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Association between Striatal Reduction and Poor Wisconsin Card Sorting Test Performance in Patients with Schizophrenia
Association between Striatal Reduction and Poor Wisconsin Card Sorting Test Performance in Patients with Schizophrenia Paolo Stratta, Fabrizio Mancini, Paolo Mattei, Enrico Daneluzzo, Massimo Casacchia, and Alessandro Rossi
Several findings support the hypothesis that the striatum is implicated in executive functions and in the modulation of goal-directed behavior, and could play a key role in the pathophysiology and in the production of symptoms and signs in schizophrenia. We have studied the relationship between the objective measures of the striatal structures, as evaluated by magnetic resonance imaging (MRI), and the Wisconsin Card Sorting Test (WCST) performance in a schizophrenic sample. Thirty-five schizophrenic patients underwent MRI scans of striatal structure and neuropsychological evaluation of executive functions by WCST. Poor WCST performers had a reduction of the left caudate nucleus and putamen, and right total striatum when compared to 24 healthy controls. Significant correlation coefficients were also observed between neuropsychological indexes and left striatal measures. The findings suggest the existence of a relationship between abnormalities of striatal structure and abnormal executive-type or organizational cognitive functions. © 1997 Society of Biological Psychiatry Key Words: Striatum, magnetic resonance imaging, neuropsychology, wisconsin card sorting test, schizophrenia BIOL PSYCHIATRY 1997;42:816 – 820
Introduction Existing evidence suggests that the striatum, classically considered a component of the motor system, is implicated in executive functions and in the modulation of goaldirected behavior (Marsden 1980, 1982; Rolls and WilFrom the Department of Psychiatry, S. Salvatore Hospital, L’Aquila, Italy (PS); and Department of Clinical Psychiatry, University of L’Aquila, Institute of Experimental Medicine, L’Aquila, Italy (FM, PM, ED, MC, AR). Address reprint requests to Dr. Paolo Stratta, Dipartimento di Psichiatria, c/o Ospedale S. Salvatore, 67100 L’Aquila, Italy. Received May 8, 1995; revised October 10, 1996.
© 1997 Society of Biological Psychiatry
liams 1987). A body of findings from neuromorphological (McKenna 1987), neurophysiological (Braff and Geyer 1990), and neuropsychological (Gray et al 1991) studies support the hypothesis that the striatum could play a key role in the pathophysiology and in the production of symptoms and signs in schizophrenia. Impairment in executive functioning is a well-documented phenomenon in schizophrenia (Taylor and Abrams 1984; Goldman et al 1991) significantly associated with disability (Jaeger and Douglas 1992; Bilder 1992). The Wisconsin Card Sorting Test (WCST) is a neuropsycho0006-3223/97/$17.00 PII S0006-3223(97)00017-6
Striatum and WCST in Schizophrenia
logical device that evaluates functions dealing with organizational processes, executive functioning, and problem solving strategies, primarily involved in goal-directed behaviors (Lezak 1983). On the basis of the hypothesis that neuromorphological variables have a direct impact on cognitive performance, we have studied the relationship between the objective measure of the striatal structure, as evaluated by magnetic resonance imaging (MRI), and the WCST performance in a schizophrenic sample.
Methods Subjects The index group consisted of 35 consecutively admitted schizophrenic patients (9 women, 26 men; mean age 34.06 6 7.54 years; mean length of illness 11.97 6 6.58 years) and 24 healthy control subjects (7 women, 17 men; mean age 32.00 6 4.96 years) chosen from the employees and relatives of the hospital staff, individually matched for age, sex, and educational level. All subjects were righthanded according to the Edinburgh Inventory (Oldfield 1971). Subjects were excluded if they had any history of alcohol or drug abuse, neurological or physical disease, morphological insults to the brain, or had any surgical metal or electronic implants that could interfere with MRI evaluation. Healthy controls were also screened for any current or past history of psychiatric disorders. All patients were taking neuroleptics, and the mean chlorpromazine-equivalent dose (Kessler and Waletzky 1981) was 905.77 6 684.37.
MRI Protocol All subjects were examined with a 0.25-T Ansaldo MRI scanner. An initial 3-mm sagittal series was used for slice orientation, identifying the anterior commissure (AC)– posterior commissure (PC) line. The anterior and posterior commissures of the brain are easily visible on a midsagittal inversion recovery (IR) image [repetition time (TR) 300 msec, echo time (TE) 20 msec]. The AC–PC line was then traced on the console. From this line, six subsequent coronal sections (TR 1500 msec, TE 38 msec, 5 mm thick, 1 mm interslice gap) perpendicular to the AC–PC line were taken. The adoption of such reference lines allowed us to identify the neuroanatomical structures relevant to our research with the assistance of the Talairach atlas (Talairach and Tournoux 1988) widely used in several MR localization studies (Vanier et al 1987; Steinmetz et al 1989, 1990). This is an attempt to standardize brain position in all subjects and thus to standardize a method of measurement of specific subcortical structures.
BIOL PSYCHIATRY 1997;42:816 – 820
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Neuroanatomical Measurements The striatal structures, caudate nucleus, the putamen, and the nucleus accumbens were identified on the brain atlas and traced and drawn on a transparent overlay by two of the authors (A.R. and F.M.) (for a more detailed description see Rossi et al 1994). The putamen was measured together with the nucleus accumbens in 7 subjects, because of the difficulty in separating the two structures. Independent measures of these two striatal structures were eventually obtained for only 28 schizophrenics. Brain structure areas from film and transparent overlay were obtained with a semiautomated image analyzer (Eidoips by Eidosoft, Milan; a full set of information about this image analysis is available from us on request). In brief, to obtain measurable images, a binarization of the regions of interest was obtained by contrast enhancement. Area measurements were made independently by two of the authors (A.R. and F.M.), who were unaware of the diagnosis. The measurements used in subsequent calculations were the average of the two evaluations. Intra- and interrater reliabilities were strong (r 5 .92 and .88, respectively). The volumes of the striatal structures were then determined by summing these areas and multiplying them by the thickness of the slice and expressed in cubic centimeters. These volumes were also summed to obtain a global measurement of the target region.
Neuropsychological Procedure The WCST was administered to patients in a stable state of illness, the day after the MRI evaluation, just before discharge, according to the standard instructions described by Heaton (Heaton 1981). The schizophrenic sample was divided into good and poor performers on the basis of the number of categories achieved in WCST: four or more categories achieved were considered to be a successful performance as recommended by Seidman et al (1992).
Statistical Analysis Neuromorphological measures in cubic centimeters were log transformed to obtain an acceptable Gaussian distribution. The striatal measures of schizophrenics were stratified on the basis of good or poor performance in WCST. Multivariate analysis of variance (MANOVA) was used to explore group and hemisphere differences (Statistical Package for Social Sciences, SPSS, Norusis 1992). When Hotelling’s T statistic was significant in the MANOVA, we proceeded to examine the two-way ANOVA (analysis
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Table 1. Magnetic Resonance Imaging Measuresa of Striatum for Schizophrenics with Poor and Good Performance, and Healthy Controls Two-way mixed Analysis of Variance
Caudate Nucleus R L Putamen R L Accumbens R L Putamen 1 accumbens R L Total striatum R L
Poor WCST (n 5 23)
Good WCST (n 5 12)
Healthy controls (n 5 24)
Group factor
Side factor
Group 3 side interaction
6.75 6 0.30 (23) 6.63 6 0.26 (23)b
6.82 6 0.31 (12) 6.73 6 0.19 (12)
6.94 6 0.20 (24) 6.82 6 0.28 (24)
F 5 3.63 p 5 .03
F 5 15.24 p 5 .000
F 5 0.13 p 5 .87
4.82 6 3.34 (21) 3.85 6 1.17 (21)b,c
5.67 6 0.44 (7) 5.67 6 0.64 (7)
5.52 6 0.86 (24) 5.50 6 0.70 (24)
F 5 2.62 p 5 .08
F 5 1.42 p 5 .23
F 5 1.92 p 5 .15
4.78 6 0.63 (21) 4.92 6 0.49 (21)
5.18 6 0.30 (7) 5.33 6 0.34 (7)
5.06 6 0.52 (24) 5.07 6 0.45 (24)
F 5 2.20 p 5 .12
F 5 3.18 p 5 .08
F 5 0.93 p 5 .40
5.79 6 0.80 (23)c 5.82 6 0.71 (23)c
6.20 6 0.31 (12) 6.35 6 0.41 (12)
6.05 6 0.61 (24) 6.05 6 0.48 (24)
F 5 2.69 p 5 .07
F 5 1.23 p 5 .27
F 5 0.62 p 5 .54
7.14 6 0.30 (23)b 7.04 6 0.33 (23)
7.26 6 0.24 (12) 7.27 6 0.20 (12)
7.33 6 0.18 (24) 7.24 6 0.24 (24)
F 5 4.06 p 5 .02
F 5 7.97 p 5 .007
F 5 1.98 p 5 .14
In parentheses are the number of subjects who could be evaluated. a Measures are log transformed. b Schizophrenics poor WCST , healthy controls at .05 level, post hoc analysis, Scheffe procedure. c Schizophrenics poor WCST , schizophrenics good WCST at .05 level, post hoc analysis, Scheffe procedure.
of variance) results for each striatal structure separately. The ANOVA used a between-subject factor of diagnosis (poor performer–schizophrenics, good performer–schizophrenics, and controls) and a within-subject factor of hemisphere (left vs. right). Predetermined post hoc analyses by Scheffe procedure were conducted separately for right and left striatal measures. Student’s t test for unpaired data, chi-squared test, and Pearson’s Product–Moment Correlation Coefficient (r) for correlation analysis were used when appropriate. All analyses yielding a p value of # .05 were considered significant.
Results Twelve of the 35 patients evaluated by the WCST achieved successful performance. No differences were found between poor and good WCST performers in age (poor WCST 33.83 6 6.83 and good WCST 34.17 6 8.03; t 5 .13, ns), length of illness (poor WCST 12.25 6 6.74 and good WCST 11.82 6 6.65; t 5 .18, ns), or sex distribution (M/F: poor WCST 10/2 and good WCST 16/7; x2 5 .82, ns). The MANOVA results indicated that the average volumes of caudate nucleus and putamen–accumbens structures were significantly different between groups (Hotellings 5 0.21, p 5 .02) and hemispheres with larger
right-sided structures (Hotellings 5 0.27, p 5 .001), but no interaction was seen (Hotellings 5 0.03, ns). As previously described (see neuroanatomical measurements paragraph) we used the putamen–accumbens measure obtained from all the patient group in this analysis instead of the two separate measurements available only from 28 patients. The analysis of variance has revealed that the poor WCST performers, 23 patients, had a reduction of the striatum complex and caudate nucleus with respect to controls (Table 1). A highly significant side factor was also evidenced, but no interaction was observed. Appreciable trends toward significant group factor were observed for putamen and putamen–accumbens structures (p 5 .08 and p 5 .07 respectively). Poor WCST schizophrenic performers showed a significant reduction of left caudate nucleus and putamen, and in the right total striatum compared to healthy controls. Left putamen and putamen–accumbens complex were significantly smaller compared to good WCST schizophrenic performers who also reported higher mean values than healthy controls. Significant correlation coefficients were found between the number of WCST categories achieved and left striatum and putamen–accumbens complex (r 5 .36 and r 5 .39, respectively; p , .05); unique responses inversely correlated with left putamen, accumbens, and putamen–accumbens (r 5 2.48, p , .01; r 5 2.42, p , .05; and r 5
Striatum and WCST in Schizophrenia
BIOL PSYCHIATRY 1997;42:816 – 820
Table 2. Pearson’s Product–Moment Coefficients between WCST Performance and Striatal Measures in Schizophrenics
Total striatum (35) R L Caudate nucleus (35) R L Putamen (28) R L Accumbens (28) R L Putamen 1 accumbens (35) R L
Achieved categories
Perseverative errors
Unique responses
.20 .36a
2.01 .04
2.17 2.31
.09 .22
2.24 2.15
2.02 2.10
.25 .31
.26 .28
2.35 2.48b
.27 .30
.09 2.00
2.30 2.42a
.20 .24
2.30 2.46b
.28 .39a
In parentheses are the number of evaluated subjects. a p , .05. b p , .01.
2.46, p , .01, respectively). Perserverative errors correlated poorly with striatal measures (Table 2). Patients with good WCST performance were given a lower dosage of neuroleptics than poor performers, but the difference between the two groups of patients was not statistically significant (mean chlorpromazine-equivalent dose: poor performers 1019.80 6 704.39 vs. good performers 698.45 6 623.74; t 5 1.33, df 5 33, p , .20).
Discussion Our findings provide support for a possible relationship between poor performance on WCST, as an index of executive-type or organizational cognitive functions, and abnormalities of striatal structure in schizophrenia. The WCST is a neuropsychological device that is considered to be quite sensitive to a prefrontal deficit (Milner 1963; Weinberger et al 1986), but the specificity of such a deficit has not been uniformly replicated (Robinson et al 1980; Anderson et al 1991). It is probable that complex higher cognitive functions, evaluated by WCST, involve a network of neural interconnections (Frith and Done 1988; Weinberger 1993; Goldberg et al 1994). A defect in one part of this network could result in a dysfunctional reverberation throughout the network. This pathway involves cerebral regions, rich in dopaminergic terminals, particularly in striatal structures. Other
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authors further addressed the issue of dopamine (DA) involvement in the cognitive impairment of schizophrenia (Frith and Done 1988; Gray et al 1991). Although speculatively, if structural reduction can be regarded as a hypofunction, our data are in agreement with the hypothesis of a decreased striatal DA activity in some schizophrenic patients with cognitive deficit, and in other neurocognitive disorders (Bermanzohn and Siris 1992; Lee et al 1994). Furthermore, the involvement of the left-sided striatal structures we observed could be considered an anomaly of the striatopallidal system leading to a dopaminergic dysregulation in schizophrenia, in agreement with Early’s hypothesis (Early et al 1989a, 1989b). To our knowledge no other studies have addressed the issue of the relationship between cognitive functions and basal ganglia morphology in schizophrenia, even though quite recently the effects of antipsychotic drugs on basal ganglia morphology and the mediating effects of these structures on drug efficacy have been explored (Bilder et al 1994). We did not find a significant increase in striatal structures in our schizophrenic patients, as reported by other studies (Heckers et al 1990, 1991; Chakos et al 1994; Elkashef et al 1994); however, larger dimensions of putamen and accumbens in good WCST performer schizophrenics compared with controls were observed. These patients also assumed lower mean dosages of neuroleptics, thereby not confirming the hypothesis of Chakos et al (1994) of an interaction between neuroleptic treatment and the plasticity of the dopaminergic neuronal system. Several limitations of the study have to be considered. The number of the subjects studied was relatively small. The high costs and intensive elaboration of imaging technologies such as MRI often led investigators to limit sample sizes, so that statistical data become rather limited. This may have affected our results. The correlation findings we have reported have to be considered exploratory and the amount of variance they account for relatively small (r2 range .12–.23). The findings we reported require replication before further theorizing about their substantive significance; nevertheless, they suggest an intriguing “structure–function” pattern. Further work is needed to better characterize the extent and localization of the pathological anatomy in schizophrenia and to bridge the gap between neuroanatomical and neuropsychological research, enhancing our neurobehavioral knowledge of schizophrenia.
This research was supported in part by a 40% (1993, n.940386) grant to Professor Casacchia and 60% (1994) grant to Professor Rossi from the Ministero della Pubblica Istruzione, Italy.
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Several findings support the hypothesis that the striatum is implicated in executive functions and in the modulation of goal-directed behavior, and could play a key role in the pathophysiology and in the production of symptoms and signs in schizophrenia. We have studied the relationship between the objective measures of the striatal structures, as evaluated by magnetic resonance imaging (MRI), and the Wisconsin Card Sorting Test (WCST) performance in a schizophrenic sample. Thirty-five schizophrenic patients underwent MRI scans of striatal structure and neuropsychological evaluation of executive functions by WCST. Poor WCST performers had a reduction of the left caudate nucleus and putamen, and right total striatum when compared to 24 healthy controls. Significant correlation coefficients were also observed between neuropsychological indexes and left striatal measures. The findings suggest the existence of a relationship between abnormalities of striatal structure and abnormal executive-type or organizational cognitive functions. © 1997 Society of Biological Psychiatry Key Words: Striatum, magnetic resonance imaging, neuropsychology, wisconsin card sorting test, schizophrenia BIOL PSYCHIATRY 1997;42:816 – 820
Introduction Existing evidence suggests that the striatum, classically considered a component of the motor system, is implicated in executive functions and in the modulation of goaldirected behavior (Marsden 1980, 1982; Rolls and WilFrom the Department of Psychiatry, S. Salvatore Hospital, L’Aquila, Italy (PS); and Department of Clinical Psychiatry, University of L’Aquila, Institute of Experimental Medicine, L’Aquila, Italy (FM, PM, ED, MC, AR). Address reprint requests to Dr. Paolo Stratta, Dipartimento di Psichiatria, c/o Ospedale S. Salvatore, 67100 L’Aquila, Italy. Received May 8, 1995; revised October 10, 1996.
© 1997 Society of Biological Psychiatry
liams 1987). A body of findings from neuromorphological (McKenna 1987), neurophysiological (Braff and Geyer 1990), and neuropsychological (Gray et al 1991) studies support the hypothesis that the striatum could play a key role in the pathophysiology and in the production of symptoms and signs in schizophrenia. Impairment in executive functioning is a well-documented phenomenon in schizophrenia (Taylor and Abrams 1984; Goldman et al 1991) significantly associated with disability (Jaeger and Douglas 1992; Bilder 1992). The Wisconsin Card Sorting Test (WCST) is a neuropsycho0006-3223/97/$17.00 PII S0006-3223(97)00017-6
Striatum and WCST in Schizophrenia
logical device that evaluates functions dealing with organizational processes, executive functioning, and problem solving strategies, primarily involved in goal-directed behaviors (Lezak 1983). On the basis of the hypothesis that neuromorphological variables have a direct impact on cognitive performance, we have studied the relationship between the objective measure of the striatal structure, as evaluated by magnetic resonance imaging (MRI), and the WCST performance in a schizophrenic sample.
Methods Subjects The index group consisted of 35 consecutively admitted schizophrenic patients (9 women, 26 men; mean age 34.06 6 7.54 years; mean length of illness 11.97 6 6.58 years) and 24 healthy control subjects (7 women, 17 men; mean age 32.00 6 4.96 years) chosen from the employees and relatives of the hospital staff, individually matched for age, sex, and educational level. All subjects were righthanded according to the Edinburgh Inventory (Oldfield 1971). Subjects were excluded if they had any history of alcohol or drug abuse, neurological or physical disease, morphological insults to the brain, or had any surgical metal or electronic implants that could interfere with MRI evaluation. Healthy controls were also screened for any current or past history of psychiatric disorders. All patients were taking neuroleptics, and the mean chlorpromazine-equivalent dose (Kessler and Waletzky 1981) was 905.77 6 684.37.
MRI Protocol All subjects were examined with a 0.25-T Ansaldo MRI scanner. An initial 3-mm sagittal series was used for slice orientation, identifying the anterior commissure (AC)– posterior commissure (PC) line. The anterior and posterior commissures of the brain are easily visible on a midsagittal inversion recovery (IR) image [repetition time (TR) 300 msec, echo time (TE) 20 msec]. The AC–PC line was then traced on the console. From this line, six subsequent coronal sections (TR 1500 msec, TE 38 msec, 5 mm thick, 1 mm interslice gap) perpendicular to the AC–PC line were taken. The adoption of such reference lines allowed us to identify the neuroanatomical structures relevant to our research with the assistance of the Talairach atlas (Talairach and Tournoux 1988) widely used in several MR localization studies (Vanier et al 1987; Steinmetz et al 1989, 1990). This is an attempt to standardize brain position in all subjects and thus to standardize a method of measurement of specific subcortical structures.
BIOL PSYCHIATRY 1997;42:816 – 820
817
Neuroanatomical Measurements The striatal structures, caudate nucleus, the putamen, and the nucleus accumbens were identified on the brain atlas and traced and drawn on a transparent overlay by two of the authors (A.R. and F.M.) (for a more detailed description see Rossi et al 1994). The putamen was measured together with the nucleus accumbens in 7 subjects, because of the difficulty in separating the two structures. Independent measures of these two striatal structures were eventually obtained for only 28 schizophrenics. Brain structure areas from film and transparent overlay were obtained with a semiautomated image analyzer (Eidoips by Eidosoft, Milan; a full set of information about this image analysis is available from us on request). In brief, to obtain measurable images, a binarization of the regions of interest was obtained by contrast enhancement. Area measurements were made independently by two of the authors (A.R. and F.M.), who were unaware of the diagnosis. The measurements used in subsequent calculations were the average of the two evaluations. Intra- and interrater reliabilities were strong (r 5 .92 and .88, respectively). The volumes of the striatal structures were then determined by summing these areas and multiplying them by the thickness of the slice and expressed in cubic centimeters. These volumes were also summed to obtain a global measurement of the target region.
Neuropsychological Procedure The WCST was administered to patients in a stable state of illness, the day after the MRI evaluation, just before discharge, according to the standard instructions described by Heaton (Heaton 1981). The schizophrenic sample was divided into good and poor performers on the basis of the number of categories achieved in WCST: four or more categories achieved were considered to be a successful performance as recommended by Seidman et al (1992).
Statistical Analysis Neuromorphological measures in cubic centimeters were log transformed to obtain an acceptable Gaussian distribution. The striatal measures of schizophrenics were stratified on the basis of good or poor performance in WCST. Multivariate analysis of variance (MANOVA) was used to explore group and hemisphere differences (Statistical Package for Social Sciences, SPSS, Norusis 1992). When Hotelling’s T statistic was significant in the MANOVA, we proceeded to examine the two-way ANOVA (analysis
818
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BIOL PSYCHIATRY 1997;42:816 – 820
Table 1. Magnetic Resonance Imaging Measuresa of Striatum for Schizophrenics with Poor and Good Performance, and Healthy Controls Two-way mixed Analysis of Variance
Caudate Nucleus R L Putamen R L Accumbens R L Putamen 1 accumbens R L Total striatum R L
Poor WCST (n 5 23)
Good WCST (n 5 12)
Healthy controls (n 5 24)
Group factor
Side factor
Group 3 side interaction
6.75 6 0.30 (23) 6.63 6 0.26 (23)b
6.82 6 0.31 (12) 6.73 6 0.19 (12)
6.94 6 0.20 (24) 6.82 6 0.28 (24)
F 5 3.63 p 5 .03
F 5 15.24 p 5 .000
F 5 0.13 p 5 .87
4.82 6 3.34 (21) 3.85 6 1.17 (21)b,c
5.67 6 0.44 (7) 5.67 6 0.64 (7)
5.52 6 0.86 (24) 5.50 6 0.70 (24)
F 5 2.62 p 5 .08
F 5 1.42 p 5 .23
F 5 1.92 p 5 .15
4.78 6 0.63 (21) 4.92 6 0.49 (21)
5.18 6 0.30 (7) 5.33 6 0.34 (7)
5.06 6 0.52 (24) 5.07 6 0.45 (24)
F 5 2.20 p 5 .12
F 5 3.18 p 5 .08
F 5 0.93 p 5 .40
5.79 6 0.80 (23)c 5.82 6 0.71 (23)c
6.20 6 0.31 (12) 6.35 6 0.41 (12)
6.05 6 0.61 (24) 6.05 6 0.48 (24)
F 5 2.69 p 5 .07
F 5 1.23 p 5 .27
F 5 0.62 p 5 .54
7.14 6 0.30 (23)b 7.04 6 0.33 (23)
7.26 6 0.24 (12) 7.27 6 0.20 (12)
7.33 6 0.18 (24) 7.24 6 0.24 (24)
F 5 4.06 p 5 .02
F 5 7.97 p 5 .007
F 5 1.98 p 5 .14
In parentheses are the number of subjects who could be evaluated. a Measures are log transformed. b Schizophrenics poor WCST , healthy controls at .05 level, post hoc analysis, Scheffe procedure. c Schizophrenics poor WCST , schizophrenics good WCST at .05 level, post hoc analysis, Scheffe procedure.
of variance) results for each striatal structure separately. The ANOVA used a between-subject factor of diagnosis (poor performer–schizophrenics, good performer–schizophrenics, and controls) and a within-subject factor of hemisphere (left vs. right). Predetermined post hoc analyses by Scheffe procedure were conducted separately for right and left striatal measures. Student’s t test for unpaired data, chi-squared test, and Pearson’s Product–Moment Correlation Coefficient (r) for correlation analysis were used when appropriate. All analyses yielding a p value of # .05 were considered significant.
Results Twelve of the 35 patients evaluated by the WCST achieved successful performance. No differences were found between poor and good WCST performers in age (poor WCST 33.83 6 6.83 and good WCST 34.17 6 8.03; t 5 .13, ns), length of illness (poor WCST 12.25 6 6.74 and good WCST 11.82 6 6.65; t 5 .18, ns), or sex distribution (M/F: poor WCST 10/2 and good WCST 16/7; x2 5 .82, ns). The MANOVA results indicated that the average volumes of caudate nucleus and putamen–accumbens structures were significantly different between groups (Hotellings 5 0.21, p 5 .02) and hemispheres with larger
right-sided structures (Hotellings 5 0.27, p 5 .001), but no interaction was seen (Hotellings 5 0.03, ns). As previously described (see neuroanatomical measurements paragraph) we used the putamen–accumbens measure obtained from all the patient group in this analysis instead of the two separate measurements available only from 28 patients. The analysis of variance has revealed that the poor WCST performers, 23 patients, had a reduction of the striatum complex and caudate nucleus with respect to controls (Table 1). A highly significant side factor was also evidenced, but no interaction was observed. Appreciable trends toward significant group factor were observed for putamen and putamen–accumbens structures (p 5 .08 and p 5 .07 respectively). Poor WCST schizophrenic performers showed a significant reduction of left caudate nucleus and putamen, and in the right total striatum compared to healthy controls. Left putamen and putamen–accumbens complex were significantly smaller compared to good WCST schizophrenic performers who also reported higher mean values than healthy controls. Significant correlation coefficients were found between the number of WCST categories achieved and left striatum and putamen–accumbens complex (r 5 .36 and r 5 .39, respectively; p , .05); unique responses inversely correlated with left putamen, accumbens, and putamen–accumbens (r 5 2.48, p , .01; r 5 2.42, p , .05; and r 5
Striatum and WCST in Schizophrenia
BIOL PSYCHIATRY 1997;42:816 – 820
Table 2. Pearson’s Product–Moment Coefficients between WCST Performance and Striatal Measures in Schizophrenics
Total striatum (35) R L Caudate nucleus (35) R L Putamen (28) R L Accumbens (28) R L Putamen 1 accumbens (35) R L
Achieved categories
Perseverative errors
Unique responses
.20 .36a
2.01 .04
2.17 2.31
.09 .22
2.24 2.15
2.02 2.10
.25 .31
.26 .28
2.35 2.48b
.27 .30
.09 2.00
2.30 2.42a
.20 .24
2.30 2.46b
.28 .39a
In parentheses are the number of evaluated subjects. a p , .05. b p , .01.
2.46, p , .01, respectively). Perserverative errors correlated poorly with striatal measures (Table 2). Patients with good WCST performance were given a lower dosage of neuroleptics than poor performers, but the difference between the two groups of patients was not statistically significant (mean chlorpromazine-equivalent dose: poor performers 1019.80 6 704.39 vs. good performers 698.45 6 623.74; t 5 1.33, df 5 33, p , .20).
Discussion Our findings provide support for a possible relationship between poor performance on WCST, as an index of executive-type or organizational cognitive functions, and abnormalities of striatal structure in schizophrenia. The WCST is a neuropsychological device that is considered to be quite sensitive to a prefrontal deficit (Milner 1963; Weinberger et al 1986), but the specificity of such a deficit has not been uniformly replicated (Robinson et al 1980; Anderson et al 1991). It is probable that complex higher cognitive functions, evaluated by WCST, involve a network of neural interconnections (Frith and Done 1988; Weinberger 1993; Goldberg et al 1994). A defect in one part of this network could result in a dysfunctional reverberation throughout the network. This pathway involves cerebral regions, rich in dopaminergic terminals, particularly in striatal structures. Other
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authors further addressed the issue of dopamine (DA) involvement in the cognitive impairment of schizophrenia (Frith and Done 1988; Gray et al 1991). Although speculatively, if structural reduction can be regarded as a hypofunction, our data are in agreement with the hypothesis of a decreased striatal DA activity in some schizophrenic patients with cognitive deficit, and in other neurocognitive disorders (Bermanzohn and Siris 1992; Lee et al 1994). Furthermore, the involvement of the left-sided striatal structures we observed could be considered an anomaly of the striatopallidal system leading to a dopaminergic dysregulation in schizophrenia, in agreement with Early’s hypothesis (Early et al 1989a, 1989b). To our knowledge no other studies have addressed the issue of the relationship between cognitive functions and basal ganglia morphology in schizophrenia, even though quite recently the effects of antipsychotic drugs on basal ganglia morphology and the mediating effects of these structures on drug efficacy have been explored (Bilder et al 1994). We did not find a significant increase in striatal structures in our schizophrenic patients, as reported by other studies (Heckers et al 1990, 1991; Chakos et al 1994; Elkashef et al 1994); however, larger dimensions of putamen and accumbens in good WCST performer schizophrenics compared with controls were observed. These patients also assumed lower mean dosages of neuroleptics, thereby not confirming the hypothesis of Chakos et al (1994) of an interaction between neuroleptic treatment and the plasticity of the dopaminergic neuronal system. Several limitations of the study have to be considered. The number of the subjects studied was relatively small. The high costs and intensive elaboration of imaging technologies such as MRI often led investigators to limit sample sizes, so that statistical data become rather limited. This may have affected our results. The correlation findings we have reported have to be considered exploratory and the amount of variance they account for relatively small (r2 range .12–.23). The findings we reported require replication before further theorizing about their substantive significance; nevertheless, they suggest an intriguing “structure–function” pattern. Further work is needed to better characterize the extent and localization of the pathological anatomy in schizophrenia and to bridge the gap between neuroanatomical and neuropsychological research, enhancing our neurobehavioral knowledge of schizophrenia.
This research was supported in part by a 40% (1993, n.940386) grant to Professor Casacchia and 60% (1994) grant to Professor Rossi from the Ministero della Pubblica Istruzione, Italy.
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