Working memory constrains abstraction in schizophrenia

Working Memory Constrains Abstraction in Schizophrenia David C. Glahn, Tyrone D. Cannon, Raquel E. Gur, J. Daniel Ragland, and Ruben C. Gur Background: Abstraction has long been considered an area of differential cognitive deficit in schizophrenia, primarily because of patients’ poor performance on the Wisconsin Card Sorting Test (WCST). Yet, the complexity and multidimensional nature of the WCST increases the likelihood that several different cognitive processes, perhaps mediated by different neural systems, are being tapped. Methods: In the current study, the Abstraction and Working Memory (AIM) task was designed to disentangle abstraction and working memory so that the effects of each cognitive domain could be independently analyzed. The AIM task and a battery of neuropsychological tests were administered to 62 patients with schizophrenia and 62 matched healthy volunteers. Results: Whereas patients with schizophrenia demonstrated deficits in simple abstraction, they were disproportionately impaired with the addition of a minimal memory requirement. Conclusions: Group differences on WCST performance appear to be attributable to patients’ inability to maintain information over a short delay, before that information is used for more complex cognitive operations. Biol Psychiatry 2000;47:34 – 42 © 1999 Society of Biological Psychiatry Key Words: Schizophrenia, frontal lobes, Wisconsin Card Sorting Test, abstraction, working memory, problem solving

Introduction

S

chizophrenia is associated with neuropsychological impairments across multiple cognitive domains (e.g., Malec 1978; Goldberg et al 1987; Saykin et al 1991). Recently, cognitive neuroscience models of schizophrenia From the Department of Psychology (DCG) and the Brain Behavior Laboratory, Department of Psychiatry (REG, JDR, RCG), University of Pennsylvania, Philadelphia, Pennsylvania and the Department of Psychology, University of California at Los Angeles, Los Angeles (TDC). Address reprint requests to David Glahn, University of California at Los Angeles, Department of Psychology, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095-1563. Received February 19, 1999; revised July 13, 1999; accepted July 19, 1999.

© 1999 Society of Biological Psychiatry

have proposed that some of these impairments are markers and, in some cases, mediators of important aspects of the pathophysiology of schizophrenia. Effective isolation of a cognitive pathophysiologic process depends, in part, on elucidating one or more specific cognitive functions that are more prominently impaired within the context of diffuse dysfunction. Abstraction, the ability to use information to group stimuli in some meaningful way, has long been considered such a function (Goldstein 1959). At the descriptive level, patients with schizophrenia seem to have difficulty selecting relevant information from their environment and attaching an appropriate meaning to that information. A commonly used measure of abstraction and cognitive flexibility in schizophrenia is the Wisconsin Card Sorting Test (WCST; Berg 1948; Grant and Berg 1948; Heaton et al 1993). The WCST requires participants to sort a series of cards to one of four key cards that vary in shape, color, and number. Participants use feedback (correct or incorrect) to ascertain the correct matching rule, which shifts after 10 consecutive correct responses. Patients with schizophrenia achieve fewer categories and make more perseverative errors than healthy volunteers (Goldberg et al 1989; Braff et al 1991), a pattern similar to that found in patients who have sustained frontal lobe damage (Bornstein 1986; Heaton et al 1993; Milner 1963). The notion of impaired abstraction due to frontal lobe dysfunction has been extended by evidence from several neuroimaging studies that found that patients with schizophrenia have metabolic and perfusion deficits in the prefrontal cortex (e.g., Franzen and Ingvar 1975). Although initial evidence of frontal lobe hypometabolism during a resting state has not been consistently replicated (Gur and Gur 1995), more recent activation studies have demonstrated abnormal frontal lobe perfusion when patients were engaged in a task designed to challenge this area (i.e., the WCST). Whereas healthy participants activated the prefrontal cortex over baseline during the WCST, poorer-performing patients showed a pattern of “hypofrontality” in that the principal sulcal region of lateral prefrontal cortex was underactivated (Weinberger et al 1986, 1988; Berman et al 1986, 1988; Rubin et al 0006-3223/00/$20.00 PII S0006-3223(99)00187-0

Abstraction and Memory in Schizophrenia

1991); however, this finding is also subject to debate and may depend on sample selection or data analysis methods (Gur and Gur 1995). The complexity and multidimensional nature of the WCST increases the likelihood that several different cognitive processes, perhaps mediated by different neural systems, are being tapped (Koren et al 1998). Indeed, poor performance on the WCST has been reported in patients with focal nonfrontal lesions or diffuse injuries (Anderson et al 1991). Recent positron emission tomography–activation studies have demonstrated that healthy participants engage not only the frontal cortex, but also a complex network of regions, including the inferior parietal lobule, the inferior temporal cortex, and the occipitotemporal cortex, when performing the WCST (Berman et al 1995; Ragland et al 1997). This elaborate pattern of physiologic activation and the multidimensional nature of the WCST complicate interpretation of WCST impairment in schizophrenia. One approach to determining the significance of poor WCST performance and its neuroanatomical and neurofunctional correlates in schizophrenia is to examine the contributions of simpler, potentially more localizable, cognitive processes required for WCST performance. To perform the WCST, a subject must determine a rule or set of rules that govern the current response. To generate a rule, the subject must abstract information provided on each card, recall the outcome of the previous trial, and possibly inhibit a response pattern that has been successful in the past. These behaviors may be broadly defined as processes requiring the manipulation of information and those that require the simple maintenance of that information. At some levels this distinction is confounded, given that the two processes are not entirely independent, because any task that requires the manipulation of information also requires a stored internal representation of that information; however, there are several advantages to this division. Most notably, this division differentiates between early (the creation and maintenance of an internal representation) and late (the subsequent manipulation of that representation) stages of information processing. Goldman-Rakic (1994) has proposed that patients’ inability to maintain information for short periods of time undermines their WCST performance and may have broader implications for clinical symptomatology. Yet, the effect of the maintenance impairment within the context of more complex cognitive processes has not been directly examined in schizophrenia. In the current study, a new cognitive task is introduced that allows the independent measurement of these processes: the Abstraction and Working Memory (AIM) task. In this task, manipulation of information is operationalized as visual abstraction. Participants are shown five shapes: two shapes in the upper-right corner and two shapes in the

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upper-left corner of a computer screen, with a fifth target object appearing in the center of the screen, below the other stimuli. The participant’s task is to pair the target object with the objects on either the left or right. In some trials, an additional maintenance requirement is superimposed on this basic module by adding a delay between the presentation of the target and other objects. By comparing performance in these different trial types, the effects of increasing maintenance requirements can be segregated from abstraction (manipulation). The goal of this study is to test the hypothesis that patients with schizophrenia are impaired in abstraction and that this impairment increases with additional maintenance requirements, as revealed through the AIM task. Subsequently, the relationship between AIM and WCST performance will be explored. Finally, to relate the cognitive measures to clinical symptomatology, correlations between AIM and WCST scores and measures of clinical severity will also be examined.

Methods and Materials Participants Patients and controls were drawn from an ongoing longitudinal investigation of brain function in schizophrenia conducted in the Schizophrenia Research Center at the University of Pennsylvania. After informed consent was obtained, participants underwent comprehensive screening and assessment, performed by the clinical research team (Shtasel et al 1991). This process included screening with the Patient Edition of the Structured Clinical Interview (SCID-P; Spitzer et al 1996a) for DSM-IV, taking a detailed medical history, performing a physical examination, and conducting laboratory tests. Scales, which included the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham 1980), the Scale for Assessment of Negative Symptoms (SANS; Andreasen 1983), and the Scale for Assessment of Positive Symptoms (SAPS; Andreasen 1984), were administered by investigators trained to a criterion reliability of 0.90 intraclass correlation (Shtasel et al 1992). Controls were screened with the Non-Patient Edition of the SCID (Spitzer et al 1996b; Shtasel et al 1991). Entry criteria to the Schizophrenia Research Center for patients included: 1) a diagnosis of schizophrenia or schizophreniform disorder by DSM-IV criteria (American Psychiatric Association 1994); 2) no concomitant Axis I or II disorder, including past or present substance abuse or dependence; 3) no history of a medical illness that might affect brain function; and 4) no history of a neurological disorder (e.g., epilepsy, migraine, head trauma with loss of consciousness). Except for the diagnosis of schizophrenia and the additional criterion of no first-degree relatives with a diagnosis of schizophrenia or affective illness, inclusion and exclusion criteria for controls were the same as for patients. The sample included 124 participants (62 patients and 62 healthy volunteers). With the exception of education level, there were no significant demographic differences between the pa-

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Table 1. Schizophrenic and Healthy Demographic and Neuropsychological Characteristics Schizophrenic sample Sex (m/f) 32/32 Age 29.6 ⫾ 9.8 (17– 66) Education 13.0 ⫾ 2.3 Parental education 13.7 ⫾ 3.5 Vocabulary 44.6 ⫾ 15.5 Block design 25.7 ⫾ 12.3 WCS_CAT 3.90 ⫾ 2.2 WCS_PE 22.5 ⫾ 14.8 DIGFOR 6.20 ⫾ 1.2 DIGBAC 4.80 ⫾ 1.4 Trails A 37.3 ⫾ 22.8 Trails B 102.9 ⫾ 85.6 COWAT 34.1 ⫾ 12.7

Healthy sample

p value

34/30 27.2 ⫾ 9.5 (18 – 62) 15.6 ⫾ 1.1 13.8 ⫾ 2.9 58.6 ⫾ 7.2 35.3 ⫾ 9.1 5.29 ⫾ 1.5 14.4 ⫾ 7.2 7.50 ⫾ 1.7 6.20 ⫾ 1.8 21.8 ⫾ 7.8 48.6 ⫾ 10.2 47.8 ⫾ 8.7

— a

0.0001 a

0.001 0.001 0.001 0.002 0.001 0.001 0.001 0.001 0.001

Demographic and cognitive characteristics of patients with schizophrenia and healthy samples. Age, participant education, and parental education are shown in years (mean ⫾ SD [Range]). Neuropsychological measures included the Vocabulary, Block Design, and Digit Span (forward: DIGFOR; backward: DIGBAC) subtest of the WAIS-R; the number of categories achieved (WCS_CAT) and the number of perserverative errors (WCS_PE) on the WCST; total time required for Trails A and B (TRAILA and TRAILB); and the number of words generated on the Controlled Oral Word Association task (COWAT). a Nonsignificant at the ⬍.05 level.

tients and healthy samples (Resnick 1992) (see Table 1). Participants were similar to each other in their ethnic diversity and to the community from which they were drawn (West Philadelphia, PA). The schizophrenic group performed significantly worse than the healthy group on each of the neuropsychological measures presented. Of the 62 patients, 16 were in their first episode of illness and 46 were previously treated patients with treatment histories of varying lengths. Onset of illness was defined as the first time psychotic symptoms were observed in the context of a decline in functioning. The average age of onset was 22.7 ⫾ 6 years. Patients were rated on average as mildly ill across clinical scales with mean (⫾SD) BPRS, SANS, and SAPS total scores of 29.7 ⫾ 9.6, 25.5 ⫾ 17, and 11.3 ⫾ 11, respectively. Nineteen of the patients were not receiving medication at the time of the study.

Procedures The AIM task was administered with a battery of standardized neuropsychological tests over approximately an hour and a half (Saykin et al 1991). The AIM task is self-paced and administered by computer using the Power Laboratory program (Chute and Westall 1997). On average, the AIM took 7 minutes for healthy subjects and 9 minutes for patients with schizophrenia to complete. AIM TASK. The AIM task is made up of the Abstraction and Abstraction plus Memory subtests. The Abstraction subtest is based on a paradigm developed by Dr. Levi Rahamani (Rahamani et al 1990), in which participants are shown five shapes. Two shapes appear in the upper-right corner and two shapes in the upper-left corner of the screen. A fifth target object appears in the center of the screen, below the other stimuli. The participant’s task is to pair the target object with the objects on

Figure 1. A gray scale example of a trial from the Abstraction subtest of the AIM. The participant’s task is to pair the target object (center shape) with the objects on either the upper left or upper right. either the left or right (see Figure 1). This pairing rests on the ability to find commonalities between the target object and the other shapes. Although explicit categories were used to generate each trial (see below), the subject may or may not be cognizant of these categories. Stimuli included three common shapes (circles, squares, and triangles), which were distorted to reduce their verbalizability. Each shape appears in red, yellow, or blue. The subject was given visual feedback for each trial in the form of a single word, either “correct” or “incorrect,” flashed on the screen for 500 msec after a response is entered. The following five categories were used to generate each set of objects (the target object and the objects on the left or the target object and the objects on the right). 1) All three objects have the same shape but each has a different color, or, conversely, all objects have the same color but each has a different shape. 2) All three objects have the same shape and two have the same color, or, conversely, all objects have the same color and two have the same shape. 3) Two of the objects have the same shapes and two of the objects have the same color. The target object, however, must have the same color or shape, or both the same color and shape, as one of the top objects. 4) All three objects have different shapes and two have the same color, or, conversely, all objects have different colors and two have the same shape. 5) Two of the objects have the same shapes and two of the objects have the same color; however, the target objects cannot have the same color and shape as a top object. The top objects must be either the same shape or the same color. Because these categories increase in their complexity (the fifth being the most complex) and because no trial had sets created from the same category, the correct response for a trial was determined to be the more obvious, less complex set. For example, in Figure 1 the set made up of the target and the objects on the left was generated from the first category, whereas the target and the objects on the right are from category 5. Hence, in this example the left set would be considered correct, because it would be the more obvious choice (see Figure 1). This framework was extended to determine trial difficulty. Theoretically, trials with sets generated from similar categories (1 and 2) are more difficult than those generated from more distant categories (1 and 5). Using this framework, the trials in the AIM task are classified as either easy or hard.

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Table 2. Healthy Subjects AIM Performance

Total Trials Easy Trials Hard Trials

Abstraction

Abstraction & Memory

81.9 (7.6) 91.6 (7.4) 72.1 (12.7)

79.1 (10.3) 88.6 (10.8) 71.0 (13.4)

Abstraction and Working Memory task performance by a sample of 196 healthy participants (percent correct [SD]).

A delay between the presentation of the target object and the other stimuli creates an additional maintenance requirement for the Abstraction plus Memory subtest. In this subtest, participants are presented with the target stimulus for 500 msec, after which the object disappears. The screen remains blank for 2.5 sec, followed by the appearance of four shapes at the top of the screen. Thus, participants must hold the target shape in memory to determine an appropriate response. A total of 100 abstraction trials were administered to five pilot participants. Trials below chance (50%) or that showed little or no variance (100% correct) were removed. The remaining 60 trials were divided into two groups of equivalent difficulty and used to create the Abstraction and the Abstraction plus Memory subtests. Before performing the AIM task, participants were administered a set of 10 practice trials and were required to respond correctly to at least five trials. To minimize practice effects, trials from the Abstraction and the Abstraction plus Memory subtests alternate in blocks of 10 trials each. All participants mastered the practice trials. To examine the AIM task’s initial validity and reliability, 196 healthy participants (77 men and 119 women) were administered the task. As can be seen in Table 2, subjects generally performed well. A 2 ⫻ 2 multivariate analysis of variance model tested main and interaction effects of subtests (Abstraction, Abstraction plus Memory) and difficulty level (easy, hard), with both effects used as within-participant (repeated measures) factors. There was a small but significant effect of subtests (F[1,195] ⫽ 9.76, p ⬍ 0.002), suggesting that the additional memory demand was sufficient to reduce performance in healthy volunteers. There was a main effect of difficulty level (F [1,195] ⫽ 574.20, p ⬍ 0.0001) but no substantial subtest by difficulty level interaction (F [1,195] ⫽ 2.21, p ⬍ 0.1), suggesting that participants performed better on easier trials in both subtests.

Hypothesis Tests Statistical analyses addressed the following predictions: 1) patients with schizophrenia perform more poorly on the AIM task than healthy participants, with poorer performance on more difficult trials than on easier trials; 2) the addition of the delay period in the Abstraction plus Memory subtest differentially affects patient performance; 3) AIM performance correlates with the WCST and with clinical neuropsychological tests of prefrontal function; 4) between-group differences on the WCST are attenuated when performance on the AIM task is statistically controlled; and 5) AIM performance is correlated with clinical symptoms, particularly negative symptoms. To assess the first and second predictions, a 2 ⫻ 2 ⫻ 2 multivariate analysis of variance model testing main and inter-

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active effects of diagnosis, subtest (Abstraction, Abstraction plus Memory), and difficulty level (easy, hard) was used. Subtest and difficulty level were used as within-participant (repeated measures) factors. Main effects or interactions were decomposed with post hoc analysis within subject t tests. The significance criterion was set at ␣ ⫽ 0.05, two tailed. To assess the third prediction, Pearson correlations were performed separately for each group between AIM subtests and the number of categories on the WCST (WCS⫺CAT) and perseverative errors (WCS⫺PE) on the WCST (Heaton et al 1993); scores from the forward and backward Digit Span subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler 1981); total time required for Trails A and B (Reitan and Wolfson 1985); and the number of words generated on the Controlled Oral Word Association task (COWAT; Benton et al 1983). To assess the fourth prediction, a series of analyses of covariance were undertaken comparing adjusted group means on WCST measures (WCS⫺CAT; WCS⫺PE) after controlling for the effect of the AIM task. This analysis examines whether the between-group differences on the WCST can be explained by group differences on either of the AIM subtests after controlling for general intelligence. The fifth prediction was tested with Pearson correlations between AIM subtests and indices of clinical symptomatology, including the BPRS and global ratings from the SANS (affective flattening, alogia, apathy, and anhedonia) and SAPS (attention, hallucinations, delusions, bizarre behavior, and formal thought disorder).

Results AIM Performance Characteristics An overall main effect of diagnosis (F[1,122] ⫽ 2 8.42, p ⬍ 0.001) indicated that patients performed worse than healthy participants on the AIM task. A diagnosis by subtest interaction (F[1,122] ⫽ 8.53, p ⬍ 0.004) indicated that impairment was not equivalent across subtests, with patients showing significantly worse performance on the Abstraction plus Memory subtest (see Figure 2). The absence of a significant diagnosis by difficulty level interaction (F[1,122] ⫽ 2.79, p ⬍ 0.1) suggests that both healthy subjects and patient performance decreased to the same extent on harder trials. Post hoc analysis showed that both patients and healthy subjects performed significantly above chance in both subtests and at each difficulty level (not shown). This does not preclude the possibility that individual subjects may have performed at chance. Indeed, a subgroup of 12 patients were found whose performance was at or below chance in the hard condition of the Abstraction plus Memory subtest; however, removing these patients did not significantly affect the results from the previous model. The three-way interaction of diagnosis by subtest by difficulty level was not significant (F[1,122] ⫽ 0.004, p ⬍ 0.95).

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Figure 2. The AIM task performance of 64 patients with schizophrenia and 64 matched healthy volunteers. Whereas patients with schizophrenia demonstrated deficits on the Abstraction subtest, they were disproportionately impaired with the addition of a minimal maintenance requirement in the Abstraction plus Memory subtest.

Correlations between AIM and Standard Neuropsychological Measures Healthy participants’ performance on either subtest of the AIM did not significantly correlate with any of the neuropsychological measures selected (see Table 3). However, patients’ performance on both subtests of the AIM significantly correlated with the number of categories achieved on the WCST and was negatively correlated with the number of perseverative errors on the WCST and the time required for trail making (see Table 3). Patient performance on Digit Span measures significantly correlated with performance on the Abstraction plus Memory subtest but not the Abstraction subtest. Finally, the number of words generated during the COWAT did not correlate with patients’ performance on either subtest of the AIM.

Relationship between AIM, WCST, and BetweenGroup Differences To examine the possibility that the between-group differences on the WCST are mediated by differences in the

ability to manipulate information or the ability to maintain and then manipulate information, analysis of covariance was performed on the WCST, covarying scores independently for each of the AIM subtests (see Table 4). Although there were significant between-group differences for the number of categories achieved on the WCST when performance on the Abstraction subtest was used as a covariate (F[1,90] ⫽ 5.79, p ⬍ 0.01), these differences were no longer significant when the Abstraction plus Memory subtest was covaried (F[1,90] ⫽ 2.58, p ⬍ 0.11); however, when the converse analysis was performed, covarying the number of categories achieved on the WCST from each AIM subtest, between-group difference remained for the Abstraction subtest (F[1,90] ⫽ 5.41, p ⬍ 0.02) and the Abstraction plus Memory subtest (F[1,90] ⫽ 15.14, p ⬍ 0.0002). A similar pattern of results emerged when these analyses were performed with the number of perseverative errors on the WCST. Although between-group differences for the number of perseverative errors on the WCST were not significant when performance on the Abstraction subtest was used as a covariate, they were at trend level (F[1,90] ⫽ 3.20, p ⬍ 0.07). As with the number of categories achieved, group differences were no longer significant when the Abstraction plus Memory subtest was covaried from WCS⫺PE (F[1,90] ⫽ 0.98, p ⬍ 0.33). As before, when the WCST measure was covaried from each AIM subtest, between-group differences remained (Abstraction F[1,90] ⫽ 4.20, p ⬍ 0.04; Abstraction plus Memory F[1,90] ⫽ 14.84, p ⬍ 0.0002).

Correlations between AIM, WCST, and Clinical Indices Correlations between the AIM subtests, WCST indices, and measures of clinical severity (BPRS total and global ratings from the SANS and SAPS) were examined (see

Table 3. Correlations between AIM Subtest and Other Cognitive Measures Schizophrenic Subjects

WCS_CAT WCS_PE Trails A Trails B DIGFOR DIGBAC COWAT

Healthy Subjects

Abstraction

Abstraction ⫹ Memory

Abstraction

Abstraction ⫹ Memory

0.39a ⫺0.50b ⫺0.42c ⫺0.52b 0.18 0.18 0.10

0.50b ⫺0.56c ⫺0.43c ⫺0.45b 0.29d 0.27d 0.10

0.15 ⫺0.16 ⫺0.18 0.09 0.07 ⫺0.09 0.12

0.09 ⫺0.02 ⫺0.03 0.12 ⫺0.20 ⫺0.22 0.00

Pearson correlations, performed separately for each group, between AIM subtests and standard neuropsychological measures: the number of categories achieved (WCS_CAT) and the number of perseverative errors (WCS_PE) on the WCST; total time required for Trails A and B (TRAILA and TRAILB); the raw scores from the forward (DIGFOR) and backward (DIGBAC) Digit Span subtest of the WAIS-R; and the number of words generated on the Controlled Oral Word Association task (COWAT). a p ⬍ .01. b p ⬍ .0001. c p ⬍ .001. d p ⬍ .05.

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Table 4. Correlations between AIM Subtest and Measures of Clinical Symptoms Abstraction Abstraction ⫹ Memory WCS_CAT WCS_PE BPRS total Affective flattening Alogia Apathy Anhedonia Attention Hallucinations Delusions Bizarre behavior Thought disorder

⫺0.33 ⫺0.30 ⫺0.44a ⫺0.37b ⫺0.49c ⫺0.47c ⫺0.46c ⫺0.37b ⫺0.34b ⫺0.40a

⫺0.01 ⫺0.41a ⫺0.29 ⫺0.25 ⫺0.50c ⫺0.33 ⫺0.36b ⫺0.06 ⫺0.11 ⫺0.16

0.12 ⫺0.57c ⫺0.41b ⫺0.25 ⫺0.42b ⫺0.42b ⫺0.16 0.05 ⫺0.29 ⫺0.20

0.07 0.33 0.42b 0.40b 0.41b 0.57c 0.45a 0.21 0.35 0.25

Pearson correlations between cognitive indices and measures of clinical symptoms from 64 patients with schizophrenia. Cognitive measures included the percent correct from the Abstraction and Abstraction plus Memory subtests of the AIM task and the number of categories achieved (WCS_CAT) and the number of perseverative errors (WCS_PE) on the WCST. Clinical indices were the total from the BPRS and global ratings from the SANS (affective flattening, alogia, apathy, anhedonia, and attention) and SAPS (hallucinations, delusions, bizarre behavior, and formal thought disorder). a p ⬍ .01. b p ⬍ .05. c p ⬍ .001.

Table 4). Performance on the Abstraction subtest was negatively correlated with most of the clinical measures, suggesting that performance on this subtest is sensitive to severity of illness. In contrast, performance on the Abstraction plus Memory subtest and WCST measures were primarily correlated with measures of negative symptomatology (see Table 4 for complete details).

Discussion Three major findings emerge from this study. First, although patients with schizophrenia demonstrated deficits in simple abstraction, they were disproportionately impaired with the addition of a minimal maintenance requirement. Second, between-group differences on WCST performance appear to be related to patients’ inability to maintain information over a short delay, before that information is used for more complex cognitive processes. Third, whereas performance on the Abstraction subtest was correlated with general severity of clinical symptoms, performance on the Abstraction plus Memory subtest may show specificity to negative symptomatology. An advantage of the AIM paradigm is that it allows the independent analysis of difficulty level effects on performance. Given that schizophrenia is associated with diffuse cognitive dysfunction across multiple domains, impairment on specific cognitive measures must be interpreted within the context of this generalized dysfunction. Chapman and Chapman (1989) have proposed that one result of a generalized cognitive dysfunction is that as tests become more difficult, patients will perform worse, regardless of

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the cognitive domain under investigation. The AIM task allows one to test this hypothesis by comparing performance on each subtest across difficulty levels and between patient groups. The lack of a diagnosis by difficulty level or a diagnosis by subtest by difficulty level interaction indicates the primary effect of interest; namely, the greater vulnerability of patients to abstraction deficits with the addition of a working memory component applies equally for both easy and hard trials. Indeed, when only performance on easy trials was used, the diagnosis by subtest interaction continued to be significant (F[1,122] ⫽ 4.07, p ⬍ 0.04). The lack of these interaction effects also suggests that there was no major change in strategy or approach to the AIM task across subtest or diagnosis. One may question whether patients’ poorer performance on the Abstraction plus Memory subtest is due to poor maintenance and then manipulation abilities or to the possibility that the patients simply did not encode the target object because of poor attentional abilities. The finding that most directly speaks to this issue is the lack of a significant diagnosis by difficulty level interaction, which suggests that both healthy subjects and patient performance decreased to the same extent on harder trials. If patients simply did not “notice” the target object, one would expect little difference between performance on the easy versus hard trials, where difficulty level refers to the degree of abstraction required to group the objects; however, a substantial difference is present for the patients on the Abstraction plus Memory subtest (F[1,61] ⫽ 38.66, p ⬍ 0.0001; Easy Trials: 73.8 ⫾ 15.8; Hard Trials: 60.8 ⫾ 14.2; Percent Correct: mean ⫾ SD), suggesting that the patients must have encoded the target shape on many of the Abstraction plus Memory trials and found the subsequent abstraction to be more difficult on harder trials. Further support for this view comes from reaction time data from these trials, where patients took nearly 500 msec longer to respond to harder trials. Nonetheless, it is possible that on some trials subjects did not encode the target shape, and patients may have been more prone to distraction than healthy subjects. To understand AIM performance within the context of other measures of executive functioning, correlations were performed between AIM subtests and standard neuropsychological measures. Patients’ AIM performance was positively correlated with the number of categories achieved on the WCST and negatively correlated with the number of perseverative errors on the WCST and the time required for trail making. The positive correlation between performance on the Abstraction plus Memory subtest and Digit Span measures may be taken as initial convergent validity, particularly because the Abstraction subtest alone did not significantly correlate with these Digit Span measures. The lack of a significant correlation between

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AIM and COWAT performance suggests that the cognitive requirements of the AIM task may segregate from those used in the COWAT and Digit Span tests. There is evidence that the neural correlates of the COWAT may localize to regions of frontal cortex not typically associated with working memory or abstraction (Herholz et al 1996; Paulesu et al 1997). The lack of a significant correlation between the number of categories achieved on the WCST and AIM performance may be due to the relatively modest abstraction and memory demands of the WCST (Gold et al 1997). To explain a similar pattern of results, Gold et al (1997) proposed that the working memory demands of the WCST may affect WCST performance only when a subject’s working memory capacity is below a threshold. That is, if working memory (or abstraction) is impaired, it may undermine a patient’s WCST performance; however, if working memory (or abstraction) is unimpaired, WCST performance may reflect other abilities. Although there were significant between-group differences for the number of categories achieved on the WCST when performance on the Abstraction subtest was used as a covariate, these differences were no longer significant when the Abstraction plus Memory subtest was covaried. Thus, there was a significant attenuation of between-group differences on the WCST when the Abstraction plus Memory subtest was used, but not the Abstraction subtest alone (statistically controlled), suggesting that abstraction alone cannot explain patient’s impairment on the WCST. Rather, their performance seems to be linked to the maintenance of information. Recently, Gold et al (1997) reported that between-group differences are no longer significant when performance on the Letter-Number Sequencing subtest (LN) of the WAIS III is covaried from the number of categories achieved on the WCST. The present analyses add to our understanding of schizophrenic WCST impairment in that they demonstrate the importance of the maintenance component, which cannot be readily ascertained from the LN task. When the converse analysis was performed with the number of categories achieved on the WCST covaried from performance on AIM subtests, between-group differences remained, suggesting that group differences in AIM performance are not well captured by WCST performance. Similar but weaker findings occurred when the number of perseverative errors was used as the WCST measure. Whereas performance on the Abstraction subtest seems to reflect the general severity of clinical symptoms, performance on the Abstraction plus Memory subtest may show specificity to negative symptomatology and hallucinations. One potential explanation for this finding is that the additional maintenance requirement of the Abstraction plus Memory subtest increases demands on the frontal

lobes, which have been linked to negative symptoms (Weinberger et al 1992). Because both abstraction and working memory are linked to distributed networks of cortical areas (Prabhakaran et al 1997; Smith and Jonides 1997), they are affected by potential dysfunction throughout the brain; however, the increased demands of the Abstraction plus Memory subtest may require more activity from dorsolateral prefrontal areas, which have been associated with negative symptoms. This study has a number of limitations. Most patients underwent evaluation while receiving medication. Although there is evidence that antipsychotic medication enhances working memory performance (Spohn and Strauss 1989; Green et al 1997), it is unlikely that the observed deficits are secondary to treatment effects, given that no differences were found in performance between medicated and nonmedicated participants; however, the small number of patients in these groups limits the power of this analysis. A longitudinal pre–post design is indicated to understand the effects of antipsychotic and anticholinergic medications on AIM performance. Although evidence from the AIM task supports the hypothesis that impaired WCST performance in schizophrenia is related to deficits in working memory, the relative importance of working memory and its neurofunctional correlates in schizophrenia are still unclear. A direct examination of neurocognitive processes must be undertaken to clarify the neurophysiologic influences of working memory on abstraction. Hence, the AIM task is currently being administered in conjunction with functional magnetic resonance imaging.

This research was funded by grants MH-43880 and MH-52857 from the National Institutes of Mental Health. We thank Charlie Swanson and Tim Gasperoni for their comments on the manuscript.

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