Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia

SCHIZOPHRENIA RESEARCH ELSEVIER

Schizophrenia

Research

25 ( 1997 ) I 10

Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia Ileana Berman a,bqcT*,Barbara Viegner c, Amalia Merson ‘, Edward Allan ‘, Demetra Pappas a*b, Alan I. Green a*b a Taunton State Hospital, Harvard Medical School, PO Box 4007, Taunton, MA 02780-0997, USA b Commonwealth Research Center, Mussaehusetts Mental Health Center. Harvard Medical School, Boston, MA, USA ’ FDR VA Hospital, Department of Psychiatry, Mount Sinai School of Medicine, N~M. York. NY, USA Received 16 May 1996; received in revised form 4 October

1996; accepted 14 October

1996

Abstract This study assessed the relationships between positive and negative clinical symptoms and specific neuropsychological deficits in a group of stable schizophrenic patients. Method Thirty patients were assessed using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia and a battery of cognitive tests. The PANSS assessments were done by a group of raters blind to the results of cognitive tests, while the cognitive tests were conducted by a different group of raters who remained blind to the PANSS scores. Results: We found that, although positive and negative symptoms showed a trend toward direct correlation with each other. they correlated with distinct cognitive deficits. Patients with higher negative scores had more perseverative responses, perseverative errors, and completed fewer categories on the Wisconsin Card Sorting Test; they also experienced more difficulties on trail making and verbal fluency tests. On the other hand. positive symptoms were associated with poor performance on the Digit Span, particularly the Digit Span Forward. Conclusions: Our findings are in agreement with previous reports that negative symptoms may be associated with poor performance on cognitive tests reflecting particularly frontal function. Positive symptoms. on the other hand, seem to be associated with poor attention. specifically of auditory type, and thus, possibly with dysfunction within the more widespread neural networks underlying attention. Our findings support the hypothesis that positive and negative symptoms may be associated with distinct neuropsychological deficits and thus with distinct neurological substrates and point to the need to address both positive and negative dimensions when studying schizophrenia. Key~~wds:

Schizophrenia;

Positive symptoms; Negative symptoms;

1. Introduction Over the years, in order to understand the complex aspectsof schizophrenia, researchershave had

to

methodologically

* Corresponding

minimize

the

hetero-

Science B.V. All rights reserved

deficits

geneity of this disease by identifying clusters of symptoms that could best characterize patients with such a diagnosis (Carpenter et al., 1993). A

good example is the two dimensional model (involving negative and positive symptoms) proposed by Crow over a decade ago (Crow, 1985). The question

author.

0920-9964:97 ‘$17.00 d 1997 Elsevier PII SO920-9964( 96)00098-9

Neuropsychological

still remains

whether

these two symp-

tom clusters are different expressions of the same pathology or whether they are expressions of distinct neuroanatomical abnormalities. Brain imaging research and neuropsychological studies have been used to address this question and, in recent years, have led to a converging series of results. Neuroimaging data have suggested that negative symptoms may reflect primarily frontal lobe dysfunction (Andreasen et al., 1986: Weinberger, 1987) and positive symptoms may be associated with dysfunction in the more widespread neural networks underlying attention (Geraud et al., 1987; Volkow et al., 1987; Cleghorn et al., 1989; DeLisi et al., 1989; Cleghom, 1990; Gunther, 1992; Ebmeier et al., 1993). Similarly, neuropsychology studies have suggestedthat poor performance on cognitive tests measuring primarily frontal cortex function, such as the Wisconsin Card Sorting Test ( WCST) ( Milner, 1963: Robinson et al., 1980; Paulman et al., 1990; Seidman et al., 1994), trail making (Keilp et al., l988), and measures of verbal fluency ( Milner, 1963), is associated with more severe negative symptoms (Keilp et al., 1988; Addington et al., 1991) while attention deficits. thought to reflect dysfunction in more widespread neural networks (Mirsky, 1988; Goldberg and Gold, 1995), are more frequently associatedwith positive symptoms ( Walker and Harvey, 1986; Green and Walker, 1986). In comparison with the extensive number of neurocognitive studies in schizophrenia, however, only a few studies have specifically examined positive and negative symptoms and their distinct cognitive correlates (Walker and Lewine, 1988). In addition, most of these studies have examined the differences between clinical symptoms and cognitive deficits by comparing subjects that fit arbitrarily set criteria of ‘positive’ and ‘negative’ patients. This study design, however, excludes the large number of schizophrenic patients who have mixed positive and negative symptoms (Walker and Lewine, 1988; Strauss, 1993). In addition, recent factor analytic studies suggest that the twodimensional model of positive and negative symptoms may not be sufficient to capture the complexity of symptom origin and propose that a threefactor model may be more appropriate to account

for symptom patterns in schizophrenia (Amdt et al.. 1991). With this in mind, we set out to determine whether the negative and positive symptom dimensions of schizophrenia could be re-validated by studying a heterogeneous rather than a preselected group of ‘positive’ and ‘negative’ patients. Unlike other reports, our study sought to evaluate distinct relationships between the negative and positive symptom clusters and specific neurocognitive deficits within a group of patients with chronic schizophrenia. We hypothesized that the severity of positive and negative symptoms would correlate differentially with distinct cognitive impairments. Based on the existing data, we predicted that negative symptoms would be associated with impairments reflecting primarily frontal lobe activity, such as executive function and verbal fluency (Keilp et al., 1988; Addington et al., 1991; Stolar et al.. 1994), while positive symptoms would be correlated with attention deficits (Walker and Harvey, 1986; Green and Walker, 1986) and thus, possibly with dysfunction in the widespread neural networks underlying attention (Mirsky, 1988).

2. Subjects and method 2.1. &&?cts Thirty veteran patients (29 males and one female); recruited from chronic inpatient units, entered the study after signing an informed consent. All patients had a diagnosis of schizophrenia according to DSM-III-R criteria. The patients’ diagnoses were confirmed by a research psychiatrist through chart review and patient interviewing. Patients were included in the study if their treating psychiatrist considered them psychiatrically stable (e.g.. no evidence of symptom exacerbation within at least 4 weeks prior to the assessments).In addition. to be included in the study, patients had to be on stable dosesof all psychiatric medications for at least 2 weeks prior to the assessmentsand had to be able to cooperate with testing procedures (asjudged by the research psychiatrist). Exclusion criteria were organic brain syndromes (i.e., demen-

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tia, delirium), mental retardation (estimated IQ of less than 75), seizure disorder, history of head injury with documented cerebral damage, major affective disorder and active substance abuse and/or dependence. To exclude the possibility of poor cognitive performance related to underlying ‘non-schizophrenic dementia’ or other organic causes, we included only those patients who had a Mini-Mental Status Examination (MMSE) score of at least 25 (Folstein et al., 1975). The patients’ ages ranged from 35 to 71 years with an average of 50.6 years (SD = 11.1). The age of illness onset was determined by approximation through patient interviewing and chart review. The majority of patients had an early illness onset with 80% becoming ill before the age of 30 and 20% becoming ill in their 30s. The sample had an average education of 12.3 years (SD = 1.7). Patients had an estimated average IQ of 103 (SD = 15.9), ranging from 75 to 130, as determined by the Information subtest of the Weschler Adult Intelligence Scale ( Wechsler, 1981). Judging by patients’ self report and by the hand patients used during writing, 24 were right-handed, three were left-handed and one was ambidextrous (in two patients the handednesswas not documented). All patients had been treated with neuroleptic medication at the time of the assessmentsand received an average of 684.5 mg (SD = 279) chlorpromazine equivalents (Davis, 1975) (Table 1). 2.2. Psychiatric

and cognitive

assessments

Patients completed a 2-3-h psychiatric and cognitive evaluation in two or more sessions. The psychiatric evaluation was completed using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) ( Kay et al., 1987; Kay, 1991). The PANSS has subsetsof questions that assessnegative and positive symptoms separately. The positive symptom subtest includes the following items: hallucinations, delusions, suspiciousness,hostility, thought disorganization, grandiosity, and excitement. The negative symptom subtest includes blunted affect, emotional withdrawal, poor rapport, passiveapathetic social withdrawal, abstract thinking, stereotyped thinking, lack of spontaneity and flow of conversation.

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Since many schizophrenic patients have impaired executive function, memory, and attention (Goldberg and Gold, 1995), and since there is evidence that some of these deficits may be preferentially associated with either negative or positive symptoms, we selected a battery of tests to address some of these dysfunctions. Executive function was assessed through the Wisconsin Card Sorting Test (WCST) (Milner, 1963), which explores frontal lobe function (Robinson et al., 1980; Seidman et al., 1994) and appears to be completed with difficulty particularly by patients with preponderant negative symptoms (Addington et al., 1991). During this test, patients are asked to match a series of cards according to sorting criteria (i.e., color, number, or shape) that change each time 10 consecutive cards are correctly sorted. The WCST was administered manually by a trained psychologist and was scored according to Heaton’s manual (Heaton, 1981). Trails (A and B) (Reitan and Wolfson, 1985), which can reflect frontal function (Keilp et al., 1988; DeQuardo et al., 1994), were selected based on available evidence suggesting that poor performance on these tests is associated with more negative symptoms (Keilp et al., 1988). Trails A is a timed test that requires patients to connect a seriesof consecutive numbers, while Trails B, requires the subjects to connect alternating consecutive numbers and letters under timed conditions. The Controlled Oral Word Association Test (Verbal Fluency; letters ‘FAS’) (Benton and Hamsher, 1976), another indicator of frontal lobe function (Milner, 1963), was included among our assessmentssince schizophrenic patients with negative symptoms were found to have difficulties performing this test (Addington et al., 1991; Stolar et al., 1994). During the Controlled Oral Word Association Test, patients are asked to name as many words as possible starting with a specific letter over a period of 1 min. The Digit Span, a subtest from the Wechsler Adult Intelligence Scale ( WAIS-R) ( Wechsler, 1981), was selected based on findings suggesting that the severity of positive symptoms may be specifically associated with poor performance on this test (Walker and Harvey, 1986; Green and Walker, 1986). The Digit Span test has two components: Digit Span Forward and

4 Table 1 General characteristics

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sample

Characteristics

Mean

Age CPZ equivalent dose (mg) WRAT-Reading (new scores) Estimated IQ (Information subtest Years of education PANSS (total score) PANSS (positive score) PANSS (negative score) MMSE WCST categories completed WCST perseverative errors WCST perseverative responses Digit span (DS) DS forward DS backward Digit symbol Trails A Trails B Verbal fluency (FAS) Immediate visual recall Delayed visual recall Immediate visual recognition Delayed visual recognition Block design

50.6 (11.1) 684 (279.8) 61 (17.8) 103 (15.9) 12.3 (1.7) 83.6 (14.6) 20.9 (5.9) 21.8 (4.6) 28.1 (1.5) 0.03 (0.03 ) 0.30 (0.18) 0.37 (0.24) 13.14 (3.70) 7.14 (2.07) 5.82 (2.06) 32.69 (9.10) 57.55 (18.94) 149.86 (70.58) 30.11 (10.42) 6.83 (3.53) 5.3 (4.14) 2.72 (1.07) 2.31 (1.28) 31.08 (9.49)

scores)

Backward. During the Digit Span Forward the patients are asked to repeat immediately an increasing series of numbers read by the tester. During the Digit Span Backward patients are asked to repeat the numbers in a reverse order. The Digit Span Forward primarily measures attention, while the Digit Span Backward tests mental control. Our cognitive battery also included tests such as the Digit Symbol (a WAIS-R subtest) (Wechsler. 1981), the Block Design ( Wechsler, 1981), and visual memory ( Wechsler Memory Scale-Revised) ( Wechsler, 1945, 1981), which have been found to be impaired in schizophrenia but have not yet been shown to be consistently related to either positive or negative symptoms. The Digit Symbol is a test of attention, learning, and motor abilities. During this test patients are required to complete the appropriate symbol under a series of numbers, according to a known model over a period of 90 seconds. The Block Design is a test for visualspatial skills. The Wechsler Visual Memory Scale-

(SD)

Range

(minimum~maximum)

35:71 200/1000 27/87 75/l 30 8:‘16 46:104 I o/34 12129 25/30 0.00:0.08 0.05/0.73 0.05:0.98 8;‘22 4,‘12 2,‘lO I7/48 28/107 481296 13;‘50 0’13 OS14 014 0!4 6:43

Revised ( Wechsler, 1945, 1981) tests immediate and delayed visual memory, by measuring the ability to immediately reproduce (immediate recall ) and recognize (immediate recognition) visual information, and subsequently retrieve (delayed recall ) and identify (delayed recognition) this information after 30 min. The Mini-Mental Status Examination (MMSE) (Folstein et al., 1975) was used as a measure for global cognitive functioning. Patients’ premorbid level of intelligence was assessedusing the reading component of the Wide Range Achievement Test (WRAT) (Jastak and Wilkinson, 1984) and was assignedan estimated IQ based on the Information subtest ( Wechsler, 1981). Psychiatric assessmentswere done by two trained raters (IB and AM ) who reached consensus rating and achieved an interrater intraclass reliability of 0.83 on the PANSS. The neuropsychological testing was done by two psychologists (BV and LP) who remained blind to the results of the psychiatric assessments. Likewise. the clinical

raters remained blind to the results of cognitive testing. The assessments were conducted at a time when patients were judged to be cooperative with testing. 2.3. Dutu anulysis The goal of this study was to examine distinct relationships between negative and positive symptoms with specific neurocognitive deficits. Since both cognitive and psychiatric scores are continuous measures, we used two-tailed Pearson correlations to detect relationships between symptoms and cognitive performance, and we verified these results by performing Spearman rank-order correlations. To evaluate whether the cognitive deficits and their relationship to specific symptoms are not the result of a generalized impairment and whether, indeed, they represent specific processes related to schizophrenic symptoms (Chapman and Chapman, 1978; Strauss. 1993), we conducted Pearson correlations between global intelligence scores (i.e., WRAT, IQ) and schizophrenic symptoms, as well as correlations between cognitive performance and intelligence scores. Moreover, to determine the possible effect of medication states, we assessed the relationship between neuroleptic dose level and cognitive performance.

3. Results In our group, positive and negative symptoms showed a trend toward direct correlation (v =0.30, p = 0.1 ), but were associated with different cognitive deficits. For instance, we found that the severity of negative symptoms was strongly correlated with poor performance on the WCST, as reflected by a high proportion of perseverative errors (v= 0.47, p =O.Ol ) and perseverative responses (u= 0.49, p =O.Ol ) and a low number of completed categories (v= -0.48, p=O.Ol) (Table2). Moreover, negative symptom scores were also correlated with poor performance on Trails A (Y = 0.38, p=O.O4) and showed a trend toward an association with the scores on the Controlled Oral Word Association Test (Y = -0.36, p =0.07)

( Table 2 ). Positive symptom scores were correlated with poor performance on the Digit Span (u= - 0.42, p = 0.02) and showed slightly stronger correlation with poor performance on the Digit Span Forward (r= -0.43, p=O.O19) compared to that on the Digit Span Backward (Y= -0.34, p=O.l). In addition, in our group of non-demented schizophrenic patients, severity of positive symptoms was associated with low MMSE scores (r = -0.57, p =0.002) (Table 2). In our group, there were no significant correlations between positive and negative symptoms and global intelligence measures (such as the WRAT or estimated IQ). Since cognitive performance may be dependent on multiple factors, we examined the correlations between cognitive scores and age, global level of intelligence, years of education, and dose of neuroleptic. We found no statistically significant correlations between dose of neuroleptic, estimated IQ, years of education and those cognitive deficits that were significantly correlated with positive and negative symptom scores (Table 2). The performance on Trails A. however, was strongly related to age. Thus, we performed a regression analysis in which we looked at the relationship of positive and negative symptoms with Trails A scores after entering age first in the analysis. By taking into consideration the patients’ age, the negative symptoms continued to show a relationship with the performance on Trails A (F=2.5, p ~0.1 ), while the positive symptoms continued to suggest no significant association with the scores on this test (F= 0.18, p = 0.83). Since our results revealed that Block Design scores were associated with age and neuroleptic dose, we examined the relationship between positive and negative symptoms and performance on this test after we controlled for age and neuroleptic dose. Thus, we used a regression analysis in which the positive and negative symptoms were the dependent variables and we entered the age and the neuroleptic dose first, followed by the Block Design scores. After controlling for age and neuroleptic dose, the performance on this test appeared to be related to the negative (F=2.9, ~~0.06) but not the positive symptoms (F= 1.4, p=O.26). To verify our results we also performed Spearman rank-order correlations. The Spearman

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rank-order correlations led to similar results as the Pearson product-moment correlations (Table 2). In addition, the association between verbal fluency (FAS) and negative symptoms became significant (r= -0.29, p-cO.04).

4. Discussion The goal of our study was to explore whether negative and positive symptoms may represent two distinct entities associated with specific neuroanatomical dysfunctions. Although we used a study design different from that described in previous reports, our findings, suggesting that positive and negative schizophrenic symptoms are associated with different cognitive dysfunctions, continue to support the hypothesis that these symptom clusters may indeed be expressions of distinct neuroanatomical dysfunctions. Earlier studies have examined relationships between symptoms and cognitive deficits by selecting only those patients who met criteria for either ‘positive’ or ‘negative’ patients. These study designs, however, have been criticized because they exclude the majority of patients who experience mixed symptoms (Walker and Lewine, 1988; Strauss, 1993) and thus cannot conclude whether the differences reflect characteristics of the positive and negative symptoms themselves or whether they represent characteristics of two illness subtypes. Moreover, there are few studies that look simultaneously at positive and negative symptoms and their specific cognitive correlates. The goal of our study was to concomitantly examine positive and negative symptoms within one group of schizophrenic patients to determine whether the clinical symptoms themselves were associated with distinct cognitive deficits, and thus with dysfunction in distinct brain areas. Consequently, we examined a heterogeneous group of schizophrenic patients without preselecting only those with predominantly positive or negative symptoms. In our sample, the positive and negative symptoms showed a trend toward direct correlation, as has been previously reported by others (Opler et al., 1987). Despite this correlation of the positive and negative symptoms, each was associated with

distinct deficits in cognitive function. Thus, negative symptoms were associated with poor performance on frontal lobe tests such as the WCST, Trails A and verbal fluency, while positive symptoms were correlated with low scores on the Digit Span, particularly the Forward component, indicating attention deficits and, thus, possibly an involvement of the more widespread networks that underlie attention (Mirsky, 1988; Bornstein et al., 1992). Moreover, in our sample the cognitive deficits that correlated with schizophrenic symptoms did not show a consistent relationship with neuroleptic dose, general intellectual abilities, or education level. Our findings are in agreement with those from a number of previous reports: Addington et al. ( 199 1) studied a group of schizophrenic patients and found that negative symptoms were correlated with poor performance on the WCST and verbal fluency; Stolar et al. ( 1994) noticed that negative symptoms were correlated with poor performance on word fluency; Keilp et al. ( 1988) found correlations between negative symptoms and poor performance on Trails, while other authors have observed that positive symptoms were associated with low scores on the Digit Span (Walker and Harvey, 1986; Green and Walker, 1986). In fact, it is worthwhile mentioning that our study resembles that conducted by Addington et al. ( 1991) and that our correlation values between negative symptoms and cognitive scores are strikingly similar to those obtained by these authors, specifically the relations found between negative symptoms and WCST and verbal fluency scores (i.e., r had values in the 0.40s and 0.30s, respectively). Unlike Addington et al. ( 1991) we found that, in addition to negative symptoms being associated with specific cognitive impairment, positive symptoms were correlated with distinct cognitive deficits as well. The lack of significant correlations between positive symptoms and cognitive deficits in the study conducted by Addington et al. ( 1991), may be explained by the fact that these authors did not include tests of auditory attention that had previously been shown to detect cognitive deficits associated with positive symptoms (Green and Walker, 1986; Walker and Harvey, 1986). The validity of the findings obtained by Addington

et al. has been questioned (Strauss, 1993), since negative symptoms were correlated with global intelligence in their group. However, our results support the validity of the work published by Addington and collaborators since we found significant correlations between negative symptoms and cognitive deficits even in the absence of a relationship between schizophrenic symptoms and global intelligence or education’. It has been previously suggested that positive symptoms may be associated with deficits in auditory processing (Walker and Lewine, 1988). Strauss (1993), however, points to the need to study the differential associations of these symptoms with both auditory and visual ability deficits. In our group, positive symptoms showed a relationship with performance on the Digit Span, a test that measures attention through auditory skills, but showed no relationship with performance on either the Digit Symbol (which measures attention through visual processes) or other tests of visual abilities such as Block Design and visual memory. Our results, therefore, seem to support the suggestion that positive symptoms are associated with deficits in the auditory rather than visual processes (Walker and Lewine, 1988). The relationship we found between MMSE scores and positive but not negative symptoms contradicts previous data ( Andreasen and Olsen, 1982; Davidson et al., 1995). This discrepancy may be simply a result of the sample differences. Since our goal was to examine the relationship of symptoms to distinct cognitive deficits, we only included patients with a relatively intact global cognitive function as measured by the MMSE. Some authors note that neuropsychological tests must be interpreted with caution in psychotic

’ Even though previous data suggests that cognitive performance may be related to education (Addington et al., 1991). we did not find such a relationship. The majority of patients in our sample, however. had similar education levels, with more than 50% having completed 24 years beyond high school. This lack of variability in the years of education may explain the lack of a relationship between cognitive performance and education in our sample. In the context of such a lack of variability, our results are further validated. as in an intellectually homogeneous group of patients, the cognitive performance is Less likely to be confounded by the variation in intellectual abilities.

patients ( Keefe, 1995 ). Nevertheless, such tests have been helpful in finding links between symptoms and neurological dysfunction in schizophrenia (Strauss, 1993; Keefe, 1995). One of the most extensively studied neuropsychological tests has been the WCST, which has been found to measure primarily frontal lobe function ( Weinberger et al., 1986; Yates et al., 1990; Rosse et al., 1991; Seidman et al., 1994). Other combined neuropsychological and brain imaging studies in schizophrenic patients have also tried to identify the role of specific brain areas in the performance on other cognitive tests such as Trails A and B, tests of verbal fluency, and Digit Span. Reduced psychomotor speed as measured by Trails A and B has been associated with frontal atrophy (Benton and Hamsher, 1976; Keilp et al., 1988). In addition, impaired verbal fluency has been associated with frontal dysfunction (Milner, 1963), while Digit Span performance has been recently associated with third ventricle enlargement in schizophrenic patients, implying possible involvement of diencephalic structures (Bornstein et al., 1992). In conclusion, our findings would seem to support the theory that negative symptoms may be associated with cognitive deficits measuring frontal dysfunction, while positive symptoms may be associated with poor performance on tests of auditory attention and may suggest dysfunction within the more widespread neural networks underlying attention. What makes our findings important is that in our sample, positive and negative symptoms, although directly correlated, were associated with different cognitive deficits that were themselves not associated with the global level of intelligence. Based on these results one may speculate that positive and negative symptoms, although expressions of the same illness, have different anatomical substrates. Although the two dimensional model of positive and negative symptoms is not sufficient to categorize the complex symptomatology of schizophrenia (Arndt et al., 1991), our study reaffirms the idea that these two types of symptoms may represent distinct dimensions and emphasizes the need to address these two dimensions separately, especially when studying heterogeneous groups of schizophrenic patients.

Acknowledgment Authors wish to thank Miklosh F. Losonczy, M.D., Ph.D., Anthony Kalinowski. Ph.D., and Larry L. Seidman, Ph.D. for their suggestions and to Laura Parker, M.A. for her contribution toward collection of the neuropsychological data in the early phase of the study.

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