Psychiatry Research: Neuroimaging Section 108 Ž2001.

79᎐87

Hippocampus and amygdala in schizophrenia:

assessment of the relationship of neuroanatomy to
psychopathology

Rajaprabhakaran Rajarethinam a,U , John R. DeQuardo b,

John Miedler c , Stephan Arndt e, Ravi Kirbat c , James A. Brunberg d,
Rajiv Tandonc
a
Department of Psychiatry, PBMP, Wayne State Uni¨ ersity, 2751 E. Jefferson, Suite 200, Room 265, Detroit, MI 48207, USA
b
Colorado Mental Health Institute at Pueblo, Pueblo, CO 81003, USA
c
Department of Psychiatry, Uni¨ ersity of Michigan, Ann Arbor, MI 48109, USA
d
Department of Radiology, Uni¨ ersity of California Da¨ is, Sacramento, CA 95817, USA
e
Department of Psychiatry, Uni¨ ersity of Iowa, Iowa City, IA 52242, USA

Received 13 June 2001; received in revised form 24 August 2001; accepted 19 September 2001

Abstract

The hippocampus and amygdala are believed to be involved in the pathology of schizophrenia. In this study, we
attempted to replicate the reported bilateral volume reduction of the hippocampus and amygdala and to study the
relationship of the volumes of these structures to the symptoms of schizophrenia. The hippocampus-amygdala
complex ŽHAC. was manually traced on 3-mm coronal T1-weighted MRIs, resampled into 1-mm coronal slices, from
20 male patients with schizophrenia and 20 age-matched male controls. The complex was divided into three parts:
anterior one-third representing the amygdala and middle and posterior thirds representing the anterior and posterior
halves of the hippocampus. Positive and negative symptoms and severity of hallucinations and thought disorder
Žconceptual disorganization. were quantified using the Brief Psychiatric Rating Scale ŽBPRS.. None of the above
structures, controlled for brain volume, differed significantly in patients compared with normal controls. When the
relationship between volumes and symptoms was examined, the left HAC was found to inversely correlate with
thought disorder and negative symptoms. Specifically, significant inverse correlations were found between Ži. left
amygdala and thought disorder, Žii. left hippocampus and negative symptoms, and Žiii. left anterior and posterior

U
Corresponding author. Tel.: q1-313-993-3434; fax: q1-313-993-3421.
E-mail address: rrajaret@med.wayne.edu ŽR. Rajarethinam..

0925-4927r01r$ - see front matter 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 9 2 5 - 4 9 2 7 Ž 0 1 . 0 0 1 2 0 - 2
80 R. Rajarethinam et al. r Psychiatry Research: Neuroimaging 108 (2001) 79᎐87

hippocampus volumes and positive and negative symptoms, respectively. Our findings further support the role of the
HAC in the pathophysiology of schizophrenia and suggest unique associations between individual structures and
specific symptoms of the illness. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: MRI; Hippocampus; Amygdala; Schizophrenia; Hallucinations; Thought disorder; Negative symptoms; Positive symp-
toms

1. Introduction hippocampus individually, to help further eluci-

Temporal lobe structures and their projections
have been suspected to be the seat of the patho-
physiology of psychosis since Kraepelin Ž1919..
Abnormalities of the hippocampus, amygdala, and
related temporal lobe structures can produce
symptoms akin to those of schizophrenia ŽTrim-
ble, 1987; Saykin et al., 1991; Zentner et al., 1999;
Guerreiro et al., 1999.. The role of the hippocam-
pus-amygdala complex ŽHAC. in the pathophysi-
ology of schizophrenia is supported by a number
of recent imaging studies ŽBogerts et al., 1993;
Flaum et al., 1995; Becker et al., 1996; Altshuler
et al., 2000.. Nelson et al. Ž1998., in a meta-analy-
sis of 18 volumetric MRI studies, reported a
bilateral volume reduction of both hippocampus
and amygdala in schizophrenia. However, some
well-conducted studies have not found the volume
difference ŽLaakso et al., 2001.. The relevance of
these morphometric findings to schizophrenic
psychopathology has also been investigated in a
few studies. Flaum et al. Ž1995. noted an associa-
tion between a smaller left hippocampus and
greater overall severity of symptoms in
schizophrenia. Bogerts et al. Ž1993. reported a
similar association with positive symptoms,
whereas Turetsky et al. Ž1995. reported an associ-
ation between left temporal lobe volume reduc-
tion and severity of negative symptoms. Positive
psychotic symptoms have been reported in associ-
ation with lesions of the amygdala ŽFudge et al.,
1998; Guerreiro et al., 1999.. In view of dis-
crepant findings regarding symptom correlates of
neuroanatomic abnormalities in schizophrenia,
Nelson et al. Ž1998. suggested that future studies
should ideally measure hippocampus and amyg-
dala volumes separately. They also recommended
measuring anterior and posterior portions of the-
date structure ᎐symptom relationships.
The purpose of this study was to quantify hip-
pocampus and amygdala volume in male patients
with schizophrenia and age-matched male con-
trols. We chose to study only male subjects to
avoid gender differences as confounds ŽNopoulos
et al., 1997.. We hypothesized that the hippocam-
pus and amygdala would be smaller bilaterally in
patients than in controls and that the volume
reduction would be correlated to the severity of
psychopathology in patients.
2. Methods
2.1. Subjects
Twenty male patients with DSM-III-R
ŽAmerican Psychiatric Association, 1987. schizo-
phrenia and twenty age-matched Ž"2 years. male
normal controls were studied. The patients were
chosen from a pool of research subjects from our
database based on completeness of data, imaging
sequence and the availability of age- and gender-
matched controls. After complete description of
the study to the subjects, written informed con-
sent was obtained. None of the subjects had a
history of neurological illness, head trauma,
chronic medical illness or recent substance abuse.
Patients were hospitalized and diagnosis es-
tablished by senior clinical researchers using all
available clinical information including interview
data from the Structured Clinical Interview for
DSM-III-R ŽSCID. ŽSpitzer et al., 1990a,b.. Clini-
cal symptom ratings were obtained within three
days of admission using the Brief Psychiatric Rat-
ing Scale ŽBPRS; Overall and Gorham, 1962..
 R. Rajarethinam et al. r Psychiatry Research: Neuroimaging 108 (2001) 79᎐87
Positive and negative symptom subscale scores
were determined by totalling individual item
scores; positive subscale: conceptual disorganiza-
tion, suspiciousness, hallucinatory behavior and
unusual thought content; negative subscale: emo-
tional withdrawal, motor retardation and blunted
affect ŽHedlund and Vieweg, 1980; Tandon, 1995..
Controls were recruited by advertisement in the
same community from which patients were drawn
and screened with the normal control version of
the SCID ŽSpitzer et al., 1990a,b. to exclude
DSM-III-R disorders. Normal controls with major
mental illness in first-degree relatives were ex-
cluded.
The mean age Ž"S.D.. for patients was 33.5
Ž"12.7. and for controls was 33.9 Ž"12.6.. All of
the patients had previously been exposed to an-
tipsychotic medication. The patients’ mean age at
onset of illness was 22.9 Ž"8.1. years and mean
duration of illness was 10.5 Ž"12.0. years. Their
mean BPRS total score was 53.5 Ž"9.6.. The
patients and control subjects were similar in
handedness ratio: controls 16 right, 4 left; patients
17 right, 3 left.
2.2. MRI acquisition and processing
Sixty T1 weighted 3-mm coronal slices, with no
interslice gap, were obtained using a 1.5 T MR
scanner ŽSigna, General Electric Medical Sys-
tems, Milwaukee. Ž3D SPGR coronal image se-
ries, matrix 256 = 256, 22 cm field of view, TR 40
ms, TE 5 ms, one excitation.. The images were
processed separately on a Silicon Graphics work-
station using ‘BRAINS’ software ŽAndreasen et
al., 1992. by one of the authors ŽRR. who was
blind to the subject information. First, the whole
brain Žcerebrum and cerebellum. was traced man-
ually on the 3-mm coronal slices. Using ‘training
classes’, samples of gray matter from the caudate
and CSF from the lateral ventricle, a threshold
pixel value was determined and used to delineate
CSF from tissue on each image. The software
then ‘washed out’ CSF pixels for each image, and
calculated tissue Žgray and white matter. volumes
by counting the number of tissue pixels multiplied
by slice thickness. Following this procedure, the
anterior commissure ŽAC. and posterior commis-
81
sure ŽPC. points were manually located. The
whole image was then resampled Žnot morphed.
into 3D Talairach space using the AC and PC
points and whole brain outlines ŽTalairach and
Tournoux, 1988.. Resampling eliminates head po-
sition variation in three dimensions but does not
change the size of the brain, as it is not morphed.
The resampled image was used for manually trac-
ing the HAC.
2.3. Definition of region of interest (ROI)
The HAC was manually traced bilaterally on
the resampled 1-mm coronal images ŽFigs. 1᎐4..
The posterior end of the complex was defined as
the coronal slice wherein the fornix first fully
appears. Anteriorly the amygdala was traced until
it could no longer be identified. The entire HAC
was traced as a single ROI and then, using the
number of coronal slices, the ROI was divided
into three equal parts. When the ROI was not
equally divisible by three, the middle and poste-
rior thirds or the posterior third were assigned to
the additional sliceŽs.. This method proved to be
useful in dividing the ROI into tissue represent-
ing amygdala and anterior and posterior halves of
hippocampus Žconfirmed by visual inspection in
each case.. We used this model to avoid the bias
and variability inherent in manual methods used
to parse these small structures. The ROI was
traced twice independently by one of the authors
ŽRR. on five subjects. The test-retest reliability
assessed by intraclass correlation was 0.57 on the
right side and 0.79 for the left.
2.4. Statistical analysis
Volumes of hippocampus, amygdala, anterior
and posterior halves of hippocampus and the
entire HAC were the variables examined for each
hemisphere. Difference between groups was
tested using ANCOVA with total brain volume as
a covariate. In patients, the relationship between
the volume data and symptom data gleaned from
the BPRS Žconceptual disorganization, hallucina-
tory behavior, positive and negative symptom sub-
scales and total score. was examined using Spear-
man correlation coefficients controlling for total
82 R. Rajarethinam et al. r Psychiatry Research: Neuroimaging 108 (2001) 79᎐87
Fig. 1. Coronal MRI showing right and left hippocampi.
brain tissue volume. To examine the laterality
Žnature of volumetric difference between right
and left hemispheres. and group difference, a
three-way MANOVA was performed using diag-
nosis as an independent group dimension and
hemisphere and the three basic ROIs Žanterior
and posterior halves of the hippocampus and
amygdala. as repeated measures.
3. Results
The average volume of the whole brain was
1479 " 112 cc for the control group and 1401.7"
115 cc for the patients. The difference Ž77.3 cc.
was statistically significant Ž Ps 0.05. Žreported
previously.. The volumes of the three basic ROIs
Žanterior half of hippocampus, posterior half of
hippocampus and amygdala. and the combined
volumes of hippocampus and HAC are reported
in Table 1. There was no significant volume dif-
ference between patients and controls in any of
the ROIs. The three-way MANOVA revealed no
difference between groups in ROI volumes as
well as no laterality differences.
Correlation of HAC and its subdivisions with
symptom data revealed the following: Ža. left HAC
volume correlated inversely with negative symp-
tom and conceptual disorganization scores Ž r s
y0.62, Ps 0.011 and r s y0.56, Ps 0.025, re-
spectively; see Table 2.; Žb. left amygdala volume
correlated inversely with conceptual disorganiza-
tion Ž r s y0.70, Ps 0.002.; Žc. left hippocampus
volume correlated inversely with negative symp-
tom severity Ž r s y0.66, P s 0.005.; Žd. the
volume of the left anterior half of the hippocam-
 R. Rajarethinam et al. r Psychiatry Research: Neuroimaging 108 (2001) 79᎐87
Fig. 2. Showing the anterior-most slice of the HAC Žamygdala..
pus correlated inversely with hallucinatory behav-
ior and positive symptom scores Ž r s y0.52, Ps
0.04 and r s y0.51, Ps 0.043, respectively.; Že.
the volume of the left posterior half of the hip-
pocampus correlated inversely with negative
symptoms Ž r s y0.55, Ps 0.028. ŽTables 1 and
2..
4. Discussion:
The salient findings of our study were: Ža.
Fig. 3. Mid-section of the HAC Žhippocampus..
83
Fig. 4. The posterior-most slice of the HAC and fornix.
patients with schizophrenia had no significant
volumetric difference of the HAC and its compo-
nents from age-matched healthy controls; Žb.
among patients, left HAC volume negatively cor-
related with severity of negative symptoms and
formal thought disorder Žconceptual disorganiza-
tion.; Žc. left amygdala volume correlated in-
versely with the severity of thought disorder Žcon-
ceptual disorganization.; Žd. left hippocampus
volume negatively correlated with severity of neg-
ative symptoms; Že. volume of the left anterior
hippocampus correlated inversely with severity of
hallucinations and positive symptoms; and Žf.
volume of the left posterior hippocampus corre-
lated inversely with severity of negative symp-
toms. These findings are mostly consistent with
results reported by other investigators using simi-
lar methodology to assess hippocampus and
amygdala size ŽBecker et al., 1996; Nelson et al.,
1998; Altshuler et al., 2000. and symptom corre-
lates of these structures ŽBogerts et al., 1993;
Flaum et al., 1995; Turetsky et al., 1995.. It is
interesting to note that in statistical terms the
volume of the hippocampus correlates to the form
of psychopathology but is not different in patients
versus controls.
Many morphometric neuroimaging findings of
brain regions in schizophrenia have been widely
replicated but are still not consistent. Almost all
the reported positive volumetric findings have few
well-conducted negative studies to counter them
ŽShenton et al., 1997; McCarley et al., 1999.. In
light of a publication bias against negative find-
84 R. Rajarethinam et al. r Psychiatry Research: Neuroimaging 108 (2001) 79᎐87

Table 1
Volume difference between patients and controls Ž n s 20 each. ANCOVA with whole brain volume as covariate

Region of interest Hemi- Mean Mean Mean F value

ŽROI. sphere ŽS.D.. ŽS.D.. difference
Controls Žin cc. Patients Žin cc.

Hippocampus- Right 5.35 Ž0.66. 4.98 Ž0.52. 0.368 0.17

amygdala complex Left 4.99 Ž0.52. 4.75 Ž0.55. 0.244 0.29
Amygdala Right 2.47 Ž0.32. 2.32 Ž0.29. 0.142 0.41
Left 2.41 Ž0.27. 2.28 Ž0.31. 0.128 0.37
Whole Right 2.89 Ž0.49. 2.66 Ž0.36. 0.226 0.2
hippocampus Left 2.58 Ž0.36. 2.46Ž0.31. 0.116 0.36
Anterior half of Right 2.01 Ž0.39. 1.84 Ž0.29. 0.18 0.17
hippocampus Left 1.77 Ž0.3. 1.64 Ž0.24. 0.122 0.2
Posterior half of Right 0.87 Ž0.15. 0.83 Ž0.13. 0.046 0.54
hippocampus Left 0.81 Ž0.17. 0.82 Ž0.13. y0.006 0.7

ings, it can be assumed that there may be more neuroanatomic deviations associated with schizo-
negative studies that have been conducted than phrenia andror methodological differences
are reflected in the current literature. This dis- between studies including a lack of homogeneity
crepancy may reflect the subtle nature of the in the diagnosis and illness severity, as well as

Table 2
Correlation matrix of hippocampus-amygdala volumes and symptom scores from the BPRS Ž N s 20 male patients with
schizophrenia.

Region of interest Hemi- Conceptual BPRS BPRS BPRS BPRS

ŽROI. sphere disorganization Hallucination Total score Positive Negative
symptoms symptoms

Hippocampus- Right y0.18 y0.04 0.39 0.39 y0.14

amygdala complex Ps 0.51 Ps 0.88 P s 0.14 Ps 0.14 P s 0.6
Left I0.558 y0.34 y0.37 y0.26 I0.617
P s 0.025 Ps 0.2 P s 0.15 Ps 0.32 P s 0.01
Amygdala Right 0.08 y0.03 0.48 0.23 0.01
Ps 0.76 Ps 0.92 P s 0.06 Ps 0.39 P s 0.97
Left I0.7 y0.3 y0.3 y0.30 y0.44
P s 0.002 Ps 0.26 P s 0.26 Ps 0.25 P s 0.09
Whole hippocampus Right y0.29 y0.03 0.06 0.28 y0.18
Ps 0.28 Ps 0.93 P s 0.82 Ps 0.3 P s 0.5
Left y0.18 y0.29 y0.36 y0.13 I0.664
Ps 0.5 Ps 0.28 P s 0.18 Ps 0.64 P s 0.005
Anterior half of Right y0.15 y0.32 y0.28 y0.25 0.12
hippocampus Ps 0.57 Ps 0.22 P s 0.298 Ps 0.35 P s 0.66
Left y0.08 I0.517 y0.41 I0.51 y0.4
Ps 0.78 P s 0.04 P s 0.11 P s 0.04 P s 0.12
Posterior half of Right y0.26 0.11 0.19 0.42 y0.26
hippocampus Ps 0.34 Ps 0.68 P s 0.48 Ps 0.11 P s 0.34
Left y0.18 y0.002 y0.16 0.19 I0.547
Ps 0.52 Ps 0.995 P s 0.56 Ps 0.47 P s 0.03

The significant values are bold-faced.

 R. Rajarethinam et al. r Psychiatry Research: Neuroimaging 108 (2001) 79᎐87
variations in the study groups and imaging meth-
ods. It is also possible that the structures under
study contribute to the pathology of the disease
on a microscopic level ŽScheibel and Kovelman,
1981. that possibly is not always reflected in a
statistically significant volume difference. For ex-
ample, even small structures like the hippocam-
pus and the amygdala have several distinct subre-
gions that project to different parts of the brain,
suggesting multiple functions for a given structure
ŽDuvernoy, 1998.. Some of these anatomical sub-
regions may be involved in the pathology of
schizophrenia while others may not. Since volu-
metric measurements are limited to the entire
structure on a relatively larger scale, structure ᎐
function relationships may be difficult to demon-
strate consistently. Studies at the subregion, histo-
logical and functional levels may be more helpful
in discerning relevant pathology in these small yet
complex structures. Despite these caveats, mor-
phometric findings support a number of hypothe-
ses about the disease process.
Abnormalities in different limbic structures may
be uniquely related to different dimensions of
schizophrenic psychopathology ŽLiddle et al.,
1989; Arndt et al., 1995; Flaum et al., 1995.. For
example, the amygdala has substantial feedback
projections to temporal lobe language association
cortex and other association cortices ŽBraak et al.,
1996. and is believed to be involved in assigning
emotional valence to memories. Consequently, it
is believed to play a major role in processing
thought ŽCahill et al., 1995.. The inverse correla-
tion between left amygdala volume and severity
of conceptual disorganization observed in our
study may indicate a possible involvement of this
structure in the pathophysiology of formal thought
disorder, and the ‘schizm’ between thought and
affect which is a hallmark of schizophrenia.
The hippocampus projects to the orbitofrontal
and medial frontal cortices, and these circuits
may play an important role in psychomotor exec-
utive function ŽWeinberger et al., 1992.. Our data,
revealing a significant inverse correlation between
negative symptoms and volume of the left hip-
pocampus, support the involvement of hippocam-
pus and so the hypothesis of hippocampal-frontal
85
system dysfunction in the pathophysiology of neg-
ative symptoms of schizophrenia.
Hippocampal subregions also project to the
temporal pole of the superior temporal gyrus
ŽSTG. ŽDuvernoy, 1998., which has been specifi-
cally implicated in the production of hallucina-
tions ŽBarta et al., 1990; Rajarethinam et al.,
2000.. Our observation of an inverse correlation
between volume of the left anterior hippocampus
and severity of hallucinatory behavior may indi-
cate that the hippocampus, along with the STG
and the reciprocal connections, may be involved
in the production of positive symptoms Žreality
distortion.. It is conceivable that poorly co-
ordinated ‘working memory’ input from the hip-
pocampus is presented as an internal stimulus for
the ‘cortical perception’ at the STG resulting in
hallucination.
One of the limitations of this study is that
multiple comparisons were made with symptom
correlations. This creates a high risk for one or
more Type I errors, especially with a small sample
size. Considering this, if the significance value is
lowered to 0.01 or lower, the relationships
between the hippocampus and negative symptoms
and the amygdala and thought disorder stand out.
These two findings are more robust than the
others, and further studies and larger sample
sizes will clarify this relationship.
It should be noted that the histological subdivi-
sions and the distribution of the nuclei in the
hippocampus and the amygdala are complex and
not exactly reflected in this MRI study. Current
MRI methodology should be considered relatively
gross. Therefore, the findings described above in
relation to the HAC and its divisions should be
viewed with caution. Other limitations of the study
include relatively small sample size, modest test-
retest reliability of HAC volumes, use of a rela-
tively crude symptom scale ŽBPRS., and lack of
control for some potential confounding factors,
such as treatment history and timing of scan in
the course of illness, subject education level, and
parental SES. These data must therefore be
viewed as preliminary and the findings as reason-
able indicators but not conclusive evidence of
pathophysiological relationships. This research is
86 R. Rajarethinam et al. r Psychiatry Research: Neuroimaging 108 (2001) 79᎐87
an attempt to implement the recommendation of
Nelson et al. Ž1998. to study the amygdala and
anterior and posterior hippocampus and their in-
dividual relationships to various symptoms of
schizophrenia separately. Our findings, which sug-
gest distinct syndromic associations with different
limbic structures, may help to reconcile some
prior discrepant morphometric findings in
schizophrenia. Future studies involving specific
subregions and nuclei, their histology, projections,
functional and neurotransmitter systems will likely
enhance understanding of the possible involve-
ment of these structures in the pathophysiology
of this disease.
Acknowledgements
The research performed was supported in part
by a grant from the National Alliance for Re-
search on Schizophrenia and Depression
ŽNARSAD. ŽJ.R.D..
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