with initial TBI severity and the interaction
between TBI and other pre- and post-injury factors.13,29,38,41 These other factors - ie, the
brain that is injured and the events that follow TBI - are increasingly recognized as
important, sources of variance in TBI outcome, and their influence on post-traumatic
neuropsychiatric status is considered later in this article. Incorporating those
considerations into clinical practice and research requires first, however, an
understanding of initial TBI severity.
The range and assessment of initial TBI severities

Characterizing TBI severity informs usefully on clinical phenomenology and narrows the
range of neuropathophysiologies that, are explanatorily relevant and potential targets of
clinical intervention22,29,34 (discussed further below). Initial TBI severity also informs on
the prognosis for post-injury mortality, morbidity, and disability.38,42-46

Accordingly, initial TBI severity is an important element, of the body of clinical

information needed when discussing prognosis and probable post-hospitalization
treatment/resource needs with patients, their families, and other healthcare providers.

Although TBI severity occurs along a continuum, it is commonly described in categorical

terms. For example, clinical case definitions2,47 generally categorize TBI as mild or
moderate-to-severe (ie, more-than-mild). Similarly, clinical metrics like the Glasgow
Coma Scale (GCS)48 and/or duration of post-traumatic amnesia (the peri-injury period
during which there is a dense impairment in the ability to learn new information,
including events following injury [anterograde amnesia] as well as those immediately
preceding it [retrograde amnesia]49,50) often are used to assign TBI to a severity category,
ie, mild, moderate, or severe51 or subdivisions thereof (Table III). 50,52-55

Table III.
Classification of traumatic brain injury (TBI) severity used in the Department of Veterans Affairs
and Department of Defense Clinical Practice Guideline: Management of Concussion/mild
Traumatic Brain injury (April, 2009), modified to include complicated ...

Post-traumatic amnesia durations 24 hours are consistent, with a diagnosis of mild TBI
(uncomplicated or complicated) whereas durations 24 hours suggest moderate-to-severe
TBI2-4 - provided that other factors contributing to or confounding assessment, of post-
traumatic amnesia (eg, medications, other medical illnesses, substance withdrawal) do
not better account for amnesia during this period. Recent, evidence,53 however, suggests
that 1-year post-injury outcomes (defined as percent returning to productive employment)
among persons with more-than-mild injuries are defined more usefully by post-traumatic
amnesia durations of 1 to 14 days (70%), 14 to 28 days (40%), and >28 days (20%).
These findings support regarding initial TBI severity as a continuous variable and suggest
further that describing it as such may inform more usefully on injury outcomes than does
strict adherence to TBI severity categories.

In short, initial TBI severity is a substantial source of within-diagnosis heterogeneity.

Additionally, there is heterogeneity within the severity categories defined by GCS scores
and/or post-traumatic amnesia duration, especially at, the mild and severe ends of the TBI
spectrum. Acknowledging this heterogeneity is needed to better understand the variability
in neuropsychiatric presentations and outcomes after TBI, and may inform on the types
and timings of interventions designed to improve those outcomes. This latter issue will be
considered further after a brief review of the neuropathophysiological heterogeneity of
TBI.

Neuropathophysiology of TBI

When an external physical force, including acceleration/deceleration forces, is applied to

the head, the brain is subjected to two types of forces within the intracranial vault: inertial
and contact.37,56 Inertial forces refer to rotation, translation, angular acceleration of brain
tissue within the intracranial vault. The effects of these forces are greatest: (i) at planes of
brain diffuses of different density (ie, gray-white matter junctions); (ii) in areas within the
skull where there is more room for free movement, (ie, anterior and middle cranial
fossae) and, by extension, across white matter tracts connecting brain within those areas
to less mobile brain structures (ie, connections between frontal and temporal areas,
between anterior and posterior areas); and (iii) where differential movement (ie,
interhemispheric tissue - greatest at the anterior and posterior corpus callosum) or
rotation occurs (ie, between the supraand infra-tentorial compartments - upper brain stem
and brain stem-diencephalic junction). Stretching and straining of neural tissues at these
locations disrupts their function and/or structure and, in turn, incites a complex cascade
of potentially injurious cellular and metabolic processes.

This cascade includes: dysrcgulation of calcium, magnesium, and potassium across

disrupted cell membranes; biomechanically induced axon potentials; neurotransmitter and
excitatory amino acid release (discussed below); calcium-regulated protein activation,
mitochondrial dysfunction; altered cellular energetics and metabolism, free radical
formation and oxidative stress; activation of proteolytic enzymes; and, in some cases,
activation of cellular processes that, initiate apoptosis (programmed cell death). These
processes are initiated at the time of injury and gradually wane over the hours, days, or
weeks there after. 22,34,35,57,58

Because neurotransmitter systems are a common target, of pharmacotherapies for

cognitive, emotional, behavioral, and sensorimotor disturbances after TBI, additional
specific comment on this element of the cytotoxic cascade is warranted. Experimental
injury studies59 and cerebrospinal fluid sampling studies among persons with severe TBI36
identify significant neurotransmitter excesses in the early post-injury period; these
include marked elevations of glutamate, L-aspartate, acetylcholine, dopamine,
norepinephrine, serotonin, and y-aminobutyric acid (GABA).This neurotransmitter
storm appears to abate over the course of the first, several weeks following severe TBI,
during which levels of excitatory amino acids (eg, glutamate, aspartate) and the
monoamine neurotransmitters (ie, dopamine, norepinephrine, serotonin) normalize
among survivors of such injuries. The interval over which acute cholinergic excesses
wane after TBI in humans is not well established, but there is at present no evidence to
suggest that the time course of this process differs from that of other neurotransmitter
excesses. However, early post-injury cholinergic excesses are followed by late cortical
cholinergic deficits in a substantial subpopulation of patients.60 There also is evidence of
altered catecholaminergic function after TBI,61,63 and interactions between injuryrelated
alterations in these systems and geneticallymediated individual vulnerabilities may
influence their clinical expression.

Application of an external physical force also may subject the brain to contact, forces -
that is, injury produced when the brain strikes the inner table of the skull, especially the
bony ridges and protuberances within and between the anterior and middle cranial
fossae.37 In addition to compressive damage to brain tissue caused by forceful brain-skull
contacts, local (ie, focal) vascular/hemorrhagic, cytotoxic, and inflammatory injury also
is induced.

The combination of inertial forces, contact, forces, and cellular/metabolic events

associated with the application of biomechanical force tends to disrupt, the function (and,
as initial injury severity increases, the structure) of a relatively predictable set of brain
areas - including, and especially, anterior and ventral frontal and temporal areas, cerebral
hemispheric white matter, and the upper brain stem/brain stem-diencephalic junction. In
light of the neuropsychiatric functions served by these brain structures, TBI therefore also
produces a relatively predictable set, of neuropsychiatric disturbances (Table IV).

Table IV.
Brain areas most vulnerable to traumatic brain injury, the neuropsychiatric functions in which
they are involved, and the neuropsychiatric consequences of injury to these areas. GABA, -
aminobutyric acid; DA, dopamine; NE, norepinephrine; 5HT, ...

Although these disturbances in brain-behavior relationships are typical of TBI, the

ncurobiological consequences of such injuries vary greatly between patients and even
within patients with clinically similar initial TBI severities.29,64 Some, but, not all,
individuals with TBI experience overt structural injury; when structural injury occurs, the
locations and severities of those injuries are highly variable, as are the magnitudes and
durations of concomitant, local and diffuse cytotoxic disturbances.34,35,59,65
Neurophysiologically, there are at least five hypothetical sets of processes that contribute
to acute alterations of consciousness and/or sensorimotor function; these are described by
Shaw59 as the vascular, reticular, centripetal, pontine cholinergic system, and convulsive
hypotheses of concussion. Some of these processes may develop in the absence of
disruptions of brain structure, and some elements of these also are quite transient.
However, some of these evolve over time after injur}' and may entail chronic alterations
of the function of modulatory cerebral neurotransmitter systems.60-62 All TBIs involve
some, but not, all, of these processes.

Unfortunately, presently available clinical neurodiagnostics do not afford comprehensive

identification of the entire spectrum of functional and structural consequences of
biomcchanically induced neurotrauma at the single-patient level - especially at the mild
end of the TBI severity continuum and, at all levels of TBI severity, the microcellular
aspects of neuropathophysiology. As such, the clinical evaluation of persons with TBI
and post-traumatic neuropsychiatric disturbances necessarily leaves unaccountable a
portion - perhaps, in some cases, a majority - of the variance in neuropathobiology
contributing to clinical presentation.

Finally, the neuropathophysiology of TBI may be complicated by secondary neurological

and systemic medical problems. Some develop as a consequence of TBI (eg, post-
traumatic seizures, cerebral edema, subfalcinc or transtentorial herniation, vasconstrictive
ischemic infarctions), some arise as concurrent, consequences of biomechanical
craniocerebral trauma (eg, epidural or subdural hematoma, subarachnoid hemorrhage,
intracranial infection), and others are the result, of concurrent physical injuries or medical
interventions (eg, hypovolemia, hypotension, hypoxia-ischemia, systemic
infection/sepsis, iatrogenic sedation). Although these arc most, commonly problems
among persons hospitalized as a result, of TBI, their development is not, limited to
hospitalized patients and they require consideration in all cases as potential contributors
to neuropsychiatric disturbances and targets of medical and neurorehabilitative
interventions.

Go to:

Post-traumatic encephalopathy; a framework for

addressing neuropsychiatric disturbances during
TBI rehabilitation
Evaluation and treatment approaches follow logically from the philosophy within which
clinical phenomena are observed and interpreted and diagnoses formulated.66 This is
particularly so when facing the diagnostic and therapeutic challenges presented by post-
traumatic cognitive, emotional, behavioral, and sensorimotor (ie, neuropsychiatric)
disturbances: an understanding of such problems borne of traditional guild-like
perspectives of neurosurgery, neurology, psychiatry, or rehabilitation medicine (and
related disciplines) increases these challenges by focusing narrowly or emphasizing
disproportionately one or another elements of the patient's presentation germane to (ie,
within the more limited scope of practice of) each of these disciplines.

The information presented in the preceding sections of this article highlights the need for
a transdisciplinary understanding of traumatic brain injury and its consequences, and calls
for a neuropsychiatrically-informed, neurobiologically-anchored clinical approach. Our
group suggested previously6,22 that the pattern and course of clinical phenomena typical
of the early post-injury period are usefully conceptualized as a post-traumatic
encephalopathy. In the following section, it is suggested that this concept serves usefully
as a foundation upon which to develop such an transdisciplinary clinical approach.

Definition of post-traumatic encephalopathy

Post-traumatic encephalopathy (PTE) denotes the clinical manifestations of brain

dysfunction that develop immediately following application of an external physical force
(including acceleration/deceleration and/or blast-related forces) to the brain. The term
encephalopathy (meaning disorder or disease of the brain) captures the broad range of
neuropsychiatric manifestations of neurotrauma-induced brain dysfunction and the term
post-traumatic anchors the context, of their occurrence to the post-injury period and
their cause to TBI. Given that there is a broad differential diagnosis for eventrelated
neuropsychiatric disturbances, this last point is especially important: proper use of the
term PTE necessitates establishing with confidence that the encephalopathy represents
neurotrauma-induced brain dysfunction and is not simply post-traumatic in that it occurs
after trauma.

Taxonomically, PTE is superordinate to five linearly hierarchical subordinate stages

(from lowest to highest): post-traumatic coma, post-traumatic delirium (confusion al
state), post- traumatic amnesia, and post-traumatic dysexecutive syndrome (Table V).
This organization is anchored to the most clinically salient cognitive feature of each stage
of PTE, and describes the concurrent, and/or persistent, noncognitive neuropsychiatric
symptoms of PTE at each stage as well.

Table V.
The stages of post-traumatic encephalopathy.

Using PTE as a guide to the description, evaluation, and treatment of TBI-induced

neuropsychiatric disturbances obviates the conceptual and semantic debate in this
literature,6-8,22,34,48,50,67-71 much of which derives from attempts to use any other single terms
as a global descriptor of the clinical phenomenology of the post-injury period. The
present framework acknowledges that the phenomena described by terms like post-
traumatic amnesia, posttraumatic confusional state, and post-traumatic delirium
may (and often do) occur after TBI and that each is a potentially important focus of
clinical concern, study, and treatment. However, it, encompasses all of these phenomena
within PTE and regards each as only one of several stages through which persons with
TBI transition during the post-injury period.
It would be conceptually correct, to describe patients whose early post-traumatic
neuropsychiatric disturbances become chronic problems as remaining in PTE (and the
specific stage at which recovery reached its plateau). It is possible that there is merit to
doing so, but the current practice is to describe such patients using more specific clinical
descriptors. For example, wakefulness without, awareness is usually described as a
vegetative state71 and wakefulness with minimal awareness is described as a
minimally conscious state.70,72 It, also is common to describe the clinical presentation of
patients who fail to emerge from post-traumatic delirium or post-traumatic amnesia using
the term posttraumatic dementia - that is, a syndrome of persistent and acquired
impairments in multiple cognitive domains. Similarly, persistent, mild cognitive
impairments are often described as such, or instead as elements of postconcussional
disorder or postconcussive syndrome73,76 we suggest that this may be an instance wherein
posttraumatic dysexecutive syndrome may be both a useful and accurate term to describe
these conditions. While the diagnostic terms presently in use are unlikely to be retired
from clinical parlance at any point in the near future, it will be useful conceptually (and,
perhaps, in TBI research endeavors) to regard their referents as specific subtypes of
persistent PTE.

Finally, an additional advantage of this term is its semantic consistency with chronic
traumatic encephalopathy,77-79 a delayed-onset TBI-induced neurodegenerative disorder.
Adopting a common semantic convention for the description of acute- and delayed-onset
TBI-induced encephalopathies may facilitate the development, of common clinical and
research approaches to these problems, and further reduce the nosological confusion
complicating such endeavors presently.

Neurobiological bases of post-traumatic encephalopathy

The stages of PTE described in this model are anchored to the regional vulnerability to
TBI described in Table III. Post-traumatic coma reflects disturbances in the structure and
function of upper brain stem and brain stem-diencephalic structures, including diffuse
mechanically induced depolarization and synchronized discharge of cortical neurons,
failure of ascending reticular activation system, or combinations of these and other
processes.59 These arousal-supporting systems often are the first, to resume functioning
after TBI, and their return to relative functional normalcy frequently precedes that of
systems supporting selective and basic sustained attention; these latter systems include
sensory cortical areas, the thalamic and subcortical areas to which they are connected,
and white matter comprising not, only those connections but also the ascending
modulatory neurotransmitter systems that, support them.80 Post-traumatic delirium (or
post-traumatic confusional state) reflects restoration, although not necessarily complete
normalization, of the function of neural systems serving arousal but continued
dysfunction of those serving the most, basic aspects of attention (and, by extension,
higher cognitive functions as well).7

The function of the neural systems supporting basic attention tend to normalize prior to
those supporting episodic memory, executive function, ie, anteromedial temporal and
anterior frontal networks.7,34,81 Dense impairments in declarative new learning (episodic
memory) despite relative normalization of arousal and basic attention characterizes post-
traumatic amnesia; during this stage of PTE, executive dysfunction also persists, but may
be less clinically salient (even if functionally important) in the setting of dense
anterograde amnesia.34,81 The discrepancy between restoration of basic attention and more
complex cognitive functions may be attributable, in part, to the relatively greater
vulnerability of the temporal and frontal areas supporting memory and executive function
to the effects of biomechanical forces, the cytotoxic cascade induced by biomechanical
forces, the vulnerability of these systems to the effects of cholinergic and/or
catecholamergic disturbances, or some combination of these and other factors.

Although the neurobiological bases of this recovery pattern require further investigation,
the systems supporting episodic memory appear, in clinical practice, to resume
functioning relatively normally prior to prefrontal systems - including those serving
intrinsic executive functions, executive control of basic cognitive functions,
comportment, and emotional regulation.34,81,82 The persistence of these problems despite
relative, though not necessarily complete, normalization of declarative new learning
characterizes post-traumatic dysexecutive syndrome.

The clinical and neurobiological impairments that comprise each stage of PTE occur on a
continuum and the transitions between these stages during recovery from TBI may not
proceed unidirectionally: patients functioning cognitively at the transition point, between
stages of PTE may vacillate for days (or longer) between those stages. Nonetheless,
identifying the stage of PTE that, best, describes that patient is useful in that it, facilitates
the development of a treatment plan that is appropriate to the patient's current clinical
status. It also allows clinicians and the patient's family members to anticipate the course
of continued recovery. By extension, this approach to PTE also helps clinicians to
identify deviations from the expected course of recovery after TBI and to recognize the
need to evaluate the patient for conditions that explain such deviations.

Evaluation of post-traumatc encephalopathy

The evaluation of PTE is predicated on a diagnosis of TBI using the clinical case
definitions and initial injury severity descriptions reviewed earlier in this article. As noted
above, consideration of the differential diagnosis for alterations of neuropsychiatric status
in the postinjury period is also required, as is characterization of the neuroanatomy and,
where possible, the neuropathophysiology of TBI. Even when the occurrence of TBI is
incontrovertible, it, will be necessary to entertain the possibility that a patient's
encephalopathy reflects not only TBI but also co-occurring noncerebral injuries, medical
conditions, and their interactions with other pre-or postinjury factors.

When it is clear that the patient is experiencing PTE, identifying the stage and severity of
the encephalopathy is appropriate. The evaluation of PTE is facilitated by the use of
measures that are designed to assess the key neuropsychiatric feature of each PTE stage.
Although consensus is lacking on the optimal assessments of neuropsychiatric status
during the post-injury period, expert panels, literature reviews, clinical research reports,
and common clinical practice suggest that the measures presented in Table VI may be
useful for this purpose.6,8,10,23,81-108 In general, assessment of patients with these measures
is performed serially (eg, daily for PTA assessments, at weekly or longer intervals for
many other measures) during each stage of PTE. Since patients with more severe injuries
arc likely to experience protracted periods of PTE and since they often do not, progress
unidirectionally through its stages, it, sometimes will be useful to administer measures
relevant to two of these stages (eg, post-traumatic delirium and PTA, or PTA and post-
traumatic dysexecutive syndrome) during the periods of transition between PTE stages.

Table VI.
Assessment scales relevant to the examination of patients at various stages of post-traumatic
encephalopathy. Abbreviations: PTE, post-traumatic encephalopathy; PTA, post-traumatic
amnesia

Concurrently, performing a comprehensive neuropsychiatric assessment is recommended.

This includes a detailed injury-event history; review of past and current, medications,
including those that may be contributing to neuropsychiatric disturbances or delaying
recovery; identification of pre-injury developmental, medical, neurological, psychiatric,
and substance use disorders; social history; family history, and general physical,
neurological, and mental status examinations. On this latter point, the PTE stage-relevant
assessments described in Table VI will be useful but, do not constitute an adequate
mental status examination. Direct, systematic, and repeated observation of the patient, is
often needed to identify intermittent or waxing and waning neuropsychiatric disturbances
in this population, as are structured interviews of staff and family members about such
issues. In this context, it also is essential to obtain from knowledgeable informants a
description of the patient's social history (eg, development, interpersonal style and habits,
level of education, occupation and performance, legal history, military experience) and
social supports (eg, marital status, family and friends). This information will identify
strengths and limitations of the patient, the social context from which he or she hails, and
the setting to which a return will be made after inpatient rehabilitation. This information
may help patient, family, and health care providers anticipate likely long-term outcomes
and community reintegration needs and to assess the financial resources (or lack thereof)
available to support, the rehabilitation process.

As suggested earlier, the correspondence between clinical phenomena and the

neuropathophysiology upon which they are predicated is not, absolute; there is substantial
neurobiological heterogeneity within the diagnostic category of TBI. It therefore is
important to characterize anatomic injury during the evaluation of persons in PTE. In
many (perhaps most) cases in which TBI results in hospitalization, computed tomography
(CT) of the brain will be performed in the acute injury setting. 'Ihis imaging technology
permits identification of skull fracture, acute hemorrhage, or hemorrhagic contusion, and
very severe diffuse axonal injury, but, is of limited value for more detailed
characterization of neuroanatomic injury. Accordingly, we recommend obtaining
magnetic resonance imaging (MRI) of the brain in all neurorehabilitation inpatients
receiving neuropsychiatric assessment after TBI. Tl -weighted, fluid-attenuated inversion
recovery (FLAIR), T2*-weightcd gradient echo, susceptibility-weighted (when
available), and diffusion-weighted sequences should be included in MRI examinations of
persons with TBI.109 There is emerging evidence for the application of advanced
neuroimaging technologies such as functional MRI, diffusion tensor imaging (DTI),
magnetic resonance spectroscopy, cerebral blood flow (or metabolism) focused nuclear
imaging, or ncurotransmitter-targeted nuclear imaging (eg, positron emission
tomography) to the evaluation of persons with a broad range of neuropsychiatric
disturbances after TBI,109 including those encompassed under the heading of PTE. At, the
present time, however, the usefulness of these technologies in the inpatient, rehabilitation
setting is uncertain; further research is needed to clarify the extent to which group-level
findings reported in the literature obtain at the single-patient level.

Electroencephalography (EEG), including evoked potentials, event-related potentials, and

quantitative EEG (qEEG), do not usually contribute usefully to the neuropsychiatric
assessment of patients undergoing acute neurorehabilitation after nil.110 When clinical
history suggests the possibility of seizures (particularly complex partial seizures with
postictal confusion or behavioral disturbances), then it is appropriate to obtain an EEG to
identify potentially epileptiform abnormalities. However, it is important, to remain
mindful that interictal EEG is relatively insensitive to epileptiform abnormalities and that
the decision to treat patients for post-traumatic seizures rests on the event semiology and
not on the presence or absence of electroencephalographic abnormalities.

The laboratory assessments evidence needed to guide in the acute neurorehabilitation

setting also is underdeveloped. At a minimum, reviewing and/or obtaining laboratory data
(including serum and urine studies) that may inform on contributors to, or alternate
explanations for, encephalopathy after TBI is prudent. Recent reviews also suggest, that
neuroendocrine disturbances are common and underdiagnosed in this population.111,112
Other than assessment of thyroid stimulating hormone and thyroid hormone levels,
however, the best methods of assessing and treating other post-traumatic neuroendocrine
disturbances remain matters of debate.

Treatment of PTE During rehabilitation after TBI

Perhaps the greatest challenge facing clinicians caring for persons with post-traumatic
neuropsychiatric disturbances providing clinically useful interventions. There are many
neurophysiology processes involved in eventrelated alterations of consciousness and/or
neurological function and, by extension, a broad array of potential neurobiological targets
for neuropsychiatrically-directed post-TBT clinical interventions. Accordingly, there is a
very low likelihood that any single intervention will attenuate the full complement of
acute, and potentially chronic, neurobiological consequences of TBI.
For persons in PTE receiving inpatient, rehabilitation, nursing care, treatment of medical
issues, re-injury risk reduction (eg, fall prevention), and environmental/ behavioral
management, are the cornerstones of treatment. In many patients, reducting or
eliminating of medications that may interfere with neuropsychiatric function,
rehabilitation, or recovery will be useful; for example, discontinuing anticonvulsants
prescribed for seizure prophylaxis among persons remaining seizurefree after the first,
week post-injury,113,114 and avoiding use of typical antipsychotics and
benzodiazepines.36,115 There are published guidelines for these and related interventions in
this population (see, for example, ref 113), including evidence-based analyses and
systematic reviews of the types and potential benefits of various forms cognitive
rehabilitation116-118 and pharmacotherapies.36,119-121 A comprehensive review of this
literature is beyond the scope of this article, and readers are referred to the references
cited here for more specific information on these subjects.

Regardless of the treatments prescribed for post-traumatic neuropsychiatric disturbances

during the postinjury rehabilitation period, clinicians inevitably face the challenges of
matching the treatments they provide to patients for whom they are likely to be most
useful. The literature reviewed in this article suggests that there are several critical
variables requiring consideration before prescribing rehabilitative interventions to
persons with TBI: initial TBI severity, time post-injury (ie, as a reflection of the phase of
the cytotoxic cascade), stage of PTE, and the specific neuropsychiatric treatment targets
identified in these contexts.

Initial TBI severity influences the need for treatment and the focus of treatments offered.
For example, the vast majority of persons with mild TBI require neither hospitalization
nor formal neurorehabilitation and are likely to make a relatively rapid and full recovery
without, medical or rehabilitative interventions.29,38 Indeed, the most effective
interventions for this population arc early support, education, and realistic expectation
setting.122,123 By contrast, the rate and extent of spontaneous recovery from TBI of
moderate or greater severity is typically slower and long-term outcomes (even with
rehabilitative interventions) often are less complete.39,124,125 Those whose recoveries
proceed to the point that they are effectively able to engage in rehabilitative interventions
may benefit from rehabilitation, including various forms of cognitive rehabilitation,
patient and family education, and support116-118,123,126-128 those whose deficits limit their
direct, engagement in such interventions may benefit more from family-or
caregiverdirected training.116,118

The benefits or harms presented by a rehabilitative intervention, and especially

pharmacotherapies, also are likely to vary with time post-injury. At the earliest time post-
injury, the neurochemical excesses produced by cerebral neurotrauma may make the use
of agents that augment cerebral neurotransmitter levels ineffective or neurochemically
counterproductive.121,129,130 By contrast, agents that attenuate the neurotransmitter storm
might be therapeutically useful; for example, early intervention with amantadine, a
moderate-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonist, appears to
facilitate recovery of consciousness during the first, week post-injury,121 perhaps
reflecting mitigation of early glutamate-mediated neurotoxicity. Although it might, seem
reasonable to hypothesize that antagonism other early post-injury neurotransmitter
excesses toward this same end, the available evidence from clinical studies suggests that
such interventions (eg, dopamine antagonism with halopcridol, use of agents with potent
anticholinergic properties) are not only unhelpful but also may prolong PTE.131-133

The complexity of the neurochemical cascade makes the effects of such agents (or the
lack thereof) difficult to anticipate,134 but important to consider nonetheless. These issues
might be more readily addressed by the application of in vivo imaging of
neurotransmitter systems and/or other elements of the cytotoxic cascade; such imaging
might identify specific elements of the cascade as targets for intervention or, perhaps
more realistically, identify a point, post-injury at which such treatments are likely to be
safe and effective. The examples of such applications are promising135 but remain
underexplored in this field.

Presently, treatment may be organized most usefully by identifying the cognitive targets
of treatment, the stage of PTE in which those targets occur, and (as a proxy marker for
TBI neuropathophysiology) the time postinjury at which treatment is undertaken. As a
general rule, medications that augment cholinergic function, catecholaminergic function,
or both facilitate recover}' of arousal, processing speed, attention, memory, and executive
when administered during the post-acute rehabilitation period following TBI.36,119,120
However, the cognitive effects of medications targeting these neurotransmitter systems
are not, identical: agents that augment cerebral catecholaminergic function appear to
improve processing speed and, to a lesser extent, arousal and sustained attention
(vigilance).36,136 Agents that augment, cerebral cholinergic function appear most useful for
the treatment of declarative memory impairments and, among responders, may
secondarily benefit other aspects of cognition.36-137-139 These interventions are most useful,
in general, for persons who have progressed to or beyond the post-traumatic delirium
stage of PTE.; they do not appear to be particularly useful for persons in coma, vegetative
states, or the minimally conscious state.140

Most of the medications used commonly in neurorehabilitative practices are

mechanistically pleotropic.The several possible neurochemical effects of a given
medication in the neurometabolic and neurochemical milieu into which it is introduced
therefore are necessary considerations during treatment selection and will guide treatment
response expectations. For example, early post-injury administration of uncompetitive
NMDA receptor antagonists such as amantadine (or, perhaps, memantinc) may attenuate
the adverse effects of early glutamate excesses and facilitate progression from
posttraumatic coma to higher stages of PTE. In the subacute or late post-injury period, the
clinical benefits of amantadine141 on post-traumatic disorders of consciousness (ie,
vegetative or minimally conscious states after severe TBI) may reflect its NMDA
receptor function-stabilizing properties, indirect facilitation of dopamine release by
NMDA antagonism, other synapse-related effects on dopamine neurotransmission, or
some combinations of these pharmacologic effects. When this same agent is used to treat
the cognitive and other neuropsychiatric manifestations of the post-traumatic
dysexecutive syndrome, especially after mild or moderate TBI, the beneficial effects of
amantadine most likely reflect enhanced frontal function via indirect augmentation of
cerebral dopaminergic activity.36,119,120

Zolpidem provides another example of the differential neuropsychiatric effects on a

specific cognitive target, based on the context (ie, initial injury severity, stage of PTE,
time post-injury) in which it is administered. Zolpidem binds to GABAA receptors and
thereby potentiates the effect, of G ABA, the principal inhibitory neurotransmitter in the
central nervous system. Among persons with relatively intact arousal systems and
minimal disturbances in other modulator}' neurotransmitter systems (ie, persons in post-
traumatic dysexecutive syndrome stage of PTE. during the subacute or late postinjury
periods following mild TBI), Zolpidem is likely to impair arousal - hence its common use
as an agent, with which to treat insomnia. However, when administered to individuals
with severely altered arousal and attentional systems in the subacute or late post-injury
period following severe TBI (ie, persons with persistent post traumatic disorders of
consciousness), Zolpidem may reciprocally disinhibit arousal systems among persons in
the lower stages of PTE.141,142 Whether this reflects a direct of effect of its action at
GABAA receptors or a secondary effect, of those actions on the function of other
modulatory neurotransmitter systems remains uncertain. Whichever is the case, however,
the context-dependent effects of this agent, as well as those of amantadine, highlight the
need to consider not only the phnomnologie target of treatment but also the initial
injury severity, stage of PTE, and time by post-injury (as a proxy for underlying
neuropathophysiology) when prescribing medications to address neuropsychiatric
disturbances during neurorehabilitation.

Initial TBI severity also may interact with other patientspecific factors, and particularly
neurogenetics, in a manner that influences recovery course and treatment, needs.61,143,144
Genes that confer susceptibility to adverse outcomes - for example, the apolipoprotein 4
allele - may interact, with injury severity and/ or age such that individuals of certain ages
and injury severities with these genes may be a greater risk for poor outcome than those
with other genetic characteristics.145-147 Genes coding for enzymes that affect the
metabolism of neurotransmitters involved in cognition also influence cognitive
performance after TBI.61,148 Since the neurotransmitter systems in which these genetic
effects are expressed are potential targets of pharmacotherapies, treatment response
expectations and/or medication dosing requirements might require modification based on
patient-specific neurogenetics. Additionally, the influence of neurogenetics on treatment
response or dosing requirements may vary with initial TBI severity and the state of the
cytotoxic cascade during with treatment is offered, highlighting the need to entertain all
of these factors whether one is treating an individual patient or designing a clinical trial.

In summary, the challenges of treating cognitive, emotional, behavioral, and sensorimotor

- that is, neuropsychiatric - disturbances after TBI requires evolution of the manner in
which clinicians match treatments to clinical problems. The considerations offered above
suggest that the oft-used approach of treating problem X (ie, impaired sustained
attention) with medication Y (ie, a stimulant or other catecholaminergic agent) is
overly simplified in general and potentially hazardous during the early rehabilitation
period after TBI more specifically. Rational pharmacotherapy of post-traumatic
neuropsychiatric disturbances during TBI neurorehabilitation requires consideration of
not, only the intended phnomnologie targets of treatment but, also initial TBI severity,
time post-injury (ie, phase of the cytoxic cascade), stage of PTE, and the influence and
interactions between these factors.

Go to:

Conclusion
The care provided to persons hospitalized following TBI is intrinsically and unavoidably
neuropsychiatric: cognitive, emotional, behavioral, and sensorimotor (ie,
neuropsychiatric) disturbances define TBI and remain the principal clinical
manifestations of this condition throughout, the post-injury period. These problems
present, substantial short- and long-term challenges to injured persons, their families, and
the clinicians providing their care. In this article, a neuropsychiatrically informed,
neurobiologically anchored approach to understanding and meeting challenges was
outlined. That approach begins with the diagnostic evaluation, in which well accepted
clinical case definitions are used and the differential diagnosis of TBI and injury event-
related alterations in neuropsychiatric function are considered carefully. The influence of
initial TBI severity and the neuropathophysiologies are considered with regard to the
manner in which they inform on clinical presentation and course after TBI. The clinical
manifestations of neurotrauma-induced brain dysfunction are then framed usefully as a
PTE comprising several phenomenologically distinct stages. This framework guides
clinical evaluation and treatment planning. In that context, the importance of considering
initial TBI severity, time postinjury (ie, phase of the cytoxic cascade), stage of PTE, and
the influence and interactions between these issues when selecting treatments for post-
traumatic neuropsychiatric disturbances is evident.

If this approach to the challenges of neuropsychiatric disturbances during rehabilitation

after TBI has merit, then it suggests several future research directions. First, research in
this area must, employ standard clinical case definitions of TBI and address the
differential diagnoses, common comorbidities, and within-diagnosis heterogeneity of
TBI. The Interagency Initiative toward Common Data Elements for Research on
Traumatic Brain Injury and Psychological Health1 is an example of the type of work
needed to move the field toward this end. Second, research questions about clinical
evaluations and interventions are most useful when they are predicated on robust a priori
hypotheses anchored to the neuropathophysiology of TBI rather than to clinical
phenomena alone is essential. Inferential reasoning about neuropathophysiology from the
effects of pharmacotherapies is ill-advised: ie, concluding that since an agent that,
augments the levels of a given neurotransmitter, and since administration of that agent
appears to improve cognition after TBI, then TBI must produce deficits of that
neurotransmitter. 'Ihe effects of selective or neurotransmitter-specific medications are
rarely as specific as purported, and some agents (eg, stimulants, cholinesterase inhibitors,
selective serotonin reuptake inhibitors) sometimes improve neuropsychiatric (and
especially cognitive) function among healthy individuals. Advances in our understanding
of the neuropath obiology of TBI may yield reliable neuroimaging markers, biomarkers,
or other indices that facilitate the development of neurobiologically rational, effective,
and potentially neuroprotective or neurorestorative interventions. Additional attention to
patient-specific factors such as neurogenetic factors may contribute usefully to the
development, of such interventions as well.

Ideally, research and clinical efforts in this area will integrate clinical assessments (for
example, those informed by the framework of PTE presented here) with advanced
neuroimaging, neurogenetics, and other biometrics to better match interventions studied
and deployed to the people to who they are provided. Multiccnter randomized controlled
trials guided by this type of integrated clinical, neurobiological, and patientcentered
research approach will better define optimal methods for addressing the
neurorehabilitative challenges presented by post-traumatic neuropsychiatric disturbances.

Go to:

Acknowledgments
This work was supported in part by NICHD grants R01 HD047242 and HD047242-S1 .
The author has no conflicts of interest or necessary disclosures as regards the content of
this work.

Go to:

REFERENCES
1. Menon DK., Schwab K., Wright DW., Maas Al. Positon statement: definiton of traumatc brain
injury. Arch Phys Med Rehabil. 2010;91:16371640. [PubMed]
2. Kay T., Harrington DE., Adams RE., et al. Definiton of mild traumatc brain injury: report from
the Mild Traumatc Brain Injury Committee of the Head Injury Interdisciplinary Special Interest
Group of the American Congress of Rehabilitaton Medicine. J Head Trauma Rehabil. 1993;8:86
87.
3. Helmick K., Guskiewicz KM., Barth J., et al. Defense and Veterans Brain Injury Center Working
Group on the Acute Managment of Mild Traumatc Brain Injury in Military Operatonal Settings.
Clinical Practce Guideline and Recommendatons, December 22, 2006. Washington DC: Defense
and Veterans Brain Injury Center; 2006 [February 28, 2011]; Available at: httpy/www.pdhea
lth.mil/downloads/clinical_practce_guideline_recom me ndatons.pdf. Accessed May 2011.
4. Department of Veterans Affairs and Department of Defense Clinical Practce Guideline:
Managment of Concussion/mild Traumatc Brain Injury. 2009. 2009 tbi_full_1_0.pdf. Accessed
May 2011.
5. Marr A., Coronado VG. Central Nervous System injury Surveillance Data Submission Standards
- 2002. Atlanta, GA: Natonal Center for Injury Control and Preventon, Centers for Disease
Control and Preventon; 2002.
Arciniegas DB., Frey KL., Newman J., Wortzel HS. Evaluaton and management of posttraumatc
cognitve impairments. Psychiatr Ann. 2010;40:540552. [PMC free artcle] [PubMed]
7. Stuss DT., Binns MA., Carruth FG., et al. The acute period of recovery from traumatc brain
injury: posttraumatc amnesia or posttraumatc confusional state? J Neurosurg. 1999;90:635
643. [PubMed]
8. Kean J., Trzepacz PT., Murray LL., Abell M., Trexler L. Inital validaton of a brief provisional
diagnostc scale for delirium. Brain Inj. 2010;24:12221230. [PubMed]
9. Nakase-Thompson R., Sherer M., Yablon SA., Nick TG., Trzepacz PT. Acute confusion following
traumatc brain injury. Brain Inj. 2004;18:131142. [PubMed]
10. Sherer M., Nakase-Thompson R., Yablon SA., Gontkovsky ST. Multdimensional assessment of
acute confusion after traumatc brain injury. Arch Phys Med Rehabil. 2005;86:896904.
[PubMed]
11. Wortzel HS., Frey KL., Anderson CA., Arciniegas DB. Subtle neurological signs predict the
severity of subacute cognitve and functonal impairments after traumatc brain injury. J
Neuropsychiatry Clin Neurosci. 2009;21:463466. [PubMed]
12. Levin HS. Neurobehavioral outcome of closed head injury: implicatons for clinical trials. J
Neurotrauma. 1995;12:601610. [PubMed]
13. Levin HS., Gary HE., Jr, Eisenberg HM., et al. Neurobehavioral outcome 1 year after severe
head injury. Experience of the Traumatc Coma Data Bank. J Neurosurg. 1990;73:699709.
[PubMed]
14. Rapoport M., McCauley S., Levin H., Song J., Feinstein A. The role of injury severity in
neurobehavioral outcome 3 months after traumatc brain injury. Neuropsychiatry Neuropsychol
Behav Neurol. 2002;15:123132. [PubMed]
15. Hart T., Whyte J., Polansky M., et al. Concordance of patent and family report of
neurobehavioral symptoms at 1 year after traumatc brain injury. Arch Phys Med Rehabil.
2003;84:204213. [PubMed]
16. Dikmen S., Machamer J., Miller B., Doctor J., Temkin N. Functonal status examinaton: a new
instrument for assessing outcome in traumatc brain injury. J Neurotrauma. 2001;18:127140.
[PubMed]
17. Dikmen SS., Machamer JE., Powell JM., Temkin NR. Outcome 3 to 5 years after moderate to
severe traumatc brain injury. Arch Phys Med Rehabil. 2003;84:14491457. [PubMed]
18. Hall KM., Bushnik T., Lakisic-Kazazic B., Wright J., Cantagallo A. Assessing traumatc brain
injury outcome measures for long-term followup of community-based individuals. Arch Phys
Med Rehabil. 2001;82:367374. [PubMed]
19. Doctor JN., Castro J., Temkin NR., Fraser RT., Machamer JE., Dikmen SS. Workers' risk of
unemployment after traumatc brain injury: a normed comparison. J Int Neuropsychol Soc.
2005;11:747752. [PubMed]
20. Guilmette TJ., Paglia MF. The public's misconcepton about traumatc brain injury: a follow up
survey. Arch Clin Neuropsychol. 2004;19:183189. [PubMed]
21. Swift TL., Wilson SL. Misconceptons about brain injury among the general public and non-
expert health professionals: an exploratory study. Brain Inj. 2001;15:149165. [PubMed]
22. Arciniegas DB., McAllister TW. Neurobehavioral management of traumatc brain injury in the
critcal care setting. Crit Care Clin. 2008;24:737765. [PubMed]
23. Ciurli P., Formisano R., Bivona U., Cantagallo A., Angelelli P. Neuropsychiatric disorders in
persons with severe traumatc brain injury: prevalence, phenomenology, and relatonship with
demographic clinical and functonal features. J Head Trauma Rehabil. 2011;26:116126.
[PubMed]
24. Fleminger S. Long-term psychiatric disorders after traumatc brain injury. Eur J Anaesthesiol
Suppl. 2008;42:123130. [PubMed]
25. Shaw L., Brodsky L., McMahon BT. Neuropsychiatric interventon in the rehabilitaton of head
injured patents. Psychiatr J Univ. Off. 1985;10:237240. [PubMed]
26. von Hoist H., Cassidy JD. Mandate of the WHO Collaboratng Centre Task Force on Mild
Traumatc Brain Injury. J Rehabil Med. 2004;(43 suppl):810. [PubMed]
27. Borg J., Holm L., Cassidy JD., et al. Diagnostc procedures in mild traumatc brain injury:
results of the WHO Collaboratng Centre Task Force on Mild Traumatc Brain Injury. J Rehabil
Med. 2004;(43 suppl):6175. [PubMed]
28. Kim E., Lauterbach EC., Reeve A., et al. Neuropsychiatric complicatons of traumatc brain
injury: a critcal review of the literature (a report by the ANPA Committee on Research). J
Neuropsychiatry Clin Neurosci. 2007;19:106127. [PubMed]
29. McCrea M., Iverson GL., McAllister TW., et al. An integrated review of recovery after mild
traumatc brain injury (MTBI): implicatons for clinical management. Clin Neuropsychol.
2009;23:13681390. [PubMed]
30. Novack TA., Bush BA., Meythaler JM., Canupp K. Outcome after traumatc brain injury:
pathway analysis of contributons from premorbid, injury severity, and recovery variables. Arch
Phys Med Rehabil. 2001;82:300305. [PubMed]
31. Mitten MJ. Legal issues affectng medical clearance to resume play after mild brain injury. Clin
J Sport Med. 2001;11:199202. [PubMed]
32. Montgomery K. How Doctors Think: Clinical Judgment and the Practce of Medicine. Oxford,
UK; New York, NY: Oxford University Press; 2006
33. Meythaler JM., Peduzzi JD., Eleftheriou E., Novack TA. Current concepts: diffuse axonal injury-
associated traumatc brain injury. Arch Phys Med Rehabil. 2001;82:14611471. [PubMed]
34. Povlishock JT., Katz Dl. Update of neuropathology and neurological recovery after traumatc
brain injury. J Head Trauma Rehabil. 2005;20:7694. [PubMed]
35. Giza CC., Hovda DA. The neurometabolic cascade of concussion. J Athl Train. 2001;36:228
235. [PMC free artcle] [PubMed]
36. Arciniegas DB., Silver JM. Pharmacotherapy of posttraumatc cognitve impairments. Behav
Neurol. 2006;17:2542. [PubMed]
37. Bigler ED. Anterior and middle cranial fossa in traumatc brain injury: relevant neuroanatomy
and neuropathology in the study of neuropsychological outcome. Neuropsychology.
2007;21:515531. [PubMed]
38. Carroll LJ., Cassidy JD., Peloso PM., et al. Prognosis for mild traumatc brain injury: results of
the WHO Collaboratng Centre Task Force on Mild Traumatc Brain Injury. J Rehabil Med. 2004;
(43 suppl):84105. [PubMed]
39. Dikmen SS., Corrigan JD., Levin HS., Machamer J., Sters W., Weisskopf MG. Cognitve
outcome following traumatc brain injury. J Head Trauma Rehabil. 2009;24:430438. [PubMed]
40. Kashluba S., Hanks RA., Casey JE., Millis SR. Neuropsychologic and functonal outcome after
complicated mild traumatc brain injury. Arch Phys Med Rehabil. 2008;89:904911. [PubMed]
41. Kashluba S., Paniak C., Blake T., Reynolds S., Toller-Lobe G., Nagy J. A longitudinal, controlled
study of patent complaints following treated mild traumatc brain injury. Arch Clin
Neuropsychol. 2004;19:805816. [PubMed]
42. Chamoun RB., Robertson CS., Gopinath SP. Outcome in patents with blunt head trauma and
a Glasgow Coma Scale score of 3 at presentaton. J Neurosurg. 2009; 111:683687. [PMC free
artcle] [PubMed]
43. de Guise E., LeBlanc J., Feyz M., Lamoureux J. Predicton of outcome at discharge from acute
care following traumatc brain injury. J Head Trauma Rehabil. 2006;21:527536. [PubMed]
44. Langlois JA., Kegler SR., Butler JA., et al. Traumatc brain injury-related hospital discharges.
Results from a 14-state surveillance system, 1997. MMWR Surveill Summ. 2003;52:120.
[PubMed]
45. Selassie AW., Zaloshnja E., Langlois JA., Miller T., Jones P., Steiner C. Incidence of long-term
disability following traumatc brain injury hospitalizaton. United States, 2003. J Head Trauma
Rehabil. 2008;23:123131. [PubMed]
46. Zaloshnja E., Miller T., Langlois JA., Selassie AW. Prevalence of long-term disability from
traumatc brain injury in the civilian populaton of the United States, 2005. J Head Trauma
Rehabil. 2008;23:394400. [PubMed]
47. Malec JF., Brown AW., Leibson CL., et al. The Mayo classificaton system for traumatc brain
injury severity. J Neurotrauma. 2007;24:14171424. [PubMed]
48. Teasdale G., Jennett B. Assessment of coma and impaired consciousness. A practcal scale.
Lancet. 1974;2:8184. [PubMed]
49. Symonds CP. Observatons on the differental diagnosis and treatment of cerebral states
consequent upon head injuries. BMJ. 1928;2:829832. [PMC free artcle] [PubMed]
50. Russell WR., Smith A. Post-traumatc amnesia in closed head injury. Arch Neurol. 1961;5:4
17. [PubMed]
51. Rimel RW., Jane JA., Edlich RF. An injury severity scale for comprehensive management of
central nervous system trauma. JACEP. 1979;8:6467. [PubMed]
52. Jennett B., Teasdale G. Management of Head Injuries. Philadelphia, PA: F.A. Davis Co; 1981
53. Nakase-Richardson R., Sepehri A., Sherer M., Yablon SA., Evans C., Mani T. Classificaton
schema of posttraumatc amnesia duraton-based injury severity relatve to 1-year outcome:
analysis of individuals with moderate and severe traumatc brain injury. Arch Phys Med Rehabil.
2009;90:1719. [PubMed]
54. Williams DH., Levin HS., Eisenberg HM. Mild head injury classificaton. Neurosurgery.
1990;27:422428. [PubMed]
55. van der Naalt J., Hew JM., van Zomeren AH., Sluiter WJ., Minderhoud JM. Computed
tomography and magnetc resonance imaging in mild to moderate head injury: early and late
imaging related to outcome. Ann Neurol. 1999;46:7078. [PubMed]
56. Gennarelli TA. Mechanisms of brain injury. J Emerg Med. 1993;11(suppl 1):511. [PubMed]
57. Bergsneider M., Hovda DA., Lee SM., et al. Dissociaton of cerebral glucose metabolism and
level of consciousness during the period of metabolic depression following human traumatc
brain injury. J Neurotrauma. 2000;17:389401. [PubMed]
58. Arciniegas DB. Cholinergic dysfuncton and cognitve impairment after traumatc brain injury.
Part 1: the structure and functon of cerebral cholinergic systems. J Head Trauma Rehabil.
2011;26:98101. [PubMed]
59. Shaw NA. The neurophysiology of concussion. Prog Neurobiol. 2002;67:281344. [PubMed]
60. Arciniegas DB. Cholinergic dysfuncton and cognitve impairment after traumatc brain injury.
Part 2: evidence from basic and clinical investgatons. J Head Trauma Rehabil. 2011;26:319323.
[PubMed]
61. McAllister TW. Polymorphisms in genes modulatng the dopamine system: do they inf luence
outcome and response to medicaton after traumatc brain injury? J Head Trauma Rehabil.
2009;24:6568. [PMC free artcle] [PubMed]
62. Bales JW., Wagner AK., Kline AE., Dixon CE. Persistent cognitve dysfuncton after traumatc
brain injury: a dopamine hypothesis. Neurosci Biobehav Rev. 2009;33:9811003. [PMC free
artcle] [PubMed]
63. Redell JB., Dash PK. Traumatc brain injury stmulates hippocampal catechol-O-methyl
transferase expression in microglia. Neurosci Lett. 2007;413:3641. [PMC free artcle] [PubMed]
64. Saatman KE., Duhaime AC., Bullock R., Maas AI., Valadka A., Manley GT. Classificaton of
traumatc brain injury for targeted therapies. J Neurotrauma. 2008;25:719738. [PMC free
artcle] [PubMed]
65. Barkhoudarian G., Hovda DA., Giza CC. The molecular pathophysiology of concussive brain
injury. Clin Sports Med. 2011;30:3348. [PubMed]
66. Stempsey WE. Disease and Diagnosis: Value-Dependent Realism. Dordrecht, Germany;
Boston, MA: Kluwer Academic Publishers; 2000
67. Russell WR. Some reactons of the nervous system to trauma. BMJ. 1964;2:403407. [PMC
free artcle] [PubMed]
68. Hagen C., Malkmus D., Durham P. Rancho LosAmigos Scale. Downey, CA: Communicaton
Disorders Service, Rancho Los Amigos Hospital; 1972
69. Gouvier WD., Blanton PD., LaPorte KK., Nepomuceno C. Reliability and validity of the
Disability Ratng Scale and the Levels of Cognitve Functoning Scale in monitoring recovery from
severe head injury. Arch Phys Med Rehabil. 1987;68:9497. [PubMed]
70. Giacino JT., Ashwal S., Childs N., et al. The minimally conscious state: definiton and
diagnostc criteria. Neurology. 2002;58:34953. [PubMed]
71. Jennett B., Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480
484. [PubMed]
72. Giacino JT., Kalmar K. Diagnostc and prognostc guidelines for the vegetatve and minimally
conscious states. Neuropsychol Rehabil. 2005;15:166174. [PubMed]
73. Boake C., McCauley SR., Levin HS., et al. Limited agreement between criteria-based
diagnoses of postconcussional syndrome. J Neuropsychiatry Clin Neurosci. 2004;16:493499.
[PubMed]
74. Boake C., McCauley SR., Levin HS., et al. Diagnostc criteria for postconcussional syndrome
after mild to moderate traumatc brain injury. J Neuropsychiatry Clin Neurosci. 2005;17:350356.
[PubMed]
75. McCauley SR., Boake C., Pedroza C., et al. Correlates of persistent postconcussional disorder:
DSM-IV criteria versus ICD-10. J Clin Exp Neuropsychol. 2008;30:360379. [PubMed]
76. McCauley SR., Boake C., Pedroza C., et al. Postconcussional disorder: are the DSM-IV criteria
an improvement over the ICD-10? J Nerv Ment Dis. 2005;193:540550. [PubMed]
77. Corsellis JA., Bruton CJ., Freeman-Browne D. The aftermath of boxing. Psychol Med.
1973;3:270303. [PubMed]
78. Jordan BD., Relkin NR., Ravdin LD., Jacobs AR., Bennett A., Gandy S. Apolipoprotein E
epsilon4 associated with chronic traumatc brain injury in boxing. JAMA. 1997;278:136140.
[PubMed]
79. Omalu Bl., DeKosky ST., Minster RL., Kamboh Ml., Hamilton RL., Wecht CH. Chronic traumatc
encephalopathy in a Natonal Football League player. Neurosurgery. 2005;57:128134;
discussion -34. [PubMed]
80. Mesulam M-M. Attentonal networks, confusional states, and neglect syndromes. In:
Mesulam MM, editor. Principles of Behavioral and Cognitve Neurology. Second ed. Oxford, UK:
Oxford University Press; 2000:174256.
81. Larson EB., Leahy B., Duff KM., Wilde MC. Assessing executve functons in traumatc brain
injury: an exploratory study of the Executve Interview. Percept Mot Skills. 2008;106:725736.
[PubMed]
82. Arciniegas DB., Frey K., Alderfer B., Rojas DC., Anderson CA., Filley CM. Impairments of
frontally-mediated cogniton characterize posttraumatc encephalopathy following resoluton of
posttraumatc amnesia. J Neuropsychiatry Clin Neurosci. 2006;18:281.
83. Seel RT., Sherer M., Whyte J., et al. Assessment scales for disorders of consciousness:
evidence-based recommendatons for clinical practce and research. Arch Phys Med Rehabil.
2010;91:17951813. [PubMed]
84. Giacino JT., Kalmar K., Whyte J. The JFK Coma Recovery Scale-Revised: measurement
characteristcs and diagnostc utlity. Arch Phys Med Rehabil. 2004;85:20202029. [PubMed]
85. Rader MA., Ellis DW. The Sensory Stmulaton Assessment Measure (SSAM): a tool for early
evaluaton of severely brain-injured patents. Brain Inj. 1994;8:309321. [PubMed]
86. Shiel A., Horn SA., Wilson BA., Watson MJ., Campbell MJ., McLellan DL. The Wessex Head
Injury Matrix (WHIM) main scale: a preliminary report on a scale to assess and monitor patent
recovery after severe head injury. Clin Rehabil. 2000;14:408416. [PubMed]
87. Ansell BJ., Keenan JE. The Western Neuro Sensory Stmulaton Profile: a tool for assessing
slow-to-recover head-injured patents. Arch Phys Med Rehabil. 1989;70:104108. [PubMed]
88. Gill-Thwaites H. The Sensory Modality Assessment Rehabilitaton Technique-a tool for
assessment and treatment of patents with severe brain injury in a vegetatve state. Brain inj.
1997;11:723734. [PubMed]
89. Pape TL., Heinemann AW., Kelly JP., Hurder AG., Lundgren S. A measure of neurobehavioral
functoning after coma. Part I: Theory, reliability, and validity of Disorders of Consciousness Scale.
J Rehabil Res Dev. 2005;42:117. [PubMed]
90. Trzepacz PT., Mittal D., Torres R., Kanary K., Norton J., Jimerson N. Validaton of the Delirium
Ratng Scale-revised-98: comparison with the delirium ratng scale and the cognitve test for
delirium. J Neuropsychiatry Clin Neurosci. 2001;13:229242. [PubMed]
91. Inouye SK., van Dyck CH., Alessi CA., Balkin S., Siegal AP., Horwitz Rl. Clarifying confusion: the
confusion assessment method. A new method for detecton of delirium. Ann Intern Med.
1990;113:941948. [PubMed]
92. Hart RP., Levenson JL., Sessler CN., Best AM., Schwartz SM., Rutherford LE. Validaton of a
cognitve test for delirium in medical ICU patents. Psychosomatcs. 1996;37:533546. [PubMed]
93. Jackson WT., Novack TA., Dowler RN. Effectve serial measurement of cognitve orientaton in
rehabilitaton: the Orientaton Log. Arch Phys Med Rehabil. 1998;79:718720. [PubMed]
94. Levin HS., O'Donnell VM., Grossman RG. The Galveston Orientaton and Amnesia Test. A
practcal scale to assess cogniton after head injury. J Nerv Ment Dis. 1979;167:675684.
[PubMed]
95. Hanks RA., Millis SR., Ricker JH., et al. The predictve validity of a brief inpatent
neuropsychologic battery for persons with traumatc brain injury. Arch Phys Med Rehabil.
2008;89:950957. [PubMed]
96. Shores EA., Marosszeky JE., Sandanam J., Batchelor J. Preliminary validaton of a clinical scale
for measuring the duraton of post-traumatc amnesia. MedJAust. 1986;144:569572. [PubMed]
97. Ponsford J., Willmott C., Rothwell A., Kelly AM., Nelms R., Ng KT. Use of the Westmead PTA
scale to monitor recovery of memory after mild head injury. Brain inj. 2004;18:603614.
[PubMed]
98. Artola I., Fortuny L., Briggs M., Newcombe F., Ratcliff G., Thomas C. Measuring the duraton
of post traumatc amnesia. J Neurol Neurosurg Psychiatry. 1980;43:377379. [PMC free artcle]
[PubMed]
99. Folstein MF., Folstein SE., McHugh PR. Mini-mental state. A practcal method for grading
the cognitve state of patents for the clinician. J Psychiatr Res. 1975;12:189198. [PubMed]
100. Crum RM., Anthony JC., Bassett SS., Folstein MF. Populaton-based norms for the Mini-
Mental State Examinaton by age and educatonal level. JAMA. 1993;269:23862391. [PubMed]
101. Shulman Kl. Clock-drawing: is it the ideal cognitve screening test? int J Geriatr Psychiatry.
2000;15:54855461. [PubMed]
102. Mendez MF., Ala T., Underwood KL. Development of scoring criteria for the clock drawing
task in Alzheimer's disease. J Am Geriatr Soc. 1992;40:10951099. [PubMed]
103. Dubois B., Slachevsky A., Litvan I., Pillon B. The FAB: a Frontal Assessment Battery at
bedside. Neurology. 2000;55:16211626. [PubMed]
104. Appollonio I., Leone M., Isella V., Piamarta F., Consoli T., Villa ML., et al. The Frontal
Assessment Battery (FAB): normatve values in an Italian populaton sample. Neurol Sci.
2005;26:108116. [PubMed]
105. Cummings JL., Mega M., Gray K., Rosenberg-Thompson S., Carusi DA., Gornbein J. The
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementa.
Neurology. 1994;44:23082314. [PubMed]
106. Royall DR., Mahurin RK., Gray KF. Bedside assessment of executve cognitve impairment:
the executve interview. J Am Geriatr Soc. 1992;40:12211226. [PubMed]
107. McCauley SR., Levin HS., Vanier M., et al. The neurobehavioural ratng scale-revised:
sensitvity and validity in closed head injury assessment. J Neurol Neurosurg Psychiatry.
2001;71:643651. [PMC free artcle] [PubMed]
108. Wagner PJ., Wortzel HS., Frey KL., Anderson CA., Arciniegas DB. Clock drawing performance
predicts inpatent rehabilitaton outcomes after traumatc brain injury. J Neuropsychiatry Clin
Neurosci. In press. [PubMed]
109. Haacke EM., Duhaime AC., Gean AD., et al. Common data elements in radiologic imaging of
traumatc brain injury. J Magn Reson Imaging. 2010;32:516543. [PubMed]
110. Arciniegas DB. Clinical electrophysiologic assessments and mild traumatc brain injury:
state-of-the-science and implicatons for clinical practce, int J Psychophysiol. In press. [PubMed]
111. Rothman MS., Arciniegas DB., Filley CM., Wierman ME. The neuroendocrine effects of
traumatc brain injury. J Neuropsychiatry Clin Neurosci. 2007;19:363372. [PubMed]
112. Ghigo E., Masel B., Aimaretti G., Leon-Carrion J., et al. Consensus guidelines on screening
for hypopituitarism following traumatc brain injury. Brain Inj. 2005;19:711724. [PubMed]
113. Marion DW. Evidenced-based guidelines for traumatc brain injuries. Prog Neurol Surg.
2006;19:171196. [PubMed]
114. Chang BS., Lowenstein DH. Practce parameter: antepileptc drug prophylaxis in severe
traumatc brain injury: report of the Quality Standards Subcommittee of the American Academy
of Neurology. Neurology. 2003;60:1016. [PubMed]
115. Rao N., Jellinek HM., Woolston DC. Agitaton in closed head injury: haloperidol effects on
rehabilitaton outcome. Arch Phys Med Rehabil. 1985;66:3034. [PubMed]
116. Cicerone KD., Dahlberg C., Kalmar K., et al. Evidence-based cognitve rehabilitaton:
recommendatons for clinical practce. Arch Phys Med Rehabil. 2000;81:15961615. [PubMed]
117. Cicerone KD., Dahlberg C., Malec JF., et al. Evidence-based cognitve rehabilitaton: updated
review of the literature from 1998 through 2002. Arch Phys Med Rehabil. 2005;86:16811692.
[PubMed]
118. Cicerone KD., Langenbahn DM., Braden C., et al. Evidence-based cognitve rehabilitaton:
updated review of the literature from 2003 through 2008. Arch Phys Med Rehabil. 2011;92:519
530. [PubMed]
119. Warden DL., Gordon B., McAllister TW., et al. Guidelines for the pharmacologic treatment of
neurobehavioral sequelae of traumatc brain injury. J Neurotrauma. 2006;23:14681501.
[PubMed]
120. Chew E., Zafonte RD. Pharmacological management of neurobehavioral disorders following
traumatc brain injury - a state-of-the-art review. J Rehabil Res Dev. 2009;46:851879. [PubMed]
121. Wheaton P., Mathias JL., Vink R. Impact of early pharmacological treatment on cognitve
and behavioral outcome after traumatc brain injury in adults: a meta-analysis. J. Clin
Psychopharmacol. 2009;29:468477. [PubMed]
122. Bell KR., Hoffman JM., Temkin NR., et al. The effect of telephone counselling on reducing
post-traumatc symptoms after mild traumatc brain injury: a randomised trial. J Neurol
Neurosurg Psychiatry. 2008;79:12751281. [PubMed]
123. Bombardier CH., Bell KR., Temkin NR., Fann JR. Hoffman J, Dikmen S. The efficacy of a
scheduled telephone interventon for amelioratng depressive symptoms during the first year
after traumatc brain injury. J Head Trauma Rehabil. 2009;24:230238. [PubMed]
124. Bazarian JJ., Cernak I., Noble-Haeusslein L., Potolicchio S., Temkin N. Long-term neurologic
outcomes after traumatc brain injury. J Head Trauma Rehabil. 2009;24:439451. [PubMed]
125. Colantonio A., Ratcliff G., Chase S., Kelsey S., Escobar M., Vernich L. Longterm outcomes
after moderate to severe traumatc brain injury. Disabil Rehabil. 2004;26:253261. [PubMed]
126. Bell KR., Temkin NR., Esselman PC., et al. The effect of a scheduled telephone interventon
on outcome after moderate to severe traumatc brain injury: a randomized trial. Arch Phys Med
Rehabil. 2005;86:851856. [PubMed]
127. Sarajuuri JM., Kaipio ML., Koskinen SK., Niemela MR., Servo AR., Vilkki JS. Outcome of a
comprehensive neurorehabilitaton program for patents with traumatc brain injury. Arch Phys
Med Rehabil. 2005;86:22962302. [PubMed]
128. Vanderploeg RD., Schwab K., Walker WC., et al. Rehabilitaton of traumatc brain injury in
actve duty military personnel and veterans: Defense and Veterans Brain Injury Center
randomized controlled trial of two rehabilitaton approaches. Arch Phys Med Rehabil.
2008;89:22272238. [PubMed]
129. Wilson MS., Hamm RJ. Effects of fluoxetne on the 5-HT1A receptor and recovery of
cognitve functon after traumatc brain injury in rats. Am J Phys Med Rehabil. 2002;81:364372.
[PubMed]
130. Meythaler JM., Depalma L., Devivo MJ., Guin-Renfroe S., Novack TA. Sertraline to improve
arousal and alertness in severe traumatc brain injury secondary to motor vehicle crashes. Brain
inj. 2001;15:321331. [PubMed]
131. Arciniegas D., Adler L., Topkoff J., Cawthra E., Filley CM., Reite M. Attenton and memory
dysfuncton after traumatc brain injury: cholinergic mechanisms, sensory gatng, and a
hypothesis for further investgaton. Brain Inj. 1999;13:113. [PubMed]
132. Arciniegas DB. The cholinergic hypothesis of cognitve impairment caused by traumatc
brain injury. Curr Psychiatry Rep. 2003;5:391399. [PubMed]
133. Hoffman AN., Cheng JP., Zafonte RD., Kline AE. Administraton of haloperidol and
risperidone after neurobehavioral testng hinders the recovery of traumatc brain injury-induced
deficits. Life Sci. 2008;83:602607. [PMC free artcle] [PubMed]
134. Arciniegas DB. Designing clinical trials to improve neurobehavioral outcome after traumatc
brain injury: from bench to bedside. Crit Care Med. 2009;37:784785. [PubMed]
135. Ostberg A., Virta J., Rinne JO., et al. Cholinergic dysfuncton after traumatc brain injury:
preliminary findings from a PET study. Neurology. 2011;76:10461050. [PubMed]
136. Whyte J., Hart T., Vaccaro M., et al. Effects of methylphenidate on attenton deficits after
traumatc brain injury: a multdimensional, randomized, controlled trial. Am J Phys Med Rehabil.
2004;83:401420. [PubMed]
137. Zhang L., Plotkin RC., Wang G., Sandel ME., Lee S. Cholinergic augmentaton with donepezil
enhances recovery in short-term memory and sustained attenton after traumatc brain injury.
Arch Phys Med Rehabil. 2004;85:10501055. [PubMed]
138. Silver JM., Koumaras B., Chen M., et al. Effects of rivastgmine on cognitve functon in
patents with traumatc brain injury. Neurology. 2006;67:748755. [PubMed]
139. Silver JM., Koumaras B., Meng X., et al. Long-term effects of rivastgmine capsules in
patents with traumatc brain injury. Brain Inj. 2009;23:123132. [PubMed]
140. Martn RT., Whyte J. The effects of methylphenidate on command following and yes/no
communicaton in persons with severe disorders of consciousness: a meta-analysis of n-of-1
studies. Am J Phys Med Rehabil. 2007;86:613620. [PubMed]
141. Whyte J., Katz D., Long D., et al. Predictors of outcome in prolonged posttraumatc disorders
of consciousness and assessment of medicaton effects: A multcenter study. Arch Phys Med
Rehabil. 2005;86:453462. [PubMed]
142. Whyte J., Myers R. Incidence of clinically significant responses to Zolpidem among patents
with disorders of consciousness: a preliminary placebo controlled trial. Am J Phys Med Rehabil.
2009;88:410418. [PubMed]
143. McAllister TW., Flashman LA., McDonald BC., Saykin AJ. Mechanisms of working memory
dysfuncton after mild and moderate TBI: evidence from functonal MRI and neurogenetcs. J
Neurotrauma. 2006;23:14501467. [PubMed]
144. Jordan BD. Genetc influences on outcome following traumatc brain injury. Neurochem Res.
2007;32:905915. [PubMed]
145. Rapoport M., Wolf U., Herrmann N., et al. Traumatc brain injury, Apolipoprotein E-epsilon4,
and cogniton in older adults: a two-year longitudinal study. J Neuropsychiatry Clin Neurosci.
2008;20:6873. [PubMed]
146. Alexander S., Kerr ME., Kim Y., Kamboh Ml., Beers SR., Conley YP. Apolipoprotein E4 allele
presence and functonal outcome after severe traumatc brain injury. J Neurotrauma.
2007;24:790797. [PubMed]
147. Ariza M., Pueyo R., Matarin Mdel M., et al. Influence of APOE polymorphism on cognitve
and behavioural outcome in moderate and severe traumatc brain injury. J Neurol Neurosurg
Psychiatry. 2006;77:11911193. [PMC free artcle] [PubMed]
148. Lipsky RH., Sparling MB., Ryan LM., et al. Associaton of COMT Val158Met genotype with
executve functoning following traumatc brain injury. J Neuropsychiatry Clin Neurosci.
2005;17:465471. [PubMed]

Artcles from Dialogues in Clinical Neuroscience are provided here

Jurnal 8
Int J Dev Neurosci. Author manuscript; available in PMC 2013 May 1.
Published in final edited form as:
Int J Dev Neurosci. 2012 May; 30(3): 239245.
Published online 2011 December 17. doi: 10.1016/j.ijdevneu.2011.12.005
PMCID: PMC3322312
NIHMSID: NIHMS348515
Depression in Children and Adolescents in the First Six Months After Traumatc Brain Injury
Jeffrey E. Max, M.B.B.Ch,a Eva Keatley, B.S.,b Elisabeth A. Wilde, Ph.D.,c Erin D. Bigler, Ph.D.,d
Russell J. Schachar, M.D.,e Ann E. Saunders, M.D.,f Linda Ewing-Cobbs, Ph.D.,g Sandra B.
Chapman, Ph.D.,h Maureen Dennis, Ph.D.,i Tony T. Yang, M.D., Ph.D.,j and Harvey S. Levin, Ph.D.k
Author informaton Copyright and License informaton
The publisher's final edited version of this artcle is available at Int J Dev Neurosci
See other artcles in PMC that cite the published artcle.
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Abstract
The objectve was to assess the nature, rate, predictve factors, and neuroimaging correlates of
novel (new-onset) depressive disorders, both definite and subclinical, after traumatc brain injury
(TBI). Children with TBI from consecutve admissions were enrolled and studied with psychiatric
interviews soon after injury (baseline), and again 6 months post-injury. Novel definite/subclinical
depressive disorders at 6-month follow up occurred in 11% (n=15) of the children and subsets of
children with non-anxious depression (n=9) and anxious depression (n=6) were identfied. Novel
definite/subclinical depressive disorder was significantly associated with older age at the tme of
injury, family history of anxiety disorder, left inferior frontal gyrus (IFG) lesions, and right frontal
white matter lesions. Non-anxious depressions were associated with older age at injury, left IFG
and left temporal pole lesions. Anxious depressions were associated with family history of
anxiety disorder, Personality Change due to TBI, right frontal white matter lesions, and left
parietal lesions. These findings, which are similar to those reported after adult TBI, identfy both
similarites and differences in non-anxious and anxious depression following childhood TBI with
respect to lesion laterality, genetc factors (in the form of family psychiatric history of anxiety
disorder), age at injury, and more generalized affectve dysregulaton.
Keywords: Depression, Anxiety, Traumatc Brain Injury, Children, Adolescents, Frontal Lobe
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1. Introducton

Pediatric traumatc brain injury (TBI) is a major public health problem (Langlois et al., 2005).
Preinjury psychiatric disorders are very common in children who sustain TBI, with occurrence
ranging from 33-50% in prospectvely studied samples (Brown et al., 1981; Max et al., 1997b).
Psychiatric disorders with their onset after TBI are common and varied (Brown et al., 1981; Max
et al., 1997a). Depression in children and adolescents in the non-TBI general populaton is an
important problem and increases with age, such that the prevalence rate in children is up to
2.5% and for adolescents is up to 8.3% (Birmaher et al., 1996). Part of the morbidity of pediatric
TBI is new-onset depressive symptomatology, although this topic has previously received
minimal systematc study. A retrospectve psychiatric interview study of severe TBI found that
ongoing postnjury-onset depressive disorder occurred in 25% of children with severe TBI and
that 1/3 of the children had a depressive disorder at some point after the injury (Max et al.,
1998b). A prospectve study found that TBI increased the risk of depressive symptoms, recorded
from child self-report and parent questonnaires, especially among more socially disadvantaged
children, and that depressive symptoms were not strongly related to post-injury neurocognitve
scores (Kirkwood et al., 2000). A prospectve psychiatric interview study suggested a link
between preinjury depressive disorder, family history of major depression and preinjury anxiety
disorder in cases of postnjury depressive disorder (Max, 2011). There have been no published
studies systematcally examining lesions in relaton to new-onset depressive symptomatology in
pediatric TBI.

In adults with TBI, new-onset depression has been studied more extensively. Prevalence rates of
new-onset psychiatric disorders in adults post TBI range from 18-50% with the most common
being depressive and anxiety disorders, which have a high rate of comorbidity (Holsinger et al.,
2002; Jorge et al., 2004; Bryant et al., 2010). Personal history of mood and anxiety disorders are
associated with postnjury major depression (Jorge et al., 1993a; Jorge et al., 2004). Studies in
adult TBI suggest that new-onset depression may be associated with left hemisphere lesions,
especially lesions in the left lateral frontal cortex. The investgators found depression post TBI
associated with decreased left frontal gray matter volumes, specifically in the left inferior, middle
and superior frontal gyri (Jorge et al., 2004), and lesions in the left dorsolateral frontal cortex and
left basal ganglia (Jorge et al., 1993b). Furthermore, the investgators found that anxious
depressions (depressive disorder comorbid with an anxiety disorder) were associated with right-
sided lesions (Jorge et al., 1993b).

Our goal was to study the demographic, psychosocial, and lesion predictors as well as the
occurrence and phenomenology of new-onset depressive symptomatology in children after TBI.
Based on the above review we hypothesized that new-onset depression symptomatology post
TBI would be positvely associated with 1) demographic, 2) psychiatric, and 3) injury variables as
follows: 1) older age of injury; 2) family history of depressive disorder, family history of anxiety
disorder, preinjury anxiety, other symptoms of affectve dysregulaton i.e., Personality Change
due to TBI; and 3) lesion locaton and lesion laterality (for the combined group of non-anxious
and anxious depression we predicted lesions of left and right frontal lobe; for those with non-
anxious depression we predicted lesions of the left frontal lobe; and for those with anxious
depression we predicted right frontal lesion locaton).
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2. Materials and Methods

Partcipants in this study were 177 children aged 5-14 years who had a TBI from 1998-2003. The
children were recruited from consecutve admissions to 5 medical centers (3 in Texas, 1 in San
Diego, and 1 in Toronto). Children with mild to severe TBI were enrolled from all centers except
San Diego where only those with complicated mild TBI (i.e., with neuroimaging abnormalites)
to severe TBI patents were recruited. Exclusion criteria included pre-existng schizophrenia or
autstc disorder, mental retardaton, and injury due to child abuse or penetratng missile injury.
In San Diego only, children with pre-existng attenton-deficit/hyperactvity disorder were
excluded. Data regarding the number of children who were approached, the proporton who
were eligible for recruitment, and partcipaton rate among those eligible is missing, due in part
to the fact that children were not required to answer eligibility questons prior to deciding
whether to partcipate in the study. Consistent with the requirements of the Insttutonal Review
Boards, all legal guardians signed informed consent and all children signed an assent form to
partcipate. Demographic, pre-injury psychosocial variables and injury indices for partcipants are
shown in Table 1.
Table 1
Table 1
Demographic, psychosocial, and injury data of enrolled partcipants.
2.1 Psychiatric Diagnoses

DSM-IV-TR psychiatric diagnoses (American Psychiatric Associaton, 2000) were based on data
using the Schedule for Affectve Disorders and Schizophrenia for School-Age Children, Present
and Lifetme Version (K-SADS-PL) (Kaufman et al., 1997) and the Neuropsychiatric Ratng
Schedule (NPRS) (Max et al., 1998a). The K-SADS-PL and NPRS were administered at baseline
(after resoluton of post-traumatc amnesia documented by administraton of the Childrens
Orientaton and Amnesia Scale) (Ewing-Cobbs et al., 1990) to record pre-injury diagnoses and
repeated 6 months after injury to record new-onset diagnoses. The K-SADS-PL is a semi-
structured diagnostc integrated parent-child interview designed to generate diagnoses in
children and adolescents based on DSM-IV-TR criteria. The questons address present and
lifetme symptoms and tming of the onset of psychiatric symptoms in relaton to TBI. The NPRS
is structured similarly to the K-SADS-PL and assesses specifically for Personality Change due to
TBI.

The category of definite/subclinical depressive disorder consisted of children who met full
criteria or had a subclinical depressive disorder including: major depressive disorder (MDD),
depressive disorder not otherwise specified, dysthymia, or adjustment disorder with depressed
mood. A designaton of subclinical depressive disorder was made in situatons where there was
no clear functonal impairment even though partcipants met or were one symptom short of
meetng criteria for a specific depressive disorder. Children with anxiety were diagnosed with at
least one of the following definite and/or subclinical disorders: general anxiety disorder (GAD),
post traumatc stress disorder (PTSD), adjustment disorder with anxious mood, separaton
anxiety disorder, obsessive compulsive disorder (OCD), simple phobia, social phobia, or panic
disorder. Children with an adjustment disorder with depressed or anxious mood were
considered subclinical cases in our classificaton because although the DSM-IV-TR does not
include the respectve adjustment disorders under the depressive or anxiety disorder
classificaton, depressive symptoms or anxious symptoms are specifically noted. We chose to
investgate subclinical depression and anxiety because of the compelling empirical data
supportng the validity of these constructs and their relatonship with corresponding full clinical
disorders with naturalistc follow up (Klein et al., 2009; Shankman et al., 2009).

Definite/subclinical depressive disorders and definite/subclinical anxiety disorders were further

classified as preinjury or novel. Consistent with the pediatric TBI literature, we use the term
novel rather than new to draw a distncton from studies that exclude children with preinjury
psychiatric disorders from analysis in studies focused on postnjury psychiatric disorders (Max et
al., 1997b). Novel definite/subclinical disorders refer to new-onset disorders that occurred within
the first 6 months after TBI. Children with preinjury MDD were ineligible to develop novel
definite/subclinical depressive disorders because they already had the most severe form of
depressive disorder. However, children with preinjury definite/subclinical depressive disorders
who developed a more severe form of depressive disorder (e.g., preinjury history of adjustment
disorder with depressed mood who then developed a postnjury MDD) were classified as having
a novel definite/subclinical depressive disorder. An example of a novel definite/subclinical
anxiety disorder would be a partcipant with no preinjury definite/subclinical anxiety disorder or
with preinjury separaton anxiety disorder who then developed a different anxiety disorder such
as panic disorder after the injury.

Children identfied as having a novel definite/subclinical depressive disorder were further

categorized as either having anxious depression, i.e., comorbid novel definite/subclinical
depressive disorder and novel definite/subclinical anxiety disorder, or non-anxious depression,
i.e., no comorbid definite/subclinical anxiety disorder.

Interviews were conducted by Ph.D. and Masters level clinicians who were trained by the first
author in a pre-study workshop and a mid-study workshop. A child psychiatrist (4 sites) or a child
psychologist (1 site) supervised the assessments at each center. The next level of supervision
involved the first author reviewing written summaries composed by the interviewer and
discussion of cases at monthly teleconferences between the interviewers and the first author. All
disagreements about diagnosis were resolved through consensus among the interviewer and the
first author. This expert quality of interview and supervision is necessary to minimize the
potental of spurious diagnoses of depression considering that brain injury, in the absence of a
depressive disorder, can generate symptoms that overlap with depressive disorder such as
irritability, anhedonia, sleep disturbance, psychomotor changes, fatgue, and concentraton
difficultes.
2.2 Family Psychiatric History

The Family History Research Diagnostc Criteria (Andreasen et al., 1977) interview was
administered by trained research assistants. At least one parent of each child was interviewed
regarding psychiatric disorders for every first-degree relatve of the child with TBI. Criteria were
modified to conform to DSM-IV-TR. Family history of mood disorder (MDD, dysthymia, mania, or
cyclothymia) and family history of anxiety disorder was coded present/absent depending if a
first-degree relatve met diagnostc criteria.
2.3 Adaptve Functon

The Vineland Adaptve Behavior Scales (Sparrow et al., 1984) was used to assess adaptve
functon. The instrument is a nondirectve interview conducted with the childs primary
caretaker surveying behaviors that the child habitually demonstrates in the environment giving
an overall adaptve behavior composite score.
2.4 Family Functon

An assessment of global family functoning was made using the Family Assessment Device
general functoning scale (Miller et al., 1985). The scale is a self-report questonnaire of 12 items
with a four-point scale. The questonnaire is completed by the primary caretaker of each child.
Every response is given a number from a range of 1-4. Lower scores represent better functoning.
2.5 Socioeconomic Status

The Four Factor Index (Hollingshead, 1975) was used to assess socioeconomic status (SES).
Scores take into account both the maternal and paternal educatonal and occupatonal levels.
The scores range from 8-66 with higher scores indicatng higher SES.
2.6 Neurological Assessments

Magnetc Resonance Imaging (MRI) was conducted 3 months after the injury, a tmeframe
sufficient for the major aspects of trauma-related pathology to be expressed (Bigler et al., 1997).
The protocol included fluid attenuated-inversion recovery sequences (3mm slices) and T1
volumetric spoiled gradient recalled echo (1.5mm slices), acquired in coronal and sagittal planes
according to a research protocol applied uniformly across sites. Of the 177 enrolled children, 162
(92%) returned to complete their research MRI. A study neuroradiologist at each center coded
each lesion from the multple slice hard copy films. Pathology (e.g., shearing, encephalomalacia,
hemorrhage) was coded from a list. Anatomical locaton was coded from a list of brain structures
including cortcal gray matter (frontal, temporal, parietal, occipital), subcortcal gray matter
(basal ganglia, thalamus), and white matter (Max et al., 2005). Specific coding of frontal lobe gyri
was made only when gray matter lesions were present in those gyri. Since lesion coding was by
judgment of expert neuroradiologists, and volumetric analyses were not conducted, there was
no attempt to register images or to segment tssue types.

The Glasgow Coma Scale (GCS) (Teasdale and Jennett, 1974), recorded from clinical notes, was
used to classify the severity of TBI based on the lowest post-resuscitaton score. Score ranges for
mild, moderate, and severe TBI are respectvely 13-15, 9-12, and 3-8.
2.7 Statstcal analyses
The outcome variables of interest were novel definite/subclinical depression (all), novel
definite/subclinical non-anxious depression, and novel definite/subclinical anxious depression.
These will be referred to hereafter as depression (all), non-anxious depression, and anxious
depression, respectvely. The associaton of 6-month post-injury depression (all), non-anxious
depression, and anxious depression with the hypothesized predictve variables was tested by
independent sample t-tests for contnuous variables and Fishers exact Test and chi-square
statstcs for categorical variables. The hypothesized associated variable analyzed with an
independent sample t-test was age at injury. The hypothesized associated variables analyzed
with Fishers exact Test were family history of anxiety disorder, family history of mood disorder,
Personality Change due to TBI, pre-injury definite/subclinical anxiety disorder, and neuroimaging
lesions.
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3. Results

One hundred forty one of the original 177 children (80%) returned for the 6-month psychiatric
assessment. The children who did not return were not significantly different from the children
who did with respect to age, gender, race, SES, or GCS score. The children who returned had
significantly higher pre-injury adaptve functon measured by the Vineland Adaptve Behavior
Composite than those who did not return (95.6 +/ 14.6 versus 89.5 +/ 18.0; t=2.02; df=163;
p<.05). Children with basal ganglia lesions were more likely to be in the group not returning
versus those returning (4/20 versus 6/131; Fishers exact = .028), however lesion distributon
was not significantly different in the other 21 areas coded. Partcipants in the 6-month
psychiatric assessment had MRI lesions visualized in 34/63 (54%) of mild TBI cases, 12/17 (71%)
of moderate TBI cases, and 48/51 (94%) of severe TBI cases.
3.1 Incidence

Analyses were done on three different groups of subjects; (1) depression (all), which included all
subjects with a novel definite/subclinical depressive disorder, (2) non-anxious depression, which
consisted of those diagnosed with a novel definite/subclinical depressive disorder but without a
comorbid novel definite/subclinical anxiety disorder, and (3) anxious depression, which included
those with both a novel definite/subclinical anxiety and a novel definite/subclinical depressive
disorder. Three of the children returning for the 6-month follow up had preinjury major
depressive disorder (the most severe form of depressive disorder) and were therefore ineligible
to develop a novel definite/subclinical depressive disorder. Fifteen (11%) of the remaining 138
subjects had a novel definite/subclinical depressive disorder at 6 months following TBI of which
9 (60%) had novel definite/subclinical non-anxious depression and 6 (40%) had novel
definite/subclinical anxious depression. Of the non-anxious depressed subjects 5 were
diagnosed with adjustment disorder depressed mood, 3 were diagnosed with major depressive
disorder (MDD), and one with subclinical dysthymia. Of the subjects with anxious depression 4
were diagnosed with MDD (one subclinical diagnosis), 1 with adjustment disorder depressed
mood and 1 with depressive disorder not otherwise specified. The anxiety diagnoses for this
group were as follows (1 subject had 3 diagnoses); 2 with separaton anxiety, 2 with adjustment
disorder anxious mood, 3 with PTSD (two of which were subclinical), and 1 with simple phobia.

Analyses of each of the depression groups (all; non-anxious; anxious) showed no significant
differences from children without depression regarding demographic variables (gender, race,
SES) and preinjury psychosocial variables (family functon, adaptve functon) as outlined in Table
2. There were no significant between-group differences in injury severity between those with
and without novel definite/subclinical depressive disorder. The numbers of mild and
moderate/severe TBI in the respectve depression groups (all; non-anxious; anxious) were 7 and
8, 6 and 3, and 1 and 5.
Table 2
Table 2
Demographic and psychosocial characteristcs of novel depressive disorder and no novel
depressive disorder groups.
3.2 Predictors of Depression (Table 3)

Age at injury was significantly greater in children with depression (all) versus no depression and
also in non-anxious depression versus no depression. The mean (SD) age in years of children
with depression (all) was 11.9 (2.2) while those without depression 9.9 (2.8) (t=2.55; df=136;
p=.012). For example, there was a 5-fold increase in the rate of depression for children with age
of injury 12 years (18.2%) compared with age of injury < 9 years (3.5%). The mean (SD) age in
years of children with non-anxious depression was 12.7 (1.8) while those without depression
was 9.9 (2.8) (t=4.25; df=11.2; p=.001). Similarly, the rate of non-anxious depression in children
with age of injury 12 years was 14% compared with 0% with age of injury < 9 years.

Family history of anxiety disorder significantly predicted novel depression (all) (Fishers exact
=.008) and novel anxious depression (Fishers exact = .006), but not novel non-anxious
depression. Family history of a mood disorder including depressive disorders was not a predictor
for novel depression (all), non-anxious depression or anxious depression. Comorbid Personality
Change due to TBI at 6 months post injury was significantly correlated with novel anxious
depression only (Fishers exact = .020). Preinjury anxiety did not predict any category of novel
depression.
Table 3
Table 3
Age, injury severity, psychiatric, and lesion characteristcs of novel depressive disorder and no
novel depressive disorder groups.
3.3 Lesion Correlates (Table 3)

Depression (all) was significantly correlated with lesions in the left and right hemispheres
specifically in the left inferior frontal gyrus (IFG) (lesion present in 5/15 versus 8/114 children
with versus without depression; Fishers exact = .008) and right frontal lobe white matter (lesion
present in 5/15 versus 12/114 children with versus without depression; Fishers exact = .029).
There was a non-significant trend associaton between depression (all) and lesions in the left
temporal pole.

Non-anxious depression was significantly correlated with only left hemisphere lesions,
specifically lesions of the left IFG (lesion present in 4/9 versus 8/114 children with versus without
depression; Fishers exact = .005) and the left temporal pole (lesion present in 2/9 versus 2/114
children with versus without depression; Fishers exact = .027).

Anxious depression was significantly correlated with right frontal white matter lesions (lesion
present in 3/6 versus 12/114 children with versus without depression; Fishers exact = .025) and
with left parietal lesions (lesion present in 3/6 versus 10/114 children with versus without
depression; Fishers exact = .014).
3.4 Logistc Regression examining significant demographic, psychiatric, and lesion correlates

The demographic, psychiatric, and lesion correlates of depression which were significant in the
univariate analyses were entered into logistc regression analyses to determine the relatve
independence and significance of these variables in accountng for depression. In the first logistc
regression, depression (all) was the dependent variable and age at injury, family history of
anxiety disorder, left inferior frontal gyrus lesions, and right frontal white matter lesions were the
independent variables. The regression was significant (2 log likelihood 2 = 21.16, df=4,
p=.0003) and correctly predicted 90% of cases. The significance was accounted for
independently by left inferior frontal gyrus lesions (Wald 2 = 6.27, df=1, p=.012), family history
of anxiety (Wald 2 = 4.24, df=1, p=.039), age at injury (Wald 2 = 4.21, df=1, p=.040), but not by
right frontal white matter lesions.

In the second logistc regression, non-anxious depression was the dependent variable and age at
injury, left inferior frontal gyrus lesions, and left temporal pole lesions were the independent
variables. The regression was significant (-2 log likelihood 2 = 17.58, df=3, p = .0005) and
correctly predicted 95% of cases. The significance was accounted for independently by left
inferior frontal gyrus lesions (Wald 2 = 6.13, df=1, p=.013), by age at injury (Wald 2 = 4.54,
df=1, p=.033), but not by left temporal pole lesions.

In the third logistc regression, anxious depression was the dependent variable and right frontal
white matter lesions, left parietal lesions, Personality Change due to TBI, and family history of
anxiety were the independent variables. The regression was significant (-2 log likelihood 2 =
18.02, df=4, p = .0012) and correctly predicted 97% of cases. The significance was accounted for
independently by left parietal lesions (Wald 2 = 4.33, df=1, p=.038), by family history of anxiety
disorder (Wald 2 = 4.96, df=1, p=.026), but not by right frontal white matter lesions or
Personality Change due to TBI.
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4. Discussion

This is the first prospectve psychiatric interview study of pediatric TBI that investgated the
occurrence and phenomenology of new-onset depression and its demographic, psychiatric, and
lesion correlates. Our most important finding is that the pathophysiological mechanisms of TBI-
associated depression may be robust and common across the lifespan. We found non-anxious
depression to be associated with left inferior frontal gyrus and left temporal pole lesions and
anxious depression to be associated with right frontal white matter lesions and left parietal
lesions. These laterality distnctons and lesion-behavior correlates are similar to the findings of
depression studies of adult TBI (Jorge et al., 1993b; Jorge et al., 2004).

The second important finding relates to the relatonship between depressive and anxiety
disorders. Forty-percent of children with novel definite/subclinical depressive disorder had a
comorbid novel definite/subclinical anxiety disorder. This comorbidity is typical in children and
adolescents who have not been injured (Moffitt et al., 2007), as well as in adults with depression
post-TBI (Jorge et al., 2004). Research has shown that there are both similarites and distnctons
in the neural correlates of these disorders (Beesdo et al., 2009). It is not surprising therefore that
lesion correlates of depression vary depending on the presence of comorbid anxiety because
emotonal reactvity is both a neurobiologic risk factor for, and hallmark of, non-anxious
depression as well as anxious depression (Pine et al., 2001). We extend this observaton with the
new finding that emotonal reactvity appears to be broader in the case of anxious depression
evidenced not merely by the presence of comorbid depression and anxiety, but by its significant
associaton with Personality Change due to TBI. Personality Change due to TBI is the classic
example of affectve dysregulaton after TBI and most commonly is characterized by clinically
significant irritability and anger (Max et al., 2005; Max et al., 2006). Postnjury anxiety, we have
found, is related to lesions of the superior frontal gyrus, younger age at injury, and to other
manifestatons of affectve dysregulaton including depression and Personality Change due to TBI
(Max et al., 2011).

An additonal new finding was that family history of anxiety disorder was significantly related to
new-onset depression (combined non-anxious and anxious depression), as well as to anxious
depression although not to non-anxious depression. Family history of mood disorder was not
related to new-onset depression. These findings again demonstrate that there are similarites in
the pathophysiology of depression and anxiety and that genetc factors likely influence the
expression of depression after pediatric TBI.

Older age at injury was significantly related to new onset depression (all) and to non-anxious
depression, but not to anxious depression, consistent with the pattern of increasing rates of
depression from childhood to adolescence (Birmaher et al., 1996). We have previously shown
that younger age at injury is associated with new-onset anxiety in this cohort (Max et al., 2011)
and this likely neutralized the influence of age at injury on anxious depression.

Assessment of the relatve importance of demographic (age at injury), psychiatric (family history
of anxiety disorder, Personality Change due to TBI), and lesion correlates (left IFG, left temporal
pole, right frontal white matter lesions, left parietal lesions) were instructve. In adults with TBI,
abnormal magnetc resonance spectroscopy findings in left temporal and cingulate areas are
related to mood disorder (Capizzano et al., 2010). It is likely that disturbance of critcal limbic
areas and their relatonship to emotonal control underlie important neuropathological
determinants in the development of post-TBI depression (Maller et al., 2010), especially given
the commonness of frontotemperolimbic damage in pediatric TBI (Bigler et al., 2010). The
associaton of anxious depression with left parietal lobe lesions was unexpected, however
anxious depression in adults has been associated with absence of frontal lesions (Jorge et al.,
1993b).

Our findings must be appreciated within its limitatons. Despite the fact that this is the largest
prospectve psychiatric interview of pediatric TBI, the total number of children with depression
was small and subgroups of non-anxious and anxious depression were yet smaller. As with
almost all prospectve studies, attriton is an important limitaton and was 20% of the sample,
although, to be sure, we identfied few differences between partcipants and non-partcipants.
Specifically, children with lower preinjury adaptve functon and children with basal ganglia
lesions were less likely to follow up. We might have expected a higher rate of depression if not
for this pattern of attriton. Another limitaton relates to how neuropathology was identfied, i.e.,
coding of lesions from hard copy films from different scanners. It is possible that even more
insightful markers of neuropathology as it relates to novel onset depressive disorder following
TBI would be observed with advanced neuroimaging analysis methods. The San Diego sample
was different in terms of exclusion of mild TBI partcipants with no lesions and exclusion of
children with pre-injury ADHD. However, the findings are unlikely to be skewed because the San
Diego contngent was relatvely small accountng for 19/141 (13%) of 6-month follow up
partcipants. Another limitaton was the lack of an injured control group which could provide a
comparison of new-onset depression in brain-injured versus orthopaedic injured children.
However, a control group would not be relevant to the important lesion findings.

In conclusion, non-anxious depression after pediatric TBI appears to be linked to specific left-
sided (IFG and temporal pole) lesions and anxious depression is related to different specific left-
sided lesions (parietal lobe) and right-sided lesions (frontal white matter). This lesion-behavior
relatonship is similar to that occurring after adult TBI and suggests a common pathophysiology
despite that fact that depression is less common after pediatric versus adult TBI. Older age at
injury independently accounts for depression, probably because of the increased incidence of
depression noted between childhood and adolescence/adulthood in the general populaton.
Finally, familial factors in the form of family psychiatric history of anxiety disorder, independently
accounts for post-TBI depression.

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Highlights

This prospectve study of pediatric TBI investgated the development of depression postnjury.
Non-anxious depression is associated with older age, left sided lesions.
Anxious depression is linked to familial anxiety, mood lability, and left and right lesions.

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Acknowledgements

This study was supported by Natonal insttute of Mental health (NIMH) Grant K-08 MH01800
(Dr. Max) and Natonal Insttute of Neurological Disorders and Stroke (NINDS) Grant NS-21889
(Dr. Levin). Disclosures: Dr. Schachar is a consultant for Eli Lily Corporaton and Purdue Pharma
(Canada). None of the other authors has financial disclosures to make relatve to for-profit
enterprises.
Go to:
Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for
publicaton. As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyeditng, typesetting, and review of the resultng proof before it
is published in its final citable form. Please note that during the producton process errors may
be discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.

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References

American Psychiatric Associaton Diagnostc and statstcal manual of mental disorders.

American Psychiatric Press; Washington, DC: 2000.
Andreasen NC, Endicott J, Spitzer RL, Winokur G. The family history method using diagnostc
criteria. Reliability and validity. Arch Gen Psychiatry. 1977;34(10):122935. [PubMed]
Beesdo K, Lau JY, Guyer AE, McClure-Tone EB, Monk CS, Nelson EE, Fromm SJ, Goldwin MA,
Wittchen HU, Leibenluft E, Ernst M, Pine DS. Common and distnct amygdala-functon
perturbatons in depressed vs anxious adolescents. Arch Gen Psychiatry. 2009;66(3):27585.
[PMC free artcle] [PubMed]
Bigler ED, Abildskov TJ, Wilde EA, McCauley SR, Li X, Merkley TL, Fearing MA, Newsome MR,
Scheibel RS, Hunter JV, Chu Z, Levin HS. Diffuse damage in pediatric traumatc brain injury: a
comparison of automated versus operator-controlled quantficaton methods. Neuroimage.
2010;50(3):101726. [PubMed]
Bigler ED, Blatter DD, Anderson CV, Johnson SC, Gale SD, Hopkins RO, Burnett B. Hippocampal
volume in normal aging and traumatc brain injury. AJNR Am J Neuroradiol. 1997;18(1):1123.
[PubMed]
Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl RE, Perel J, Nelson B.
Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child
Adolesc Psychiatry. 1996;35(11):142739. [PubMed]
Brown G, Chadwick O, Shaffer D, Rutter M, Traub M. A prospectve study of children with head
injuries: III. Psychiatric sequelae. Psychol Med. 1981;11(1):6378. [PubMed]
Bryant RA, ODonnell ML, Creamer M, McFarlane AC, Clark CR, Silove D. The psychiatric
sequelae of traumatc injury. Am J Psychiatry. 2010;167(3):31220. [PubMed]
Capizzano AA, Jorge RE, Robinson RG. Limbic metabolic abnormalites in remote traumatc
brain injury and correlaton with psychiatric morbidity and social functoning. J Neuropsychiatry
Clin Neurosci. 2010;22(4):3707. [PMC free artcle] [PubMed]
Ewing-Cobbs L, Levin HS, Fletcher JM, Miner ME, Eisenberg HM. The Childrens Orientaton
and Amnesia Test: relatonship to severity of acute head injury and to recovery of memory.
Neurosurgery. 1990;27(5):68391. discussion 691. [PubMed]
Hollingshead A. Four factor index of social status. Yale University, Department of Sociology;
1975.
Holsinger T, Steffens DC, Phillips C, Helms MJ, Havlik RJ, Breitner JC, Guralnik JM, Plassman BL.
Head injury in early adulthood and the lifetme risk of depression. Arch Gen Psychiatry.
2002;59(1):1722. [PubMed]
Jorge RE, Robinson RG, Arndt SV, Starkstein SE, Forrester AW, Geisler F. Depression following
traumatc brain injury: a 1 year longitudinal study. J Affect Disord. 1993a;27(4):23343.
[PubMed]
Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S. Major depression
following traumatc brain injury. Arch Gen Psychiatry. 2004;61(1):4250. [PubMed]
Jorge RE, Robinson RG, Starkstein SE, Arndt SV. Depression and anxiety following traumatc
brain injury. Journal of Neuropsychiatry & Clinical Neurosciences. 1993b;5(4):369374.
[PubMed]
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N. Schedule for
Affectve Disorders and Schizophrenia for School-Age Children-Present and Lifetme Version (K-
SADS-PL): inital reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36(7):980
988. [PubMed]
Kirkwood M, Janusz J, Yeates KO, Taylor HG, Wade SL, Stancin T, Drotar D. Prevalence and
correlates of depressive symptoms following traumatc brain injuries in children. Child
Neuropsychology. 2000;6(3):195208. [PubMed]
Klein DN, Shankman SA, Lewinsohn PM, Seeley JR. Subthreshold depressive disorder in
adolescents: predictors of escalaton to full-syndrome depressive disorders. J Am Acad Child
Adolesc Psychiatry. 2009;48(7):70310. [PMC free artcle] [PubMed]
Langlois JA, Rutland-Brown W, Thomas KE. The incidence of traumatc brain injury among
children in the United States: differences by race. J Head Trauma Rehabil. 2005;20(3):22938.
[PubMed]
 Maller JJ, Thomson RH, Lewis PM, Rose SE, Pannek K, Fitzgerald PB. Traumatc brain injury,
major depression, and diffusion tensor imaging: making connectons. Brain Res Rev.
2010;64(1):21340. [PubMed]
Max JE. Children and Adolescents: Traumatc Brain Injury. In: Silver JM, McAllister TW,
Yudofsky SC, editors. Textbook of Traumatc Brain Injury. Second Editon American Psychiatric
Publishing, Inc.; Washington, D.C.: 2011. pp. 438450.
Max JE, Castllo CS, Lindgren SD, Arndt S. The Neuropsychiatric Ratng Schedule: reliability and
validity. Journal of the American Academy of Child and Adolescent Psychiatry. 1998a;37(3):297
304. [PubMed]
Max JE, Keatley E, Wilde EA, Bigler ED, Levin HS, Schachar RJ, Saunders A, Ewing-Cobbs L,
Chapman SB, Dennis M, Yang TT. Anxiety disorders in children and adolescents in the first six
months after traumatc brain injury. J Neuropsychiatry Clin Neurosci. 2011;23(1):2939.
[PubMed]
Max JE, Koele SL, Smith WL, Jr., Sato Y, Lindgren SD, Robin DA, Arndt S. Psychiatric disorders in
children and adolescents after severe traumatc brain injury: a controlled study. Journal of the
American Academy of Child & Adolescent Psychiatry. 1998b;37(8):832840. [PubMed]
Max JE, Levin HS, Landis J, Schachar R, Saunders A, Ewing-Cobbs L, Chapman SB, Dennis M.
Predictors of personality change due to traumatc brain injury in children and adolescents in the
first six months after injury. J Am Acad Child Adolesc Psychiatry. 2005;44(5):43442. [PubMed]
Max JE, Levin HS, Schachar RJ, Landis J, Saunders AE, Ewing-Cobbs L, Chapman SB, Dennis M.
Predictors of personality change due to traumatc brain injury in children and adolescents six to
twenty-four months after injury. J Neuropsychiatry Clin Neurosci. 2006;18(1):2132. [PubMed]
Max JE, Robin DA, Lindgren SD, Smith WL, Jr., Sato Y, Mattheis PJ, Sterwalt JAG, Castllo CS.
Traumatc brain injury in children and adolescents: Psychiatric disorders at two years. Journal of
the American Academy of Child & Adolescent Psychiatry. 1997a;36(9):12781285. [PubMed]
Max JE, Smith WL, Jr, Sato Y, Mattheis PJ, Castllo CS, Lindgren SD, Robin DA, Sterwalt JAG.
Traumatc brain injury in children and adolescents: Psychiatric disorders in the first three
months. Journal of the American Academy of Child & Adolescent Psychiatry. 1997b;36(1):94
102. [PubMed]
Miller IW, Epstein NB, Bishop DS, Keitner GI. The McMaster Family Assessment Device:
reliability and validity. Journal of Marital & Family Therapy. 1985;11(4):345356.
Moffitt TE, Harrington H, Caspi A, Kim-Cohen J, Goldberg D, Gregory AM, Poulton R.
Depression and generalized anxiety disorder: cumulatve and sequental comorbidity in a birth
cohort followed prospectvely to age 32 years. Arch Gen Psychiatry. 2007;64(6):65160.
[PubMed]
Pine DS, Cohen P, Brook JS. Emotonal reactvity and risk for psychopathology among
adolescents. CNS Spectr. 2001;6(1):2735. [PubMed]
Shankman SA, Lewinsohn PM, Klein DN, Small JW, Seeley JR, Altman SE. Subthreshold
conditons as precursors for full syndrome disorders: a 15-year longitudinal study of multple
diagnostc classes. J Child Psychol Psychiatry. 2009;50(12):148594. [PMC free artcle] [PubMed]
Sparrow S, Balla D, Cicchetti D. The Vineland Adaptve Behavior Scales. American Guidance
Services; Circle Pines, MN: 1984.
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practcal scale.
Lancet. 1974;2(7872):814. [PubMed]

Jurnal 9
Dialogues Clin Neurosci. 2011 September; 13(3): 251262.
PMCID: PMC3182010

Post-traumatic stress disorder vs

traumatic brain injury
Go to:

L'tat de stress post-traumatique versus lsion

crbrale traumatique
Richard Bryant, PhD*
Author information Copyright and License information
This article has been cited by other articles in PMC.
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Abstract
Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) often coexist
because brain injuries are often sustained in traumatic experiences. This review outlines
the significant overlap between PTSD and TBI by commencing with a critical outline of
the overlapping symptoms and problems of differential diagnosis. The impact of TBI on
PTSD is then described, with increasing evidence suggesting that mild TBI can increase
risk for PTSD. Several explanations are offered for this enhanced risk. Recent evidence
suggests that impairment secondary to mild TBI is largely attributable to stress reactions
after TBI, which challenges the long-held belief that postconcussive symptoms are a
function of neurological insult This recent evidence is pointing to new directions for
treatment of postconcussive symptoms that acknowledge that treating stress factors
following TBI may be the optimal means to manage the effects of many TBIs,

Keywords: post-traumatic stress disorder, traumatic brain injury, trauma,

postconcussive syndrome
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Rsum
L'tat de stress post-traumatique (ESPT) et la lsion crbrale traumatique (LCT)
coexistent souvent car la survenue de lsions crbrales est souvent retarde lors des
vnements traumatjques. Cet article souligne le chevauchement significatif entre l'ESPT
et les LCT en dbutant par une description indispensable des symptmes communs et des
problmes lis au diagnostic diffrentiel. L'influence de la LCT sur l'ESPT est ensuite
dcrite, de plus en plus d'arguments suggrant qu'une lgre LCT augmenterait le risque
d'ESPT, ce qui s'explique de diffrents faons : d'aprs des rsultats rcents, le dficit
secondaire une lgre LCT est largement attribuable aux ractions de stress aprs la
LCT, ce qui contredit une croyance ancienne selon laquelle les symptmes post-
commotionnels sont fonction d'une lsion neurologique. Ceci ouvre de nouvelles voies de
traitement des symptmes post-commotionnels, traiter les facteurs de stress aprs une
LCT s'avrant peut-tre le meilleur moyen de prendre en charge les effets des LCT.

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Overview
The intersection between traumatic brain injury (TBI) and post-traumatic stress disorder
(PTSD) has become a major focus of attention in recent years. Stimulated largely by
injuries sustained in the Iraq and Afghanistan wars, this issue has been debated widely
because these conditions, both independently and additively, are regarded as being
responsible for much impairment following deployments. This review will commence
with defining these conditions, explain potential overlaps between them, and discuss the
differential diagnosis challenges of determining the extent to which presenting symptoms
can be attributed to organic or psychological factors. The review then discusses evidence
of PTSD following TBI, and possible mechanisms that may impact on the nature of
PTSD following TBI. The respective roles of PTSD and TBI in impairment after TBI are
then addressed, with specific focus on the understanding of postconcussive symptoms.
Finally, the implications for managing the effects of TBI and PTSD are discussed in
terms of recent developments in how each condition can affect the other.

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Definitional issues
TBI

TBI involves damage to the brain from an external force.Brain injuries can involve
contusion, brain laceration, intracranial hematoma, contrecoup injury, shearing of nerve
fibers, intracranial hypertension, hypoxia, anemia, metabolic anomalies, hydrocephalus,
and subarachnoid hemorrhage. Severity of TBI is typically described in terms of mild or
moderate/severe; however, the exact definitions vary. Mild traumatic brain injury (MTBI)
is usually defined as: (i) an external injur}' to the brain; (ii) confusion, disorientation, or
loss of consciousness for 30 minutes or less; (iii) Glasgow Coma Scale score of 13 to 15;
and (iv) post-traumatic amnesia for less than 24 hours.1-3 Moderate TBI often involves
loss of consciousness between 30 minutes and 24 hours, Glasgow Coma Scale score of 9
to 12, and post-traumatic amnesia between 1 and 7 days. Severe TBI involves more
extended loss of consciousness and post-traumatic amnesia, which typically results in
more severe cognitive impairment. These differences in TBI severity are important
because they appear to interact differentially with PTSD.

PTSD
It is important to distinguish between immediate and longer-term PTSD reactions. Most
diagnostic systems have distinguished between these two types of trauma response
because acute stress reactions are frequent, but often transient, and they need to be
distinguished from the less common persistent PTSD responses. In terms of the persistent
responses, PTSD is described in the American Psychiatric Association's DSM-IV as an
anxiety disorder that comprises five major criteria.4 First, one must have been exposed to
or witness an event that is threatening to safety, and one must respond to this event with
fear, horror, or helplessness. Second, one must report a re-experiencing symptom, which
may include intrusive memories, nightmares, a sense of reliving the trauma, or
psychological or physiological distress when reminded of the trauma. Third, there need to
be at least three avoidance symptoms, which can include active avoidance of thoughts,
feelings, or reminders of the trauma, inability to recall some aspect of the trauma,
withdrawal from others, or emotional numbing. Fourth, one must suffer marked arousal,
which can include insomnia, irritability, difficulty concentrating, hypervigilence, or
heightened startle response. These symptoms must cause marked impairment to one's
functioning, and can only be diagnosed when they are present at least 1 month after the
trauma.

DSM.-IV also introduced a new diagnosis, acute stress disorder (ASD), to describe acute
trauma reactions that occur in the initial month following a trauma. As PTSD is only
diagnosed 1 month after trauma, it was decided that there was a need to fill the
nosological gap between the traumatic event and PTSD, in part to facilitate diagnosis and
access to health care. A second major goal of the ASD diagnosis was to describe acute
stress responses that precede longer-term PTSD, and therefore could be used to identify
people who were at high risk for subsequent disorder and could benefit from early
intervention. ASD is conceptually similar to PTSD and shares many of the same
symptoms.5 A key difference between ASD and PTSD is the former's emphasis on
dissociative symptoms. Specifically, ASD requires the individual to experience at least
three of the following: emotional numbing, reduced awareness of one's surroundings,
derealization, depersonalization, and dissociative amnesia. These symptoms may occur
either at the time of the trauma or during the subsequent month. The dissociative
symptoms were included in ASD on the premise that dissociative responses following
trauma are predictive of subsequent PTSD, presumably because they limit emotional
processing of the traumatic experience.5 Support for the inclusion of dissociative
symptoms in the ASD diagnosis to predict subsequent PTSD came from evidence
demonstrating an association between peritraumatic dissociation and subsequent levels of
PTSD, a finding that has been replicated across several longitudinal studies.6-10 Across
many longitudinal studies, the ASD diagnosis has been shown to be a flawed predictor of
subsecpent PTSD.11 Nonetheless, ASD is being retained in DSM-5 as a descriptor of acute
stress reactions.12

Differential diagnosis

A key issue in this discussion is the overlap between symptoms accompanying each
condition. In terms of the dissociative symptoms often observed in PTSD, and especially
in the acute phase in ASD, there is much evidence that TBI can result in emotional
numbing, derealization, reduced awareness of surroundings, depersonalization, and
amnesia.13-15 The issue of amnesia is particularly important in cases of TBI and PTSD
because of the difficulty in differentiating between organic and psychogenic amnesia.16
Some commentators have adopted the approach of excluding dissociative amnesia as a
possible symptom of ASD and PTSD following TBI to reduce the likelihood of falsely
increasing diagnostic rates.17,18 In diagnosing PTSD, it is probably safer to not include
dissociative amnesia as a potential symptom.

Relevant to the interplay with TBI is the proposed revision of PTSD in the upcoming
revision of DSM-5, which suggests several changes to the PTSD criteria.19 The subjective
response to the trauma at the time of the event (Criterion A2) is to be deleted because it
does not enhance accuracy of identifying people with PTSD. This is important for
patients with 1131 because many patients, especially those with more severe TBI, do not
initially respond with a sense of fear or helplessness because of their impaired
consciousness. Avoidance is being redefined to only include active avoidance of thoughts
and situations, in recognition of the fact that numerous factor analytic studies have
identified four factors of PTSD: reexperiencing, active avoidance, numbing/passive
avoidance, and arousal.20-24 Most of these studies have found that emotional numbing and
social withdrawal are distinct from more active avoidance strategies. This is relevant
because numbing and withdrawal can often be observed in more severe TBI; by
separating these passive responses into a separate requisite cluster, it raises the possibility
of differential diagnosis problems for more severe TBI patients, many of whom will
display these symptoms. This cluster also includes alterations in mood and cognition, and
comprises a range of symptoms that may include a range of emotional responses beyond
fear and anxiety.25 This may also be problematic in terms of differential diagnosis because
of the frequent depressive and generalized anxiety seen in more severe TBI patients.
Although the arousal cluster is retained, there is the expansion of several symptoms,
including aggressive behavior and self-destructive/reckless behavior. These latter
symptoms can be observed in the context of reduced inhibition in more severe TBI
patients, thereby raising further differential diagnosis problems in distinguishing between
symptoms of severe TBI and PTSD.

In contrast to ASD, the International Classification of Diseases26 conceptualizes acute

stress reaction as a transient reaction that can be evident immediately after the traumatic
event and usually resolves within 2 to 3 days after trauma exposure. The ICD description
of acute stress reaction includes dissociative (daze, stupor, amnesia), anxiety
(tachycardia, sweating, flushing), anger, or depressive reactions, which may have more
utility for clinicians than the more focused ASD criteria.27 This position presumes that the
initial period after trauma exposure may result in a rather general state of distress that can
include many emotional responses that cannot be readily classified into different
responses.28 This construct has particular relevance for the acute phase of TBI, especially
more severe TBI, when many of the symptoms described as acute stress reactions may be
a function of impaired consciousness.

A further complicating issue in the differential diagnosis between PTSD and TBI is the
range of other comorbid problems that commonly coexist with both TBI and PTSD. For
example, depression is highly prevalent with both conditions. Numerous studies have
suggested that TBI increases the risk for developing depression,29,30 eg, refs 31,32,33.
Some of the core symptoms noted across TBI and PTSD are also seen in depression,
especially the more severe forms of TBI, including concentration problems, memory
problems, irritability, reduced motivation, and fatigue. Highlighting this problem in one
study was a finding that more than 50% of depressed patients met symptom criteria for
moderate/severe postconcussive syndrome.34 This contributes to the conclusion that some
of the symptoms attributed to TBI may in fact be generic symptoms of psychological
malaise, which are observed across anxiety and depressive responses. Complicating the
issue of comorbidity is compounded by the fact that TBI, PTSD, and depression
commonly occur in the context of chronic pain, which also results in symptoms that
overlap with each of these conditions.35-41

Prevalence

PTSD and TBI are not uncommon. Epidemiological studies indicate that most people in
the community have been exposed to traumatic stressors,42,43 although anly a minority
develop PTSD. For example, the National Comorbidity Survey found that 21 % of the
women and 8% of the men had developed PTSD.42 Similarly, a Detroit study found that
13% of the women and 6% of the men had developed PTSD.43 That is, although men are
more likely to be exposed to trauma than women, women have at least a twofold risk of
developing PTSD compared with men. 44 More severe traumas tend to result in more
severe PTSD. Interpersonal violence leads to more PTSD than impersonal trauma; for
example, whereas 55% of rape victims develop PTSD, only 7.5% of accident victims
develop PTSD:42,45

In terms of TBI, there are between 1.5 and 2 million people in the USA alone who sustain
a TBI, with approximately 70 000 to 90 000 experiencing persistent functional
difficulties.46 The Centers for Disease Control and Prevention estimates that
approximately 5.3 million people in the USA are living with a disability due to TBI.47
Certain populations appear to be more at risk of sustaining TBIs. For example, military
estimates of mild TBI of deployed (non-mcdically evacuated) personnel indicate that
between 10% and 20% may have suffered a mild TBI during deployment.48 One study
reported a rate as high as 23% in personnel assessed after returning to the USA.49

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Can PTSD develop following TBI?

Some earlier commentators argued that PTSD could not develop following TBI because
the impaired consciousness at the time of trauma precluded encoding of the traumatic
experience, and this prevented trauma memories that are necessary for PTSD
development.50,51 In contrast, evidence has accumulated that PTSD can develop following
mild TBI.52-60 Intriguingly, both case studies61-66 and cohort studies17 have noted the
existence of PTSD developing following severe TBI. In many of the latter cases, these
individuals suffer very significant periods of retrograde and anterograde amnesia, such
that they do not recall any episodes of the traumatic experience.

Fear conditioning

Several mechanisms have been put forward to explain how PTSD can develop following
TBI. Fear conditioning models posit that the fear elicited during a traumatic event results
in conditioning in which subsequent reminders of the trauma elicit anxiety in response to
trauma reminders (conditioned stimuli).67 This model proposes that extreme sympathetic
arousal at the time of a traumatic event may result in the release of stress neurochemicals
(including norepinephrine and epinephrine), mediating an overconsolidation of trauma
memories. This proposal is consistent with animal studies that indicate that epinephrine
administration after an aversivc experience enhances fear conditioning.68 Fear
conditioning models are also supported by considerable evidence that people with
chronic PTSD are hyperresponsive to trauma reminders.69-71 The adrenergic increase
occurring after trauma exposure that may contribute to fear conditioning may be reflected
in increased sympathetic nervous system activation, including resting heart rate. Indirect
support for this hypothesis comes from multiple longitudinal studies that indicate that
elevated heart rate in the acute post-trauma phase is associated with subsequent
development of PTSD72; elevated heart rate in the initial days after trauma may reflect
stronger conditioning, which can then translate into longer-term PTSD. Although
conditioning occurs optimally when one is aware of the contingency between the
unconditioned and conditioned stimuli,73 conditioning may occur with varying levels of
awareness of the contingency between the trauma and the consequences, which may
allow for some fear conditioning following TBI. Consistent with this proposal, there is
evidence that people can develop PTSD following severe TBI, even though these patients
do not recall the trauma and do not suffer intrusive memories of the event.17 These
patients display reactivity to reminders of the trauma in the absence of recall of the event;
this observation is consistent with fear conditioning explanations of Unrelated PTSD.
Further support for the possibility of fear conditioning leading to PTSD after severe TBI
patients is evidence of higher heart rates immediately after the trauma in severe TBI
patients who develop PTSD (even during dense post-traumatic amnesia) than those who
do not develop PTSD.74

Memory reconstruction

An alternate mechanism is that TBI patients reconstruct trauma memories in ways that
result in a traumatic representation of what occurred during impaired consciousness. A
prospective study of mild TBI patients assessed motor vehicle accident survivors
immediately after the accident, and subsequently reassessed for their memory of the
event 2 years later; this study found that although all patients initially reported amnesia of
some aspect of the accident, 40% reported 2 years later that they had subsequently
achieved full recall of the experience.75 Supporting this view, case reports describe severe
TBI patients developing images of the traumatic event based on police reports, dreams,
and other secondary sources.61,65 For example, Bryant76 reported a man who developed
PTSD 12 months after his injury, which involved an extended period of anterograde and
retrograde amnesia. When this man was directed to resume driving he developed
distressing and intrusive images of his accident that were based on a newspaper
photograph of his wrecked car. Although he was densely amnesic of the accident, he
developed a series of images that were founded on his memory of the photograph.
Interestingly, these images changed with time. For example, when he became concerned
that his children may be harmed when he was driving, his intrusive images changed to
include his children lying dead in the car. Bryant and Harvey62 compared the intrusive
imagery of motor vehicle survivors who either (i) had PTSD and no TBI; (ii) had PTSD
following severe 1131 and reported intrusive memories that were inconsistent with
objective reports of the accident; or (iii) had no PTSD. All participants were asked to
listen to an audio tape of a car crash sound effect, and were then interviewed about their
cognitive and emotional responses. When these responses were independently rated on a
range of constructs, it was found that those PTSD participants with and without TBI
reported comparable levels of vivid imagery, emotional response, in voluntariness, and
sense of reality. The only difference was that those with a TBI tended to report stationary
images rather than moving sequential imagery. This finding highlights that the
reconstructed memories that develop in TBI patients can be subjectively compelling and
share may of the attributes of imager}' experienced by people who have continuous recall
of their trauma.

Postamnesia resolution

A third possible mechanism is that many people who sustain a TBI, and frequently those
with MTBI, suffer traumatic experiences following resolution of their posttraumatic
amnesia. One may be knocked unconscious in a motor vehicle accident victim but be
fully aware of the experience of being cut out of the car by paramedics, experiencing
severe pain, being treated in an emergency room, and fearing for their safety. These
experiences function similarly to any traumatic scenario observed by people who develop
PTSD in the absence of any TBI. Many MTBI patients will report distressing memories
of their experience, despite islands of amnesia in which they cannot recall the point of
impact in which they sustained their MTBI.

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The impact of TBI on PTSD

One of the intriguing findings in recent years is that MTBI appears to increase the risk
for PTSD. For example, Fann and colleagues reported from a large-scale study of 939
health plan members that patients with a history of mild TBI were 2.8 times more likely
to develop a psychiatric disorder than patients with no TBI history.77 In a large military
survey, whereas 16% of troops who sustained a bodily injury indicated PTSD, 44% of
those with MTBI screened positive for PTSD.59 Further, a large civilian study that
employed rigorous clinical interviews found that sustaining a MTBI significantly
increased the risk for PTSD.78 This development is in stark contrast to previously held
views that TBI was protective of PTSD development.
This observation may have several possible explanations. The prevailing neurobiological
model posits that PTSD involves exaggerated amygdala response associated with
impaired regulation by the medial prefrontal cortex.79 The amygdala appears to be pivotal
to development and expression of conditioned fear reactions in human and animal
studies, and that learning to inhibit these fear reactions (extinction learning) involves
inhibition by the ventral medial prefrontal cortex.80 Consistent with this model, numerous
studies have reported that patients with PTSD have diminished medial prefrontal cortex
during processing of fear.81 It is possible that MTBI enhances risk for PTSD because
neural damage sustained in the injury compromises the critical neural circuitry required
to regulate fear following the traumatic experience.82

Alternately, the management of post-traumatic stress, as well as problems caused by

ongoing stressors in one's environment, requires adequate working memory and cognitive
resources83; it is possible that TBI depletes these resources to some extent, and this may
contribute to increased PTSD risk. There is much evidence that PTSD is influenced by
the compounding effects of stressors that occur following the precipitating trauma.84,85
Pain, medical procedures, loss of employment, legal issues, and interpersonal conflict are
commonplace following MTBI, and it is possible that the marginal deficits that may be
attributed to MTBI could limit optimal management of these stressors.

Although MTBI does appear to increase the risk of PTSD, it needs to be remembered that
the association between TBI and PTSD is complex, and much is not understood. There is
evidence of an inverse relationship between extent of one's memory of the traumatic
experience and the occurrence of re-experiencing memories. One study of 228 motor
vehicle accident survivors indexed the extent to which patients with MUM recalled
details of the traumatic accident,87 and found that the less patients recalled of their
traumatic event, the less likely they were to develop PTSD. Another study assessed 1167
traumatic injury patients in hospital (459 with mild TBI and 708 with no TBI) for post-
traumatic amnesia and PTSD in hospital immediately, and subsequently reassessed them
for PTSD 3 months later.87 Although this study found an inverse relationship between the
length of post-traumatic amnesia and intrusive memories in the initial phase after trauma,
MTBI patients were more likely to develop PTSD than no-TBI patients, after controlling
for injury severity (adjusted odds ratio: 1.86, 95% confidence interval, 1 .78-2.94). This
finding suggests that although duration of amnesia appears protective of development of
intrusive traumatic memories, MTBI nonetheless confers risk for developing PTSD. It is
for this reason that whereas mild TBI appears to increase risk for PTSD, presence of
PTSD after more severe TBI (in which there is limited encoding of trauma memories) is
less common.

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Delayed-onset PTSD
Post-traumatic stress symptoms typically occur in the initial days and weeks after trauma
exposure, and then gradually abate in most people; a minority of trauma survivors can
suffer persistent PTSD.88 Delayed-onset PTSD refers to cases of PTSD in which the
condition develops at least 6 months after the trauma. Most studies indicate that delayed-
onset PTSD is rare. Although uncommon following civilian trauma, it has been reported
to occur more frequently in troops returning home from deployment.89,90 A review of
delayed-onset PTSD studies found that it was rare for PTSD to develop outside military
samples, with up to one third of military cases presenting as delayed-onset91; specifically,
it is reported in 38% of military cases compared with 15% in civilian cases.

To date, there has not been any systematic study of delayed-onset PTSD following
MTBI. It is possible that sustaining an mild TBI may contribute to delayed-onset PTSD
in the military, and this may be one factor in the increased rates of delayed-onset PTSD in
the military. It is possible that following MTBI sustained in combat, one feels the need to
fill the gap of knowledge of the events that affected them. Consistent with reports of TBI
patients confabulating events in order to make sense of what occurred to them during the
loss of consciousness,61 it is possible that one explanation of delayed-onset PTSD,
especially in the military, is the pattern of subsequently reconstructing the traumatic
events in the wake of impaired consciousness. The possibility that trauma memory
reconstruction in the post-deployment period contributes to PTSD needs to be studied in
military populations, and points to the potential importance of ensuring that adaptive,
rather than maladaptive, reconstructions of events occur in the months after injury.

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Impairment following MTBI

There is enormous concern in the wake of the Iraq/Afghanistan wars over the impairment
caused by MTBI. Many millions of dollars arc being devoted to rehabilitation procedures
to minimize the potential adverse effects of MTBI on soldiers affected by it. Recent
studies are indicating, however, that MTBI itself is responsible for minimal impairment.
One large-scale survey of US troops reported that health impairment was markedly
higher in deployed personnel who sustained a MTBI, including reported poor general
health, days off work, and medical visits. Importantly, the influence of MTBI on these
measures of impairment was not significant after controlling for the effects of PTSD and
depression.59 This conclusion was supported in a second large-scale military study.92
Similarly, a large-scale study of civilians found that impaired functioning was not
increased by the presence of MTBI; however, there were very significant functioning
deficits if a patient sustained a psychological disorder in conjunction with the MTBI.78
This convergent evidence points to physical, social, and occupational impairment being
strongly related to psychological factors occurring after trauma exposure, such as PTSD
and depression, rather than the presence of MTBI.

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Postconcussive syndrome and PTSD

The issue of postconcussive syndrome is a vexed one, both in terms of its definition and
its purported causes. It is also an issue that intersects with symptoms of PTSD. PCS is
generally defined as a syndrome that involves headache, dizziness, fatigue, sensitivity to
light or sound, sleep disturbance, and concentration difficulties.93 The definitions of PCS
vary, and generally overlap somewhat with symptoms of PTSD. For example, the
International Classification of Diseases (ICD-10) 26 stipulates that PCS is defined by
headaches, dizziness, general malaise, fatigue, noise intolerance, irritability, emotional
lability, depression, or anxiety, concentration or memory difficulty, sleep disturbance,
reduced tolerance to alcohol, and a preoccupation with these symptoms and fear of
permanent brain damage. The Appendix of the DSM.-IV 4 describes PCS as fatigue, sleep
disturbance, headaches, dizziness, irritability, anxiety or depression, changes in
personality, and apathy. These descriptions clearly overlap with common symptoms of
post-traumatic stress, and represent differential diagnosis problems insofar as how one
attributes these symptoms to PCS or PTSD.

Recent evidence is highlighting that symptoms described as PCS are common in many
populations, and actually reflect a diffuse collection of frequently experienced sensations.
In healthy individuals, headaches, sleep difficulty, irritability, and memory failures are
relatively common in daily life.97-98 One study found that 72% to 79% of healthy adults
reported at least three or more PCS symptoms; further, a significant minority of subjects
met DSM-TV (14.6%) or FCD-10 (12.5%) criteria for PCS.99 Interestingly, these observed
rates of PCS in non-MTBI are comparable to the rates noted in TBI populations,
highlighting the fact that PCS are not unique to TBI.

There has been much debate over the extent to which persistent PCS develops as a result
of neurological damage,100 psychological distress,101 or a combination of both.102 One
recent study that assessed PCS in both MTBI and non-MTBI injured patients found that
comparable proportions of patients reported PCS (MTBI: 40%; no-TBI: 50 %).103 A
subsequent follow-up at 3 months post-injury found that a similar pattern (mild TBI:
46.8%; control: 48.3%).104 Interestingly, across these studies, PCS was predicted by pain
levels and PTSD symptoms. rFh cse data indicate that PCS is not unique to MTBI, and
that these symptoms that are commonly attributed to MTBI are more parsimoniously
explained by the effects of high arousal associated with the stress of surviving a traumatic
injury.

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The problem of confusing MTBI and PTSD

Military agencies have implemented programs for troops in Iraq and Afghanistan targeted
towards treating the effects of MTBI. Much attention has been given to the problem of
mild TBI, communicating to troops that MTBI is a syndrome that causes marked
problems. Given the evidence that so-called postconcussion-like symptoms and general
health problems are largely related to psychological factors, there are likely risks in
suggesting to troops that the problems experienced following MTBI should be attributed
to neurological damage. Communicating to personnel who sustained a MTBI that a range
of nonspecific symptoms are caused by brain damage communicates a cause with a poor
prognosis. This expectation that common sensations are signs of permanent dysfunction
can result in hypervigilance to every sensation, followed by catastrophic attributions
about the adverse consequences of the sensations. This pattern has been well-documented
across a range of disorders, including panic disorder, health anxiety, and
hypochondriasis.105-107 In these disorders, people tend to be hypervigilant to somatic cues
because they believe they represent a threat to their physical well-being. For example, the
patient with panic disorder may believe that an alteration in his or her respiration is a sign
of imminent choking or that a slight pain in the chest is indicative of an approaching
cardiac arrest. Similarly, someone with health anxiety may constantly search their body
for any alterations in appearance of function to determine if there arc signs of
malignancy. Once the sensation or sign is detected, the person can catastrophize the sign
in an extremely negative manner, such that the slightest somatic cue is perceived as
indicative of dire outcomes. This is a common pattern in people with PTSD. Fear
network models of PTSD propose that these individuals preferentially allocate attention
to stimuli of concern because of their fear of threat.108 Consistent with this proposal,
people with PTSD are hypervigilent to threat on a range of paradigms.109-111 Further,
people with PTSD not only catastrophize about external threats,112 they also catastrophize
about somatic and physical sensations.113 Therefore, people who are suffering the effects
of PTSD will be attentive to any information that is perceived as threatening, and will
likely attribute a range of physical, cognitive, and emotional responses to brain injury if
this is provided as a salient explanation. This response may exacerbate the PTSD
reaction, as well as promote continued hypervigilence to sensations and subsecpent
maladaptive appraisals that these reactions arc indicative of permanent brain injury.

This pattern was reflected in the aftermath of the 1991 Gulf War, when there were
widespread concern of chemical weapons, which apparently contributed to medically
unexplained symptoms that were linked to concerns about somatic sensations purportedly
linked to chemical agents. 106,114,115 It seems that a cohort of soldiers after the 1991 Gulf
War misattributed somatic experiences to chemical agents, which led to persistent
concerns about their health. There are potential similarities between Gulf War Syndrome
and the manner in which MTBI is currently being understood; both comprise general
sensations that are commonly reported in stress responses, and both mistakenly attributed
to common stress reactions. This can be problematic because it can reduce people's
optimism or expectancy for recovery.

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Implications for treatment

This review has several implications for how symptoms following TBI are addressed in
treatment. In terms of treating the symptoms of PCS, current evidence suggests that
simple neuropsychological education is modestly useful in reducing symptoms of PCS.116
The emerging evidence that PCS is predominantly influenced by posttraumatic stress
reactions suggests that addressing these problems may be crucial in alleviating PCS. That
is, by reducing the arousal-inducing symptoms of PTSD, it is possible that many of the
symptoms associated with PCS will be alleviated. Similarly, by minimizing catastrophic
appraisals that exaggerate the severity or adversity of PCS sensations it is probable that
anxiety about these reactions would be eased. For example, patients who are overly
concerned about the adverse outcomes of dizziness or sensitivity to light can be taught to
normalize these reactions in ways that minimize distress about these sensations.
Cognitively reframing the perception of these reactions is akin to established treatments
for panic disorder or health anxiety, in which patients are taught to tolerate somatic
experiences in ways that discourage inferences involving an adverse outcome. Although
this approach has been proven to be very effective in treating panic disorder117 and health
anxiety,118 it has yet to be tested with PCS.

In terms of treating symptoms of PTSD, prevailing cognitive models posit that recovery
from a traumatic experience involves integrating the trauma memory into one's
autobiographical memory base in a way that allows a coherent narrative of the experience
in which the person can contextualize the experience and consequently currently feel
safe.112 This perspective proposes that a major reason trauma memories are difficult to
integrate into memory is the manner in which they are encoded119; specifically,
experiences are often fragmented because they are encoded under conditions of extreme
arousal, and this purportedly disturbs the ability to form the required coherent narrative.
Fragmented memories of the traumatic experience can also occur in the context of TBI
because of the impaired consciousness secondary to the injury. As noted above, TBI
patients can reconstruct aspects of the traumatic experience that were not adequately
encoded during the period of impaired consciousness. This scenario raises the possibility
that treating PTSD after TBI will require adaptive reconstruction of this narrative in a
way that facilitates adaptation rather than retraumatization. For example, a patient who
reconstructs their memory of a car accident in which they were excessively responsible
for someone's death will have marked depressive responses relative to a patient who
reconstructs the memory in a way that accepts a more reasonable level of responsibility.
Alternately, a patient can be encouraged to tolerate a level of uncertainty insofar as there
is permanent amnesia of some aspect of the event; inability to tolerate uncertainty is
linked to enhanced anxiety and worry.120 One of the challenges for treating PTSD after
TBI is the patient's ability to either reconstruct events in a coherent and adaptive way or
to accept the uncertainty of how events transpired when they suffered their TBI.

The extent to which a person with TBI needs to reconstruct the trauma narrative to
recover from PTSD has yet to be empirically determined. As noted above, several large-
scale studies have reported that MTBI is associated with increased risk for PTSD.59,92,78
One possibility for this observation may be that people who sustain a MTBI do not have a
coherent narrative of their traumatic experience because of the impaired consciousness
secondary to the brain injury, and this may impede their capacity to contextualize the
experience in their autobiographical memory base.

A second implication for PTSD treatment after TBI is that the treatment of choice for
PTSD involves traumafocused exposure therapy.121 This treatment is based on extinction
learning, which occurs when a conditioned stimulus is repeatedly presented in the
absence of an aversive outcome, thereby facilitating new learning that the stimulus is no
longer signaling threat. In the context of therapy, presenting memories or reminders of
the trauma to the patient in the safety of therapy typically leads to symptom reduction.
Exposure can either be imaginai, which involves focusing on one's memories of the
traumatic event, or in vivo, in which approaches and remains with reminders that usually
trigger anxiety about the event. On the premise that fear conditioning and extinction still
occurs in the context of TBI, it would seem that that exposure-based therapy is the
indicated intervention for PTSD following TBI. Supporting this conclusion is evidence in
one controlled trial of patients with acute stress disorder following MTBI that CBT
effectively treated PTSD symptoms to a similar extent as when applied to non -TBI
samples.122

Imaginal exposure with people following TBI will usually be dependent on the amount of
memory that the patient is reporting. It may not be as useful to patients with more severe
TBI because they are largely amnesic of their trauma. As noted above, some severe TBI
patients can have nightmares or intrusive memories on the basis of reconstructions of
their trauma; in these cases, imaginable exposure to those mental representations that are
causing anxiety. In most cases of moderate/severe TBI, however, it is more useful to
employ in vivo exposure because reminders of the trauma can elicit stronger anxiety in
the absence of actual memories or images. A survivor of a motor vehicle accident who
sustained a severe TBI may experience marked fear when watching film footage of
traffic; in such a case, the patient could complete exposure by repeatedly watching traffic
footage. Through these techniques it would be hoped that extinction learning can be
achieved, even though the patient may never retrieve direct memories of the traumatic
event.

Go to:

Conclusions
The coexistence of TBI and PTSD is frequent, and the extent to which the symptoms of
TBI and PTSD are confused may be as frequent. Increasing evidence indicates that many
previously termed PCS responses are a function of psychological responses, and it
hampers a patient's recovery if they mistakenly perceive these reactions as indicators of a
brain injury that may be permanent. In this sense, the field is recognizing the distinction
between TBI as an event rather than a syndrome, whereas PTSD or PCS are symptoms
that arise secondary to the event. The likelihood that the presumed secpelae of MTBI are
actually attributed to psychological responses to the traumatic experience is becoming
more apparent. Accurate identification of the true nature and cause of the symptoms
experienced after TBI is important because if stress-related disturbances are mistakenly
attributed to neurological factors, patients may be deprived of effective treatments that
can, in most cases, alleviate the symptoms. As we learn more about the interaction of TBI
and PTSD, it seems that we will be discovering much about how the brain responds to
traumatic experiences, both in cases when there has and has not been a TBI.
Understanding this interaction between neurological insult and psychological response
has the potential to shed light on the key mechanisms underpinning trauma response
generally, and how it is impacted by different levels of brain injury.
Go to:

REFERENCES
1. American Congress of Rehabilitation Medicine. Definition of mild traumatic brain
injury. J Head Trauma Rehab. 1993;8:8687.
2. Carroll LJ., Cassidy JD., Holm L., Kraus J., Coronado VG. Methodological issues and
research recommendations for mild traumatic brain injury: The WHO Collaborating
Centre Task Force on Mild Traumatic Brain Injury. J Rehab Med. 2004;36:113125.
[PubMed]
3. Ruff RM., Iverson GL., Barth JT., Bush SS., Broshek DK. Recommendations for
diagnosing a mild traumatic brain injury: a National Academy of Neuropsychology
education paper. Arch Clin Neuropsychol. 2009;24:310. [PubMed]
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Washington, DC: American Psychiatric Association. 1994
5. Harvey AG., Bryant RA. Acute stress disorder: a synthesis and critique. Psychol Bull.
2002;128:886902. [PubMed]
6. Ehlers A., Mayou RA., Bryant B. Psychological predictors of chronic posttraumatic
stress disorder after motor vehicle accidents. J Abn Psychol. 1998;107:508519.
[PubMed]
7. Koopman C., Classen C., Spiegel DA. Predictors of posttraumatic stress symptoms
among survivors of the Oakland/Berkeley firestorm. Am J Psychiatry. 1994;151:888894.
[PubMed]
8. Murray J., Ehlers A., Mayou RA. Dissociation and post-traumatic stress disorder: two
prospective studies of road traffic accident survivors. Br J Psychiatry. 2002;180:363368.
[PubMed]
9. Ozer EJ., Best SR., Lipsey TL., Weiss DS. Predictors of posttraumatic stress disorder
and symptoms in adults: a meta-analysis. Psychol Bull. 2003;129:5273. [PubMed]
10. Shalev AY., Freedman S., Peri T., Brandes D., Sahar T. Predicting PTSD in trauma
survivors: Prospective evaluation of self-report and clinicianadministered instruments. Br
J Psychiatry. 1997;170:558564. [PubMed]
11. Bryant RA. Acute stress disorder as a predictor of posttraumatic stress disorder: a
systematic review. J. Clin Psychiatry. 2011;72:233239. [PubMed]
12. Bryant RA., Friedman MJ., Spiegel D., Ursano R., Strain J. A review of acute stress
disorder in DSM-V. Depress Anxiety. In press
13. Gronwall D., Wrightson P. Memory and information processing capacity after closed
head injury. J Neurol Neurosurg Psychiatry. 1981;44:889895. [PMC free article]
[PubMed]
14. Alexander MP. Mild traumatic brain injury: Pathophysiology, natural history and
clinical management. Neurology. 1995;45:12531260. [PubMed]
15. Grigsby J. Depersonalisation following minor closed head injury. IntJ Clin
Neuropsychol. 1986;8:6569.
16. Bryant RA. Posttraumatic stress disorder and mild brain injury: controversies, causes
and consequences. J Clin Exp Neuropsychol. 2001;23:718728. [PubMed]
17. Bryant RA., Marosszeky JE., Crooks J., Gurka JA. Posttraumatic stress disorder after
severe traumatic brain injury. Am J Psychiatry. 2000;157:629631. [PubMed]
18. Schnyder U., Moergeli H., Klaghofer R., Buddeberg C. Incidence and prediction of
posttraumatic stress disorder symptoms in severely injured accident victims. Am J
Psychiatry. 2001;158:594599. [PubMed]
19. Friedman MJ., Resick PA., Bryant RA., Brewin CR. Considering PTSD for DSM-V.
Depress Anxiety. In press
20. King DW., Leskin GA., King LA., Weathers FW. Confirmatory factor analysis of the
clinician-administered PTSD Scale: Evidence for the dimensionality of posttraumatic
stress disorder. Psychol Assess. 1998;10:9096.
21. McWilliams LA., Cox BJ., Asmundson GJG. Symptom structure of posttraumatic
stress disorder in a nationally representative sample. J Anxiety Disord. 2005;19:626641.
[PubMed]
22. Asmundson GJ., Frombach I., McQuaid J., Pedrelli P., Lenox R., Stein MB.
Dimensionality of posttraumatic stress symptoms: A confirmatory factor analysis of
DSM-IV symptom clusters and other symptom models. Behav Res Ther. 2000;38:203
214. [PubMed]
23. Palmieri PA., Weathers FW., Difede J., King DW. Confirmatory factor analysis of the
PTSD Checklist and the Clinician-Administered PTSD Scale in disaster workers exposed
to the World Trade Center Ground Zero. J Abnorrn Psychol. 2007;116:329341.
[PubMed]
24. Palmieri PA., Fitzgerald LR. Confirmatory factor analysis of posttraumatic stress
symptoms in sexually harassed women. J Trauma Stress. 2005;18:657666. [PubMed]
25. Brewin CR., Andrews B., Valentine JD. Meta-analysis of risk factors for
posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol.
2000;68:748766. [PubMed]
26. World Health Organization. The ICD-10 Classification of Mental and Behavioural
Disorders: Clinical Descriptions and Diagnostic Guidelines. 1995 d. Geneva,
Switzerland: World Health Organization. 1995
27. Isserlin L., Zerach G., Solomon Z. Acute stress responses: a review and synthesis of
ASD, ASR, and CSR. Am J Orthopsychiatry. 2008;78:423429. [PubMed]
28. Yitzhaki T., Solomon Z., Kotler M. The clinical picture of acute combat stress
reaction among Israeli soldiers in the 1982 Lebanon war. Mil Med. 1991;156:193197.
[PubMed]
29. Kreutzer JS., Seel RT., Gourley E. The prevalence and symptom rates of depression
after traumatic brain injury: a comprehensive examination. Brain Injury. 2001;15:563
576. [PubMed]
30. Seel RT., Kreutzer JS., Rosenthal M., Hammond FM., Corrigan JD., Black K.
Depression after traumatic brain injury: a National Institute on Disability and
Rehabilitation Research Model Systems multicenter investigation. Arch Phys Med
Rehabil. 2003;84:177184. [PubMed]
31. Silver JM., Kramer R., Greenwald S. Weissman M. The association between head
injuries and psychiatric disorders: findings from the New Haven NIMH Epidemiologic
Catchment Area Study. Brain Inj. 2001;15:935945. [PubMed]
32. Jorge RE., Robinson RG., Starkstein SE., Arndt SV. Depression and anxiety
following traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1993;5:369374.
[PubMed]
33. Varney N., Martzke J., Roberts R. Major depression in patients with closed head
injury. Neuropsychology. 1987;1:78.
34. Iverson GL. Misdiagnosis of persistent postconcussion syndrome in patients with
depression. Arch Clin Neuropsychol. 2006;21:303310. [PubMed]
35. Gasquoine PG. Postconcussional symptoms in chronic back pain. Appl Neuropsychol.
2000;7:8389. [PubMed]
36. Guez M., Brannstrom R., Nyberg L., Toolanen G., Hildingsson C.
Neuropsychological functioning and MMPI-2 profiles in chronic neck pain: a comparison
of whiplash and non-traumatic groups. J Clin Exp Neuropsychol. 2005;27:151163.
[PubMed]
37. Haldorsen T., Waterloo K., Dahl A., Mellgren SI., Davidsen PE., Molin PK.
Symptoms and cognitive dysfunction in patients with the late whiplash syndrome. Appl
Neuropsychol. 2003;10:170175. [PubMed]
38. Iverson GL., McCracken LM. 'Postconcussive' symptoms in persons with chronic
pain. Brain Inj. 1997;11:783790. [PubMed]
39. Smith-Seemiller L., Fow NR., Kant R., Franzen MD. Presence of post-concussion
syndrome symptoms in patients with chronic pain vs mild traumatic brain injury. Brain
inj. 2003;17:199206. [PubMed]
40. Jamison RN., Sbrocco T., Parris WC. The influence of problems with concentration
and memory on emotional distress and daily activities in chronic pain patients. Int J
Psychiatry Med. 1988;18:183191. [PubMed]
41. Iverson GL., King RJ., Scott JG., Adams RL. Cognitive complaints in litigating
patients with head injuries or chronic pain. J Forensic Neuropsychol. 2001;2:1930.
42. Kessler RC., Sonnega A., Bromet E., Hughes M., Nelson CB. Posttraumatic stress
disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:10481060.
[PubMed]
43. Breslau N., Davis G., Andreski P., Peterson E. Traumatic events and posttraumatic
stress disorder in an urban population of young adults. Arch Gen Psychiatry.
1991;48:216222. [PubMed]
44. Breslau N., Davis GC., Andreski P., Peterson EL., Schultz LR. Sex differences in
posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54:10441048. [PubMed]
45. Creamer M., Burgess P., McFarlane AC. Post-traumatic stress disorder: findings from
the Australian National Survey of Mental Health and Wellbeing. Psychol Med.
2001;31:12371247. [PubMed]
46. No authors listed. Rehabilitation of persons with traumatic brain injury. JAMA.
1991;282:974983. [PubMed]
47. Langlois JA., Rutland-Brown W., Wald MM. The epidemiology and impact of
traumatic brain injury: a brief overview. J Head Traum Rehab. 2006;21:375378.
[PubMed]
48. TBI Task Force Report. 2008; http://www.armymedicine.army.mil/
reports/tbi/TBITaskForceReportJanuary2008.pdf. Accessed May 17, 2010
49. Terrio H., Brenner LA., Ivins B., et al. Traumatic brain injury screening: preliminary
findings in a U.S. Army brigade combat team. J Head Trauma Rehab. 2009;24:1423.
[PubMed]
50. Sbordone RJ., Liter JC. Mild traumatic brain injury does not produce post-traumatic
stress disorder. Brain Inj. 1995;9:405412. [PubMed]
51. Price KP. Posttraumatic stress disorder and concussion: are they incompatible?
Defense. Law J. 1994;43:113120.
52. Bryant RA., Harvey AG. Relationship between acute stress disorder and
posttraumatic stress disorder following mild traumatic brain injury. Am J Psychiatry.
1998;155:625629. [PubMed]
53. Middelboe T., Andersen HS., Birket Smith M., Friis ML. Psychiatric sequelae of
minor head injury: a prospective follow-up study. Eur Psychiatry. 1992;7:183189.
54. Ohry A., Rattok J., Solomon Z. Post-traumatic stress disorder in brain injury patients.
Brain inj. 1996;10:687695. [PubMed]
55. Hickling EJ., Gillen R., Blanchard EB., Buckley T., Taylor A. Traumatic brain injury
and posttraumatic stress disorder: a preliminary investigation of neuropsychological test
results in PTSD secondary to motor vehicle accidents. Brain inj. 1998;12:265274.
[PubMed]
56. Castro CA., Gaylord KM. Incidence of posttraumatic stress disorder and mild
traumatic brain injury in burned service members: preliminary report - discussion. J
Trauma-lnj Infect Crit Care. 2008;64:S205S206. [PubMed]
57. Greenspan AI., Stringer AY., Phillips VL., Hammond FM., Goldstein FC. Symptoms
of post -traumatic stress: Intrusion and avoidance 6 and 12 months after TBI. Brain Inj.
2006;20:733742. [PubMed]
58. Harvey AG., Bryant RA. Two-year prospective evaluation of the relationship between
acute stress disorder and posttraumatic stress disorder following mild traumatic brain
injury. Am J Psychiatry. 2000;157:626628. [PubMed]
59. Hoge CW., McGurk D., Thomas JL., Cox AL., Engel CC., Castro CA. Mild traumatic
brain injury in US Soldiers returning from Iraq. N Engl J Med. 2008;358:453463.
[PubMed]
60. Levin HS., Brown SA., Song JX., et al. Depression and posttraumatic stress disorder
at three months after mild to moderate traumatic brain injury. J Clin Exp Neuropsychol.
2001;23:754769. [PubMed]
61. Bryant RA. Posttraumatic stress disorder, flashbacks, and pseudomemories in closed
head injury. J. Trauma Stress. 1996;9:621629. [PubMed]
62. Bryant RA., Harvey AG. Traumatic memories and pseudomemories in posttraumatic
stress disorder. Appl Cogn Psychol. 1998;12:8188.
63. Koch WJ., Taylor S. Assessment and treatment of motor vehicle accident victims.
Cogn BehavPract. 1995;2:327342.
64. Layton BS., Wardi Zonna K. Posttraumatic stress disorder with neurogenic amnesia
for the traumatic event. Clin Neuropsychologist. 1995;9:210.
65. McMillan TM. Post-traumatic stress disorder and severe head injury. Br J Psychiatry.
1991;159:431433. [PubMed]
66. McMillan TM. Posttraumatic stress disorder following minor and severe closed head
injury: 10 single cases. Brain Inj. 1996;10:749758. [PubMed]
67. Charney DS., Deutch AY., Krystal JH., Southwick SM., Davis M. Psychobiologic
mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry. 1993;50:294305.
[PubMed]
68. Quirk GJ., Mueller D. Neural mechanisms of extinction learning and retrieval.
Neuropsychopharmacology. 2008;33:5672. [PMC free article] [PubMed]
69. Orr SP., Lasko NB., Metzger LJ., Berry NJ., Ahern CE., Pitman RK.
Psychophysiologic assessment of women with posttraumatic stress disorder resulting
from childhood sexual abuse. J Consult Clin Psychol. 1998;66:906913. [PubMed]
70. Pitman RK., Lanes DM., Williston SK., et al. Psychophysiologic assessment of
posttraumatic stress disorder in breast cancer patients. Psychosomatics. 2001;42:133
140. [PubMed]
71. Pitman RK., Orr SP., Forgue DF., de Jong JT., Claiborn J. Psychophysiologic
assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch
Gen Psychiatry. 1987;44:970975. [PubMed]
72. Bryant RA. Longitudinal psychophysiological studies of heart rate: mediating effects
and implications for treatment. Ann N Y Acad Sci. 2006;1071:1926. [PubMed]
73. Lovibond PF., Shanks DR. The role of awareness in Pavlovian conditioning:
empirical evidence and theoretical implications. J Exp Psychol Anim Behav Process.
2002;28:326. [PubMed]
74. Bryant RA., Marosszeky JE., Crooks J., Gurka JA. Elevated resting heart rate as a
predictor of posttraumatic stress disorder after severe traumatic brain injury. Psychosom
Med. 2004;66:760761. [PubMed]
75. Harvey AG., Bryant RA. Reconstructing trauma memories: a prospective study of
amnesic trauma survivors. J Trauma Stress. 2001;14:277282. [PubMed]
76. Bryant RA. Posttraumatic stress disorder, flashbacks, and pseudomemories in closed
head injury. Trauma Stress. 1996;9:621629. [PubMed]
77. Fann JR., Burington B., Leonetti A., Jaffe K., Katon WJ., Thompson RS. Psychiatric
illness following traumatic brain injury in an adult health maintenance organization
population. Arch Gen Psychiatry. 2004;61:5361. [PubMed]
78. Bryant RA., Creamer M., O'Donnell M., Silove D., Clark CR., McFarlane AC. The
psychiatric sequelae of traumatic injury. Am J Psychiatry. 2010;167:312320. [PubMed]
79. Rauch SL., Shin LM., Phelps EA. Neurocircuitry models of posttraumatic stress
disorder and extinction: human neuroimaging research-past, present, and future. Biol
Psychiatry. 2006;60:376382. [PubMed]
80. Milad MR., Rauch SL., Pitman RK., Quirk GJ. Fear extinction in rats: Implications
for human brain imaging and anxiety disorders. Biol Psychology. 2006;73:6171.
[PubMed]
81. Lanius RA., Bluhm R., Lanius U., Pain C. A review of neuroimaging studies in
PTSD: heterogeneity of response to symptom provocation. J Psych Res. 2006;40:709
729. [PubMed]
82. Bryant RA. Disentangling mild traumatic brain injury and stress reactions. N Engl J
Med. 2008;358:525527. [PubMed]
83. Landre N., Poppe CJ., Davis N., Schmaus B., Hobbs SE. Cognitive functioning and
postconcussive symptoms in trauma patients with and without mild TBI. Arch Clin
Neuropsychol. 2006;21:255273. [PubMed]
84. Bryant RA., Harvey AG. Psychological impairment following motor vehicle
accidents. AustJ Public Health. 1995;19:185188. [PubMed]
85. King DW., King LA., Foy DW., Keane TM., Fairbank JA. Posttraumatic stress
disorder in a national sample of female and male Vietnam veterans: Risk factors, war-
zone stressors, and resilience-recovery variables. J Abn Psychol. 1999;108:164170.
[PubMed]
86. Gil S., Caspi Y., Ben-Ari IZ., Koren D., Klein E. Does memory of a traumatic event
increase the risk for posttraumatic stress disorder in patients with traumatic brain injury?
A prospective study. Am J Psychiatry. 2005;162:963969. [PubMed]
87. Bryant RA., Creamer M., O'Donnell M., Silove D., Clark CR., McFarlane AC. Post-
traumatic amnesia and the nature of post-traumatic stress disorder after mild traumatic
brain injury. J int Neuropsychol Soc. 2009;15:862867. [PubMed]
88. Bryant RA. Early predictors of posttraumatic stress disorder. Biol Psychiatry.
2003;53:789795. [PubMed]
89. Solomon Z., Shklar R., Singer Y., Mikulincer M. Reactions to combat stress in Israeli
Veterans twenty years after the 1982 Lebanon war. J Nerv Ment Dis. 2006;194:935939.
[PubMed]
90. Southwick SM., Morgan CA., Darnell A., et al. Trauma-related symptoms in veterans
of Operation Desert Storm: a 2-year follow-up. Am J Psychiatry. 1995;152:11501155.
[PubMed]
91. Andrews B., Brewin CR., Philpott R., Stewart L. Delayed-onset posttraumatic stress
disorder: a systematic review of the evidence. Am J Psychiatry. 2007;164:13191326.
[PubMed]
92. Schneiderman AI., Braver ER., Kang HK. Understanding sequelae of injury
mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and
Afghanistan: persistent postconcussive symptoms and posttraumatic stress disorder. Am J
Epidemiol. 2008;167:14461452. [PubMed]
93. Bohnen N., Jolies J. Neurobehavioral aspects of postconcussive symptoms after mild
head injury. J Nerv Ment Dis. 1992;180:183192. [PubMed]
94. Gouvier WD., Uddo-Crane M., Brown LM. Base rates of post-concussional
symptoms. Arch Clin Neuropsychol. 1988;3:273278. [PubMed]
95. Machulda MM., Bergquist TF., Ito V., Chew S. Relationship between stress, coping,
and post concussion symptoms in a healthy adult population. Arch Clin Neuropsychol.
1998;13:415424. [PubMed]
96. Iverson GL., Lange RT. Examination of postconcussion-like symptoms in a healthy
sample. Appl Neuropsychol. 2003;10:137144. [PubMed]
97. Mittenberg W., DiGiulio DV., Perrin S., Bass AE. Symptoms following mild head
injury: Expectation as aetiology. J Neurol Neurosurg Psychiatry. 1992;55:200204.
[PMC free article] [PubMed]
98. Trahan DE., Ross CE., Trahan SL. Relationships among postconcussionaltype
symptoms, depression, and anxiety in neurologically normal young adults and victims of
brain injury. Arch Clin Neuropsychol. 2001;16:435445. [PubMed]
99. Iverson GL., Lange RT. Examination of postconcussion-like symptoms in a health
sample. Appl Neuropsychol. 2003;10:137144. [PubMed]
100. Levin HS., Gary HE., High WM., et al. Minor head injury and the postconcussive
sydrome: methodological issues in outcome studies. In: Levin HS, Grafman J, Eisenberg
HM, eds. Neurobehavioral Recovery from Head Injury. New York, NY: Oxford
University Press. 1987:262275.
101. Lishman WA. Physiogenesis and psychogenesis in the 'post-concussional syndrome'.
Br J Psychiatry. 1988;153:460469. [PubMed]
102. Rutherford WH. Postconcussive symptoms: Relationship to acute neurological
indices, individual differences, and circumstances of injury. In: Levin HS, Grafman, J,
Eisenberg, HM, eds. Neurobehavioral Recovery from Head Injury. New York, NY:
Oxford University Press. 1989:217228.
103. Meares S., Shores EA., Taylor AJ., et al. Mild traumatic brain injury does not predict
acute postconcussion syndrome. J Neurol Neurosurg Psychiatry. 2008;79:300306.
[PubMed]
104. Meares S., Shores EA., Taylor AJ., et al. The prospective course of postconcussion
syndrome: the role of mild TBI. Neuropsychology. 2011;25:454465. [PubMed]
105. Clark DM., Wells A. Cognitive therapy for anxiety disorders. In: Dickstein LJ, Riba
M, Oldham JM, eds. American Psychiatric Press Review of Psychiatry. Vol 16.
Washington, DC: American Psychiatric Press. 1996
106. Clauw D. The health consequences of the first Gulf war: The lessons are general
(and for many patients) rather than specific to that war. BMJ. 2003;327:13571358.
[PMC free article] [PubMed]
107. Engel CC., Jr Somatization and multiple idiopathic physical symptoms: Relationship
to traumatic events and posttraumatic stress disorder. In: Schnurr PP, Green BL, eds.
Trauma and Health: Physical Health Consequences of Exposure to Extreme Stress.
Washington, DC: American Psychological Association. 2004:191215.
108. Foa EB., Kozak MJ. Emotional processing of fear: Exposure to corrective
information. Psychol Bull. 1986;99:2035. [PubMed]
109. Bryant RA., Harvey AG. Processing threatening information in posttraumatic stress
disorder. J Abnorm Psychol. 1995;104:537541. [PubMed]
110. McNally RJ., Kaspi SP., Riemann BC., Zeitlin SB. Selective processing of threat
cues in posttraumatic stress disorder. J Abnorm Psychol. 1990;99:398402. [PubMed]
111. Bryant RA., Harvey AG. Attentional bias in posttraumatic stress disorder. J Trauma
Stress. 1997;10:635644. [PubMed]
112. Ehlers A., Clark DM. A cognitive model of posttraumatic stress disorder. BehavP.es
Ther. 2000;38:319345. [PubMed]
113. Smith K., Bryant RA. The generality of cognitive bias in acute stress disorder.
BehavRes Ther. 2000;38:709715. [PubMed]
114. lversen A., Chalder T., Wessely S. Gulf War Illness: Lessons from medically
unexplained symptoms. Clin Psychol Rev. 2007;27:842854. [PubMed]
115. Lee HA., Gabriel R., Bolton JP., Bale AJ., Jackson M. Health status and clinical
diagnoses of 3000 UK Gulf War veterans. J Roy Soc Med. 2002;95:491497. [PMC free
article] [PubMed]
116. Ponsford J., Willmott C., Rothwell A., et al. Impact of early intervention on
outcomes following mild head injury in adults. J Neurol Neurosurg Psychiatry.
2002;73:330-332497. [PMC free article] [PubMed]
117. Barlow DH., Gorman JM., Shear MK., Woods SW. Cognitive-behavioral therapy,
imipramine, or their combination for panic disorder: A randomized controlled trial.
JAMA. 2000;283:25292536. [PubMed]
118. Nezu AM., Nezu CM., Lombarde ER. Cognitive-behavior therapy for medically
unexplained symptoms: a critical review of the treatment literature. Behav Ther.
2001;32:537583.
119. Kramer T., Buckhout R., Eugenio P. Weapon focus, arousal, and eyewitness
memory: Attention must be paid. Law Hum Behav. 1990;14:167184.
120. Dugas MJ., Gagnon F., Ladouceur R., Freeston H. Generalized anxiety disorder: a
preliminary test of a conceptual model. Behav Res Ther. 1998;36:215226. [PubMed]
121. Foa EB., Keane TM., Friedman MJ., Cohen JA., eds Effective treatments for PTSD:
Practice guidelines from the International Society of Traumatic Stress Studies. 2nd ed.
New York, NY: Guilford. 2009
122. Bryant RA., Moulds M., Guthrie R., Nixon RD.. Treating acute stress disorder
following mild traumatic brain injury. Am J Psychiatry. 2003;160:585587. [PubMed]

Jurnal 10
Schizophr Bull. 2011 November; 37(6): 11041110.
Published online 2011 August 2. doi: 10.1093/schbul/sbr091
PMCID: PMC3196949

Is Traumatic Brain Injury A Risk Factor

for Schizophrenia? A Meta-Analysis of
Case-Controlled Population-Based
Studies
Charlene Molloy,1 Ronan M. Conroy,2 David R. Cotter,1,3 and Mary Cannon*,1,3
Author informaton Copyright and License informaton
This artcle has been cited by other artcles in PMC.
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Abstract
Traumatic brain injury (TBI) is known to lead to a range of adverse psychiatric sequelae
but the question of whether TBI is a risk factor for psychosis and, in particular,
schizophrenia remains unclear. Studies examining this issue have yielded conflicting
results. We carried out a systematic review of the literature on TBI and psychosis in order
to identify all population-based controlled studies which provide estimates of risk for
schizophrenia following TBI. Odds ratios (ORs) were combined using random effects
meta-analysis. Our literature search yielded 172 studies which were considered to be
potentially relevant. From these, we identified 9 studies that could provide estimates of
risk in the form of ORs. The pooled analysis revealed a significant association between
TBI and schizophrenia (OR = 1.65; 95% CI = 1.172.32), with significant heterogeneity
between the studies. Estimates from the family studies (OR = 2.8: 95% CI =1.764.47)
were higher than those from the cohort/nested case-control studies (OR = 1.42: 95% CI =
1.021.97) by a factor of almost 2. There did not appear to be a dose-response
relationship between severity of head injury and subsequent risk of schizophrenia. This
meta-analysis supports an increased risk of schizophrenia following TBI, with a larger
effect in those with a genetic predisposition to psychosis. Further epidemiological and
neuroscientific studies to elucidate the mechanisms underlying this association are
warranted.

Keywords: traumatc brain injury, psychosis, systematc review, meta-analysis

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Introduction
Traumatic brain injury (TBI) is associated with significant adverse mental health
outcomes in up to one-third of survivors.1 It is well established that TBI increases the risk
for a wide range of neuropsychiatric disturbances such as mood disorders, anxiety
disorders, substance use disorders, personality change, and cognitive impairment,2 but the
question of whether TBI is a risk factor for schizophrenia or psychosis remains somewhat
controversial. A classic review published in 1969 by Davison and Bagley3 concluded
that . . . among individuals who had experienced TBI, the observed incidence (of
psychosis) over 10- to 20-year periods is 2 to 3 times the expected incidence . . . Three
decades later, David and Prince4 reexamined this issue in a critical review and came to
the conclusion that the classical case-control studies report apparently irreconcilably
different estimates for the association between head injury and schizophrenia and that
. . . given the available published data, one must conclude that it is unlikely that head
injury causes schizophrenia. Kim5 published a narrative review of the literature which
concluded that the evidence supported a risk-modifying effect of TBI in individuals who
are genetically at risk of schizophrenia but did not support TBI as an independent risk
factor for schizophrenia. A recent systematic review by Hesdorffer et al6 has concluded
that there is limited/suggestive evidence of an association between moderate or severe
head injury and psychosis. A comprehensive overview in a textbook chapter by
Fleminger2 stated that it is not possible to come to any definite conclusion about
whether head injury can cause a chronic psychotic illness, schizophrenia, or
schizophreniform psychosis, although he goes on to say that . . . a reasonable
conclusion to draw is that head injury does increase the risk of psychosis, perhaps
doubling it. Therefore, it can be seen that there is little consensus between the previous
reviewers of this topic. However, only one of the previous reviews6 had used systematic
review methodology and none had used meta-analytic techniques to give pooled
measures of risk. To help clarify this issue and move the debate forward, we conducted a
systematic review and meta-analysis of the population-based literature to date on risk of
schizophrenia among individuals who have suffered TBI compared with the risk of
schizophrenia among a control group. To our knowledge, this is the first meta-analysis on
this topic.

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Methods
Literature Search
Standard methods for systematic review were used in this article. The following
databases were searched from their inception to October 2010: PUBMED, OVID
MEDLINE, PsychINFO, and EMBASE. We searched using the format [psychosis OR
schizophrenia OR psychotic disorder OR delusional disorder OR delusions OR
nonaffective psychosis OR psychiatric illness OR psychiatric disorder] AND [TBI OR
cerebral trauma OR head injury OR craniocerebral injury OR concussion OR open head
injuries OR closed head injuries OR skull fractures] using text words and indexing
(MeSH) terms.

Inclusion Criteria

We included published articles that reported on

1. the risk of schizophrenia among individuals who have suffered TBI compared with the
risk of schizophrenia in a nonbrain injured populaton-based control group and
2. allowed calculaton of a risk estmate from data provided in the artcle.

TBI was not limited by severity.

Exclusion Criteria

Studies were excluded (1) if they were reviews, case reports, or case series, (2) if they
comprised solely a follow-up study of a cohort of brain-injured patients with no
comparison group, (3) if there was a nonpopulation-based control group (ie, a patient
control group), or (4) if insufficient information was available to allow calculation of risk
estimates.

Study Selection and Data Extraction

We examined all titles and abstracts and obtained full texts of potentially relevant studies.
We read each article to determine whether it met inclusion criteria for the review. We
searched reference lists of included studies. We extracted data relating to risk for
schizophrenia following TBI from each article or calculated risk estimates from data
available in the article. In extraction of data from the articles, we took a conservative
approach and used the risk estimates pertaining to narrow definition of schizophrenia and
the longest follow-rate reported in the articles for the main analysis. We contacted authors
where necessary to obtain extra information to calculate risk estimates. We extracted
information on source of information about TBI, severity of head injury, age at onset of
head injury, and source of information on psychotic outcomes.

Data Analysis

Estmates of risk of schizophrenia associated with TBI from different studies were combined
using random-effects meta-analysis, with heterogeneity among studies estmated using Cochran
Q and the I2 statstc.7 The I2 statstc describes the percentage of variaton among studies that is
due to heterogeneity rather than chance, and I2 values of 25%, 50%, and 75% can be taken to
indicate low, moderate, and high levels of heterogeneity, respectvely. We carried out subgroup
analyses on mild vs severe TBI, childhood TBI and on broadly defined psychosis because there
was felt to be sufficient numbers of studies in each group to allow these analyses. Meta-
regression was undertaken to examine the influence of study design (family vs nested case-
control/cohort). All of the analyses were undertaken with Stata statstcal software package, 8
using the metan package.9
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Results
Our literature search and search of reference lists yielded 9131 references and, after perusing
the ttles, 172 were considered to be potentally relevant. From examinaton of the abstracts
and, where indicated, full texts of the artcles, we identfied 9 studies (see table 1) which met
our inclusion criteria, of which 2 were nested case-control studies, 12,17 5 were cohort
studies,10,13,15,16,18 and 2 were family studies.11,14 Two studies15,16 reported from the same dataset
but for different age groups and therefore, both were included in this analysis. A summary of the
9 studies included in the analysis is presented in table 1.

Table 1.
Details of Studies Included in the Meta-Analysis of Risk of Psychosis Following Traumatc Brain
Injury (TBI)
The overall pooled analysis revealed significant heterogeneity (in the high range) between
studies (I2 = 83.2%, P < .001). Accordingly, a random effects model was used. There was an
overall associaton between TBI and subsequent schizophrenia (pooled OR = 1.65, 95% CI = 1.17
2.32) (see figure 1). When studies were subdivided by study design, the 2 family studies 11,14
yielded a pooled OR of 2.8 (95% CI = 1.74.5) with no heterogeneity (I2 = 0.0%, P = .43) and the 7
cohort/nested case-control studies yielded a pooled OR of 1.42 (95% CI = 1.01.9) with a high
degree of heterogeneity (I2 = 79%, P < .002). Family studies found larger effect than cohort/case-
control studies, by a factor of almost 2, with trend-level significance on meta-regression (OR =
1.94 [95% CI = 0.94.3]; P = .08). When subdivided by severity of TBI, the pooled ORs were
similar with studies providing rates for mild TBI specifically, 12,13,15 yielding a pooled OR of 1.17
(95% CI = 0.72.1) with low heterogeneity (I2 = 44%, P < .17), (see figure 2) and the studies giving
estmates for severe TBI specifically,10,12,13,16 yielding a pooled OR of 1.18 (95% CI = 0.91.6) with
moderate heterogeneity (I2 = 61%, P < .04) (see figure 3). Subgroup analysis of the risk of TBI
associated with a broadly defined psychosis14,17 yielded a pooled OR of 1.3 (95% CI = 1.11.48)
with no heterogeneity. Subgroup analysis of the risk associated with Childhood TBI (less than 15
y)1315 yielded a pooled OR of 1.6 (95% CI = 0.62.6) with no heterogeneity.

Fig. 1.
Overall pooled risk estmate for risk of psychosis following traumatc brain injury.

Fig. 2.
Pooled risk estmate for psychosis following mild traumatc brain injury.
Fig. 3.
Pooled risk estmate for psychosis following severe traumatc brain injury.
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Discussion
This artcle adds to the literature on the associaton between TBI and subsequent schizophrenia.
Following a systematc review and meta-analysis, we report an increased risk of schizophrenia
following TBI of about 60%. However, finding an associaton does not mean that causality is
definitvely established. As discussed in detail by David and Prince, 4 it is difficult to tease apart
whether the TBI caused the psychosis or whether a partcular individual was already on the
trajectory toward psychosis before the injury occurred. The associaton could also be due to
confounds such as substance abuse19 or the existence of premorbid factors including motor and
attentonal problems, which are known to be associated with later schizophrenia. 20
The contributon of TBI seems to be greater among those with an inherited vulnerablity to
schizophrenia.11,14. Malaspina11 found that TBI doubled the risk for schizophrenia in family
members of probands with schizophrenia but also noted that TBI was more frequent among
relatves of schizophrenia probands than among relatves of control probands suggestng that
genes for schizophrenia may influence the exposure to TBI, as well as the consequences. Fann
and colleagues16 also found an increased rate of preexistng psychosis among individuals with
head injury and speculated that psychosis increases the risk for TBI. The apparent complexity of
the causal pathway between TBI and schizophrenia adds to the difficulty in investgatng this
relatonship.
The apparent lack of a dose-response relatonship between severity of head injury and risk for
psychosis is intriguing, partcularly in view of the recent interest in outcomes of mild head injury
among athletes and soldiers.1 This lack of effect of severity of TBI has been noted previously in
studies comparing characteristcs of cases with head injury and psychosis with matched head
injury controls with no psychosis.21,22 On the one hand, a strong dose-response relatonship
between exposure and outcome would provide some reassurance that an associaton may be
causal. On the other hand, it is possible that some other aspect of the head injury, such as
locaton of trauma, or psychosocial stress associated with the trauma, may be more relevant
than the clinical measure of severity in increasing risk of psychosis.
Our analysis did not support the hypothesis that childhood or adolescent head injury is more
likely to be associated with later schizophrenia. 23,24 However, this subgroup analysis was based on
just 3 studies.1315 Two of these studies14,15 did find significant associatons between childhood or
adolescent onset TBI and later schizophrenia but the largest study did not find an associaton. 13
Previously, Wilcox and Nasrallah24 reported a highly significant 10-fold increase in risk for
schizophrenia following head injury before the age of 10 years, but this study was not included in
the meta-analysis because it used surgical controls.

Limitations

Methodological heterogeneity: As discussed in previous reviews of this topic, 47 there are
many methodological differences between the studies examining TBI and psychosis such
as: (1) different sources of informaton about the head injuryself-report 10,11,14 vs
hospital admission data; (2) different degrees of severity of head injury studied; (3)
different definitons of psychotc illnessnarrow schizophrenia outcomes, 1013 vs broader
 definitons,14,17 and (4) variatons in length of follow-up post TBI ranging from 3 years 1316
to 35 years.14 Nevertheless, we felt that there was sufficient similarity between the
exposure and outcome variables in these case-controlled populaton-based studies to
allow us to proceed to meta-analysis. Although there was a high degree of statstcal
heterogeneity in the data for the cohort and nested case-control studies, there was no
heterogeneity for the family studies. We used a random effects meta-analysis and meta-
regression to take account of heterogeneity.

Locaton of TBI: We were not able to examine the effect of locaton of the TBI in this
analysis. One of the limitatons of the use of hospital discharge registers as a source of
exposure informaton is that exact locaton of the brain injury cannot be determined. It
has been proposed by some investgators that temporal and frontal lobe lesions are
more likely to be associated with an increased risk of later psychosis compared with
lesions in other brain regions.3,21,22 However, the classic 22-year follow-up study of 3532
Finnish soldiers by Achte and colleagues25 found no associaton between locaton of
head injury and the subsequent development of psychosis

Another limitaton is that none of the studies included in this review provided
informaton on epilepsy. This could be a potental confounder of the associaton as head
injury can cause epilepsy2 and epilepsy is associated with an increased risk of
psychosis.26,27

In conclusion, our systematc review and meta-analysis has found that there is an increased risk
of schizophrenia following TBI. The increase in risk associated with TBI is not large, in the order
of about 60%, but this is not unusual for environmental risk factors for schizophrenia. 28 In
partcular, the risk appears higher in those who have a family history of schizophrenia suggestng
a gene-environment interacton29 or an epigenetc mechanism.30 Investgaton of the molecular
or epigenetc consequences of TBI in relaton to psychosis risk, or genetc investgaton of
families in which TBI and psychosis cluster, may be fruitful lines of enquiry.
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Funding
European Community's Seventh Framework Program (HEALTH-F2-2009-241909; Project EU-GEI).
M.C. is supported by a Clinician Scientst Award from the Health Research Board Ireland
(CSA/2004/1) and also recieves support from a 2009 NARSAD Essel Foundaton Independent
Investgator Award and The Stanley Medical Research Insttute. D.C. is supported by the Health
Research Board Ireland, NARSAD, Science Foundaton Ireland, and the Stanley Medical Research
Insttute.
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Acknowledgments
We thank Dearbhla Connor for help with the systematc review. The authors have declared that
there are no conflicts of interest in relaton to the subject of this study.
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References
1. Bryant RA, ODonnell ML, Creamer M, McFarlane AC, Clark CR, Silove D. The psychiatric
consequences of traumatc injury. Am J Psychiatry. 2010;167:312320. [PubMed]
2. Fleminger S. Head injury. In: David A, Fleminger S, Kopelman MD, Lovestone S, Mellers JDC,
editors. Lishmans Organic Psychiatry: A Textbook of Neuropsychiatry. 4th ed. Chichester, UK:
Blackwell Publishing; 2009. pp. 167279.
3. Davison K, Bagley CR. Schizophrenia-like psychoses associated with organic disorders of the
central nervous system: a review of the literature. Current problems of neuropsychiatry. Br J
Psychiatry. 1969;(Special Publicaton 4):S113S184.
4. David A, Prince M. Psychosis following head injury: a critcal review. J Neurol Neurosurg
Psychiatry. 2005;76(suppl 1):i53i60. [PMC free artcle] [PubMed]
5. Kim E. Does traumatc brain injury predispose individuals to develop schizophrenia? Curr Opin
Psychiatry. 2009;21:286289. [PubMed]
6. Hesdorffer DC, Rauch SL, Tamminga CA. Long-term psychiatric outcomes following traumatc
brain injury: a review of the literature. J Head Trauma Rehabil. 2009;24:452459. [PubMed]
7. Higgins JP, Thompson SG. Quantfying heterogeneity in a Meta- Analysis. Stat Med.
2002;21:15391558. [PubMed]
8. StataCorp. Stata Statstcal Software: Release 10. College Staton, TX: StataCorp LP; 2007.
9. Harris RJ, Bradburn MJ, Deeks JJ, Harbord RM, Altman DG, Sterne JAC. Metan: fixed- and
random-effects meta-analysis. Stata J. 2008;8:328.
10. Silver JM, Kramer R, Greenwald S, Weissman M. The associaton between head injuries and
psychiatric disorders: findings from the New Haven NIMH Epidemiologic Catchment Area Study.
Brain Inj. 2001;15:935945. [PubMed]
11. Malaspina D, Goetz RR, Friedman JH, Blehar MC, et al. Traumatc brain injury and
schizophrenia in members of schizophrenia and bipolar disorder pedigrees. Am J Psychiatry.
2001;158:440446. [PubMed]
12. Nielsen AS, Mortensen PB, O Callaghan E, Mors O, Ewald H. Is head injury a risk factor for
schizophrenia? Schizophr Res. 2002;55:9398. [PubMed]
13. Timonen M, Miettunen J, Hakko H, et al. The associaton of preceding traumatc brain injury
with mental disorders, alcoholism and criminality: the Northern Finland 1966 Birth Cohort Study.
Psychiatry Res. 2002;113:217226. [PubMed]
14. Abdel Malik P, Husted J, Chow EW, Bassett AS. Childhood head injury and expression of
schizophrenia in multply affected families. Arch Gen Psychiatry. 2003;60:231236. [PubMed]
15. Massagli TL, Fann JR, Burington BE, Jaffe KM, Katon WJ, Thompson RS. Psychiatric illness after
mild traumatc brain injury in children. Arch Phys Med Rehabil. 2004;85:14281434. [PubMed]
16. Fann JR, Burington MS, Leonetti A, Jaffe K, Katon WJ, Thompson RS. Psychiatric illness
following traumatc brain injury in an adult health maintenance organisaton populaton. Arch
Gen Psychiatry. 2004;61:5361. [PubMed]
17. Harrison G, Whitley E, Rasmussen F, Lewis G, Dalman C, Gunnell D. Risk of schizophrenia and
other non-affectve psychosis among individuals exposed to head injury: case control study.
Schizophr Res. 2006;88:119126. [PubMed]
18. Chen Y-H, Chui W-T, Chu S-F, Lin H- C. Increased risk of schizophrenia following traumatc
brain injury: a 5-year follow-up study in Taiwan. Psychol Med. September 22, 2010
doi:10.1017/S00332917. [PubMed]
19. Arseneault L, Cannon M, Witton J, Murray R. The causal associaton between cannabis and
psychosis: an examinaton of the evidence. Br J Psychiatry. 2004;184:110117. [PubMed]
20. Cannon M, Caspi A, Moffitt TE, et al. Evidence for early childhood, pan-developmental
impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch
Gen Psychiatry. 2002;59:449457. [PubMed]
21. Sachdev P, Smith JS, Cathcart S. Schizophrenia-like psychosis following traumatc injury: a
chart-based descriptve and case-control study. Psychol Med. 2001;31:231239. [PubMed]
22. Fujii D, Ahmed I. Characteristcs of psychotc disorder due to traumatc brain injury: an
analysis of case studies in the literature. J Neuropsychiatry Clin Neurosci. 2002;14:130140.
[PubMed]
23. OCallaghan E, Larkin C, Redmond O, Stack J, Ennis JT, Waddington JW. Early-onset
schizophrenia after teenage head injury. A case-report with magnetc resonance imaging. Br J
Psychiatry. 1988;153:394396. [PubMed]
24. Wilcox JA, Nasrallah HA. Childhood head trauma and psychosis. Psychiatry Res. 1987;21:303
306. [PubMed]
25. Achte KA, Hillbom E, Aalberg V. Psychoses following war brain injuries. Acta Psychiatr Scand.
1969;45:118. [PubMed]
26. Qin P, Xu H, Laursen TM, Vestergaard M, Mortensen PB. Risk for schizophrenia and
schizophrenia-like psychosis among patents with epilepsy. Br Med J. 2005;331:23. [PMC free
artcle] [PubMed]
27. Sundram F, Cannon M, Doherty CP, et al. Neuroanatomical correlates of psychosis in epilepsy:
a voxel-based morphometry study. Br J Psychiatry. 2010;197:48292. [PubMed]
28. Cannon M, Clarke MC. Risk factors for schizophrenia: broadening the concept, pushing back
the boundaries. Schizophr Res. 2005;79:513. [PubMed]
29. Van Os J, Rutten BP, Poulton R. Gene-environment interactons in schizophrenia: review of
epidemiological findings and future directons. Schizophr Bull. 2008;34:10661082. [PMC free
artcle] [PubMed]
30. Rutten BPF, Mill J. Epigenetc mediaton of environmental influences in major psychotc
disorders. Schizophr Bull. 2009;35:10451056. [PMC free artcle] [PubMed]