Association between cognitive performance and striatal dopamine binding is higher in timing and motor tasks in patients with schizophrenia

Psychiatry Research: Neuroimaging 131 (2004) 209 – 216 www.elsevier.com/locate/psychresns

Association between cognitive performance and striatal dopamine binding is higher in timing and motor tasks in patients with schizophrenia Yen Kuang Yang a,*, Tzung Lieh Yeh a, Nan Tsing Chiu b, I Hui Lee a, Po See Chen a, Li-Ching Lee c, Keith J. Jeffries d a

Department of Psychiatry, College of Medicine, National Cheng Kung University and University Hospital, 138 Sheng Li Road, Tainan 70428, Taiwan b Department of Nuclear Medicine, College of Medicine, National Cheng Kung University and University Hospital, Tainan, Taiwan c Department of Epidemiology, John Hopkins University School of Public Health, Baltimore, MD, USA d National Institutes of Health, Bethesda, MD, USA Received 14 November 2001; received in revised form 25 October 2002; accepted 21 July 2003

Abstract The basal ganglia have received increasing attention with regard to their role in time pacing, motor function and other components of cognition. The aim of this study was to test whether the finer the motor activity and/or time perception performance were, the higher the striatal dopamine D2 binding would be. Single photon emission computed tomography (SPECT) with [123I]iodobenzamide (IBZM) was performed to measure striatal D2 receptor densities. A battery of neuropsychological tests, including the Wisconsin Card Sorting Test (WCST), the finger tapping test (FTT), and an attention test, was performed by patients with schizophrenia. Results indicated a strong correlation between the FTT score and striatal D2 receptor binding. Neuroleptic dosage plays an important role in the relationship between cognitive tasks and striatal dopamine receptor densities. In addition, the striatal D2 receptor density is more significantly correlated with attentional tests that consider the time effect than those that do not. Among the three tests performed, the WCST was least significantly correlated with striatal D2 receptor densities. A decrease in striatal dopamine D2 receptor density seems to be associated with impaired performance on optimal timing tasks and motor processing in patients with schizophrenia. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Cognitive function; Striatal D2 receptor density; Neuroleptics; Schizophrenia

1. Introduction Schizophrenia is a disorder characterized by positive symptoms, negative symptoms, and cognitive * Corresponding author. Tel.: +886-6-276-6188; fax: +886-6275-9259. E-mail address: [email protected] (Y.K. Yang).

impairment. However, the mechanisms that underlie the clinical symptomatology and cognitive impairments of schizophrenia are still not well understood, particularly at the neurobiological level. The prefrontal cortex is critical for cognitive processes. Dopamine can exert a neuromodulatory influence on the cognitive functions of the prefrontal cortex (Kahn et al., 1994; Braver et al., 1999). It has been postulated that the

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cortico-striato-thalamic cortical circuit plays an important role in processing information (Andreasen et al., 1999). In the cognitive system involved in this circuit, some mechanism is needed to guide, coordinate, and update behaviors in a flexible fashion—particularly in many novel or complex tasks. The literature on cognitive function in schizophrenia points to impairments in a set of basic cognitive functions, including attentional deficit and executive function impairment (Braver et al., 1999). Cortical deficits may have a significant impact on the functions of the subcortical structure. Studies suggest that the striatal region functions at the level of a motor – limbic interface (Mogenson et al., 1980; Jentsch et al., 2000) and that it is involved in schizophrenia (Pantelis et al., 1997). Imaging studies implicate the basal ganglia in perceptual timekeeping processes (Jueptner et al., 1995; Meck, 1996; Harrington et al., 1998a). In addition, time-dependent attention may also contribute to temporal perception deficits observed after damage to cortical networks (Harrington et al., 1998b). However, temporal processing of short duration (in the ms range) appears to be beyond cortical control and modulated by dopaminergic activity in the basal ganglia (Rammsayer, 1999). Therefore, it is reasonable to speculate that the basal ganglia play an important role in cognitive functions, particularly those related to time perception and motor activity (Graybiel, 1997). Lawrence et al. (1998) demonstrated that both striatal dopamine receptor levels and cognitive performance were lower in asymptomatic individuals with Huntington’s disease. In addition, performance of cognitive tasks was found to correlate with striatal D2 receptor binding (Volkow et al., 1998). It has also been demonstrated that grafts of embryonic striatal tissue can improve both motor and cognitive function in some patients with Parkinson’s or Huntington’s disease (Dunnett, 1999; Bachoud-Levi et al., 2000). The contribution of striatal dopaminergic function in the pathogenesis of schizophrenia and to the performance of some cognitive functions has long attracted investigative interest. However, few studies have explored the relationship between striatal dopamine D2 receptor densities and the performance of different cognitive tasks in patients with schizophrenia. Regarding the importance of the basal ganglia in time pacing and motor activities, the aim of this study is to test whether cognitive tasks that require more motor

and time perception abilities are more highly correlated with striatal dopamine D2 than those that do not. To this end, the following three cognitive tasks were studied: the finger tapping test (FTT), an attention test, and the Wisconsin Card Sorting Test (WCST). The FTT requires simple fine motor abilities and optimal time performance. The attention test requires optimal timing but does not require fine motor activity. The WCST is a test of executive functions that requires abstraction and mental flexibility but does not impose stringent time constraints. The purpose of this study is twofold: (1) to test whether the FTT score is more highly correlated with striatal dopamine D2 receptor density (St/Cb) than performance scores for the other cognitive tasks in medicated patients with schizophrenia and (2) to test whether the d V/T, an attention test score that incorporates reaction time, is more highly correlated with St/ Cb, a ratio of striatal D2 receptor density, than d Valone.

2. Methods 2.1. Subjects The patient group comprised 28 right-handed schizophrenic patients (12 males, 16 females; mean age = 29.25 F 9.63 years; range = 16 – 48 years), all of whom fulfilled DSM-IV criteria for schizophrenia and received treatment in the Department of Psychiatry at the National Cheng Kung University Hospital, Taiwan. No patient with the following conditions was included: current medical or neurological diseases, tardive dyskinesia, history of alcohol or substance dependence, head injury, exposure to electroconvulsive therapy, or lithium treatment during the month before the assessment began. Before any procedure was performed, informed consent was obtained from the patients and their key caregivers. The Ethical Committee for Human Research, National Cheng Kung University Medical Center, approved the study protocol. Table 1 presents the demographic and clinical data for each patient. The mean score on the Brief Psychiatric Rating Scale (BPRS) was 28.25 ( F 6.30). Nine of the 28 patients had been free of antipsychotic medication for at least 6 months, and most of them were antipsychotic-naive. The remaining 19 patients were stable chronic outpatients who had been maintained on oral neuroleptics for more than 6 months with the

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Table 1 Demographic data in 28 patients with schizophrenia Case no.

Age (years)

Gender

Drug

Neuroleptic dosage (mg)

CPZ* (mg)

BPRS score

Dose of trihexyphenidyl (mg)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Mean F S.D.

42 17 42 21 17 27 29 23 18 19 17 28 22 36 48 37 16 35 37 23 20 30 28 28 40 41 35 43 29.25 F 9.63

female female male male female male female male female female female female male female female male female female male male male male male male female female female female

haloperidol drug free haloperidol haloperidol risperidone sulpiride clozapine haloperidol risperidone drug free drug free haloperidol drug free risperidone drug free haloperidol drug free risperidone drug free drug free haloperidol sulpiride haloperidol haloperidol sulpiride drug free risperidone haloperidol

5 – 50a 8 8 800 100 15 4 – – 10 – 2 – 50/5b – 4 – – 5 600 50/20c 50/20d 400 – 2 50e

250 – 313 400 800 400 200 750 400 – – 500 – 200 – 406 – 400 – – 250 300 1313 1156 200 – 200 156 452.29 F 183.54

25 18 30 25 29 21 35 42 28 31 30 20 23 31 31 23 35 24 25 29 22 45 32 22 23 31 28 33 28.25 F 6.30

0 – 0 5 3 10 10 10 10 – – 10 – 0 – 10 – 10 – – 0 10 5 5 10 0 0 0 5.40 F 4.59

BPRS: Brief Psychiatric Rating Scale. CPZ: Chlorpromazine equivalent dosage. a 50 mg IM Q2W. b 50 mg IM Q4W and 5 mg QHS. c 50 mg IM Q2W and 20 mg QN. d 50 mg IM Q4W and 20 mg QN. e 50 mg IM Q4W. * Only 19 patients took neuroleptics.

exception of five patients who were treated with longacting neuroleptics (patient nos. 3, 16, 23, 24, and 28). The mean score on the Simpson –Angus Scale (SAS) was 2.50 ( F 2.67). 2.2. Finger tapping test The purpose of this test is to measure the motor speed of the index finger of each hand. The finger tapping score is defined as the mean number of taps per 10 s collected over five trials. Using a specially adapted tapper, the subject tapped as fast as possible

using the index finger of the dominant hand. A comparable set of measurements was then obtained for the index finger of the nondominant hand. The FFT score was computed separately for each hand. In general, better performance is associated with younger age (Heaton et al., 1991). The FTT scores were obtained by averaging the scores of both hands. 2.3. Wisconsin Card Sorting Test Using a computerized version of the WCST, the patients were required to match response cards to four

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stimulus cards along one of three dimensions (color, form, or number) on the basis of verbal feedback (correct or wrong); subjects were not given any information about the dimensions. After sorting a series of 10 cards in one category, the subject was asked to sort the cards again in a different category. There were 64 cards in the present test. All definitions of indices are as described in the WCST manual (Heaton et al., 1991). There are many measures for determining WCST performance. We chose the number of WCST categories patients completed as the index of WCST performance because it is a frequently used index in imaging studies (Volkow et al., 1998). 2.4. Attention test This test includes a total of 780 signals. Subjects were asked to identify 107 target signals out of the 780 trials using paper and pencil (Chang and Ko, 1993). In accord with signal detection theory, the fundamental task was to discriminate the signal (target) from noise (nontarget) (Davies and Parasuraman, 1982). The dV score measured the subject’s ability to discriminate a signal from the background noise. A higher dV score indicates better processing capability. In addition, the dV/T score included the total time consumed (in s) to make the discrimination.

structed transverse images were realigned parallel to the canthomeatal line. The slice thickness of each transverse image was 2.89 mm. For semiquantitative analysis, six consecutive transverse slices on which the striatum (St) was best visualized were combined to obtain a 17.34-mm-thick slice. Then regions of interest (ROIs) were placed over the striatum and the cerebellum. All of the subjects underwent magnetic resonance imaging (MRI; GE, Sigma CV-I, 1.5 Tesla, General Electric Medical Systems, USA) as a reference for defining the area of the striatum on the SPECT images. An experienced nuclear medicine specialist without knowledge of the patients’ clinical data drew the regions of interest (ROIs) based on the individual MRIs. The size of all ROIs was at least twice the FWHM. The ratio of the radioactivity in the striatum (St) and the cerebellum (Cb; St/Cb ratio) was derived by dividing the average counts per pixel in the striatum by the average counts per pixel in the cerebellum. In the present study, the FTT, WCST, the attention test, and brain SPECT imaging were performed starting at 1000 h (12 h after the last drug intake). All participants completed FTT, WCST, and attention test and underwent brain SPECT imaging within 2 consecutive days. 2.6. Statistical methods

2.5. Measurement of striatal dopamine D2 receptors Before the single photon emission computed tomography (SPECT) examination with [123I]iodobenzamide (IBZM), the thyroid gland was protected with 9 ml of Lugol’s solution. For brain SPECT imaging, each subject was intravenously administered with 185 MBq (5 mCi) of [123I]IBZM in a quiet environment about 10 min after the setting of the intravenous lines. Imaging was initiated approximately 120 min later. We used a triple-headed rotating gamma camera (Multispect 3, Siemens) with ultrahigh resolution fan-beam collimators. Image resolution yielded by the instrument is approximately 8.5-mm full-width at half-maximum (FWHM). The SPECT images were acquired over a circular 360j rotation, 120 steps, 50 s per step, in a 128  128  16 matrix. The images were then reconstructed using Butterworth and Ramp filters (cutoff frequency = 0.3 Nyquist, power factor = 7) with attenuation by the Chang method. The recon-

A correlation matrix was obtained for age, neuroleptic dosage (using chlorpromazine-equivalent dosage), St/Cb, and different cognitive tasks. Multiple linear regression was performed to compare the associations between striatal dopamine D2 receptor binding and the three cognitive tasks. Because cognitive function declines as neuroleptic dose increases (Lieberman and Mailman, 1998), neuroleptic dose was controlled in the regression model. The Mann – Whitney test was performed to assess differences in cognitive performance between high and low St/Cb ratios and different drug groups. All analyses were performed with an SPSS computer package (SPSS, Chicago, IL).

3. Results Mean performance scores were as follows: FTT, mean = 43.94 ( F 9.75), range = 19.80 –62.20; WCST

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categories completed, mean = 1.61 ( F 1.42); range = 0 –5; attention test dV, mean = 3.18 ( F 0.98), range = 2.50 –4.98; attention test dV/T, mean = 0.01 ( F 0.0025), range = 0.0045 –0.015. For the D2 binding measures, the mean ratio of St/Cb was 1.47 F 0.29; St/Cb ranged from 1.02 to 1.98. The correlation analysis between age and striatal D2 dopamine binding did not show an age effect on the striatum or the cerebellum. Both the FTT (Spearman’s rho = 0.67, P < 0.00) and the attention test dV/T (Spearman’s rho = 0.44, P = 0.015) scores were significantly correlated with striatal D2 dopamine binding. However, the St/Cb ratio was not significantly correlated with either the dV attention score or the WCST score. The dV/T scores were more closely associated with striatal D2 receptor density (b = 0.45, S.E. = 0.57, P = 0.016) than the d V scores (b = 0.062, S.E. = 0.48, P = 0.73). The dV/T scores were also more significantly associated with the St/ Cb ratio (b = 0.45, S.E. = 0.55, P = 0.011) than were the WCST scores (b = 0.30, S.E. = 0.02, P = 0.082). The results from multivariate analysis showed that the FTT score was significantly associated with the St/Cb ratio (b = 0.558, S.E. = 0.005, P = 0.004) after the attention test and WCST scores were controlled for in the model, and the WCST score was the least significantly correlated with the St/Cb ratio (b = 0.138, S.E. = 0.018, P = 0.37). Because age was not significantly associated with dopamine binding in the bivariate analysis, we removed it from the regression model. To explore the influence of neuroleptic treatment on cognitive functions, neuroleptic dose was included in the multiple linear regression model along with the three cognitive tasks. The results from multivariate analysis showed that neuroleptic dose was a significant dependent variable for the St/Cb ratio (b = 0.403, S.E. = 0.000, P = 0.033), while the FTT score was also a significant dependent variable for the St/Cb ratio (b = 0.426, S.E. = 0.006, P =0.037). Scores on the other two tasks, which were nonsignificant, were excluded from this regression model. The patients were then divided into high and lower St/Cb ratio groups, where low St/Cb was defined as a St/Cb ratio lower than the healthy subjects’ mean St/Cb ratio (1.71) minus two standard deviations (2  0.16), according to our previous results (Yang et al., 2003b). The cutoff point for the St/Cb ratio in these two groups was 1.29. The low St/Cb group showed poor FTT scores (l = 41, P = 0.005)

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and dV/T scores (l = 50, P = 0.028) but not WCST scores (l = 73, P = 0.185). Comparison between patients taking atypical and typical neuroleptics revealed no significant differences between these two groups related to their performance on the cognitive tasks.

4. Discussion When cognitive performance on the three cognitive tasks was related to striatal dopamine D2 receptor density, the FTT showed the strongest correlation with D2 receptor binding, while the WCST and dV had no correlation with D2 receptor binding. Only the association between the FTT and striatal D2 receptor binding reached a statistically significant level in the multiple linear regression. Findings from positron emission tomography (PET) and electrophysiological observations have implicated the basal ganglia as playing an important role in the cognitive function of movement (Brooks, 1995). In addition, impaired motor activity has been associated with the basal ganglia, particularly in the form of low FTT scores in patients with Parkinson’s disease (PD; Agostino et al., 1998). Motor deficits have been shown to be correlated with the degeneration of the putamen (Alegret et al., 2001). Moreover, the basal ganglia are also involved in the optimal processing of duration (in the ms range; Rammsayer, 1999). The strong association between the FTT score and striatal D2 receptor binding was expected because the FTT requires both motor performance and optimal timing, two functions in which the basal ganglia are known to be involved. The FTT, which measures the motor speed of the index finger, requires low cognitive effort. It is known that a decline in fine motor activity is highly correlated with striatal D2 receptor density (Kuenstler et al., 1999; Yang et al., 2003b). However, measurements of rigidity, tremor, and bradykinesia (Fitzgerald et al., 2000) are not strongly correlated changes in striatal D2 receptor densities. In our previous study (Yang et al., 2003b), we showed that the FTT score alone shows a stronger correlation with changes in striatal receptor density than the Simpson – Angus score, which measures extrapyramidal side effects. In addition to fine motor activity, further study is needed to

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explore the relationship between striatal function and other motor functions. In contrast to the FTT, the WCST is a test of executive functions. It requires abstraction and mental flexibility (a function of the frontal lobe) and exerts little time pressure during performance—a weak association with striatal D2 receptor binding was therefore to be expected. Significant WCST-associated activation in the prefrontal cortex has been reported in healthy persons (Berman et al., 1995; Nagahama et al., 1996). However, the prefrontal lobe is not the only significant region for WCST performance. It is suggested that not only the cortex but also the subcortex and the cerebellum may be impaired in patients with schizophrenia (Andreasen et al., 1999). In our previous study, a significant correlation between regional cerebral blood flow during WCST performance in patients with schizophrenia and the WCST score was noted in the inferior parietal lobe, superior occipital gyrus, thalami, and cerebellum, although not in the basal ganglia in medicated patients (Yang et al., 2003a). Volkow et al. (1998) also showed that WCST scores are more weakly correlated with striatal D2 receptor density than FTT scores in healthy individuals. The attentional task used in this study requires cognitive effort in which the cortex should play an important role. Various types of reaction time paradigms have demonstrated deficits in the preparation and execution of movements in Parkinsonian subjects (Jordan et al., 1992; Mu¨ller et al., 2000b; Mu¨ller et al., 2002). Mu¨ller et al. (2000b) demonstrated that there is a significant relationship between striatal dopamine presynaptic density (assessed with 123 I-beta-CIT SPECT) and reaction time in patients with Parkinson’s disease. Patients treated with levodopa show improvements in reaction time performance (Mu¨ller et al., 2000a). Moreover, Jordan et al. (1992) postulated that reaction time may be correlated with measures of global cognitive capacity and frontal-lobe function, as well as motor activity. In this study, subjects were asked to circle 107 target signals out of the 780 trials as fast as they could. The total time consumed (T), measured in s, was recorded. To evaluate the importance of time constraints in the assessment of attentional performance on this task, the score on the attention test was computed as dV divided by T, or dV/T. Because the basal ganglia are involved in the optimal processing

of duration requirements of the attention test, it was not unexpected that dV would be less correlated with striatal D2 receptor densities than dV/T, and that dV/T in turn would be less correlated with striatal D2 receptor densities than the FTT score. Alegret et al. (2001) showed that there is no relationship between caudate atrophy and cognitive deficits. However, the cognitive tasks that Alegret et al. (2001) used involved little time pressure. In other words, the reaction time was not taken into consideration. Therefore, the morphological results are similar to the striatal binding results of the current study. That is, there is no significant correlation between the WCST or the dV score and striatal D2 receptor density. Neuroleptic treatment is associated with a reduction in striatal D2 receptor densities (Farde et al., 1992), and performance on cognitive tasks is also known to be influenced by neuroleptics. Even after the dosage of neuroleptic was controlled for in the regression model, the correlation of FTT scores with striatal D2 receptor densities persisted. The patients in the low St/Cb ratio group showed not only lower FTT scores but also poor attention test performance. Volkow et al. (1998) demonstrated similar results in healthy subjects. Although atypical neuroleptics are reported to improve cognitive performance or to affect cognitive performance less than typical neuroleptics, patients taking atypical neuroleptics showed no significant difference in their cognitive performance compared with patients taking conventional neuroleptics. The small sample size and the non-doubleblind design in the current study may partially explain the inconsistencies. Neuroleptic therapy in patients with schizophrenia may induce D2 dopamine receptor up-regulation or change the volume of the basal ganglia (Schro¨der et al., 1998; Corson et al., 1999). The involvement of basal ganglia abnormalities in the pathophysiology of schizophrenia has been postulated (Busatto and Kerwin, 1997). Because the basal ganglia tend to become overactivated during the FTT task in untreated schizophrenic patients according to the findings of a functional magnetic resonance imaging study (Mu¨ller et al., 2002), one should be cautious not to generalize the results of correlations between different cognitive tasks to healthy subjects and striatal dopamine D2 receptor densities.

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A few caveats also need to be considered. First of all, the direct effect of each cognitive task on striatal D2 receptor binding cannot be determined in the current analysis. Causal effects would need to be confirmed by repeated measures on the same subject over time and during both the resting and activating phases. The changes in ratio tracer binding potential following changes in central dopamine might not be fully accounted for by a simple density model like that in this study (Laruelle, 2000). Regarding dopamine receptor up-regulation associated with neuroleptic therapy, it would have been desirable to calculate D2 receptor occupancy instead of St/Cb as a semiquantitative measure of striatal D2 receptor densities. Because of the lack of appropriate healthy controls with age and gender controlled in this study, the D2 receptor occupancy was not available. Second, because of the influence of neuroleptic drugs, our results cannot precisely demonstrate the nature of the relationship between cognitive deficits and absolute changes in striatal dopamine binding in schizophrenic patients. Lastly, due to the small sample size in this analysis, the findings have limited generalizability.

Acknowledgements The work was supported by a grant from the Atomic Energy Council (Taiwan) (N3I102; NSC90NU-7-006-004). The authors thank Mr. Mitchell Chen, Ms. Shu Chuan Lin, Ms. Ching Lin Chu, and Dr. Chwen Cheng Chen from the Department of Psychiatry, National Cheng Kung University, and Ms. Linda Chang for their editorial assistance in the preparation of the manuscript.

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