Asian Journal of Psychiatry 5 (2012) 43–47

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Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

An examination of relationship between neurological soft signs

and neurocognition
Ram Kumar Solanki a, Mukesh Kumar Swami b,*, Paramjeet Singh a
a
Department of Psychiatry, SMS Medical College, Jaipur, India
b
Department of Psychiatry, RNT Medical College, Udaipur, India

A R T I C L E I N F O A B S T R A C T

Article history: Objective: Neurological soft signs (NSS) and cognitive function had been examined in schizophrenia, but
Received 30 August 2011 their relationship has remained elusive for several years. We examined the relationship between NSS and
Received in revised form 7 December 2011 cognitive functions in the present study.
Accepted 18 December 2011
Method: A cross sectional study was carried out. Subjects were drawn from first degree relatives of
schizophrenia patients, admitted as inpatient or attending as an outpatient. Controls were recruited by
Keywords: word of mouth from hospital staff and visitors of hospitalized patients. Those subjects who satisfied the
Neurocognition
screening process were subjected to Cambridge Neurological Inventory for soft sign assessment and digit
Neurological soft signs
span test, paired associate learning test (PALT) and visuo-spatial working memory matrix (VSWMM) for
Motor coordination
Visuo-spatial working memory cognitive function assessment. Correlation analysis and structural equation modeling (SEM) was used for
Structural equation modeling analysis.
Result: Significant negative correlation of primitive reflexes with PALT; of motor coordination with
VSWMM, working memory (WM) and cognitive index; of total NSS with WM and cognitive index among
first degree relatives. SEM showed that motor soft signs have important negative influence over WM.
Conclusion: The current findings indicate that NSS have significant negative effect on cognitive
functioning.
ß 2011 Elsevier B.V. All rights reserved.

1. Background family members of subjects with schizophrenia (Hyde et al., 2007;

Neurological soft signs (NSS) have been known to be non-
localizing (Quitkin et al., 1976) and indicative of generalized
disruption in neural circuitry between cortical and subcortical
areas (Buchanan and Heinrichs, 1989). They may reflect a
phenotypic expression of neural dysmaturation and have been
proposed as an endophenotype for schizophrenia (Chan and
Gottesman, 2008). Various neuroanatomical regions have been
correlated with NSS in neuroimaging studies indicating that they
might represent localized deficit and have relation with cognitive
functioning (Hui et al., 2009).
On the other hand, cognitive dysfunction is well known to be an
integral part of schizophrenia and to have prognostic significance
as an endophenotype (Snitz et al., 2006).
NSS and cognitive function had been examined in schizophre-
nia, but their relationship has remained elusive for several years.
Studies had found that cognitive deficits are related to NSS in
schizophrenia (Arango et al., 1999; Sanders et al., 2004) and among
* Corresponding author at: 53/104, V T Road, Mansarovar, Jaipur 302020, India.
E-mail address: mukesh.swami@gmail.com (M.K. Swami).
Sanders et al., 2006). Few studies suggested that NSS and
neurocognitive functions capture similar underlying deficits in
schizophrenia (Flashman et al., 1996; Wong et al., 1997). A recent
study found significant correlation between these two and had
argued for common underlying substrate (Chan et al., 2009). A
review (Bombin et al., 2005) suggested that neurological abnor-
malities may be the result of early (pre or perinatal) disturbances
in brain function. They may remain silent for years, reappearing
during adolescence in the form of neurological signs, predating the
appearance of psychotic symptoms and possibly coinciding with
the occurrence of negative symptoms and cognitive impairment.
Relation between NSS and cognitive functions is important
since it may shed light on patho-physiology of schizophrenia.
Further, if NSS is found to have relation with cognitive functions, it
may prove useful as a clinical indicator of cognitive status.
Findings presented and discussed in this article are a byproduct
of our study of assessment of multiple risk markers of schizophre-
nia. In the current paper we examined the relationship between
NSS and cognitive functions, especially working memory, which is
a core cognitive feature of schizophrenia, has been implicated in
the pathogenesis of the schizophrenia and is a particularly strong
candidate of endophenotype (Gur et al., 2007). Among NSS, motor

1876-2018/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ajp.2011.12.006
44 R.K. Solanki et al. / Asian Journal of Psychiatry 5 (2012) 43–47
signs have been shown to be more closely related to illness
(Bombin et al., 2005). Therefore, we have focused on these domains
in the present evaluation.
2. Materials and methods
A cross sectional study was carried out. Subjects were drawn
from first degree relatives of schizophrenia patients, admitted as
inpatient or as outpatients at our institution. The study included 50
consecutive first degree relatives of schizophrenia patients (the
diagnosis of all patients was reviewed and confirmed by two
psychiatrists independently based on ICD-10 criteria) and 30
healthy controls. Controls were recruited by word of mouth from
hospital staff and visitors of hospitalized patients. Controls were
assessed by clinical interview prior to inclusion in study to rule out
any psychopathology. The study was approved by a research
review board and ethical committee of the institution. An informed
consent was obtained from the subject prior to participation in the
study. To be included in study the subjects were screened with a
specially designed screening pro forma (consists of selection
criteria). Those subjects who satisfied the screening process were
recruited into the study. Subjects of either sex, of age 18–65 years
and literate enough to read and understand the questionnaires
were included. Subjects with a lifetime history of any psychiatric
disorder, substance abuse, history of head injury with any
documented cognitive sequel or with loss of consciousness,
neurological disease or damage, mental retardation, or any medical
illnesses that may significantly impair neurocognitive function
were excluded from the study. Finally, subjects having a first-
degree relative with a psychotic disorder were excluded from the
control group.
The subject’s sociodemographic data was recorded. After that
each participant in the study was subjected to selected measures
for assessment.
2.1. The Cambridge Neurological Inventory: (Chen et al., 1995)
It is a schedule for standardized neurological assessment of
psychiatric patients. Part 2 of the inventory is for soft sign
examinations. There are mainly three groups of testing: (1) assess
‘‘primitive reflexes’’; (2) assess motor coordination (MC) and
repetitive sequential motor execution (MS); (3) assess integration
of sensory information (SI). Primitive reflexes consists of Grasp
reflex, Snout reflex and Palmomental reflex. MC and MS is assessed
with finger-nose test, finger-thumb tapping, finger-thumb oppo-
sition, Diadochokinesis, fist-edge-palm test, oseretsky test,
rhythm-tapping test and go/no-go test. Integration of SI is assessed
via extinction, finger agnosia, stereognosis, graphesthesia and left–
right orientation.
2.2. Neurocognitive tests
Digit span test (DST) (Wechsler, 1981) was used as a measure of
verbal working memory. It has two parts - digit forward test and
digit backward test. Paired associate learning test (PALT) (Pershad
and Wig, 1984) is a sub-test of Post Graduate Institute (PGI)
memory scale used to assess auditory-verbal memory on indices of
immediate recall and recognition. This is a cued recall test of verbal
memory. The test consists of two series of associative pairs (5 pair
each). One is for the similar pair and another for dissimilar pair.
Visuo-spatial working memory matrix (VSWMM) (Vecchi et al.,
1995; Roopesh, 2000) was used to measure the capacity of a
subject’s visuo-spatial working memory. It assesses two different
components: passive store and active imagery operation. The test
consists of ten 4  4 matrices each printed on a different card in
bright homogenous color. Two consecutive squares are yellow and
another one is red on a given card. In the two dimensional space of
a card, these colored squares are situated at a different location in
each card. Stimulus is given to the subject according to standard
key for each card and the subject is asked to move RED square’s
position in his mind and correct responses are noted. Scores on DST
and VSWMM were summed to get score of working memory (WM)
and sum of all test scores were taken as cognitive index.
2.3. Statistical analysis
Basic statistical analysis was done with the help of SPSS 17
software. Structural equation modeling (SEM) was conducted with
the LISREL 8.80 (student version) for Windows (Jöreskog and
Sörbom, 2006). For estimation, ‘unweighted least square’ (ULS)
method was used because of small sample size and the fact that it
does not assume multivariate normality. The validity of the model
was tested with fit indices including normed fit index (NFI), non-
normed fit index (NNFI), comparative fit index (CFI), incremental
fit index (IFI), and root mean square error of approximation
(RMSEA) and standardized root mean square residual (SRMR).
These indices represent the fit between the assumed model and the
baseline model of uncorrelatedness between the observed vari-
ables. The first four fit indices values of .90 or above, and RMSEA
and SRMR value of .08 or less indicated the model adequately fits
the data (Hu and Bentler, 1999).
3. Results
Subjects in both groups were predominantly married, Hindu
males, having income <Rs 15,000/- per month, and were living in
joint families. The majority of subjects in both groups were
educated above 8th standard, though controls had higher
education. First degree relative subjects were farmer or workers
living in rural areas while the majority of control subjects were
urban dwelling professionals.
First degree relatives (DST, Mean = 7.44, SD = 1.013; PALT,
Mean = 13.64, SD = 4.169; VSWMM, Mean = 2.18, SD = 2.283;
primitive reflexes, Mean = .06, SD = .24; motor coordination,
Mean = 2.26, SD = 1.805; motor sequencing, Mean = 5.70,
SD = 2.573; sensory integration, Mean = 3.68, SD = 2.299) scored
significantly different from the control group (DST, Mean = 8.83,
SD = 1.783; PALT, Mean = 16.80, SD = 2.51; VSWMM, Mean = 4.83,
SD = 2.71; primitive reflexes, Mean = .00; motor coordination,
Mean = .53, SD = 1.0; motor sequencing, Mean = 1.90, SD = 2.21;
sensory integration, Mean = 2.13, SD = 1.81) on all the measures.
We used partial correlation to control for age and education
which showed significant negative correlation of primitive reflexes
with PALT; of motor coordination with VSSM, WM and cognitive
index; of total NSS with WM and cognitive index among first
degree relatives (Table 1). No significant correlation was observed
in the control group.
Based on the findings of partial correlation we hypothesized a
model of relation between motor NSS and WM and tested the
model with SEM. The SEM consists of two models, namely the
measurement model and the structure model (Anderson and
Gerbing, 1988). The measurement model shows the relations
between the latent variables and their indicators, whereas the
structure model shows the potential causal dependencies between
variables. In the current study, the measurement model was based
on four factors consisting of two latent variables, namely WM, and
NSS. DST and VSWMM were ascribed to ‘‘working memory’’. On the
other hand, the MC and motor sequencing were ascribed to
‘‘neurological soft sign’’. The structural model shows the relation-
ships between the WM and the latent variable of NSS. Analysis was
conducted separately for the first degree relatives and healthy
volunteers. Raw data were used as input data for analysis (Table 4).
 R.K. Solanki et al. / Asian Journal of Psychiatry 5 (2012) 43–47 45

Table 1
Result of partial correlation between neurological soft signs and cognitive tests.

Control variable DST PALT VSWMM WM Cognitive index

Age and education First degree relatives (n = 50)

Primitive reflexes r .181 .376** .108 .021 .269
Motor coordination r .172 .119 .319* .337* .288*
Motor sequencing r .188 .192 .159 .208 .286*
Sensory integration r .055 .016 .158 .155 .098
Total NSS r .176 .168 .274 .301* .310*
Controls (n = 30)
Motor coordination r .163 .072 .082 .022 .041
Motor sequencing r .063 .080 .201 .107 .095
Sensory integration r .307 .246 .236 .306 .306
Total NSS r .241 .194 .027 .096 .109

r, correlation coefficient; DST, digit span test; NSS, neurological soft signs; PALT, paired associative learning test; VSWMM, visuo-spatial working memory matrix; WM,
working memory.
*
p < .05.
**
p < .01.

3.1. Testing the measurement model Table 2

Factor loadings for the measurement model in first degree relatives and control
group (LISREL output).
The results (Table 2 and Figs. 1 and 2) showed that the
measurement model fit the data relatively well. All of the loadings Observed variable Estimate SE Wald R2
statistics
of the observed variables on corresponding latent variables were
statistically significant. Thus, all of the latent variables appeared to Motor coordination R 1.86 0.17 10.78 1.06
have been adequately measured by their respective observed C 0.81 0.13 5.90 0.35
Motor sequencing R 1.53 0.14 10.81 0.41
variables.
C 1.43 0.25 5.74 0.65
Digit span test R 0.46 0.10 4.76 0.20
3.2. Testing the structure model C 2.22 0.46 4.85 1.55
Visuo-spatial working R 1.66 0.10 4.76 0.53
memory matrix
The results (Table 3 and Figs. 1 and 2) showed a good fit of the
C 1.43 0.46 4.85 0.28
structure model to the data in both samples. The structural paths
from NSS to WM (first degree relatives = 0.40, SE-0.06; con- R, first degree relative; C, control; SE, standard error; R2, squared multiple
correlations.
trol = 0.31, SE-0.12) was statistically significant (p < 0.05).
Squared multiple correlations for structural equations for first
degree relatives and the control group were 0.16 (medium effect
size) and 0.094 (small effect size), respectively. These results
suggest that NSS have important negative influence on WM i.e.
[(Fig._1)TD$IG]higher NSS is associated with more severe impairment of WM.

Fig. 1. The structure model of the influence of soft signs on working memory in first degree relatives. MC, motor coordination; MS, motor sequencing; DST, digit span test;
[(Fig._2)TD$IG]
VSWM, visuo-spatial working memory; NSS, neurological soft sign; WM, working memory; RMSEA, root mean square error of approximation.

Fig. 2. The structure model of the influence of soft signs on working memory in controls. MC, motor coordination; MS, motor sequencing; DST, digit span test; VSWM, visuo-
spatial working memory; NSS, neurological soft sign; WM, working memory; RMSEA, root mean square error of approximation.
46 R.K. Solanki et al. / Asian Journal of Psychiatry 5 (2012) 43–47
Table 3
Goodness of fit statistics of both the groups.
Index First degree relatives
RMSEA 0.0
NFI 1.00
NNFI 1.24
CFI 1.00
IFI 1.00
SRMR 0.027
CFI, Comparative fit index; IFI, Incremental fit index; NFI, Normed Fit Index; NNFI,
Non-normed fit index; RMSEA, Root mean square error of approximation; SRMR,
Standardized root mean square residual.
4. Discussion
The current findings indicate that NSS have significant negative
effect on cognitive functioning and indicate the probability of
being a precursor of poor cognitive functioning. Findings are in line
with Arango et al. (1999), who suggested neurological signs as a
marker of global cognitive impairment and that some subsets of
these signs are specifically related to different neuropsychological
tests thought to represent function in different brain areas.
Our study showed significant negative correlation of primitive
reflexes with PALT (assessing episodic verbal memory). Previously
Hyde et al. (2007) had shown that primitive reflexes may be
indicative of cognitive impairment. Gabalda et al. (2008) explored
frontal release signs (FRS) and their associations with verbal
memory among patients (n = 63), first-degree relatives (n = 33)
and non-psychiatric controls (n = 51). In the entire sample, greater
FRS were associated with poorer verbal memory. Studies have
shown that primitive reflexes, aka FRS, are associated with frontal
lobe function (van Boxtel et al., 2006). Relation of episodic memory
with frontal cortex has also been demonstrated in earlier studies
(Wagner, 2002; Tuulio-Henriksson et al., 2002). In a review of
functional neuroimaging studies, Fletcher et al. (1997) found that
encoding and retrieval of episodic memory is associated with
prefrontal cortex. So the possibility of similar localization may
explain correlation found in our study.
We also found significant negative correlation of MC with WM.
Cognitive index also showed significant negative correlation with
MC and sequencing and total NSS. These finding indicates that
motor soft signs may have a specific relationship with cognitive
functions, specially WM. In a recent review of NSS in schizophrenia
Hui et al. (2009) emphasized that motor NSS are specifically
associated with some cognitive impairments in schizophrenia.
In their study Mohr et al. (1996) also found correlation between
motor signs and cognitive functions. They studied neurological
signs in patients with schizophrenia using the neurological
evaluation scale (NES) and found that total score and subscale
scores of NES correlated with scores on the Wisconsin Card Sorting
Test and the Weigl Sorting Test (measures thought to represent
Table 4
Fitted covariance matrix of both groups.
Observed variable Motor coordination
Motor coordination R 3.26
C 1.02
Motor sequencing R 2.83
C 1.16
Digit span test R 0.33
C 0.55
Visuo-spatial working memory matrix R 1.22
C 0.35
R, first degree relative; C, control.
frontal lobe function). Correlations were highest for the sequenc-
ing of complex motor acts subscale of the NES. They suggested that
Controls this relationship was indicative of prefrontal cortical dysfunction.
0.0 Correlation between WM and NSS indicates the possibility of
1.00 common neurobiological substrate. In a review, Bombin et al.
1.30 (2005) suggested frontal lobes as putative neuroanatomical
1.00 localization for motor signs. Several studies (Janssen et al.,
1.00
2009; Keshavan et al., 2003) have also found correlation of motor
0.006
signs with caudate. Janssen et al. (2009) found correlation of motor
sequencing with smaller right caudate volume while another study
by Keshavan et al. (2003) found that scores for the repetitive motor
neurological examination abnormalities correlated significantly
with left caudate and cerebellum volumes. Few studies (Schroder
et al., 1991; Dazzan et al., 2002) had found smaller basal ganglia
volumes to be associated with motor deficits.
Some studies suggest that both frontal lobe and caudate may be
related to motor soft signs.
On the other hand, several studies (Gur et al., 2007) have shown
that the prefrontal cortex, particularly the dorso-lateral prefrontal
cortex (DLPFC), is critical for intact WM. Recently, studies have
found the role of the caudate nucleus to be important in the
process of WM. In one study Postle and D’Esposito (2003) found
that the caudate nucleus mediates participation of the motor
system in spatial WM performance. Caudate activity has been
observed during the encoding, maintenance, and retrieval phases
of WM tasks (Gazzaley et al., 2004; Narayanan et al., 2005;
Manoach et al., 2003). In an fMRI study Melrose et al. (2007)
concluded that the caudate body is critical for WM. Ashby et al.
(2005) suggested FROST (short for FROntal-Striatal-Thalamic) as a
model of WM maintenance. The model assigns a unique role to the
basal ganglia. It assumes that the head of the caudate and the
globus pallidus contribute to WM maintenance via sustained
activation.
In light of all these studies it can be assumed that caudate
nucleus and frontal cortex are the common neurological structures
underlying motor soft signs and WM. In tune with this, a review by
Bombin et al. (2005) found that several considerations support the
conceptualization of soft signs and cognitive functioning as
partially independent phenomena, though they may be ultimately
linked. A recent study by Chan et al. (2009) also examined the
underlying relationships between NSS and neurocognitive func-
tions with SEM among patients with schizophrenia and controls.
They found that there were modest to moderate associations
among NSS, executive attention, verbal memory, and visual
memory and concluded that NSS and neurocognitive tests are
two ways of capturing the same construct.
There is still no consensus on whether NSS is specific to
schizophrenia or not but even if they are not specific there is
consensus that they have prognostic significance (Arango et al.,
1999; Bombin et al., 2005). Keshavan et al. (2003) suggested that
neurological signs may serve as expedient bedside measures that
Motor sequencing Digit span test Visuo-spatial working
memory matrix
6.62
4.92
0.28 1.03
0.97 3.17
1.00 0.76 5.21
0.62 3.17 7.32
 R.K. Solanki et al. / Asian Journal of Psychiatry 5 (2012) 43–47
are potentially useful in the assessment of idiopathic psychoses.
Since atypical antipsychotics have been shown to have better effect
on cognitive functions, NSS may also prove useful in choice of
antipsychotic and thus probably improving long term prognosis.
Since the administration of conventional neurocognitive function
tests is time-consuming, the assessment of NSS may save time for
clinical practitioners, as a clinical screening measure for early
cognitive remediation/ rehabilitation.
Though encouraging, findings of the current study must be
viewed in light of its limitation like small sample size, cross
sectional design and representativeness of sample (multivariate
non-normal). Further, small sample size does not allowed for
inclusion of all the variables in SEM. Due to its limitations, the
current study could not conclude definitely that soft signs can
predict cognitive status of a patient. But still it provides important
insight to a possible relationship between these variables. Further
larger studies are required, with more stringent criteria and using
multiple tests for a cognitive domain, to confirm their relationship.
Role of funding source
None.
Contributors
All the three authors contributed in the design of the study and,
literature searches. The second author analyzed the data, and
wrote the first draft of the manuscript. All authors contributed to
and have approved the final manuscript.
Conflict of interest
None.
Acknowledgements
None.
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