The British Journal of Psychiatry (2007) 191: 120-125. doi: 10.1192/bjp.bp.106.026773
© 2007 The Royal College of Psychiatrists
Frontal release signs and cognition in people with schizophrenia, their siblings and healthy controls
THOMAS M. HYDE, MD, PhD,
TERRY E. GOLDBERG, PhD,
MICHAEL F. EGAN, MD,
MARC C. Lener, BA and
DANIEL R. WEINBERGER, MD
Clinical Brain Disorders Branch, Intramural Research Program, National
Institute of Mental Health, National Institutes of Health, Bethesda, Maryland,
USA
Correspondence:
Dr Thomas Hyde, Room 4N306, Building 10, National Institutes of Health, 10
Center Drive, Bethesda, Maryland 20892, USA. Tel: +1 301 496 8848; fax: +1 301
402 2751; email:
HydeT{at}mail.nih.gov
Declaration of interest None.

ABSTRACT
Background Frontal release signs, a subset of neurological soft
signs, are common in schizophrenia.
Aims To explore the relationship between frontal release signs and
neuropsychological tests of frontal lobe function in people with
schizophrenia, their siblings and healthy controls.
Method Neuropsychological tests and frontal release signs were
measured in a cohort of index cases (n=302), their siblings
(n=240) and healthy controls (n=346).
Results The mean total score of frontal release signs was 1.5
(s.d.=1.58) in the schizophrenia group, 0.54 (s.d.=0.92) for siblings and 0.42
(s.d.=0.77) for controls. Schizophrenia group scores were greater than healthy
control or sibling cohort scores (P < 0.0001), which did not
differ. In all three cohorts, right grasp reflex scores positively correlated
with number of perseverative errors on the Wisconsin Card Sort Task
(P < 0.05). In the schizophrenia group, frontal release signs
scores showed an inverse correlation with IQ (R=–0.199,
P < 0.0005).
Conclusions Our findings of relationships between frontal release
signs and cognitive assays of cortical dysfunction and the increased frequency
of these signs in people with schizophrenia implicate a cortical origin for
these clinical signs and evidence of frontal lobe dysfunction in this
disorder.

INTRODUCTION
An association between schizophrenia and subtle neurological
abnormalities
has been reported for nearly a century, with
intensive study over the past 40
years (
Woods et al,
1986).
People with schizophrenia have a high frequency of abnormal
subtle neurological findings, also known as neurological soft
signs. There may
be a genetic origin to neurological abnormalities
in schizophrenia, as
siblings without the disorder demonstrate
a greater incidence of these signs
(
Kinney et al, 1986;
Ismail et al, 1998;
Niethammer et al,
2000). Frontal release signs (also known
as primitive reflexes)
are a subset of neurological soft signs:
they consist of a group of
involuntary motor responses which
are normally found early in postnatal
development and are subsequently
inhibited, but may be released
from inhibition
by cerebral, usually frontal, damage
(
Paulson & Gottlieb, 1968;
Schott & Rossor, 2003).
Frontal release signs are common
in the general population, occurring in
roughly a quarter of
young healthy adults, and are more common with advancing
age
(
Gladstone & Black,
2002). Although a single sign is of
limited clinical significance,
multiple signs tend to correlate
with brain pathology
(
Isakov et al, 1984;
Schott & Rossor, 2003).
In
this study we examined a large cohort of people with schizophrenia,
their
healthy siblings and a healthy non-psychiatric control
comparison group to
determine the frequency with which frontal
release signs occur in these three
groups, and specifically
to assess the familiality of these signs by comparing
the schizophrenia
and sibling cohorts. Second, we sought to investigate the
association
between frontal release signs and cognitive impairment, with
a
focus on measures of frontal lobe function as well as more
general cognitive
measures such as full-scale IQ.

METHOD
Data concerning neurological soft signs were collected from
302 people with
a diagnosis of schizophrenia or schizoaffective
disorder, 240 of their full
siblings and 346 members of a healthy
control group who had participated in a
study of neurobiological
phenotypes associated with schizophrenia – the
Clinical
Brain Disorders Branch/National Institute of Mental Health (NIMH)
Sibling Study (
Egan et al,
2000). Siblings were excluded if
they were diagnosed with
schizophrenia or a schizophrenia-spectrum
disorder; otherwise, they were
included irrespective of their
psychiatric status. In a previous analysis of
neurological
soft signs in our laboratory, 407 out of the 888 participants
in
this study overlapped (45.8%;
Egan et
al, 2001b). The NIMH
institutional review board
approved all procedures and testing.
Details of recruitment and exclusion
criteria have been described
previously
(
Egan et al, 2000).
Briefly, families were recruited
from local and national sources; the
comparison group was recruited
from the National Institutes of Health
volunteer office and
was matched to the sibling group on age, gender,
education
and performance on the Wide Range Achievement Test (WRAT;
Jastak & Wilkinson, 1984).
In order to reduce the sample heterogeneity, only White participants
(who were
Caucasians of European ancestry) were included in
this analysis. All
participants were screened to exclude those
with a premorbid full-scale IQ
below 70, those with recent
(within 1 year) significant drug or alcohol misuse
or more
than 5 years of prior dependence, and those with significant
medical
or neurological conditions. The healthy control group
was selected with the
additional requirement that they should
not have a first-degree relative with
a schizophrenia-spectrum
disorder (
Egan
et al, 2000). All patients were clinically stable,
with
no psychiatric hospitalisation within 6 months of entry
into the study.
Written informed consent was obtained after
complete description of the study
to the participants.
Procedure
All participants were interviewed by a research psychiatrist (masked to
family status) using the Structured Clinical Interview for DSM–IV Axis I
Disorders (SCID; First et al,
1996). A second research psychiatrist reviewed all diagnostic data
and the consensus diagnosis was used. All participants had a thorough medical
evaluation, including magnetic resonance imaging of the brain. They were
administered an extensive battery of neuropsychological tests as described in
detail elsewhere (Weickert et al,
2000). These included the short form of the Wechsler Adult
Intelligence Scale – Revised (WAIS–R;
Wechsler, 1981), a measure of
full-scale IQ. The WRAT was administered to assess premorbid IQ. Participants
were tested also on a variety of cognitive measures that assay prefrontal
function: working memory/executive function was tested with the Wisconsin Card
Sorting Test (WCST; Heaton,
1981) and Letter fluency
(Benton et al, 1983);
psychomotor speed and oculomotor scanning were tested with Trail making test
part B (Reitan, 1986); and
working memory/updating was tested with the n-back task
(Goldberg et al,
2003) (one-back and two-back)
(Egan et al,
2001a). Demographic data are presented in
Table 1.
Participants underwent a detailed neurological examination by one of two
research neurologists who were formally masked to diagnosis and familial
relationships. Interrater reliability was assessed on 10 participants and
revealed that all ratings were significantly correlated (intraclass
correlation coefficients 0.54–0.90, P < 0.02). The
examination included the Neurological Evaluation Scale (NES;
Buchanan & Heinrichs, 1989)
scored as previously described (Sanders
& Keshavan, 1998). The examiners followed the previously
published clinical procedures for assessing each frontal release sign
(Paulson & Gottleib, 1968;
Ovsiew, 1997)
Data analyses
The primary outcome measures were the individual and summed frontal release
sign scores from the NES (Buchanan &
Heinrichs, 1989). For these measures, which are not independent,
P=0.05 was accepted as significant. Data analyses were performed
using SAS (version 9.1 for Windows). Mean scores were contrasted by mixed
model analysis of variance (ANOVA), treating family status as a random effect.
In order to investigate the relationships between frontal release signs and
cognitive function, the summed frontal release sign scores were calculated
from the individual tests of frontal lobe function from the NES: these
included ratings of glabellar, suck, snout, and right and left grasp reflexes.
Correlations between averages of the total and individual frontal release sign
scores were obtained for each diagnostic group (schizophrenia, sibling and
healthy control), using Pearson correlation coefficients. When shared
environmental factors are not considered causative of a shared trait in family
members, relative risk is commonly thought to reflect shared genetic factors.
Relative risk was assessed by comparing the proportion of affected individuals
in the sibling cohort v. the proportion of affected individuals in
the control cohort (affected was defined by a summed frontal
release sign score greater than 1 standard deviation above the control group
mean). A chi-squared analysis was performed to test the significance of the
relative risk. As an additional test of possible heritability in sibships, an
intraclass correlation coefficient was calculated for total frontal release
sign scores.

RESULTS
In the schizophrenia cohort the maximum individual frontal release
sign
score (on a scale of 0–10) was 7, with an average
of 1.50 (s.d.=1.58).
In the control cohort, the maximum score
was 4, with a mean of 0.42
(s.d.=0.77. In the sibling cohort
the maximum score was 6, with a mean of 0.54
(s.d.=0.92) (
Fig. 1).
Using a
mixed model ANOVA, contrasting total frontal release
sign scores with
diagnostic group, the schizophrenia cohort
had significantly higher average
scores than the control and
sibling cohorts (d.f.=746,
F=76.26;
t=10.77 and
t=10.52 respectively;
P < 0.0001).
The control and sibling cohorts did not differ
(
t=–1.23;
P=0.22). The relative risk was 1.40 (
P=0.25
by
2 analysis), suggesting that frontal release signs are not
a
strongly familial characteristic in schizophrenia. An alternative
method of
testing heritability, the intraclass correlation
coefficient, was not
significant at 0.14 for total frontal
release sign score
(
P=0.98).
The schizophrenia cohort had the greatest number of significant
correlations between total and individual frontal release sign scores and
performance on the neuropsychological testing battery, although all were weak
(Table 2). In particular, total
and individual frontal release sign scores had highly significant inverse
correlations with performance on the WAIS–R full-scale IQ. In fact, if
the results are Bonferroni-corrected, the only result that meets the corrected
criteria of P < 0.0006 is the correlation between total FRS score
and WAIS–R full-scale IQ in the schizophrenia group. Within the
uncorrected data-set, in the control group there was a trend towards an
inverse correlation between total frontal release sign scores and WAIS–R
full-scale IQ (Table 3).
View this table:
[in this window]
[in a new window]
|
Table 2 Correlations between frontal release sign scores and neuropsychological
performance in the schizophrenia group
|
For percentage of perseverative errors on the WCST, a number of significant
correlations were noted across all three cohorts. In the schizophrenia cohort
the presence of a right grasp reflex positively correlated with number of
perseverative errors, whereas in the control cohort, total and several
individual frontal release sign scores positively correlated with number of
perseverative errors. In the sibling cohort, right grasp reflex scores
positively correlated with number of perseverative errors
(Table 4). Finally, in the
sibling cohort there was a positive correlation between left grasp reflex
scores and time to complete the Trails B test.
View this table:
[in this window]
[in a new window]
|
Table 4 Correlations between frontal release sign scores and neuropsychological
performance in the siblings group
|

DISCUSSION
Classical clinical–pathological correlations have suggested
that
frontal release signs in adults are one of the few bedside
indices of
prefrontal cortical dysfunction. Participants with
schizophrenia in our study
had a much higher number of frontal
release signs on average than controls or
their unaffected
siblings. This finding is largely in agreement with a number
of previous studies (
Taylor & Abrams,
1984;
Woods et al,
1986;
Liddle,
1987;
Ismail et al,
1998;
Sanders & Keshavan,
1998;
Egan et al,
2001b;
Lawrie et
al, 2001;
Cuesta et
al, 2002;
Gourion et
al, 2004). In this study, both individual and summed
frontal
release sign scores showed weak inverse correlations
with several
neuropsychological measures, including full-scale
IQ, and a positive
correlation with number of perseverative
errors on the WCST (a test of
executive function that reliably
engages the dorsolateral prefrontal cortex).
These findings
were most apparent in the schizophrenia group, perhaps as a
result of a greater dynamic range in frontal release sign and
cognitive
scores.
The greater number of frontal release signs in people with schizophrenia
compared with siblings and normal controls was reported previously
(Ismail et al, 1998).
In fact, a grouping of neurological soft signs that included frontal release
signs, abnormalities in eye movements and short-term memory deficits
differentiated people with schizophrenia from a healthy control group better
than any other sub-scale from the Neurological Evaluation Score
(Arango et al, 1999).
Both genetic and environmental factors have been cited as the cause of
neurological soft signs in schizophrenia; in these studies frontal release
signs were subsumed within a larger set of clinical measures (neurological
soft signs) and were not examined independently
(Ismail et al, 1998;
Egan et al,
2001b).
Neurological soft signs previously have been associated with cognitive
impairment (Taylor & Abrams,
1984; Liddle,
1987; Schonfeld et
al, 1989; Cuesta et
al, 2002), including a propensity towards lower IQ
(Obiols et al, 1999;
Fellick et al, 2001)
and a poor long-term functional outcome in first-episode patients
(Johnstone et al,
1990). Patients with schizophrenia who had a higher number of soft
signs had lower IQ (Kennard,
1960; Mosher et al,
1971; Marcus et al,
1985) and deficits on measures of executive function such as
working memory, learning and attention
(Saykin et al, 1991;
Franke et al, 1992;
Braff, 1993;
Paulsen et al, 1995).
Neuroanatomically, soft signs have been associated with regional grey-matter
volume changes that may be an index of perturbed cortical–subcortical
connectivity (Dazzan et al,
2004). Although not specific to schizophrenia, neurological soft
signs appear to be an intrinsic element of this disorder and have a negative
connotation with respect to illness severity.
Heritability of frontal release signs
There is a suggestion of the heritability of neurological soft signs in
general, when studying people with schizophrenia and their non-affected
siblings (Egan et al,
2001b; Gourion et al,
2003;
2004). Some-what unexpectedly,
frontal release signs do not appear to share the same characteristic, at least
when siblings are compared with healthy controls using a chi-squared analysis
of relative risk. Moreover, the intraclass correlation coefficient also was
not significant. This suggests that environmental factors may have a
significant role in the development of frontal release signs, and by
extension, some aspects of frontal pathology in schizophrenia. It should be
noted, however, that our study rigorously excluded siblings with schizophrenia
and schizophrenia-spectrum disorders.
The notion that neurological abnormalities in schizophrenia might be due to
genetic factors came from studies that found a higher incidence of these
abnormalities in family members without schizophrenia of patients with this
disorder (Ismail et al,
1998; Niethammer et
al, 2000). However, the genetic contribution to the liability
towards the development of neurological abnormalities in schizophrenia is
modest at best (Kinney et al,
1986; Rossi et al,
1990; Ismail et al,
1998; Niethammer et
al, 2000; Egan et
al, 2001b). In our study we also found very modest
evidence of the heritability of frontal release signs, as measured by relative
risk or intraclass correlation. The greater incidence of frontal release signs
in people with schizophrenia compared with their non-affected siblings
suggests a significant role for environmental factors. Alternatively, in any
given individual, genetic susceptibility to schizophrenia is probably
secondary to the interaction of polymorphisms in several genes with small
interacting effects, acting in conjunction with the effects of environmental
factors (Wildenauer et al,
1996; Harrison &
Weinberger, 2005). People with schizophrenia most probably have
both a much greater genetic load and a greater exposure to predisposing
environmental factors than their non-affected siblings. Hence, the lack of
heritability of frontal release signs may reflect the effects of these
genetic–environmental interactions.
Frontal release signs and cognitive impairment
In general our correlation between the presence of frontal release signs
and poor performance on neuropsychological tests of prefrontal function in
schizophrenia agrees with previous reports. However, previous studies differ
in some of the details of the findings from our study. One group found that
frontal release sign scores correlated with a higher number of random errors
but not with perseverative errors on the WCST in people with schizophrenia
(Wong et al, 1997).
In two studies, global scores of neurological soft signs correlated with
perseverative errors on the WCST in schizophrenia, but frontal release signs
were not specifically examined (Braun
et al, 1995; Mohr
et al, 2003). Poor performance by people with
schizophrenia on the WCST (as measured by achieved categories) directly
correlated with a greater number of neurological soft signs
(Bersani et al, 2004).
Most studies of frontal release signs have relied upon much smaller samples
and therefore have less statistical power than our study. Moreover, most
studies of the relationship between neurological abnormalities and prefrontal
dysfunction in schizophrenia have not examined frontal release signs
separately from other neurological soft signs.
The inverse correlation between full-scale IQ and frontal release signs in
schizophrenia is the clearest result in our data. In fact, this is the only
correlation that withstands a rigorous Bonferroni correction. This suggests
that at least in this sample frontal release signs implicate a more widespread
pathology of higher cortical systems. Barnes et al
(1995) measured frontal release
sign scores and performance on the WAIS–R in people with schizophrenia:
no significant correlation was found, but the total sample size of 48 gave
limited power. Two studies have reported an inverse relationship between high
scores on more broad-based measures of neurological soft signs and low scores
on IQ tests. Neither of these studies evaluated the participants for the
presence of frontal release signs; instead, they relied upon other
neurological soft signs (Obiols et
al, 1999; Fellick et
al, 2001). Mohr et al
(2003) found that overall
neuropsychological performance inversely correlated with the total score on a
battery of neurological soft signs. However, that study did not assay frontal
release signs. They did note that higher soft sign scores inversely correlated
with a number of sub-tests from the WAIS–R. In general, our findings
agree with these previous reports.
Side-effects of antipsychotics might account for our findings. However,
similar neurological abnormalities have been noted in schizophrenia for nearly
a century, decades before the introduction of antipsychotic therapy
(Bleuler, 1950;
Kraepelin, 1971). Other
studies support the notion that neurological soft signs are an intrinsic part
of schizophrenia rather than a direct or indirect consequence of treatment
(Johnstone et al,
1990; Gupta et al,
1995; Browne et al,
2000; Mohr et al,
2003; Dazzan et al,
2004). Neurological soft signs and frontal release signs are
common in first-episode schizophrenia
(Browne et al, 2000);
in fact it has been reported that frontal release signs are more common in
people with schizophrenia who have never been treated with antipsychotics than
in treated patients (Gupta et al,
1995). In addition, unmedicated participants at high risk of
schizophrenia have more neurological soft signs than healthy control
individuals (Lawrie et al,
2001). These findings suggest that exposure to antipsychotics is
not necessary for the appearance of neurological soft signs in general and
frontal release signs in particular. In addition, both typical
(Mishara & Goldberg, 2004)
and atypical (Weickert et al,
2003) antipsychotics may sometimes improve cognitive performance,
militating against antipsychotics as a cause. As a whole, the preponderance of
the findings in the psychiatric literature makes it highly unlikely that the
findings in our study are solely directly attributable to the deleterious
effects of antipsychotic medications.
In summary, people with schizophrenia had more frontal release signs than
their siblings or the control group. In the schizophrenia group both
individual and summed frontal release sign scores inversely correlated with
several neuropsychological measures, including full-scale IQ and the number of
perseverative errors on the WCST (a relatively selective test of prefrontal
function). Although these findings were most apparent in the participants with
schizophrenia, perhaps as a result of a greater range in frontal release sign
scores, a trend for similar relationships was also seen in the control group.
This suggests that frontal release signs are at best a weak index of
prefrontal cognitive dysfunction, particularly in schizophrenia, but also in
healthy individuals.

ACKNOWLEDGMENTS
This research was supported in its entirety by the intramural
research
programme of the National Institute of Mental Health.
The authors would also
like to thank the clinical staff of
the Clinical Brain Disorders Branch,
Genes, Cognition and Psychosis
Program, for their efforts in patient
recruitment and characterisation,
and Dr Llewellyn Bigelow in particular for
his efforts in clinical
diagnosis.

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Received for publication May 24, 2006.
Revision received January 12, 2007.
Accepted for publication January 30, 2007.
Related articles in BJP:
- Highlights of this issue
- KIMBERLIE DEAN
BJP 2007 191: A5.
[Full Text]