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Delayed habituation of the skin-conductance orienting response correlates with impaired performance on the wisconsin card sorting task in schizophrenia
PSYCHIATRY RESEARCH ELSEVIER
Psychiatry Research 65 (1996) 107-112
Delayed habituation of the skin-conductance orienting response correlates with impaired performance on the Wisconsin Card Sorting Task in schizophrenia Richard A. Schiffer”, Mircha Sigal”, Matti Mintz* b aLev Hasharon Mental Health Hospital, Hasharon, Israel bPsychobiology Research Unit, Depattment of Psychology, Tel-Aviv University, Ramat Aviv, P. 0. B. 39040, Tel-Auiv 69978, Israel Received 22 May 1995; revised 26 April 1996; accepted 6 June 1996
Abstract The skin-conductance orienting response (SCOR) in schizophrenia is often characterized by either nonresponding or delayed habituation to repeated nonsignal tones. These abnormalities are poorly related to other dimensions of schizophrenia. In the present study, we confirmed that about 50% of patients with chronic schizophrenia are SCOR nonresponders. Nonresponders, however, did not differ from responders on postmorbid psychiatric or pharmacological course, and we therefore could not confirm the hypothesis that course of illness follows a more marked pattern of increasing severity in nonresponders. Performance on the Wisconsin Card Sorting Test (WCST) was particularly poor in a subgroup of responders who exhibited either delayed habituation and/or dishabituation of SCORs to tones applied after a short rest period. It is possible that pathology of the prefrontal cortex mediates the SCOR abnormalities that characterize schizophrenic patients who perform poorly on the WCST. Copyright 0 1996 Elsevier Science Ireland Ltd. Keywords:
Autonomic
function;
Psychophysiology;
Neuropsychology;
1. Introduction
Nearly half of schizophrenic patients fail to generate skin-conductance orienting responses
*Corresponding author. Tel.: + 972 3 6408625; fax: + 972 3 6409547; e-mail: mintzfreud.tau.ac.il
Prefrontal
cortex
(SCORs) to repeated innocuous tones (Bernstein et al., 1982). The relation between SCOR nonresponding and the clinical state is uncertain. Nonresponders have been reported to be characterized by severe past and present symptomatology, poor response to neuroleptic treatment, and poor prognosis (Mednick and Schulsinger, 1968; Straube, 1979; Zahn, 1980; Bernstein et al., 1982; Schneider, 1982; Alm et al., 1984; Green et al.,
0165-1781/96/$15.00 Copyright 0 1996 Elsevier Science Ireland Ltd. All rights reserved. PIlSOl65-1781(96)02845-4
108
R.A. Schiffer Edal. /Psychiatry Research 65 (1996) 107-I 12
1989). Others showed, however, that slow SCOR habituators, rather than nonresponders, demonstrate poor premorbid adjustment (Bartfai et al., 1987) and poor prognosis or response to treatment (Frith et al., 1979; Zahn et al., 1981; Dawson et al., 1992). Similarly inconclusive is the relation between SCOR nonresponding and patients’ negative/ positive symptoms. Nonresponders are considered withdrawn and disorganized, while responders are considered excited and high on active symptoms, manic state, anxiety, psychotic belbehaviour ligerence, and attention-demanding (Gruzelier, 1976; Straube, 1979; Bernstein et al., 1981). In antithesis to these findings, other reports show that severely ill patients with chronic schizophrenia are characterized by slow SCOR habituation (Deakin et al., 1979) and that SCOR relates to factors of behavioral and emotional activation rather than to negative or positive items of the Brief Psychiatric Rating Scale (Dawson et al., 1992). Finally, there are reports that nonresponders have higher ratings of both negative and positive symptoms than do responders (Kim et al., 1993). In the present study, we attempted to relate SCOR nonresponding in schizophrenia to performance on the Wisconsin Card Sorting Test (WCST), a neuropsychological measure that may reflect the integrity of the dorsolateral prefrontal cortex (DLPFC; Milner, 1963).
1970) and the Akathisia Scale (Braude et al., 1983), respectively. Patients suspected of organic brain damage on the basis of known history and neurological examination were excluded from the experiment. The WCST was administered and scored according to the recommendations of Heaton (1981). 2.2. SCOR
2. Methods
Silver-silver chloride electrodes (l-cm* contact area> were attached to the fingers of the left hand. A 10 PA constant current was applied, and skin conductance level @CL) and SCOR were amplified (Beckman Instruments), digitized (CED1404), and stored for off-line analysis. The no-task habituation paradigm consisted of 20 white-noise tones of l-s duration, 75-dB intensity, and 20-ms rise/fall gradient delivered binaurally through headphones. The CED1404 was programmed to deliver the tones only during periods that were free of spontaneous SC fluctuations. This resulted in a semirandom interstimulus interval that ranged from 10 to 40 s. The subject was then asked to rest for 5 min and SCOR dishabituation was tested to one additional tone. Response was defined as an increase of conductance 2 0.05 $S within a time window of l-4 s after tone onset. SCOR habituation was defined as the number of trials before a failure to respond to three consecutive tones occurred. SCL was averaged across a 50-ms period just preceding each tone.
2.1. Subjects and clinical evaluation
3. Results
Twenty-nine patients with schizophrenia (10 women, 19 men, mean age = 35 years, SD = 11) were recruited from the chronic wards of LevHasharon Psychiatric Hospital. Diagnoses were made on the basis of DSM-III-R (American Psychiatric Association, 1987), and psychiatric state was assessed with the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1988). Tardive dyskinesia, parkinsonism and akathisia were assessed using the Abbreviated Dyskinesia Rating Scale (Simpson et al., 19791, the Scale for Extrapyramidal Side Effects (Simpson and Angus,
3.1. SCOR and SCL
Table 1 shows that 14 patients (48%) were SCOR nonresponders during the habituation session. Among the 15 responders, 11 habituated after one to four trials while four required more than eight trials to habituation (late habituators). SCOR dishabituation was noted in seven responders but in none of the nonresponders. Occurrence and amplitude of the dishabituation response were not related to the number of trials to habituation.
RA
Table 1 Data of the SCOR responding schizophrenics (Mean * SD).
Schiffer et al. /Psychiatry Research 6.5 (1996) 107-112
and
Nonresponders
nonresponding
Responders
Skin conductance
Patients (n’s) SCOR rate Dishabituators scLa ( PcLs) Course of illness Chronic@ (years) Admissions All hospitalizations (months) Familial morbidity
14 (48%) 0.4 + 0.6 0 (0%) 5.5 f 3.6
15 (52%) 6.7 k 4.2 7 (47%) 9.5 f 6.0
10.8 f 9.9 5.9 f 4.8 10.7 f 8.6 36%
8.7 f 7.1 4.7 f 3.0 35.2 f 72.4 27%
196 i 253 29.2 f 24.7 43% 21%
275 + 205 27.4 + 14.7 47% 33%
21% 57% 7%
33% 60% 7%
64%
73% 7% 13% 7%
Pharmacology
Neuroleptics (CPZ, mg/day) Present treatment (months) Antimuscarinic drugs Antimuscarinic neuroleptics Side effects
Akathisia Parkinsonism Tardive dyskinesia Schizophrenia
Paranoid Disorganized Residual Schizoaffective
7% 21% 7%
PANSS
Positive scale Negative scale General scale Total score
11*4 19f4 30 + 5 6Ok 11
14 f 4 18 f 5 31+4 64 f 8
WCST
Responses Trials to 1st category Categories achieved Nonperseverative errors (%) Perseverative errors (%o) Learning index
107 29 4.2 12.6 23.1 -4.1
+ k k f + f
25 34 2 8 17 9.2
118 f 18 40+43 3.5 * 2 15.8 i 8.7 26.9 f 18 - 6.0 * 9.9
aIndependent t test: t = 2.2, d.f. = 27, P < 0.05. Note. Data are presented as mean f SD or percentages. SCOR, skin conductance orienting response. SCL, skin conductance level. CPZ, chlorpromazine-equivalent dosage. PANSS, Positive and Negative Syndrome Scale. WCST, Wisconsin Card Sorting Test.
Responders and particularly late habituators demonstrated the highest XL (nonresponders: mean = of 5.5 PUS,SD = 3.6; habituators: mean = 7.9 pS, SD = 4.9; late habituators: mean = 14.0 pS, SD=7.3; F= 5.1, d.f.=2, P
109
SCL compared with nondishabituators (dishabituators: mean = 9.9 PS, SD = 6.3; nondishabituators: mean = 8.8 @, SD = 6.61, but the difference was not significant (t = 0.3, d.f. = 12, P = 0.75). 3.2. Clinical and demographic characteristics Table 1 shows that SCOR responders and nonresponders did not differ significantly on variables of illness course, pharmacology, motor side effects, and psychiatric subdiagnosis. In particular, they did not differ on prevalence of neuroleptics with high antimuscarinic potency, prevalence of antimuscarinic drugs, or cumulative muscarinic receptor occupancy [ X(dose x IC,, )I. Responders did not differ significantly from nonresponders on demographic variables of age (responders: mean = 34.6 years, SD = 8; nonresponders: mean = 38.6 years, SD = 121, education (responders: mean = 11.3 years, SD = 2; nonresponders: mean = 10.5 years, SD = 4), or distribution of male vs. female subjects (42% of males and 67% of females were nonresponders). Finally, SCOR habituation or SCL could not be predicted by either the clinical or demographic variables in a multiple regression stepwise analysis. 3.3. PANSS Patients scored higher on the negative vs. the positive symptoms subscale (t = 5.3, d.f. = 27, P < 0.001). Familial morbidity of schizophrenia contributed to positive scores CR2 = 0.39, P < 0.05). SCOR responders and nonresponders did not differ significantly on PANSS subscales (Table 1). SCOR habituation or SCL could not be predicted by scores on PANSS subscales in a multiple regression analysis. WCST indices of perseveration, inefficiency of sorting, and nonperseverative errors (Sullivan et al., 1993) served to predict the PANSS scores in multiple regression stepwise tests. A high total score on negative symptoms was predicted by a high rate of perseverative errors (adjusted R2 = 0.20, P < 0.02). Regression on individual items of the PANSS negative scale revealed that an in-
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R.A. Schiffer et al. /Psychiatry Research 65 (1996) 107-112
creased difficulty in abstract thinking was predicted by a high rate of perseverative responses (adjusted R2 = 0.24, P < 0.011, and an increase in stereotyped thinking was predicted by a high rate of perseverative errors (adjusted R2 = 0.23, P < 0.01). 3.4. WCST Table 1 shows that the performance of SCOR responders was consistently inferior compared with the performance of nonresponders, but a c test failed to confirm a significant difference between the two subgroups on any index of the WCST. On the other hand, multiple regression revealed that delayed habituation of SCOR was predicted by a high rate of perseverative responses (first step: adjusted R2 = 0.15, P < 0.03) and by a high rate of perseverative errors (second step: adjusted R2 = 0.56, P < 0.0001). The above predictions were confirmed when the regression analysis considered the responders’ data only (adjusted R2 = 0.40, P< 0.01 and R2 = 0.82, P < 0.001). Higher SCL was predicted by a lower rate of conceptual responses (adjusted R2 = 0.24, P < 0.01). The dishabituation pattern further helped in demarcation of patients’ performance on the WCST. Responders who showed dishabituation had the highest rate of nonperseverative errors (mean = 20.3, SD = 7.8) compared with rates in responding-nondishabituating (mean = 10.4, SD = 7.3) and nonresponding-nondishabituating patients (mean = 12.6, SD = 8.0) (F = 3.3, d.f. = 2,24, P = 0.05). High SCOR amplitude on the dishabituation trial was predicted by a low rate of conceptual responses (adjusted R* = 0.2, P < 0.02) and by a high rate of perseverative errors (adjusted R2 = 0.38, P < 0.01). 4. Discussion These findings confirm that about half of patients with chronic schizophrenia do not show SCORs to nonsignal-innocuous tones, although the great majority of patients do respond with defensive SCRs to noxious tones (Mintz et al., 1990). We tested whether the SCOR re-
sponding/nonresponding dichotomy was relevant to other schizophrenia-related variables. The groups did not differ in postmorbid clinical history, present state, or PANSS profile. The groups had a similar pharmacological profile, and nonresponding was not related to either neuroleptic or anticholinergic treatment. Nonresponders and responders had a similar incidence of iatrogenic motor side effects in the form of tardive dyskinesia, parkinsonism, or akathisia. In effect, the present findings based on a small group of chronic schizophrenic patients provide no support for the assumption that the SCOR responding/nonresponding dichotomy categorizes clinically relevant features of schizophrenia. In line with the report of Katsanis and Iacono (1992), findings in our small sample showed that the SCOR dichotomy does not aid in predicting performance on the WCST. On the other hand, we identified a subgroup of ‘hyperresponders’ whose performance on the WCST seemed to be particularly deficient. These were either late habituators, who showed the highest rate of perseverative responses and perseverative errors, or dishabituators, who showed the highest rate of nonperseverative errors. Dishabituators with high amplitude response showed a low rate of conceptual responses and a high rate of perseverative errors. The possibility that SCOR hyperresponding is related to a specific neuropsychological deficiency is supported by findings of deficient performance of nonhabituators, compared with habituators, on Trail Making and Finger Tapping tests (Bartfai et al., 1987). The SCOR responding/nonresponding dichotomy does not aid in predicting performance on tests of temporal lobe function in the study of Katsanis and Iacono (1992). It is of interest that these authors isolated a subgroup of SCOR nonresponders who, in addition, failed to generate defensive SCRs to noxious tones and who were particularly deficient on temporal lobe tests. The other SCOR nonresponders, who did show defensive SCRs, performed similarly to SCOR responders, and both groups scored higher than the persistent nonresponders. It seems therefore that measures of autonomic reactivity may indeed be of clinical relevance as they are related to specific
111
R.A. Schiffer et al. /Psychiatry Research 65 (1996) 107-I 12
neuropsychological deficiencies in schizophrenia. Of note, this relevance seems to be achieved only when the SCOR responding/nonresponding dichotomy is supplemented by finer details of the patient’s pattern of autonomic reactivity. We suggest that details about the rate of SCOR habituation, emergence of SCOR dishabituation, and emergence of defensive SCR be provided in future reports. SCOR hyperresponding and deficient WCST performance might have a common anatomical denominator. Structural lesions of the DLPFC impair performance on the WCST (Milner, 1963). A corollary outcome of these lesions is an excessive behavioral orientation/responding to environmental cues (see Grueninger and Grueninger, 1973; Goldman-Rakic, 1987), which surprisingly is accompanied by either decreased or even absent SCOR (see Grueninger and Grueninger, 1973). The structural and/or metabolic DLPFC deficiency in schizophrenia might be expected to produce similar pathology. Prefrontal hypometabolism is indeed associated with perseveration on the WCST (Weinberger et al., 1986; Goldberg et al., 1987; Seidman et al., 1994) and with SCOR nonresponding (Hazlett et al., 1993). Accordingly, we inferred that SCOR nonresponders will be particularly deficient on the WCST. In contrast to this hypothesis, we found that SCOR hyperresponders were particularly deficient on the WCST. This inconsistency may indicate that the present association between perseverations on the WCST and SCOR hyperresponding is not mediated by prefrontal pathology. Indeed, prefrontal damage cannot be deduced reliably from the WCST as perseveration is seen after extrafrontal lesions as well (Benton, 1994). Nevertheless, prefrontal involvement in SCOR responding in schizophrenia is far from being defined. Although Hazlett et al. (1993) related SCOR nonresponding to prefrontal hypometabolism, their conclusion is based on a small number of schizophrenic patients who were characterized by a diffuse pattern of cortical and subcortical hypometabolism. Thus, SCOR nonresponding in these patients might be attributed to extrafrontal pathology. To determine whether prefrontal hypometabolism leads to SCOR nonre-
sponding, as suggested by Hazlett et al., or leads to hyperresponding, as may be deduced from the present study, one may need to test a sample of schizophrenic patients with more localized signs of hypometabolism. We are also uncomfortable with the assumption that if prefrontal structural lesions in neurologic patients lead to SCOR nonresponding, then prefrontal hypometabolism in schizophrenia should lead to similar SCOR abnormality. Indeed, the massive structural lesions encountered in neurological patients include damage to the cortical efferents and therefore some of the emerging symptoms reflect the reactivity of extrafrontal systems (Myslobodsky, 1993). Accordingly, abolition of SCOR in neurological patients indicates that these extrafrontal systems fail to generate and maintain sympathetic reactivity to a sequence of nonsignal stimuli. On the other hand, the subtle prefrontal pathology in schizophrenia may be caused by a dysfunction of cortical afferents (Weinberger and Berman, 1988). Under these assumptions, we do not expect that prefrontal dysfunction would abolish SCOR reactivity. Present results indicate that in fact prefrontal dysfunction may be associated with a delay of sympathetic habituation to a sequence of nonsignal stimuli. As indicated by Morgan et al. (19931, the delayed habituation of SCOR in patients with poor performance on the WCST may be interpreted as an extension of perseverative tendencies into the emotional domain.
References
Aim, T., Lindstriim, L., 6st, L.G. and 6hman, A. (1984) Electrodermal nonresponding in schizophrenia: relationship to attentional, clinical, biochemical, computed tomographical and genetic factors. Int J Pqxhophysio/ 1,195-208. American Psychiatric Association. (1987) DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC. Bartfai, A., Levander, SE., Nyback, H. and Schalling, D. (1987) Skin conductance nonresponding and nonhabituation in schizophrenic patients. Acta Psychiatr Stand 75, 321-329. Benton, A.L. (1994) Neuropsychological Rev Psycho1 45, l-23. Bernstein,
AS.,
Frith,
C.D.,
Gruzelier,
assessment. J.H.,
Patterson,
Anna T.,
112
R.A. Schiffer et al. /Psychiatry Research 65 (1996) 107-112
Straube, E., Venables, P.H. and Zahn, T.P. (1982) An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol Psycho1 14, 155-211. Bernstein, AS., Taylor, K.W., Starkey, P., Juni, S., Lubowsky, J. and Pauley, H. (1981) Bilateral skin conductance, finger pulse volume, and EEG orienting response to tones of differing intensities in chronic schizophrenics and controls. J Nerv Ment Dis 169, 513-528. Braude, W.M., Barnes, T.R.E. and Gore, S.M. (1983) Clinical characteristics of akathisia: a systematic investigation of acute psychiatric inpatient admission. Br J Psychiatry 143, 139-150. Dawson, M.E., Nuechterlein, K.N., Schell, A.M. and Mintz, J. (1992) Concurrent and predictive electrodermal correlates of symptomatology in recent-onset schizophrenic patients. J Abnorm Psycho1 101, 153-164. Deakin, J., Baker, H., Frith, C., Joseph, M. and Johnstone, E. (1979) Arousal related excretion of noradrenaline metabolites and clinical aspects of unmedicated chronic schizophrenic patients. J Psychiatr Res 15, 57-65. Frith, CD., Stevens, M., Johnstone, E.C. and Crow, T.J. (1979) Skin conductance responsivity during acute episodes of schizophrenia as a predictor of symptomatic improvement. Psycho1 Med 9, 101-106. Goldberg, T.E., Weinberger, D.R., Berman, K.F., Pliskin, N.H. and Podd, M.H. (1987) Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test. Arch Gen Psychiatry 44, 1008-1014. Goldman-Rakic, P.S. (1987) Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: Plum, F. (Ed.), Handbook of Physiology: The Nervous System. Vol. 5. University Press, New York, pp. 373-417. Green, M.F., Nuechterlein, K.H. and Satz, P. (1989) The relationship of symptomatology and medication to electrodermal activity in schizophrenia. Psychophysiology 26, 148-157. Grueninger, W. and Grueninger, J. (1973) The primate frontal cortex and allassostasis. In: Pribram, K.H. and Luria, A.R. (Eds.), Psychophysiology of the Frontal Lobes. Academic Press, New York, pp. 253-290. Gruzelier, J.H. (1976) Clinical attributes of schizophrenic skin conductance responders and nonresponders. Psycho/ Med 6, 245-249. Hazlett, E.A., Dawson, M.E., Buchsbaum, MS. and Nuechterlein, K.H. (1993) Reduced regional brain glucose metabolism assessed by positron emission tomography in electrodetmal nonresponder schizophrenics: A pilot study. J Abnorm Psycho1 102,39-46. Heaton, R.K. (1981) Wisconsin Card Sorting Test Manual. Psychological Assessment Resources, Odessa, FL. Katsanis, J. and Iacono, W.G. (1992) Temporal lobe dysfunction and electrodermal nonresponding in schizophrenia. Biol Psychiatry 31, 159-170. Kay, S.R., Opler, L.A. and Lindenmayer, J.P. (1988) Reliability and validity of the Positive and Negative Syndrome
Scale for schizophrenics. Psychiatry Res 23, 99-110. Kim, D.K., Shin, Y.M., Kim, C.E., Cho, H.S. and Kim, Y.S. (1993) Electrodermal responsiveness, clinical variables, and brain imaging in male chronic schizophrenics. Biol Psychiatry 33, 786-793. Mednick, S.A. and Schulsinger, F. (1968) Some premorbid characteristics related to breakdown in children with schizophrenic mothers. In: Rosenthal, D. and Kety, S.S. (Eds.), The Transmission of Schizophrenia. Pergamon Press, Oxford, pp. 267-291. Milner, B. (1963) Effects of different brain lesions on card sorting: The role of the frontal lobes. Arch Neurol 9, 90-100. Mintz, M., Alfisi, S. and Sigal, M. (1990) Skin conductance responding in schizophrenic patients with abnormal involuntary movements. Pqchiatly Res 34, 19-27. Morgan, M.A., Romanski, L.M. and LeDoux, J.E. (1993) Extinction of emotional learning: Contribution of medial prefrontal cortex. Neurosci Lett 163, 109-113. Myslobodsky, M.S. (1993) Central determinants of attention and mood disorder in tardive dyskinesia (‘tardive dysmentia’). Brain Cogn 23, 88-101. Schneider, S.J. (1982) Electrodermal activity and therapeutic response to neuroleptic treatment in chronic schizophrenic in-patients. Psychol Med 12, 607-613. Seidman, L.J., Yurgelun-Todd, D., Kremen, W.S., Woods, B.T., Goldstein, J.M., Faraone, S.V. and Tsuang, M.T. (1994) Relationship of prefrontal and temporal lobe MRI measures to neuropsychological performance in chronic schizophrenia. Biol Psychiatry 35, 235-246. Simpson, G.M. and Angus, J.W.S. (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Stand 212 (SuppI.), 11-19. Simpson, G.M., Lee, J.H., Zoubok, B. and Gardos, G. (1979) A rating scale for tardive dyskinesia. Psychopharmacology 64,171-179. Straube, E.R. (1979) On the meaning of electrodermal nonresponding in schizophrenia. J Nerv Ment Dis 167, 601-611. Sullivan, E.V., Mathalon, D.H., Zipursky, R.B., KersteenTucker, Z., Knight, R.T. and Pfefferbaum, A. (1993) Factors of the Wisconsin Card Sorting Test as measures of frontal-lobe function in schizophrenia and in chronic alcoholism. Psychiatry Res 46, 175-199. Weinberger, D.R. and Berman, K.F. (1988) Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia. Schizophr Bull 14, 157-168. Weinberger, D.R., Berman, K.F. and Zec, R.F. (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 43, 114-125. Zahn, T.P. (1980) Predicting outcome from measures of attention and autonomic functioning. In: Baxter, C. and Melnechuk, T. (Eds.), Perspectives in Schizophrenia Research. Raven Press, New York, pp. 81-104. Zahn, T.P., Carpenter, W.T. and McGlashan, T.H. (1981) Autonomic nervous system activity in acute schizophrenia: II. Relationship to short-term prognosis and clinical state. Arch Gen Psychiatry 38, 260-266.
Psychiatry Research 65 (1996) 107-112
Delayed habituation of the skin-conductance orienting response correlates with impaired performance on the Wisconsin Card Sorting Task in schizophrenia Richard A. Schiffer”, Mircha Sigal”, Matti Mintz* b aLev Hasharon Mental Health Hospital, Hasharon, Israel bPsychobiology Research Unit, Depattment of Psychology, Tel-Aviv University, Ramat Aviv, P. 0. B. 39040, Tel-Auiv 69978, Israel Received 22 May 1995; revised 26 April 1996; accepted 6 June 1996
Abstract The skin-conductance orienting response (SCOR) in schizophrenia is often characterized by either nonresponding or delayed habituation to repeated nonsignal tones. These abnormalities are poorly related to other dimensions of schizophrenia. In the present study, we confirmed that about 50% of patients with chronic schizophrenia are SCOR nonresponders. Nonresponders, however, did not differ from responders on postmorbid psychiatric or pharmacological course, and we therefore could not confirm the hypothesis that course of illness follows a more marked pattern of increasing severity in nonresponders. Performance on the Wisconsin Card Sorting Test (WCST) was particularly poor in a subgroup of responders who exhibited either delayed habituation and/or dishabituation of SCORs to tones applied after a short rest period. It is possible that pathology of the prefrontal cortex mediates the SCOR abnormalities that characterize schizophrenic patients who perform poorly on the WCST. Copyright 0 1996 Elsevier Science Ireland Ltd. Keywords:
Autonomic
function;
Psychophysiology;
Neuropsychology;
1. Introduction
Nearly half of schizophrenic patients fail to generate skin-conductance orienting responses
*Corresponding author. Tel.: + 972 3 6408625; fax: + 972 3 6409547; e-mail: mintzfreud.tau.ac.il
Prefrontal
cortex
(SCORs) to repeated innocuous tones (Bernstein et al., 1982). The relation between SCOR nonresponding and the clinical state is uncertain. Nonresponders have been reported to be characterized by severe past and present symptomatology, poor response to neuroleptic treatment, and poor prognosis (Mednick and Schulsinger, 1968; Straube, 1979; Zahn, 1980; Bernstein et al., 1982; Schneider, 1982; Alm et al., 1984; Green et al.,
0165-1781/96/$15.00 Copyright 0 1996 Elsevier Science Ireland Ltd. All rights reserved. PIlSOl65-1781(96)02845-4
108
R.A. Schiffer Edal. /Psychiatry Research 65 (1996) 107-I 12
1989). Others showed, however, that slow SCOR habituators, rather than nonresponders, demonstrate poor premorbid adjustment (Bartfai et al., 1987) and poor prognosis or response to treatment (Frith et al., 1979; Zahn et al., 1981; Dawson et al., 1992). Similarly inconclusive is the relation between SCOR nonresponding and patients’ negative/ positive symptoms. Nonresponders are considered withdrawn and disorganized, while responders are considered excited and high on active symptoms, manic state, anxiety, psychotic belbehaviour ligerence, and attention-demanding (Gruzelier, 1976; Straube, 1979; Bernstein et al., 1981). In antithesis to these findings, other reports show that severely ill patients with chronic schizophrenia are characterized by slow SCOR habituation (Deakin et al., 1979) and that SCOR relates to factors of behavioral and emotional activation rather than to negative or positive items of the Brief Psychiatric Rating Scale (Dawson et al., 1992). Finally, there are reports that nonresponders have higher ratings of both negative and positive symptoms than do responders (Kim et al., 1993). In the present study, we attempted to relate SCOR nonresponding in schizophrenia to performance on the Wisconsin Card Sorting Test (WCST), a neuropsychological measure that may reflect the integrity of the dorsolateral prefrontal cortex (DLPFC; Milner, 1963).
1970) and the Akathisia Scale (Braude et al., 1983), respectively. Patients suspected of organic brain damage on the basis of known history and neurological examination were excluded from the experiment. The WCST was administered and scored according to the recommendations of Heaton (1981). 2.2. SCOR
2. Methods
Silver-silver chloride electrodes (l-cm* contact area> were attached to the fingers of the left hand. A 10 PA constant current was applied, and skin conductance level @CL) and SCOR were amplified (Beckman Instruments), digitized (CED1404), and stored for off-line analysis. The no-task habituation paradigm consisted of 20 white-noise tones of l-s duration, 75-dB intensity, and 20-ms rise/fall gradient delivered binaurally through headphones. The CED1404 was programmed to deliver the tones only during periods that were free of spontaneous SC fluctuations. This resulted in a semirandom interstimulus interval that ranged from 10 to 40 s. The subject was then asked to rest for 5 min and SCOR dishabituation was tested to one additional tone. Response was defined as an increase of conductance 2 0.05 $S within a time window of l-4 s after tone onset. SCOR habituation was defined as the number of trials before a failure to respond to three consecutive tones occurred. SCL was averaged across a 50-ms period just preceding each tone.
2.1. Subjects and clinical evaluation
3. Results
Twenty-nine patients with schizophrenia (10 women, 19 men, mean age = 35 years, SD = 11) were recruited from the chronic wards of LevHasharon Psychiatric Hospital. Diagnoses were made on the basis of DSM-III-R (American Psychiatric Association, 1987), and psychiatric state was assessed with the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1988). Tardive dyskinesia, parkinsonism and akathisia were assessed using the Abbreviated Dyskinesia Rating Scale (Simpson et al., 19791, the Scale for Extrapyramidal Side Effects (Simpson and Angus,
3.1. SCOR and SCL
Table 1 shows that 14 patients (48%) were SCOR nonresponders during the habituation session. Among the 15 responders, 11 habituated after one to four trials while four required more than eight trials to habituation (late habituators). SCOR dishabituation was noted in seven responders but in none of the nonresponders. Occurrence and amplitude of the dishabituation response were not related to the number of trials to habituation.
RA
Table 1 Data of the SCOR responding schizophrenics (Mean * SD).
Schiffer et al. /Psychiatry Research 6.5 (1996) 107-112
and
Nonresponders
nonresponding
Responders
Skin conductance
Patients (n’s) SCOR rate Dishabituators scLa ( PcLs) Course of illness Chronic@ (years) Admissions All hospitalizations (months) Familial morbidity
14 (48%) 0.4 + 0.6 0 (0%) 5.5 f 3.6
15 (52%) 6.7 k 4.2 7 (47%) 9.5 f 6.0
10.8 f 9.9 5.9 f 4.8 10.7 f 8.6 36%
8.7 f 7.1 4.7 f 3.0 35.2 f 72.4 27%
196 i 253 29.2 f 24.7 43% 21%
275 + 205 27.4 + 14.7 47% 33%
21% 57% 7%
33% 60% 7%
64%
73% 7% 13% 7%
Pharmacology
Neuroleptics (CPZ, mg/day) Present treatment (months) Antimuscarinic drugs Antimuscarinic neuroleptics Side effects
Akathisia Parkinsonism Tardive dyskinesia Schizophrenia
Paranoid Disorganized Residual Schizoaffective
7% 21% 7%
PANSS
Positive scale Negative scale General scale Total score
11*4 19f4 30 + 5 6Ok 11
14 f 4 18 f 5 31+4 64 f 8
WCST
Responses Trials to 1st category Categories achieved Nonperseverative errors (%) Perseverative errors (%o) Learning index
107 29 4.2 12.6 23.1 -4.1
+ k k f + f
25 34 2 8 17 9.2
118 f 18 40+43 3.5 * 2 15.8 i 8.7 26.9 f 18 - 6.0 * 9.9
aIndependent t test: t = 2.2, d.f. = 27, P < 0.05. Note. Data are presented as mean f SD or percentages. SCOR, skin conductance orienting response. SCL, skin conductance level. CPZ, chlorpromazine-equivalent dosage. PANSS, Positive and Negative Syndrome Scale. WCST, Wisconsin Card Sorting Test.
Responders and particularly late habituators demonstrated the highest XL (nonresponders: mean = of 5.5 PUS,SD = 3.6; habituators: mean = 7.9 pS, SD = 4.9; late habituators: mean = 14.0 pS, SD=7.3; F= 5.1, d.f.=2, P
109
SCL compared with nondishabituators (dishabituators: mean = 9.9 PS, SD = 6.3; nondishabituators: mean = 8.8 @, SD = 6.61, but the difference was not significant (t = 0.3, d.f. = 12, P = 0.75). 3.2. Clinical and demographic characteristics Table 1 shows that SCOR responders and nonresponders did not differ significantly on variables of illness course, pharmacology, motor side effects, and psychiatric subdiagnosis. In particular, they did not differ on prevalence of neuroleptics with high antimuscarinic potency, prevalence of antimuscarinic drugs, or cumulative muscarinic receptor occupancy [ X(dose x IC,, )I. Responders did not differ significantly from nonresponders on demographic variables of age (responders: mean = 34.6 years, SD = 8; nonresponders: mean = 38.6 years, SD = 121, education (responders: mean = 11.3 years, SD = 2; nonresponders: mean = 10.5 years, SD = 4), or distribution of male vs. female subjects (42% of males and 67% of females were nonresponders). Finally, SCOR habituation or SCL could not be predicted by either the clinical or demographic variables in a multiple regression stepwise analysis. 3.3. PANSS Patients scored higher on the negative vs. the positive symptoms subscale (t = 5.3, d.f. = 27, P < 0.001). Familial morbidity of schizophrenia contributed to positive scores CR2 = 0.39, P < 0.05). SCOR responders and nonresponders did not differ significantly on PANSS subscales (Table 1). SCOR habituation or SCL could not be predicted by scores on PANSS subscales in a multiple regression analysis. WCST indices of perseveration, inefficiency of sorting, and nonperseverative errors (Sullivan et al., 1993) served to predict the PANSS scores in multiple regression stepwise tests. A high total score on negative symptoms was predicted by a high rate of perseverative errors (adjusted R2 = 0.20, P < 0.02). Regression on individual items of the PANSS negative scale revealed that an in-
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creased difficulty in abstract thinking was predicted by a high rate of perseverative responses (adjusted R2 = 0.24, P < 0.011, and an increase in stereotyped thinking was predicted by a high rate of perseverative errors (adjusted R2 = 0.23, P < 0.01). 3.4. WCST Table 1 shows that the performance of SCOR responders was consistently inferior compared with the performance of nonresponders, but a c test failed to confirm a significant difference between the two subgroups on any index of the WCST. On the other hand, multiple regression revealed that delayed habituation of SCOR was predicted by a high rate of perseverative responses (first step: adjusted R2 = 0.15, P < 0.03) and by a high rate of perseverative errors (second step: adjusted R2 = 0.56, P < 0.0001). The above predictions were confirmed when the regression analysis considered the responders’ data only (adjusted R2 = 0.40, P< 0.01 and R2 = 0.82, P < 0.001). Higher SCL was predicted by a lower rate of conceptual responses (adjusted R2 = 0.24, P < 0.01). The dishabituation pattern further helped in demarcation of patients’ performance on the WCST. Responders who showed dishabituation had the highest rate of nonperseverative errors (mean = 20.3, SD = 7.8) compared with rates in responding-nondishabituating (mean = 10.4, SD = 7.3) and nonresponding-nondishabituating patients (mean = 12.6, SD = 8.0) (F = 3.3, d.f. = 2,24, P = 0.05). High SCOR amplitude on the dishabituation trial was predicted by a low rate of conceptual responses (adjusted R* = 0.2, P < 0.02) and by a high rate of perseverative errors (adjusted R2 = 0.38, P < 0.01). 4. Discussion These findings confirm that about half of patients with chronic schizophrenia do not show SCORs to nonsignal-innocuous tones, although the great majority of patients do respond with defensive SCRs to noxious tones (Mintz et al., 1990). We tested whether the SCOR re-
sponding/nonresponding dichotomy was relevant to other schizophrenia-related variables. The groups did not differ in postmorbid clinical history, present state, or PANSS profile. The groups had a similar pharmacological profile, and nonresponding was not related to either neuroleptic or anticholinergic treatment. Nonresponders and responders had a similar incidence of iatrogenic motor side effects in the form of tardive dyskinesia, parkinsonism, or akathisia. In effect, the present findings based on a small group of chronic schizophrenic patients provide no support for the assumption that the SCOR responding/nonresponding dichotomy categorizes clinically relevant features of schizophrenia. In line with the report of Katsanis and Iacono (1992), findings in our small sample showed that the SCOR dichotomy does not aid in predicting performance on the WCST. On the other hand, we identified a subgroup of ‘hyperresponders’ whose performance on the WCST seemed to be particularly deficient. These were either late habituators, who showed the highest rate of perseverative responses and perseverative errors, or dishabituators, who showed the highest rate of nonperseverative errors. Dishabituators with high amplitude response showed a low rate of conceptual responses and a high rate of perseverative errors. The possibility that SCOR hyperresponding is related to a specific neuropsychological deficiency is supported by findings of deficient performance of nonhabituators, compared with habituators, on Trail Making and Finger Tapping tests (Bartfai et al., 1987). The SCOR responding/nonresponding dichotomy does not aid in predicting performance on tests of temporal lobe function in the study of Katsanis and Iacono (1992). It is of interest that these authors isolated a subgroup of SCOR nonresponders who, in addition, failed to generate defensive SCRs to noxious tones and who were particularly deficient on temporal lobe tests. The other SCOR nonresponders, who did show defensive SCRs, performed similarly to SCOR responders, and both groups scored higher than the persistent nonresponders. It seems therefore that measures of autonomic reactivity may indeed be of clinical relevance as they are related to specific
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neuropsychological deficiencies in schizophrenia. Of note, this relevance seems to be achieved only when the SCOR responding/nonresponding dichotomy is supplemented by finer details of the patient’s pattern of autonomic reactivity. We suggest that details about the rate of SCOR habituation, emergence of SCOR dishabituation, and emergence of defensive SCR be provided in future reports. SCOR hyperresponding and deficient WCST performance might have a common anatomical denominator. Structural lesions of the DLPFC impair performance on the WCST (Milner, 1963). A corollary outcome of these lesions is an excessive behavioral orientation/responding to environmental cues (see Grueninger and Grueninger, 1973; Goldman-Rakic, 1987), which surprisingly is accompanied by either decreased or even absent SCOR (see Grueninger and Grueninger, 1973). The structural and/or metabolic DLPFC deficiency in schizophrenia might be expected to produce similar pathology. Prefrontal hypometabolism is indeed associated with perseveration on the WCST (Weinberger et al., 1986; Goldberg et al., 1987; Seidman et al., 1994) and with SCOR nonresponding (Hazlett et al., 1993). Accordingly, we inferred that SCOR nonresponders will be particularly deficient on the WCST. In contrast to this hypothesis, we found that SCOR hyperresponders were particularly deficient on the WCST. This inconsistency may indicate that the present association between perseverations on the WCST and SCOR hyperresponding is not mediated by prefrontal pathology. Indeed, prefrontal damage cannot be deduced reliably from the WCST as perseveration is seen after extrafrontal lesions as well (Benton, 1994). Nevertheless, prefrontal involvement in SCOR responding in schizophrenia is far from being defined. Although Hazlett et al. (1993) related SCOR nonresponding to prefrontal hypometabolism, their conclusion is based on a small number of schizophrenic patients who were characterized by a diffuse pattern of cortical and subcortical hypometabolism. Thus, SCOR nonresponding in these patients might be attributed to extrafrontal pathology. To determine whether prefrontal hypometabolism leads to SCOR nonre-
sponding, as suggested by Hazlett et al., or leads to hyperresponding, as may be deduced from the present study, one may need to test a sample of schizophrenic patients with more localized signs of hypometabolism. We are also uncomfortable with the assumption that if prefrontal structural lesions in neurologic patients lead to SCOR nonresponding, then prefrontal hypometabolism in schizophrenia should lead to similar SCOR abnormality. Indeed, the massive structural lesions encountered in neurological patients include damage to the cortical efferents and therefore some of the emerging symptoms reflect the reactivity of extrafrontal systems (Myslobodsky, 1993). Accordingly, abolition of SCOR in neurological patients indicates that these extrafrontal systems fail to generate and maintain sympathetic reactivity to a sequence of nonsignal stimuli. On the other hand, the subtle prefrontal pathology in schizophrenia may be caused by a dysfunction of cortical afferents (Weinberger and Berman, 1988). Under these assumptions, we do not expect that prefrontal dysfunction would abolish SCOR reactivity. Present results indicate that in fact prefrontal dysfunction may be associated with a delay of sympathetic habituation to a sequence of nonsignal stimuli. As indicated by Morgan et al. (19931, the delayed habituation of SCOR in patients with poor performance on the WCST may be interpreted as an extension of perseverative tendencies into the emotional domain.
References
Aim, T., Lindstriim, L., 6st, L.G. and 6hman, A. (1984) Electrodermal nonresponding in schizophrenia: relationship to attentional, clinical, biochemical, computed tomographical and genetic factors. Int J Pqxhophysio/ 1,195-208. American Psychiatric Association. (1987) DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC. Bartfai, A., Levander, SE., Nyback, H. and Schalling, D. (1987) Skin conductance nonresponding and nonhabituation in schizophrenic patients. Acta Psychiatr Stand 75, 321-329. Benton, A.L. (1994) Neuropsychological Rev Psycho1 45, l-23. Bernstein,
AS.,
Frith,
C.D.,
Gruzelier,
assessment. J.H.,
Patterson,
Anna T.,
112
R.A. Schiffer et al. /Psychiatry Research 65 (1996) 107-112
Straube, E., Venables, P.H. and Zahn, T.P. (1982) An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol Psycho1 14, 155-211. Bernstein, AS., Taylor, K.W., Starkey, P., Juni, S., Lubowsky, J. and Pauley, H. (1981) Bilateral skin conductance, finger pulse volume, and EEG orienting response to tones of differing intensities in chronic schizophrenics and controls. J Nerv Ment Dis 169, 513-528. Braude, W.M., Barnes, T.R.E. and Gore, S.M. (1983) Clinical characteristics of akathisia: a systematic investigation of acute psychiatric inpatient admission. Br J Psychiatry 143, 139-150. Dawson, M.E., Nuechterlein, K.N., Schell, A.M. and Mintz, J. (1992) Concurrent and predictive electrodermal correlates of symptomatology in recent-onset schizophrenic patients. J Abnorm Psycho1 101, 153-164. Deakin, J., Baker, H., Frith, C., Joseph, M. and Johnstone, E. (1979) Arousal related excretion of noradrenaline metabolites and clinical aspects of unmedicated chronic schizophrenic patients. J Psychiatr Res 15, 57-65. Frith, CD., Stevens, M., Johnstone, E.C. and Crow, T.J. (1979) Skin conductance responsivity during acute episodes of schizophrenia as a predictor of symptomatic improvement. Psycho1 Med 9, 101-106. Goldberg, T.E., Weinberger, D.R., Berman, K.F., Pliskin, N.H. and Podd, M.H. (1987) Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test. Arch Gen Psychiatry 44, 1008-1014. Goldman-Rakic, P.S. (1987) Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: Plum, F. (Ed.), Handbook of Physiology: The Nervous System. Vol. 5. University Press, New York, pp. 373-417. Green, M.F., Nuechterlein, K.H. and Satz, P. (1989) The relationship of symptomatology and medication to electrodermal activity in schizophrenia. Psychophysiology 26, 148-157. Grueninger, W. and Grueninger, J. (1973) The primate frontal cortex and allassostasis. In: Pribram, K.H. and Luria, A.R. (Eds.), Psychophysiology of the Frontal Lobes. Academic Press, New York, pp. 253-290. Gruzelier, J.H. (1976) Clinical attributes of schizophrenic skin conductance responders and nonresponders. Psycho/ Med 6, 245-249. Hazlett, E.A., Dawson, M.E., Buchsbaum, MS. and Nuechterlein, K.H. (1993) Reduced regional brain glucose metabolism assessed by positron emission tomography in electrodetmal nonresponder schizophrenics: A pilot study. J Abnorm Psycho1 102,39-46. Heaton, R.K. (1981) Wisconsin Card Sorting Test Manual. Psychological Assessment Resources, Odessa, FL. Katsanis, J. and Iacono, W.G. (1992) Temporal lobe dysfunction and electrodermal nonresponding in schizophrenia. Biol Psychiatry 31, 159-170. Kay, S.R., Opler, L.A. and Lindenmayer, J.P. (1988) Reliability and validity of the Positive and Negative Syndrome
Scale for schizophrenics. Psychiatry Res 23, 99-110. Kim, D.K., Shin, Y.M., Kim, C.E., Cho, H.S. and Kim, Y.S. (1993) Electrodermal responsiveness, clinical variables, and brain imaging in male chronic schizophrenics. Biol Psychiatry 33, 786-793. Mednick, S.A. and Schulsinger, F. (1968) Some premorbid characteristics related to breakdown in children with schizophrenic mothers. In: Rosenthal, D. and Kety, S.S. (Eds.), The Transmission of Schizophrenia. Pergamon Press, Oxford, pp. 267-291. Milner, B. (1963) Effects of different brain lesions on card sorting: The role of the frontal lobes. Arch Neurol 9, 90-100. Mintz, M., Alfisi, S. and Sigal, M. (1990) Skin conductance responding in schizophrenic patients with abnormal involuntary movements. Pqchiatly Res 34, 19-27. Morgan, M.A., Romanski, L.M. and LeDoux, J.E. (1993) Extinction of emotional learning: Contribution of medial prefrontal cortex. Neurosci Lett 163, 109-113. Myslobodsky, M.S. (1993) Central determinants of attention and mood disorder in tardive dyskinesia (‘tardive dysmentia’). Brain Cogn 23, 88-101. Schneider, S.J. (1982) Electrodermal activity and therapeutic response to neuroleptic treatment in chronic schizophrenic in-patients. Psychol Med 12, 607-613. Seidman, L.J., Yurgelun-Todd, D., Kremen, W.S., Woods, B.T., Goldstein, J.M., Faraone, S.V. and Tsuang, M.T. (1994) Relationship of prefrontal and temporal lobe MRI measures to neuropsychological performance in chronic schizophrenia. Biol Psychiatry 35, 235-246. Simpson, G.M. and Angus, J.W.S. (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Stand 212 (SuppI.), 11-19. Simpson, G.M., Lee, J.H., Zoubok, B. and Gardos, G. (1979) A rating scale for tardive dyskinesia. Psychopharmacology 64,171-179. Straube, E.R. (1979) On the meaning of electrodermal nonresponding in schizophrenia. J Nerv Ment Dis 167, 601-611. Sullivan, E.V., Mathalon, D.H., Zipursky, R.B., KersteenTucker, Z., Knight, R.T. and Pfefferbaum, A. (1993) Factors of the Wisconsin Card Sorting Test as measures of frontal-lobe function in schizophrenia and in chronic alcoholism. Psychiatry Res 46, 175-199. Weinberger, D.R. and Berman, K.F. (1988) Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia. Schizophr Bull 14, 157-168. Weinberger, D.R., Berman, K.F. and Zec, R.F. (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 43, 114-125. Zahn, T.P. (1980) Predicting outcome from measures of attention and autonomic functioning. In: Baxter, C. and Melnechuk, T. (Eds.), Perspectives in Schizophrenia Research. Raven Press, New York, pp. 81-104. Zahn, T.P., Carpenter, W.T. and McGlashan, T.H. (1981) Autonomic nervous system activity in acute schizophrenia: II. Relationship to short-term prognosis and clinical state. Arch Gen Psychiatry 38, 260-266.