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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
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ABSTRACT |
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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.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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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.
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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.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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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).
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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.
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DISCUSSION |
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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.
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ACKNOWLEDGMENTS |
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Received for publication May 24, 2006. Revision received January 12, 2007. Accepted for publication January 30, 2007.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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