Working Memory in Schizophrenia: Transient "Online" Storage Versus Executive Functioning

Transcription

1 Working Memory in Schizophrenia: Transient "Online" Storage Versus Executive Functioning William Perry, Robert K. Heaton, Eric Potterat, Tresa Roebuck, Arpi Minassian, and David L. Braff Abstract Working memory has been described as the temporary "online" storage and the subsequent manipulation and retrieval of information. It has been suggested that the prefrontal cortex is a primary site of working memory. Schizophrenia patients, who are thought to have prefrontal cortical dysfunction, have demonstrated inconsistent deficits on a variety of verbal and spatial working memory tests. This has led to questions about how to define and measure working memory, whether these deficits are distinct to one cognitive domain, and what role factors such as intelligence and play in working memory performance. We compared schizophrenia patients to normal comparison subjects in four separate studies. Based upon the results we recommend that working memory tests be characterized as either transient "online" storage and retrieval tasks (where short-term storage and retrieval of information is required) or executive-functioning working memory tasks (where storage, manipulation, and retrieval of information is required). The importance of clearly identifying which distinct aspects of working memory are assessed is discussed. Keywords: Working memory, executive functioning, schizophrenia, intellectual functioning,, frontal cortex. Schizophrenia Bulletin, 27(1): ,2001. Baddeley and Hitch (1974) introduced the dynamic concept of working memory to describe a limited-capacity "working space" for information processing. Baddeley explained that the working memory system is active and subject to rapid decay unless rehearsal processes are initiated (Salame and Baddeley 1982). In Baddeley and Hitch's conceptualization of working memory there is a superordinate "central executive" system and two slave systems for the transient storage of visuospatial and verbal information. Information is encoded as visuospatial or verbal (phonological) traces and is maintained by the two slave systems via the "visuospatial sketchpad" or subvocal "phonological or articulatory loop" (Baddeley and Hitch 1974). These subsystems and the central executive controller are responsible for the allocation of and direction of attentional resources, the manipulation of the visual and phonological material, and the selection and execution of strategies. Collectively, the working memory system provides "temporary storage and manipulation of the information necessary for such complex cognitive tasks as language comprehension, learning, and reasoning" (Baddeley 1992, p. 556). Baddeley and Hitch (1994) have found that "the term working memory is used in a number of different ways" (p. 485), and these different usages can lead to substantial variation in how working memory is defined and studied. Goldman-Rakic and her colleagues (Goldman-Rakic 1987, 1991; Funuhashi et al. 1989; Funuhashi et al. 1993; Wilson et al. 1993) have employed the classic delayed response paradigm to study the ability of nonhuman primates to guide behavior by symbolic representation in the absence of external cues. Their work has provided strong evidence that in nonhuman primates, the prefrontal cortex is a primary site of transient "online" visuospatial information storage. Goldman-Rakic (1991) suggested that "At the most elementary level, our basic conceptual ability to appreciate that an object exists when out of view depends on the capacity to keep events in mind beyond the direct experience of those events" (p. 3), and this capacity entails some form of online storage or rehearsal. Thus, in the model presented by Goldman-Rakic, the storage of the existence and location of the object, in the absence of the object, is the critical component of working memory. Petrides (1995) has focused upon self-ordered and externally ordered aspects of working memory. According to Send reprint requests to Prof. W. Perry, University of California, San Diego, Department of Psychiatry, La Jolla, CA ; wperry@ucsd.edu. 157

2 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. the view presented by Petrides, the monitoring of increasing amounts of information and the active retrieval of information are the critical areas of working memory that need to be considered. In this context, we propose that working memory can be defined as transient online storage and recall working memory, when short-term information storage but not manipulation is used. In contrast, "executive-functioning working memory" should be used when, in addition to short-term information storage, manipulation and recall of that information are used via central executive functioning. Recently, the role of working memory deficits has been highlighted in schizophrenia patients. Several authors have shown that schizophrenia patients and their relatives have impaired performance on a variety of working memory tasks. These findings have been used to support the hypothesis that the prefrontal cortex is impaired in schizophrenia spectrum patients (Park and Holzman 1992; Goldberg et al. 1993; Park et al. 1995; Gold et al. 1997). Park and Holzman (1992) have used constructs that depend on the more limited transient storage definition of working memory in schizophrenia patients by using a human analogue of the delayed response paradigm employed by Goldman-Rakic. The authors found that schizophrenia patients exhibited impaired visuospatial working memory performance but not impaired auditory working memory as assessed by Digit Span. Goldberg et al. (1993) found that schizophrenia probands had performances similar to their clinically nonaffected identical twin on Digit Span forward but exhibited poorer performance on Digit Span backward. They noted that during Digit Span backward, numbers are held and manipulated in working memory and recalled in reverse order. The authors suggested that the Digit Span backward task places a greater cognitive load upon the central executive controller of working memory than a pure "hold and repeat" forward span task, thus accounting for the poor performance of the schizophrenia twins. In addition to working memory studies using transient-storage working memory tasks, there have been numerous neuropsychological studies of schizophrenia patients using complex executive function tasks to assess working memory. Although these measures are not typically considered working memory measures per se, they are conceptualized as requiring online storage, manipulation, and then retrieval of information, and the deficient performance of schizophrenia patients on these tasks is often attributed to impaired working memory (Gold et al. 1997). Among the most widely used tasks that tap into executive function working memory are the Wisconsin Card Sorting Test (WCST); the Category Test; puzzle tests such as the three "tower" tests of Hanoi, Toronto, and London; and delayed response tasks that require sustained attention and simultaneous information processing, such as the Auditory Consonant Trigram Test. Goldman- Rakic (1991) reported that all of these tasks require that "symbolic representations are accessed and held 'online' to guide behavior in the absence of or despite discriminative stimuli in the outside world" (p. 13). In other words, these tasks require an individual to "keep instruction, concepts, and goals 'in mind' " (Goldman-Rakic 1991, p. 17). Furthermore, Goldman-Rakic states that these tests all share a common prefrontal cortex neurobiological substrate. To assess how schizophrenia patients perform on tasks that require online storage as well as manipulation and then retrieval of information, Gold and colleagues (Gold et al. 1997) studied a Letter-Number Span (LNS) task to increase the cognitive (central executive) demand characteristics of simple Digit Span tasks. Similar to the Digit Span backward test, the LNS requires the subject to hold information in temporary storage but also requires the subject to sort out the letters from the numbers and to separately recall the letters and numbers in successive order. The authors explained that Digit Span forward or the simple recall of a series of digits did not require the "cognitive manipulation of stored information and therefore, demanded little of the working memory system" (Gold et al. 1997, p. 161). They compared the performance of schizophrenia patients on the LNS to patients' performance on the WCST. Gold and colleagues demonstrated that schizophrenia patients do exhibit performance deficits on the LNS task, and they attributed these deficits to an impaired auditory working memory system. Furthermore, this impaired LNS performance was highly correlated with WCST perseverative responses (r ). The authors suggested that a next step in understanding the critical role of working memory would be to assess the relationship between working memory and symptomatic state (Gold et al. 1997). Pantelis and colleagues (Pantelis et al. 1997) also demonstrated deficits in short-term memory, visuospatial working memory, and strategy generation and planning ability in schizophrenia patients. They reported a lack of significant correlations between the different executive functioning tasks, which they interpreted as suggesting "impaired functional connectivity between different regions of the neocortex" (Pantelis et al. 1997, p. 1823). The authors further suggested that schizophrenia patients' performance resembled the performance of patients with both frontal and basal ganglia pathology. Compared with tests of transient-storage working memory functioning, executive functioning tasks are more complex, use more cognitive operations, and appear to be more highly correlated with general intelligence. For 158

3 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, 2001 example, Chen and McKenna (1996) pointed out that the observed working memory deficits could be related to task difficulty rather than the construct of working memory. Kyllonen and Christal (1990) addressed the relationship between working memory and reasoning ability and concluded that working memory and reasoning ability, considered to be at the core of intelligence, are "similar if not identical" (p. 410). They further propose that reasoning ability is the primary determinant of how well a person benefits from instruction and "governs the success of the life-long process of accumulating crystallized knowledge" (p. 392). In general, studies of working memory have not adequately addressed whether the observed deficits are best explained by working memory capacity limitations or deficient reasoning or intelligence. Thus, despite the widespread usage of the term "working memory," there remains considerable debate regarding its definition, how best to measure the construct (or constructs), and which (if any) other factors better explain the deficits observed among schizophrenia patients. To resolve the differing views of working memory that are summarized above, and to extend the assessment of working memory in schizophrenia patients, several questions were addressed in the current research: (1) Do schizophrenia patients have impaired working memory performance compared to age-, education-, and gender-matched normal comparison subjects? (2) Do schizophrenia patients have working memory deficits in a specific cognitive domain (i.e., auditory versus visuospatial)? (3) Do schizophrenia patients have selective deficits in working memory that are distinct from impairment in areas of attention and intellectual functioning? (4) Because schizophrenia patients are thought to have primary working memory deficits that impact their performance on executive functioning tests, is there a difference between executive functioning test performance for schizophrenia patients and that for nonpatients? (5) Does a relationship exist between performance on tests of executive functioning and symptom factor scores, especially those thought to reflect deficits in the prefrontal cortex? To address these questions we conducted four separate studies using separate samples of schizophrenia patients. Study 1 In this study we compared the performance of schizophrenia patients to normal subjects on the Digit Span forward and backward test. We hypothesized that if schizophrenia patients have selective deficits in central executive working memory then they should have differentially greater deficits on the backward portion of the test when compared to a group of normal subjects, and these deficits should be distinct from moderating factors such as intellectual functioning. Method Subjects. Fifty schizophrenia patients (24 males and 26 females; 37 Caucasian, 4 African-American, 4 Hispanic, 2 Asian, and 3 other) participated. All met the DSM-HI-R (American Psychiatric Association 1987) criteria for schizophrenia, as determined by the use of the Structured Clinical Interview for DSM-III-R (SCID-m-R; Spitzer et al. 1990), conducted by experienced doctoral-level clinicians. We established a 98 percent agreement for determining an Axis I diagnosis using the SCID-III-R. Subjects were excluded if they were determined to have an additional Axis I diagnosis, met DSM-III-R criteria for substance abuse or dependence within the past 6 months, had an unstable medical condition, had a history of a neurological disorder (e.g., a head injury with loss of consciousness), or were treated in the past with electroconvulsive therapy. The 50 schizophrenia patients consisted of the following subtypes: 21 paranoid, 25 undifferentiated, 3 disorganized, and 1 residual. Five patients were recruited from an acute inpatient psychiatry service, 37 were recruited from a long-term subacute inpatient facility, and 8 were outpatients. Seventeen of the schizophrenia patients were being treated with traditional neuroleptic medication (mean chlorpromazine equivalents = 624 mg, standard deviation [SD] = 495 mg). Twelve patients were treated with clozapine (mean dose = mg, SD = mg), six were on olanzapine (mean dose = 12.8 mg, SD = 3.9 mg), seven patients were treated with risperidone (mean dose = 6.43 mg, SD = 2.65 mg), four patients were on a combination of typical and atypical antipsychotic medication, and four were not treated with antipsychotic medication. Thirty subjects were taking anticholinergic medications with a mean benzotropine equivalent of 2.7 mg (SD = 1.8) with a range of mg (Jeste and Wyatt 1982). A normal comparison group consisting of 50 subjects (23 females and 27 males; 34 Caucasian, 9 African- American, 3 Hispanic, 2 Asian, and 2 other) also participated. The normal comparison subjects were recruited from newspaper advertisements and were screened for the exclusionary criteria of Axis I pathology (using the Structured Clinical Interview for DSM-Non Patient version), substance abuse or dependence within the past 6 months, an unstable medical condition, or history of neurological disorder (e.g., head injury with loss of consciousness). The mean age for schizophrenia patients was 35.8 (SD = 8.4) and for the normal comparison subjects 32.0 (SD = 10.2). There was no significant difference between the groups for age (<[98] = -2.05). The mean years of education for the schizophrenia patients was 12.6 (SD = 2.2) and for the normal comparison subjects was 159

4 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al (SD = 1.6). There were no significant differences between the groups with respect to years of education (/[98] = 2.71). The mean age of onset of illness for the schizophrenia patients was 21.9 (SD = 5.6). After a complete description of the study was given to the subjects, written informed consent was obtained. Subjects were then tested on the Vocabulary and Digit Span subtests from the Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler 1981). Vocabulary subtest scores were converted to age-corrected scaled scores. Digit Span is typically presented as a single score combining forward and backward performance. To compare forward to backward performance, the raw numbers of correctly obtained items for forward and backward were analyzed independently. Results Schizophrenia patients achieved a mean WAIS-R Vocabulary scaled score of 8.4 (SD = 2.5) compared to 10.6 (SD = 2.5) for the normal comparison subjects (t [98] = 4.48, p < 0.001). On the Digit Span subtest, schizophrenia patients achieved a mean forward span score of 6.7 (SD = 1.8) compared to 9.3 (SD = 2.1) for the normal comparison subjects; corresponding means (SDs) for backward Digit Span were 5.4 (1.9) and 7.6 (2.4) for the respective groups. A two-way analysis of variance (ANOVA) was conducted, with diagnosis (schizophrenia or normal) as the between-subject factor and test condition (forward versus backward) as the within factor. This yielded a significant main effect for diagnosis (schizophrenia patients versus normal comparison subjects) (F[l,98] = 41.66, p < 0.001), indicating that the schizophrenia patients performed significantly lower on Digit Span than did the normal comparison subjects. Also there was a significant difference between forward and backward Digit Span regardless of diagnosis (F[l,98] = 59.02, p < 0.001]. There was no significant interaction of diagnosis by Digit Span type (F[l,98] = 1.14) (see figure 1). Therefore, schizophrenia patients do not appear to perform differentially worse than normal comparison subjects on the backward relative to the forward component of Digit Span. The analyses were repeated with WAIS-R Vocabulary performance covaried. This did not, however, change the results (i.e., significant effects were obtained for diagnosis and forward versus backward Digit Span, Figure 1. Forward and backward Digit Span performance for normal subjects and schizophrenia patients (Study 1) FORWARD BACKWARD Normal Subjects (N=50) Schizophrenia Patients (N=50) 160

5 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, 2001 but the interaction was nonsignificant). There was also no significant difference found between patients treated with typical neuroleptics and patients treated with atypical neuroleptics. To further explore whether working memory and intellectual functioning are relatively distinct processes, we covaried the effects of Digit Span forward and backward performance on Vocabulary performance. Removing the influence of Digit Span forward resulted in nonsignificant differences between schizophrenia and normal comparison subjects on WAIS-R Vocabulary performance (F[l,97] = 2.79). Covarying out Digit Span backward did not significantly change the difference in Vocabulary test performance found between schizophrenia and normal comparison subjects (F[l,97] = 8.83, p < 0.005). Finally, Pearson correlation coefficients between WAIS-R Vocabulary and Digit Span forward (r = 0.20) and backward (r = 0.31) were not significant for the schizophrenia patients. Among the normal comparison subjects WAIS-R Vocabulary was significantly correlated with Digit Span forward (r = 0.54) but not Digit Span backward (r = 0.22). These results suggest that Digit Span backward may be relatively distinct from verbal intellectual functioning, particularly for schizophrenia patients. Conclusion The results support the hypothesis that schizophrenia patients perform worse on both components of Digit Span than do normal comparison subjects. The unexpected finding, however, is that there was no significant interaction of diagnosis by Digit Span type. This indicates a lack of differentially greater impairment on the backward versus forward version of the test. Schizophrenia patients also performed significantly worse on the WAIS-R Vocabulary test, despite there being no differences between the patients and normal comparison subjects in level of education completed. These results suggest that these schizophrenia patients have a generalized deficit across numerous cognitive domains, including short-term memory of digits. Finally, covarying out the influence of Digit Span forward from Vocabulary performance eliminated the significant differences observed between schizophrenia patients and normal comparison subjects, whereas covarying Digit Span backward did not. Thus, Digit Span backward and Vocabulary performance may represent unrelated deficits. Still, the impaired performance of schizophrenia patients on Digit Span forward or backward cannot simply be attributed to the taxing of an impaired working memory system. Schizophrenia patients performed approximately one SD below normal comparison subjects on both the backward and the forward components of Digit Span, achieving a very short span. Study 2 In this study we examined the performance of schizophrenia patients on five measures from three tests of memory span from the Wechsler Memory Scale-Third Edition (WMS-III): Digit Span (forward and backward), Spatial Span (forward and backward), and Letter-Number Sequencing. We selected these tests to study whether schizophrenia patients have differential deficits in spatial versus verbal aspects of working memory, as proposed by Park and Holzman (1992). Method Twenty-eight schizophrenia patients (21 males and 7 females; 17 Caucasian, 4 African-American, 4 Hispanic, 1 Asian, and 2 other) who were diagnosed using the Structured Clinical Interview for DSM-IV (SCID-IV, First et al. 1995) participated in this study. Their performance on multiple tests of working memory was compared to standardized published norms; none of these subjects participated in any of the other studies reported here. The diagnostic interviews were administered by doctoral-level clinicians. All diagnostic and exclusion criteria are as described above in Study 1. All of the patients were tested once they were deemed stable by their treatment team. The schizophrenia patients consisted of the following subtypes: 16 paranoid, 7 undifferentiated, and 5 disorganized. Twenty-one patients were recruited from the University of California, San Diego, inpatient psychiatry service and seven were recruited from a long-term subacute inpatient facility. The patients ranged in age from 23 to 65 (mean age = 41.14, SD = 9.9) and had a mean of 12.8 years of education (SD = 2.7). The mean age of onset of illness was 23.2 years (SD = 6.2). All of the patients were undergoing treatment with a neuroleptic medication at the time of testing. Most patients (n = 20) were treated with risperidone (mean daily dose = 4.2 mg, SD = 1.4) and did not require anticholinergic medication. Among the 20 patients treated with risperidone, 5 were receiving concomitant therapy consisting of a typical neuroleptic. The eight remaining patients were treated with haloperidol (n = 4, mean daily dose = 10 mg, SD = 1.6) and olanzapine (n = 4, mean daily dose = 18.7 mg, SD = 2.5). Of the 28 patients, 12 were also receiving low-dose benzodiazepines. There were no significant differences between the patients who received different medications on working memory test performance. After a complete description of the study was given to the subjects, written informed consent was obtained. Twenty-one subjects were assessed for level of verbal intellectual functioning using either the Adult North American Reading Test (Blair and Spreen 1989) (n = 12) 161

6 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. or the Reading subtest from the Wide Range Achievement Test-Hi (n = 9). The use of two separate measures of premorbid intellectual functioning is a limitation in this study. Still, we combined the data in the following manner. The performance on the two tests ranged from 45 to 118, and the collapsed mean for the overall sample was 99.4 (SD = 18.2). Subjects were then tested on the following measures: the Digit Span and Letter-Number Sequencing subtests from the Wechsler Adult Intelligence Scale-Third Edition (WAIS-IH) and the Spatial Span subtest from the WMS-ffl (Wechsler 1997). All of the subtests were administered according to standard directions in the manual. Raw scores from Digit Span (total), Spatial Span, and Letter-Number Sequencing were age corrected and converted to scaled scores. Because scaled scores were not available for the subject's longest Digit Span (forward and backward individually,), z scores were calculated from tables in the WAIS-in manual. The z scores were converted to scaled scores with a mean of 10 and an SD of 3 so that all five measures could be directly compared with each other and with the WMS-III standardization sample. We hypothesized that the schizophrenia patients would demonstrate significantly impaired performance across all of the working memory measures compared to the standardization sample. We then compared the performance across the five measures to examine the following: (1) whether schizophrenia patients have selective visuospatial versus auditory/verbal working memory deficits, as previously suggested (Park and Holzman 1992); and (2) whether schizophrenia patients have greater impairment on backward versus forward span tasks, because of a greater taxing of the working memory system (Goldberg et al. 1993; Pantelis et al. 1997). One-sample t tests were used to compare subjects' performance for each of the five working memory measures against published norms. The alpha criterion was conservatively set top < because of the number of analyses conducted. To compare the performance of the schizophrenia subjects across the five measures, two ANOVAs were conducted. The first was a 2 X 2 ANOVA with modality (auditory vs. visuospatial) and condition (forward vs. backward) as the within-subject factors. The second was a three-way ANOVA with subtest (Digit Span, Spatial Span, and Letter-Number Sequencing) as within-subject factors. This approach allowed us to test the two main questions of interest. For these two analyses the alpha criterion was again set at p < Results The mean performance on Digit Span forward and backward, Spatial Span forward and backward, and Letter- Number Sequencing revealed that the patients performed significantly below average when compared to the agematched standardization sample on all but the Digit Span forward measure (table 1). The 2X2 ANOVA with modality (auditory vs.visuospatial) and condition (forward vs. backward) as the within-subject factors resulted in a trend for modality (Pillai's Trace F [1,27] = 3.65, p = 0.07) with the verbal mean being higher (mean = 8.6, SD = 2.53) than the visuospatial mean (mean = 7.6, SD = 3.06). There was a nonsignificant main effect for condition (forward vs. backward; Pillai's Trace F [1,27] = 1.03, ns) and a nonsignificant modality by condition interaction (Pillai's Trace F [1,27] = 3.14, ns). Post hoc analysis of the main effect revealed that Digit Span forward performance (mean = 9.15, SD = 2.74) was not significantly better than Digit Span backward (mean = 8.08, SD = 3.19), nor was there a difference between Spatial Span forward (mean = 7.57, SD = 3.36) and backward (mean = 7.71, SD = 3.39). The three-way ANOVA with subtest (Digit Span, Spatial Span, and Letter-Number Sequencing) as the within-subject factor resulted in a significant effect (Pillai's Trace F [2,26] = 5.78, p = 0.008). Post hoc analysis of the main effect (F tests) revealed that performance on Digit Span was significantly different from that on Spatial Span (F[l,27] = 6.45, p = 0.01) and from Letter-Number Sequencing (F[l,27] = Table 1. Schizophrenia patients' (n = 28) performance on five measures of working memory compared with the standardization sample (Study 2) Measure Mean (SD) nest p value Digit Span Digit Span forward Digit Span backward Spatial Span Spatial Span forward Spatial Span backward Letter-Number Sequencing Note.SD = standard deviation (2.94) 9.15(2.74) 8.08 (3.19) 7.18(3.49) 7.57 (3.36) 7.71 (3.39) 7.18 (3.36) < < < < < <

7 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, , p = 0.008). Spatial Span and Letter-Number Sequencing performance was not significantly different from (F[l,27] = 0, ns) (figure 2). Digit Span performance was significantly better than Spatial Span and Letter-Number Sequencing. The most parsimonious explanation for these results is that Digit Span (particularly Digit Span forward) is an easier task for schizophrenia patients than the other two measures. Finally, Digit Span performance in this study was slightly higher than that observed among schizophrenia patients in Study 1. Collectively the patients performed below expectation when compared to a normal comparison or standardization sample. The slight differences in scores between Studies 1 and 2 highlight the heterogeneous performance of schizophrenia patients on working memory cognitive tasks. Conclusion The results of this study support the hypothesis that schizophrenia patients have impaired performance on working memory measures when compared to a standardization sample. The exception among the measures examined was Digit Span forward, but it has been argued that Digit Span forward is primarily a test of attention and does not tax the working memory system to the same degree as Digit Span backward (Gold et al. 1997). If Digit Span forward is the least taxing of the five measures on the working memory system then this may account for schizophrenia patients' relatively better performance on Digit Span forward. However, there were no statistically significant differences between the five working measures, thus not supporting the hypothesis of a modalityspecific working memory impairment for schizophrenia patients (Park and Holzman 1992) or the hypothesis that schizophrenia patients perform better on forward than backward tasks because of the greater taxing of the working memory system (Goldberg et al. 1993; Pantelis et al. 1997). Study 3 In this study schizophrenia patients were assessed on a battery of tests of executive-functioning working memory measures. Each of the tasks used in this study requires online storage, manipulation, and then retrieval of information. Given the hypothesis that central executive processing and its prefrontal cortex substrate are impaired in Figure 2. Scaled scores for the five working memory measures (Study 2) SCALED SCORES FOR WORKING MEMORY MEASURES FOR SCHIZOPHRENIA PATIENTS LJJ OH o o </) Q LLJ _L 8 T m. 0 Digrt Span Forward Digit Span Backward Spatial Span Forward 163 Spatial Span Backward Letter-Number Sequencing

8 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. schizophrenia patients (Gold et al. 1997), we predicted that schizophrenia patients would perform significantly more poorly than a sample of age-, education-, and gender-matched normal subjects. We further hypothesized that, given that tests of executive functioning are mediated by central executive processing, there should be a moderate relationship between performance across the more complex working memory measures for both schizophrenia and normal comparison subjects. In other words, if the central executive functioning of working memory is the cognitive domain that is impaired in schizophrenia, then the commonality should be expressed by a higher degree of shared variance than that of normal comparison subjects (Gold et al. 1997). Method Forty schizophrenia patients (32 males and 8 females; 35 Caucasian, 2 African-American, 2 Hispanic, 1 Asian) who were diagnosed using the SCID-III-R were age, education, and gender matched to 40 normal comparison subjects (32 males and 8 females; 31 Caucasian, 8 African- American, 1 Hispanic); again, none of these subjects were participants in any of the other studies presented here. The SCID-III-R was administered by an experienced doctoral-level clinician. All diagnostic and exclusion criteria are as described above in Study 1. The schizophrenia patients consisted of the following subtypes: 32 paranoid, 3 undifferentiated, 3 disorganized, and 2 residual. Nineteen were recruited from an acute inpatient psychiatric service, 11 were recruited from a long-term subacute inpatient facility, and 10 were outpatients. Twenty-nine of the schizophrenia patients were being treated with neuroleptic medication (mean chlorpromazine equivalents = mg, SD = mg). The 10 outpatients were all medication-free at the time of testing. None of the patients were treated with an atypical neuroleptic. The mean Brief Psychiatric Rating Scale (Overall and Gorham 1962) score for the patients was 26.5 (SD = 8.6). The normal comparison subjects were recruited from newspaper advertisements and were screened for the presence of Axis I pathology, active substance abuse or dependence, an unstable medical condition, or a history of neurological disorder (e.g., head injury with loss of consciousness). Potential comparison subjects were excluded if they met criteria of an algorithm based on the Minnesota Multiphasic Personality Inventory (MMPI) for identifying substance abuse and psychosis proneness because people who meet the criteria have been shown to deviate from normal performance on neuropsychological measures (Butler et al. 1993). The mean age for the schizophrenia sample was 30.4 years (SD - 7.4) with an average of 12.1 years of education (SD = 1.4), whereas the normal comparison group had a mean age of 33.5 years (SD = 8.3) and averaged 12.0 years of education (SD = 1.7). The two groups were not statistically different for age (?[78] = 1.75) or education (<[78] = -0.45). The mean age of onset of illness for the schizophrenia patients was 21.7 years (SD = 5.9). After written informed consent was obtained, subjects were tested on the WAIS-R Vocabulary test and the following neuropsychological tests of executive and working memory functioning: the WCST (Heaton et al. 1993); Auditory Consonant Trigrams (ACT), which is a variation of the "Peterson Task" (Stuss et al. 1985); and the Category Test (Reitan and Wolfson 1993). The WCST is a sorting test of abstract reasoning and cognitive flexibility, but it also requires some working memory (see below). The subject is given two decks of 64 cards each. The cards are printed with one to four different symbols (triangle, star, cross, and circle) and in one of four different colors (red, green, yellow, blue). The subject's task is to place the cards, one by one, under one of four different stimulus cards according to an undisclosed principle. The stimulus cards also contain symbols that differ according to number, shape, and color. The examiner informs the subject after each sort whether his or her placement is "right" or "wrong." The subject must deduce the principle based upon the feedback given by the examiner. After a run of ten consecutive correct placements, the underlying principle changes without that being disclosed to the subject. The test is concluded once a subject completes six correct runs of ten correct placements or has exhausted all of the cards. Gold and colleagues (1997) have stated that "successful WCST performance requires the subject to remember his or her prior response and associated feedback and to use this information to select a new response, a form of working memory" (p. 159). A number of different scores can be derived, including the number of perseverative and nonperseverative errors, categories completed, and failure to maintain set. The perseverative response score, which is very highly correlated with perseverative errors, offers useful information regarding concept formation, profiting from feedback, and cognitive flexibility (Heaton et al. 1993). In the ACT the subject is presented with a set of three consonant letters followed by a number. The subject is then asked to recall the letters after four different time delays: 0, 3, 9, and 18 seconds later. During the delay period the subject must count backward out loud from the number provided until the delay period is over. The delay periods are presented in a pseudo-random order. Following the delay the subject is asked to recall the three consonants. There are five trials of each of the four different time periods, for a total of 20 trials. The score is the total number of letters correctly recalled. To successfully complete the task, the subject must hold the presented 164

9 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, 2001 information in short-term storage while processing auditory information. Stuss and associates (1985) described the ACT as a prefrontal measure of divided attention, and Boone and colleagues (1998) found the test to load on a factor of attention and short-term memory, two aspects of working memory performance. The Category Test is another test of abstraction, but it also requires sustained attention and short-term memory applied to logic reasoning. As in the WCST, subjects can alter their performance based upon feedback. Two hundred and eight arrays are projected on a screen, and each of these items requires a conceptually based response. The 208 trials are organized into six groups or subtests based upon different underlying principles. The seventh subtest is composed of stimuli the subject has been previously exposed to in the test and examines the subject's recall. The total number of errors is calculated across the seven subtests. Performances for schizophrenia patients and normal comparison subjects were compared using t tests, and the alpha criterion was set at p < to protect against Type I error. To address the question of whether the interrelationship of executive-function working memory tests is different for schizophrenia patients than for normal comparison subjects, Pearson correlation matrices were constructed. The alpha level was conservatively set at p < because of the number of analyses conducted. Finally, the correlation coefficients obtained for schizophrenia patients and normal comparison subjects for each of the three executive functioning tests were compared using the z test of differences between two independent correlation coefficients (Ferguson 1966). This set of analyses allowed us to determine whether the shared variance between the schizophrenia patients' performance for each of the three tests of executive-functioning working memory was greater than that of the matched normal comparison subjects, as suggested by Gold and colleagues (Gold et al. 1997). All analyses were conducted with BMDP (Dixon 1988) 3D (t tests), 3S (nonparametric statistics), and 6R (partial correlation and multiple regression). Results WAIS-R Vocabulary subtest scores were converted to age-corrected scaled scores (Wechsler 1981). Schizophrenia patients achieved a mean Vocabulary scaled score of 9.6 (SD = 2.8) compared to 9.6 (SD = 2.3) for the normal comparison subjects (/[78] = -0.04, ns). There was a trend for schizophrenia patients to commit significantly more perseverative errors on the WCST compared to the normal comparison subjects (f[78] = -2.12, p ). Schizophrenia patients completed significantly fewer WCST categories compared to the normal comparison subjects (f[78] = 2.23, p = 0.02). On the ACT and the Category Test, schizophrenia patients and normal comparison subjects did not significantly differ in their performance (ACT: t[ls] = 1.86, ns; Category Test errors (/[78] = 0.36, ns) (table 2). Two Pearson correlation matrices were constructed, one for the schizophrenia patients and the other for the normal comparison group (see tables 3A and 3B). For the schizophrenia patients, there was a moderate correlation between WCST and Category Test performance, sharing about 25 percent of the total variance. The relationship between the number of items recalled on the ACT and the perseverative responses and categories achieved on the WCST was in the expected direction but did not reach significance (see table 3A). For the normal comparison subjects, WCST, Category Test, and ACT performances were all weakly to moderately correlated with each other. The z test for the difference between two independent correlation coefficients revealed that there were no significant differences in the correlation coefficients between schizophrenia patients and normal comparison subjects on any of the three executive-functioning working memory measures. Conclusion Our first hypothesis was not supported because schizophrenia patients did not perform significantly more poorly than did normal comparison subjects on two of the three measures of executive-functioning working memory and performed identically on an estimate of gen- Table 2. Means and standard deviations for executive-functioning working memory measures for schizophrenia patients and normal comparison subjects (Study 3) Schizophrenia patients (n = 40), mean (SD) Normal comparison subjects (n 40), mean (SD) WCST (PR) WCST (Cat) ACT Category Test (errors) 26.6(19.9) 4.4(1.8) 37.8 (9.8) 66.3 (30.5) 17.0(20.5) 5.2(1.6) 41.5 (7.7) 68.8(32.1) Note.ACT = Auditory Consonant Trigrams; Cat = categories completed; PR = perseverative response score; SD = standard deviation; WCST = Wisconsin Card Sorting Test. 165

10 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. Table 3A. Pearson correlation matrix for performance on tests of executive-functioning working memory for schizophrenia patients (n = 40) (Study 3) WCST (PR) WCST (Cat) ACT (items recalled) Category Test (errors) WCST (PR) WCST (Cat) 0.53* -0.54* * Note.ACT = Auditory Consonant Trigrams; Cat = categories completed; PR = perseverative response score; WCST = Wisconsin Card Sorting Test. *p< Table 3B. Pearson correlation matrix for performance on tests of executive-functioning working memory for normal comparison subjects (n = 40) (Study 3) Category Test (errors) WCST (PR) WCST (Cat) WCST (PR) WCST (Cat) ACT (items recalled) * Note.ACT = Auditory Consonant Trigrams; Cat = categories completed; PR = perseverative response score; WCST = Wisconsin Card Sorting Test. *p< eral intelligence (i.e., Vocabulary). In fact there were no significant differences between the two groups on the ACT, which among the three tests may be the "purest" working memory measure because it is a test of holding information in transient storage while processing an auditory/verbal task. Similarly, there were no significant differences between the two groups on the Category Test, which is the "purest" abstract reasoning measure among the three tests. This nonsignificant difference in performance between the schizophrenia patients and normal comparison subjects was unexpected and is inconsistent with previous findings (Braff et al. 1991; Goldstein and Shemansky 1997) and raises questions about the generalizability of the current results. The patients did, however, perform in the mildly impaired range on the WCST (mean t score for WCST perseverative responses = 42) and the Category Test (mean t score for number of Category Test errors = 39, Heaton et al. 1991), arguing against these being a "neuropsychologically normal" group of patients. In respect to the Category Test, an alternative explanation for the lack of differences between schizophrenia patients and normal comparison subjects may involve the relatively limited education and, by normative standards, poor Category Test scores of this group of normals. Indeed, these apparently normal subjects also performed in the mildly impaired range on the Category Test, using the Heaton et al. (1991) demographically corrected norms (see t scores above). The present findings will clearly need to be replicated in other ageand education-matched samples. The relationships among performances on these tests of executive-functioning working memory were weak to moderate within both groups. This association among the three tests of executive functioning for the schizophrenia patients and normal comparison subjects may represent the degree of a common taxing of the central executive processing component of working memory across the three measures. However, the lowest correlation coefficients were observed between the ACT and the other two measures, arguing against a working memory explanation at the "core" of performance across these three tests. Additionally, the correlation coefficients for performance on the three tests were not different for the schizophrenia patients and the normal comparison subjects. Thus, the hypothesis of an expected "amplification" of correlation coefficients among the schizophrenia sample because of a hypothetically impaired working memory system was not supported. Still, it cannot be assumed that the nonsignificant differences in correlation coefficients between the schizophrenia patients and normal comparison subjects are the result of common taxing of the same working memory functions. Future studies will need to tease apart the various task components of working memory (e.g., atten- 166

11 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, 2001 tion, memory capacity) to more fully assess the similarities and differences between the groups on executivefunctioning working memory test performance. Study 4 In this study we assessed schizophrenia patients and normal control subjects on a somewhat different group of tests of executive-functioning working memory, hypothesizing that the schizophrenia patients would show significant deficits on these measures. We next examined the relationship among the executive-functioning working memory measures for both schizophrenia patients and normal control subjects. We predicted that the measures would be moderately correlated with each other. We then statistically controlled for verbal intelligence and for sustained attention capacity while correlating performance among the three measures for the schizophrenia patients. We hypothesized that, given that tests of executive functioning are mediated by central executive processing, there should be moderate relationships among performances across working memory measures for the schizophrenia subjects that are not fully explained by intellectual and attentional functioning. We next correlated the patients' performance on these tests of executive-functioning working memory with symptom factor scores. Given the suggestion that working memory performance and negative may both reflect deficits in the prefrontal cortex, we hypothesized that there should be a significant correlation between test performance and negative even after controlling for possible moderator variables such as intellectual functioning and sustained attention. Method Thirty-seven schizophrenia patients (21 males and 16 females; 22 Caucasian, 8 African-American, 4 Hispanic, 2 Asian, and 1 other) who met the DSM-IV (American Psychiatric Association 1994) criteria for schizophrenia as determined by the use of the SCID-IV conducted by experienced doctoral-level clinicians were included in the study. All diagnostic and exclusion criteria are as described above in Study 1. The schizophrenia patients consisted of the following subtypes: 18 paranoid, 12 undifferentiated, 3 disorganized, and 4 residual. Fourteen patients were recruited from the UCSD inpatient psychiatric service, 7 were recruited from a long-term subacute inpatient facility, and 16 were outpatients from a community day treatment center. Two patients were unmedicated and the mean chlorpromazine equivalents (Kessler and Waletski 1981) for the remaining subjects was 820 mg (SD = 642 mg). A normal comparison group consisting of 34 subjects (25 males and 9 females; 30 Caucasian, 3 African- American, and 1 other) were compared to the schizophrenia patients. The normal comparison subjects were recruited from newspaper advertisements and were screened for the presence of Axis I pathology, substance abuse or dependence, an unstable medical condition, or a history of neurological disorder (e.g., head injury with loss of consciousness). Potential comparison subjects were excluded if they met criteria of an MMPI-based algorithm for identifying substance abuse and psychosis proneness (Butler et al. 1993). The normal comparison subjects were comparable to schizophrenia patients with respect to age. The mean age for the schizophrenia patients was 39.1 years (SD = 8.7) and for the normal comparison subjects 36.6 years (SD = 9.7). The schizophrenia patients were less educated (mean =12.1 years, SD = 1.7) than the normal comparison subjects (mean = 14.0, SD = 2.4) (f[69] = 3.75, p < 0.001). The mean age of onset of illness for the schizophrenia patients was 22.5 years (SD = 5.9). All patients were assessed with the Scale for the Assessment of Negative Symptoms (SANS; Andreasen 1984) and the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen 1984). The SANS and SAPS scores were converted into three-factor scores, which were generated from factor coefficients derived from a principal components factor analysis on a separate sample of 160 schizophrenia patients. The latter analysis revealed a three-factor solution, consisting of a negative symptom factor, a positive symptom-reality testing factor, and a disorganization factor (Cadenhead et al. 1997). After a complete description of the study was given to the subjects, written informed consent was obtained. Subjects were then tested on the Vocabulary subtest from the WAIS-R, the Numerical Attention Test (NAT; Filley et al. 1989), the WCST (Heaton et al. 1993), the Tower of Hanoi (TOH; Loong 1989), and the LNS (Gold et al. 1997). The NAT is a digit cancellation test used to assess psychomotor speed and attention to visual details. The test consists of a page of 1,008 random digits, and the subject is required to cancel all of the 105 number 3s on the page. The test provides a score for psychomotor speed (total time to completion) as well as total errors of omission and commission (sustained attention to detail). The version of the TOH used in this study is a computer-administered complex problem solving and procedural learning test. Successful completion of the task requires the subject to hold information about his or her previous responses in visuospatial "scratch-pad" transient storage, to use self-ordered and procedural learning skills, and to benefit from feedback. This test requires the use of working memory because subjects are required to simultaneously reason logically, maintain a set of rules, and plan future 167

12 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. moves based upon stored outcomes from their immediate past actions. Glosser and Goodglass (1990) have reported that neither age nor education affect performance on the test. The version of the test used in this study consisted of four different discs and three pegs displayed on a computer screen. The discs are placed in a starting configuration on peg number one and the subject is instructed to move the discs, via computer keys, to peg number three without putting a larger disc on top of a smaller disc. The object of this test is to move the four discs from the one peg to the other peg, one disc at a time, with as few moves as possible. The number of total moves to completion was recorded. All subjects were first trained on the three-disc version of the test to make certain that they understood what was expected and were comfortable using the computer. This version of the LNS (Gold et al. 1997) is a prototype of the Letter-Number Sequencing test described in Study 2. The LNS involves the presentation of a series of alternating numbers and letters. The subject is required to repeat the presented number-letter span in rearranged sequential order beginning widi the numbers (from smallest to largest) followed by the letters (alphabetically). The test consists of 24 total items. It begins with four trials starting with a two-item string and proceeds toward a seven-item string of numbers and letters. The test is terminated when a subject fails all four trials at any one string length. The total number of correct responses (out of a possible 24) is calculated for analysis. The WCST is described in Study 3. The one exception to the standard procedure as outlined above is that subjects were administered a 64-card version of the test. WCST perseverative responses and categories achieved (Heaton et al. 1993) were scored and analyzed in this study. Schizophrenia patients were compared to normal comparison subjects on demographic variables, the WAIS-R Vocabulary subtest, NAT, the TOH, and the LNS using Student / tests. Because of the high number of comparisons we conservatively set the alpha criterion to p < Pearson correlation matrices were constructed to examine the relationship among the executive-functioning working memory measures in both groups, and between these measures and symptom rating scales for schizophrenia patients. We next generated two partial correlation matrices for the schizophrenia patients, following the removal of WAIS-R Vocabulary and NAT (number of errors) performance. Collectively, these correlation tables allowed us to address the hypotheses that there are moderate relationships among working memory measures for schizophrenia subjects independent of intellectual and attentional functioning and that there is a significant relationship between executive-functioning working memory measures and negative. Because of the moderate number of correlations conducted and the potential for inflation of Type I error rate we again conservatively set our alpha criterion at p < All analyses were conducted with BMDP 3D, 3S, and 6R (Dixon 1988). Results The schizophrenia patients had fewer years of education (f[69] = -3.75, p < 0.001) and achieved lower WAIS-R Vocabulary subtest scores (f[69] = -3.39, p < 0.01). On NAT, the schizophrenia patients were slower (f[69] = 5.00, p < 0.001) and committed more errors of commission (t[69] = 3.22, p < 0.01) (table 4). On the TOH, one normal comparison subject's data was lost because of computer error, resulting in 33 normal comparison subjects. On this task schizophrenia patients required more moves to completion than did the normal comparison subjects (f[67] = 2.90, p < 0.01). On the LNS, the patients achieved fewer correct responses than did the normal comparison subjects (t[66] = -7.58, p < ). On the WCST, schizophrenia patients committed significantly more perseverative responses than Table 4. Means and standard deviations for demographic, cognitive, and executive-functioning working memory measures for schizophrenia patients (n = 37) and normal comparison subjects (n 34) (Study 4) Numerical Attention Test (time) Numerical Attention Test (errors) Tower of Hanoi (moves) Letter-Number Span (total score) Wisconsin Card Sorting Test (PR for 64 cards) Wisconsin Card Sorting Test (Cat for 64 cards) Schizophrenia patients, mean (SD) (62.5) 8.4 (6.9) 46.2 (21.5) 9.2 (4.2) 22.7(16.3) 1.6(1.2) Normal comparison subjects, mean (SD) 172.7(38.3)" 4.1 (4.0)* 31.5 (20.5)* 16.0(3.1)** 13.1 (11.5) * 3.3(1.4)** Note.Cat = categories completed; PR = perseverative response score; SD = standard deviation. On the TOH, one normal comparison subject's data was lost because of computer error, resulting in 33 normal comparison subjects. *p < 0.01 ;**p<

13 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, 2001 did the normal comparison subjects (f[69] = 2.83, p < 0.01) and completed fewer categories (t[69] = -5.27, p < 0.001). Schizophrenia patients were significantly different from normal comparison subjects in respect to WAIS-R Vocabulary scores, a measure of premorbid intelligence. Therefore, we covaried WAIS-R Vocabulary scores from the executive-functioning working memory measures to determine whether schizophrenia patients remained impaired on executive-functioning working memory tests. Based upon our conservative acceptable significance level (alpha criterion of p < 0.01), covarying WAIS-R Vocabulary scores did not change the results for the TOH (number of moves) (F[l,66] = 4.59, p < 0.05) or for the LNS total (F[l,65] = 40.66, p < ). For WCST perseverative responses, covarying WAIS-R Vocabulary resulted in a nonsignificant difference between schizophrenia patients and normal comparison subjects (F[l,68] = 3.41, p < 0.07), while schizophrenia patients continued to complete significantly fewer categories (F[l,68] = 16.96, p < 0.001). To be conservative we also covaried out years of education, an alternative measure of premorbid intellectual status, from the executive-functioning working memory measures. Covarying did not change the results from that observed with WAIS-R Vocabulary for the TOH (number of moves) (F[l,66] = 4.43, p < 0.05), LNS total (F[l,65] = 36.59, p < ), WCST perseverative responses (F[l,68] = 4.34, p < 0.05), and WCST categories achieved (F[l,68] = 16.56, p < 0.001). It should be noted that even in cases where covarying resulted in a p value that exceeded our conservative acceptance level, the differences between the schizophrenia patients and normal comparison subjects could reasonably be considered a strong trend that nonetheless does not meet the conservative p < 0.01 level of significance. There were significant correlations among the three executive-functioning working memory measures for the schizophrenia patients. The three measures were also moderately correlated with WAIS-R Vocabulary performance. For the normal comparison subjects, the relationships among the executive and working memory measures were similar to those observed with the schizophrenia patients (tables 5A and 5B). The three measures were also moderately correlated with each other as well as with WAIS-R Vocabulary performance. A z test for the difference between two independent correlation coefficients revealed that there were no significant differences between the magnitude of the correlation coefficients for the schizophrenia patients and those for normal comparison subjects on the three tests of executive-functioning working memory. Table 5A. Correlation between WAIS-R Vocabulary and executive-functioning working memory measures in normal comparison subjects (n = 34) (Study 4) WAIS-R Vocabulary NAT (errors) TOH (moves) LNS (total) WCST (PR) WCST (Cat) WAIS-R Vocabulary " NAT (errors) TOH (moves) * LNS (total) * Note.Cat = categories completed; LNS = Letter-Number Span; NAT = Numerical Attention Test; PR = perseverative response score; TOH = Tower of Hanoi; WAIS-R = Wechsler Adult Intelligence Scale-Revised; WCST = Wisconsin Card Sorting Test. *p< 0.01 ;**p< Table 5B. Correlation between WAIS-R Vocabulary and executive-functioning working memory measures in schizophrenia patients (n = 37) (Study 4) WAIS-R Vocabulary NAT (errors) TOH (moves) LNS (total) WCST (PR) WCST (Cat) WAIS-R Vocabulary NAT (errors) TOH (moves) LNS (total) ** * ** Note.Cat = categories completed; LNS = Letter-Number Span; NAT = Numerical Attention Test; PR = perseverative response score; TOH = Tower of Hanoi; WAIS-R = Wechsler Adult Intelligence Scale-Revised; WCST = Wisconsin Card Sorting Test. * p< 0.01 ;**p<

14 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. There was only one significant correlation between a working memory measure (TOH total moves) and (Factor 1, negative ). Most of the remaining correlations with negative, however, were of moderate size and in the expected direction (table 6). To address how intelligence impacts relationships among working memory measures, we partialled out or removed the influence of the WAISR Vocabulary score, using linear regression, from the three working memory measures. This procedure allowed us to examine the relationship of the measures to each other and to, beyond that which can be explained by intelligence. We then reconstructed the correlation matrix. Several of the correlations did not reach statistical significance but were in the same direction as in the previous matrix. The relationship between the three measures and negative appeared to strengthen, as correlations with all three executive-functioning working memory measures reached significance (table 7A). We replicated the above procedure. This time, however, we controlled for the influence of sustained attention by partialling out NAT (total errors) performance from the three executive-functioning working memory measures via linear regression. The relationship between the three executive-functioning working memory measures and negative increased after controlling for the effects of attention (table 7B). Table 6. Correlation between symptom factors and executive-functioning working memory measures in schizophrenia patients (n = 37) (Study 4) NAT (errors) TOH (moves) LNS (total) WCST (PR) WCST (Cat) Factor 1, negative * Factor 2, positive Factor 3, disorganized Note.Cat = categories completed; LNS = Letter-Number Span; NAT = Numerical Attention Test; PR = perseverative response score; TOH = Tower of Hanoi; WCST = Wisconsin Card Sorting Test. *p< Table 7A. Correlations among demographic data, symptom factor scores, and executive-functioning working memory measures for schizophrenia patients after removing the influence of the WAIS-R Vocabulary score (n = 37) (Study 4) Factor 1, negative Factor 1, negative Factor 2, 0.28 positive Factor 3, 0.10 disorganized TOH (moves) 0.61" LNS (total) -0.40* WCST (PR) 0.39* WCST (Cat) Factor 2, positive Factor 3, disorganized TOH (moves) LNS (total) ** Note.Cat = categories completed; LNS = Letter-Number Span; PR = perseverative response score; TOH = Tower of Hanoi; WAIS-R : Wechsler Adult Intelligence Scale-Revised; WCST = Wisconsin Card Sorting Test. * p<0.01 ;"p<

15 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, 2001 Conclusion In this fourth study, the schizophrenia patients performed significantly worse than the normal comparison subjects on the three tests of executive-functioning working memory. There was a moderate relationship among these three measures of executive-functioning working memory. It has been suggested that the underlying relationship of the cognitive mechanisms responsible for working memory performance would be "amplified in disorders (schizophrenia) that compromise working memory" (Gold et al. 1997, p. 164). Our data do not support this position and, in fact, show that the strength of the relationships among these measures for the schizophrenia patients and normal comparison subjects was virtually identical. Furthermore, the three measures of executive-functioning working memory were highly correlated with WAIS-R Vocabulary performance for both the schizophrenia patients and the normal comparison subjects, highlighting the role of verbal intelligence in executive-functioning working memory. This relationship is expected, since encoding of visuospatial and verbal data via strategic planning and the subsequent retention of this information are central to the concept of intelligence (Kyllonen and Christal 1990). The stronger relationship between the LNS and WAIS-R Vocabulary is also expected since both tasks are presented verbally and phonologically processed. The removal of the influence of verbal intelligence shifted some of the correlations of the three executive-functioning working memory tests from satisfying our conservative alpha criterion for statistical significance but did not change the general nature of the relationship between the measures. It appears that although verbal intelligence is highly correlated with executive-functioning working memory, it does not explain the relationship among the working memory measures. Kyllonen and Christal (1990) concluded that reasoning and working memory were closely related to each other but not synonymous, which may be indirectly supported by these data. Future studies that address the question of intelligence and working memory should use several verbal and nonverbal intelligence measures. Sustained attention as measured by NAT did not yield significant correlation coefficients with the measures of executive-functioning working memory, other than for the LNS. The partialling or removal of NAT did not change the interrelationship of the executive-functioning working memory measures. This finding supports the contention of Gold and colleagues (1997), who found that attention and the more complex executive function tasks measure related but different dimensions of working memory. There was a moderate relationship between executive-functioning working memory test performance and negative, which increased following the removal of verbal intelligence and attention. It has been suggested by several authors that impairment in the working memory system may be due to a dysfunction in the prefrontal cortex (Goldman-Rakic 1991; Park and Holtzman 1992; Goldberg et al. 1993; Park et al. 1995). Although the exact underlying mechanism of negative remains somewhat ambiguous, there are numerous studies that have suggested that negative symp- Table 7B. Correlations among demographic data, symptom factor scores, and executive-functioning working memory measures for schizophrenia patients after removing the influence of NAT errors (n = 37) (Study 4) Factor 1, negative Factor 2, positive Factor 3, disorganized TOH (moves) LNS (total) WCST (PR) WCST (Cat) Factor 1, negative " -0.40* 0.40* -0.39* Factor 2, positive Factor 3, disorganized TOH (moves) -0.40* 0.39* -0.65** LNS (total) -0.42* 0.33 Note.Cat = categories completed; LNS = Letter-Number Span; NAT = Numerical Attention Test; PR = perseverative response score; TOH = Tower of Hanoi; WCST = Wisconsin Card Sorting Test. * p<0.01 ;**p<

16 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. toms are related to dysfunction of the frontal lobes (Buchanan et al. 1994; Malloy and Duffy 1994). Thus the present finding of a relationship between executive-functioning working memory performance deficits and negative provides additional indirect support that the prefrontal cortex plays a critical role in mediating executive-functioning working memory. Alternatively, the relationship between and test performance may be nonspecific since negative are related to general neuropsychological impairment (Braff et al. 1991). Discussion Although schizophrenia patients have impaired performance on a number of tests of working memory, the findings from these experiments do not support a dramatic or selective working memory deficit. These results are parallel to our previous report that schizophrenia patients have generalized neuropsychological dysfunction with variable performance on tests of executive function such as the WCST (Braff et al. 1991). The pattern of these results and previous reports support the idea that schizophrenia patients exhibit impaired performance across many neuropsychological domains. Thus, our findings do not support the contention that all schizophrenia patients have dramatic or specific working memory deficits. Future studies, however, are needed to test our new hypothesis emphasizing executive function load or task complexity. Each of the tests used across the four studies represent different layers of complexity intersecting with different cognitive domains of working memory. Illustrating this hierarchy of complexity, on the Digit Span and Spatial Span forward tests and the ACT, the subject must hold information on-line in transient storage but no manipulation of data is required. In contrast, the Digit and Spatial Span backward and LNS tests each require transient on-line storage and manipulation in the absence of visual cues. Finally, during the WCST and the Category Test the subject has access to constant visual cues but is required to retain an underlying principle as well as feedback regarding prior responses in order to solve a problem. Similarly, in the Tower tasks, there are constant visual cues but the subject uses the visuospatial sketch pad to plan out future moves and strategies. Future studies will need to address tests from this perspective of using multiple measures of working memory that range in degree of task difficulty and demand. The schizophrenia literature is replete with investigations using tests of working memory. The working memory tests used in these four studies were selected because they are good examples of tests that are being labeled or developed as measures of working memory and allow us to address our four main questions. We examined whether there are appreciable differences in working memory performance of schizophrenia patients on tasks that require transient storage and recall versus those in which the data is stored online, manipulated, and then recalled. In the present study, multiple heterogeneous groups of schizophrenia patients demonstrated impaired performance on tests of both transient and more complex executive-functioning working memory tasks, without evidence of differentially greater difficulty on the latter tasks. Results In Study 1 we tested patients on the WAIS-R Digit Span forward and backward tasks. We hypothesized that the patients would demonstrate relatively greater impairment on the backward than on the forward portion of the test, when compared to a normal comparison group, since Digit Span backward is thought to increase the load on the working memory system. Our findings, however, did not support this hypothesis. Rather, the results suggest that patients may have general deficits of attention and working memory (broadly considered) rather than a primary selective working memory deficit that becomes increasingly problematic with increasing working memory loads or levels of complexity. It is important, however, to note that the role of working memory load was not specifically tested in these four experiments and future studies will need to consider the role of increasing amounts of information on working memory. Study 2 was designed to address the question of whether schizophrenia patients have differential performance deficits on tasks of auditory versus visual working memory. The findings of our studies are consistent with previous studies (Park and Holtzman 1992; Park et al. 1995; Gold et al. 1997) that have demonstrated that schizophrenia patients have impaired performance on tasks purported to tap visuospatial as well as auditory working memory. Our findings, however, were inconsistent with the view that schizophrenia patients have a selective working memory deficit in one cognitive domain. In Study 3 we hypothesized that there should be a consistent and moderate relationship between performance deficits across a variety of measures that tap into working memory. Furthermore, we hypothesized that the relationship or pattern of the performance of schizophrenia patients on these measures should be stronger than that of normal comparison subjects because of their theoretically selective working memory impairment (Goldman-Rakic 1991; Gold et al. 1997). Our results, using three tasks of executive-functioning working memory, yielded small to moderate correlation coeffi- 172

17 Working Memory Schizophrenia Bulletin, Vol. 27, No. 1, 2001 cients among performances on these three tasks, for both schizophrenia patients and normal comparison subjects. The results revealed no difference between the size of correlations for the two groups. In fact, there was no significant difference between the schizophrenia patients and normal comparison subjects on two of the three executive-functioning working memory measures. The hypothesis of "amplified correlations" among tasks for schizophrenia patients was not supported, suggesting that the impaired performance of schizophrenia patients on these tests of working memory function is multifactorial in nature. In Study 4, we tested a fourth independent sample of schizophrenia patients and normal comparison subjects on three tests of executive-functioning working memory. We found significant differences between the two groups on two of the three measures and moderate interrelationship between these three measures for both the schizophrenia patients and normal comparison subjects. This association between the measures can be explained by a working memory deficit, since successful performance on the TOH, the LNS, and the WCST appears to be dependent, at least in part, upon temporary online storage and the processing of information. Alternatively, there may be a moderating variable, such as task difficulty, combined with a more general cognitive deficit, that accounts for the pattern of correlations. In this regard, we questioned the degree to which working memory performance is related to intelligence, attention, and. The results revealed moderate correlations between WAIS-R Vocabulary performance and the measures of executive-functioning working memory for both the schizophrenia patients and the normal comparison subjects. There was a trend in the schizophrenia patients toward a relationship between working memory performance and negative, which became even stronger once the influence of verbal intelligence was removed. It appears that verbal intelligence, although significantly correlated with working memory performance, is not responsible for the relationship between working memory and. Attention, as measured by NAT (errors), did not correlate significantly with all three measures of executive-functioning working memory and did not influence the relationship between the tests of executive-functioning working memory and. These results do not support the findings of Pantelis and colleagues (Pantelis et al. 1997), who reported a difference in the relationships between different domains of executive-functioning working memory in schizophrenia patients as compared to normal and other pathological subjects. The authors concluded that "this loss of normal relationships" (Pantelis et al. 1997, p. 1823) implied impaired functional connectivity between different regions of the neocortex. Our results, in combination with previous findings, speak to the difficulty of specifying the operational characteristics of the task from the cognitive domain that is theoretically being assessed. Comment and Recommendations Baddeley and Hitch (1974) described the concept of working memory, and there recently has been a burst of scientific activity and accompanying excitement that has supported the hypothesis that the cognitive impairment of schizophrenia patients is primarily because of working memory deficits that are associated with dysfunction of the prefrontal cortex (e.g., Buchanan et al. 1994; Malloy and Duffy 1994). The careful anatomical model of information storage and retrieval conducted by Goldman-Rakic (1987, 1991) and her colleagues on nonhuman primates and the extension of this work on schizophrenia patients by Park and Holzman (1992) have greatly expanded our understanding of the cognitive deficits of schizophrenia patients. Despite the significant contributions of the concept of working memory to understanding schizophrenia, there is a need for caution. First, there remains some disagreement regarding the definition of working memory. Baddeley's original conception of working memory requires both temporary online storage and retrieval and manipulation of information that we have labeled as executive-functioning working memory. Supporting this view, Baddeley suggested that to study working memory without attending to the central executive processes is akin to "a critical analysis of Hamlet that centers its attention on Polonius and completely ignores the Prince" (Baddeley 1986, p. 224). On the other hand, Goldman-Rakic and colleagues have emphasized the transient storage component of working memory without explicitly addressing the role of the manipulation of stored (and to be retrieved) information. Additionally, the nature of the manipulation required by the task may bring into question other cognitive constructs, a critical matter that needs further consideration. For example, the nature of "simple" reordering or sequencing in Digit Span backward or Letter-Number Sequencing is arguably different from the requirements of planning and operational strategy development (Tower tasks), or the deduction and abstraction of underlying principles (WCST and Category Test). Thus, the possibility should be considered that, while schizophrenia patients' performance on these different tasks are correlated, individual patterns of strengths and deficits may reflect differences in underlying brain substrates that may, in rum, impact everyday functioning. Thus, selection of working memory tasks involving either transient online 173

18 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 W. Perry et al. storage or various types of executive function lead us to the more complex issue of reaching a recommendation and consensus on how to define and measure working memory and apply our definitions to the array of tests used presently to measure working memory. Until this is accomplished we recommend that multiple measures be used. Working memory deficits have been assessed in schizophrenia via the utilization of an array of cognitive "candidate tests," ranging from Digit Span and the LNS (Gold et al. 1997) to the WCST (Goldberg et al. 1993). Psychophysiological measures, such as the oculomotor delayed response tasks (Park et al. 1995), have also been described as working memory tasks. Most cognitive tests, however, are multidimensional and, at least for optimal performance, require the integrity of numerous complex neural substrates and cognitive processes. Gold and colleagues (1997) highlight this point in their careful examination of the relationship between the WCST and working memory. They argue that "working memory is a necessary but not sufficient condition for successful WCST performance" (p. 159). We would extend that caveat to all of the comprehensive working memory measures used in our four studies. We agree with Baddeley's (1986) position that working memory is accessed "across a range of tasks involving different processing codes and different input modalities" (p. 35). The construct of "transient on-line" working memory has been used to help understand the core cognitive deficits in schizophrenia (Goldman-Rakic 1991). For the working memory framework to continue to be generative in schizophrenia research, a consensus on the functions of working memory that are most critical (e.g., online storage, varying types of manipulation, and retrieval) must be reached. Delayed response tasks can measure transient online storage, and animal models and functional brain imaging have been used to delineate the prefrontal cortex substrate of this construct. Executive-functioning working memory constructs undoubtedly involve far-reaching neural circuit substrates. The wide use of these extensive executive function tasks as tests of working memory may prove generative but do present profound challenges because of the complexity of the cognitive functions and complex neural substrates involved in executive functions. However, the role of transient online storage in more complex working memory function is unclear. Once working memory is clearly operationalized, cognitive studies can be designed using putative tests of working memory to help explain at least part of the variance in the widespread neurocognitive deficits observed in schizophrenia patients (Braff et al. 1991). Given this ubiquity of deficits it is unlikely that any one neurotransmitter system, any one locus, or any one neurocognitive function (e.g., working memory) will, in isolation, provide necessary and sufficient information for understanding the group of schizophrenia spectrum disorders (Braff 1999). Rather, it seems more prudent to operationalize tasks that tap specified aspects of working memory and use them in a converging measures strategy in conjunction with functional brain imaging in order to understand the neurobiology of schizophrenia (Perry et al. 1999). For now, we strongly suggest that a minimal requirement would be to designate working memory tasks as either transient online storage tasks (simpler construct) or executive-functioning working memory tasks (a very complex, far-reaching, and multifactorial set of constructs). Using a single term (working memory) to apply to such different functions is a potential source of confusion. Also, we must decide how broad the central executive concept should be and how closely linked it should be to the simpler (slave) processes. At its broadest, working memory could be said to underlie virtually every neurobehavioral task (e.g., Vocabulary requires the patient to hold the word on-line, to retrieve associations, and to formulate and check a definition response before giving the response orally). As the field advances and working memory tasks are combined with other cognitive measures and functional brain imaging, these two labels will hopefully prove generative and lead to new iterations and understandings of the cognitive deficits in schizophrenia patients. References American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: APA, American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: APA, Andreasen, N.C. 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