Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage

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1 Schizophrenia Reearch 37 (1999) Commentary Comparion of et-hifting ability in patient with chronic chizophrenia and frontal lobe damage Chrito Panteli a,*, Fiona Z. Barber a, Thoma R.E. Barne b, Hazel E. Nelon c, Adrian M. Owen d, Trevor W. Robbin d a Cognitive Neuropychiatry Reearch Unit, Department of Pychiatry, The Univerity of Melbourne, and Applied Schizophrenia Diviion, Mental Health Reearch Intitute, Parkville, Autralia b Diviion of Neurocience and Pychological Medicine, Imperial College School of Medicine, London, UK c Department of Pychology, Horton Hopital, Surrey, UK d Department of Experimental Pychology, Cambridge Univerity, Cambridge, UK Received 20 May 1998; accepted 9 November 1998 Abtract Neuropychological tudie of patient with chizophrenia have conitently identified deficit on tet enitive to frontal lobe function. One paradigm that ha been widely ued i that of attentional et-hifting uing the Wiconin Card Sorting Tet ( WCST ). In the preent tudy, patient with chronic chizophrenia and with frontal lobe leion were aeed on a computeried et-hifting tak that provide a componential analyi of the WCST by ditinguihing between intra-dimenional and extra-dimenional et-hifting. Out of 51 patient with chizophrenia, thoe with high IQ (n=24) were compared with patient with leion in prefrontal cortex (n=22) and with normal control ubject (n=18). Thee three group were well matched for age, ex and National Adult Reading Tet (NART ) IQ. The chizophrenic group howed a ignificantly higher rate of attrition at the intra-dimenional hift tage of learning compared with the other two group. At the extra-dimenional hift tage, both the chizophrenic and frontal leioned group howed greater attrition than control. Further, patient with chizophrenia who were able to learn the intradimenional reveral tage required more trial and made ignificantly more error at that tage than the other two group. In comparion with high IQ patient with chizophrenia, thoe with low IQ performed at a lower level but howed a qualitatively imilar pattern of performance, providing further evidence that the et-hifting deficit were not imply explained by any global intellectual decline. Patient with chizophrenia who dropped out at the extradimenional hift tage had higher negative ymptom core compared with patient dropping out at previou learning tage, while patient failing at the intra-dimenional hift tage had lower core for bradyphrenia (lowne of thought). The reult ugget that patient with chronic chizophrenia fail to learn et and are impaired at both ethifting and concept formation. The relevance of thee finding to undertanding the nature of prefrontal cortical deficit in chronic chizophrenia i dicued. The implication of thee finding to the rehabilitation of thee patient i conidered Elevier Science B.V. All right reerved. Keyword: Frontal-triatal; IQ; Learning; Neuropychology; Schizophrenia; Set-hifting; Symptom Correponding author. Tel: ; Fax: ; ckp@cortex.mhri.edu.au /99/$ ee front matter 1999 Elevier Science B.V. All right reerved. PII: S (98)00156-X

2 252 C. Panteli et al. / Schizophrenia Reearch 37 (1999) Introduction (Gold et al., 1994; Heaton et al., 1994; Hane Neuropychological tudie of patient with et al., 1996a,b; Panteli et al., 1997). However, no recent tudy ha directly compared patient with chizophrenia have conitently identified deficit chizophrenia and frontal leion patient on tet on tet of executive function, traditionally conidered of et-hifting ability. enitive to frontal lobe damage ( Kolb and A econd iue ariing from tudie of et- Whihaw, 1983; Stu et al., 1983) ( Taylor and hifting which ue the WCST, i that ucceful Abram, 1984, 1987; Weinberger et al., 1986, 1988; performance require motivational, attentional, Panteli et al., 1997). Deficit of executive function memory, and learning procee, in addition to or are characteried by impairment in planning, intead of intact executive function (Downe et al., maintenance of goal-directed behaviour and 1989). Therefore, imilarly poor performance behavioural flexibility. Tak employed to ae between patient with chizophrenia and patient different apect of executive function have often with pecific brain leion may reflect very different ued attentional et-hifting paradigm, uch a underlying cognitive deficit, a uggeted in a the Wiconin Card Sorting Tet ( WCST) (Berg, poitron electron tomography (PET) tudy com- 1948). In thee paradigm, ubject are required paring patient with chizophrenia and to hift attention between different timulu dimenion Huntington dieae matched for WCST perfor- on the bai of reinforcing feedback. It i mance (Goldberg et al., 1990). Recent tudie have propoed that patient with frontal leion are attempted to eparate thi complex tak into it impaired in their ability to inhibit previouly component cognitive procee. Two type of ethift learned repone and, a a conequence, are have been propoed (Downe et al., 1989): unable to hift their attention to the relevant intra-dimenional hift ( IDS), which involve the timulu, thu making error of pereveration tranfer of a rule within the ame timulu dimen- (Milner, 1963). ion (e.g. chooing circle intead of quare), and It ha been demontrated that patient with extra-dimenional hift ( EDS), which require a chizophrenia alo perform poorly on tak of tranfer of attention acro different timulu attentional et-hifting ( Kolb and Whihaw, 1983; dimenion (e.g. chooing on the bai of colour Weinberger et al., 1986; Goldberg et al., 1987; rather than the previou category of hape). In Morice, 1990). In general, the reult indicate that eence, EDS hifting i the core component of the patient with chizophrenia achieve fewer orting WCST, and i the bai for the achievement of categorie than control and diplay ignificantly novel orting categorie. IDS hifting i a more more pereverative error. The common explana- baic element of the WCST and i related to the tion provided for thi performance i that patient ability of the ubject to be aware of the conceptual with chizophrenia make pereverative error due category within which they are reponding. A to a failure to inhibit inappropriate repone ucceful IDS hift require a generaliation of (Panteli and Brewer, 1996). On the bai of thee learning or the ability to learn et. In an attempt finding, parallel have been drawn between to diect thee component procee involved in patient with chizophrenia and thoe with frontal et-hifting, everal recent tudie have ued a lobe damage and it ha been inferred that ethifting computeried verion of the WCST that i graded deficit in patient with chizophrenia are in complexity, and allow thee procee to be indicative of frontal lobe dyfunction. However, it eparated ( Robert et al., 1987; Downe et al., remain unclear whether patient with chizo- 1989; Owen et al., 1991). phrenia fail thee tak becaue of the ame underlying The preent tudy et out directly to examine cognitive deficit a frontal lobe patient. One et-hifting ability in chizophrenia and to compare trategy to help elucidate the nature of the deficit thi with patient with frontal lobe leion. in chizophrenia i directly to compare perfor- Previou tudie uing the computeried et-hifting mance with that of other neurological patient tak have hown that patient with frontal lobe ( Randolph et al., 1993), a in ome recent tudie damage are impaired at the EDS hifting tage

3 C. Panteli et al. / Schizophrenia Reearch 37 (1999) (Owen et al., 1991) and that their repone are ( Liddle, 1987a; Liddle and Morri, 1991; Brewer pereverative (Owen et al., 1993). Two tudie et al., 1996; Panteli and Brewer, 1995, 1996; have ued a related paradigm to ae patient Norman et al., 1997). Therefore, in the preent with chizophrenia ( Elliott et al., 1995; Hutton invetigation we alo invetigate the qualitative et al., 1998). While Hutton et al. (1998) found apect of performance pecifically for thoe that firt-epiode patient were relatively unimpaired patient who paed at each tage. In thi way we in et-hifting ability, Elliott et al. (1995) were able to examine, firt, whether there were demontrated that patient with etablihed chizophrenia ubgroup of patient with chizophrenia who were pereverative, with apparent imilari- could be identified on the bai of their perfor- tie to the performance oberved in patient with mance on et-hifting; and econd, whether thee frontal lobe leion. However, a age, education, ubgroup alo differed in term of their ymptomatological and IQ vary coniderably between pychiatric and and behavioural profile. neurological patient group, correct inference require direct matched comparion, a in the preent tudy. 2. Method The current invetigation further et out to addre methodological iue in the analyi of 2.1. Subject et-hifting behaviour. Previou tudie uing the computeried paradigm have typically analyed the Patient with chizophrenia data for attrition rate in a cumulative manner; A detailed decription of the election of patient that i, examining the overall number of patient with chizophrenia ha been provided elewhere who had failed the tak by a particular tage, a ( Panteli et al., 1997). Patient were excluded if oppoed to the actual number who failed at that there wa recent drug abue a aeed with urine level. Thi type of analyi aume that a patient drug creening, poor eyeight, hitory of ignificant failing a pecific tage will alo fail each ubequent head injury, epilepy, leucotomy, or other neurological tage. Additionally in previou tudie, when a diorder, or ignificant medical condition ubject failed a pecific tage they were given the conidered to affect cognitive performance (including maximum error rate for each ubequent tage, thyroid dieae) (detailed in Panteli et al., even though they did not attempt them. Alo, 1997). Fifty-one patient ( 43 male, 8 female) previou tudie have not examined the performance meeting DSM-III-R criteria for chizophrenia of ubject actually paing any particular ( American Pychiatric Aociation, 1987) parti- tage, in order to ae the level of difficulty cipated in the tudy. The patient were taken from encountered by different group in attaining crite- a chronic ample of patient who were inpatient rion. Thee aumption and data analyi technique at a long-tay pychiatric hopital on the outkirt may obcure ubtle performance difference of London. The age range wa year between patient who fail at different tage of the (mean=48.3, SE=1.6), mean length of illne wa tet. Importantly, many tudie have hown that 27.5 year (range: 8 44; SE=1.4) and the mean patient with chizophrenia are not homogeneou length of admiion wa 18.5 year (range: 1 43; in their cognitive deficit (e.g. Seidman, 1990; SE=1.7). At the time of teting, all patient were Shallice et al., 1991; Braff et al., 1991; Anderon taking neuroleptic medication. The range of doage et al., 1991). Therefore, it i likely that different expreed a milligram equivalent of chlorpromazine patient will fail at different tage and thi will (CPZEq; Rey et al., 1989; Atkin et al., 1997) reflect different cognitive abnormalitie. Previou wa (mean=1370; SE=167.6). work ha uggeted that uch variation may reflect Forty-even of the 51 patient were teted on the heterogeneou ymptomatology which charac- the National Adult Reading Tet ( NART) terie the diorder, and that different pattern of neuropychological impairment are aociated with particular ymptom or behavioural profile ( Nelon, 1982), which provide an etimate of premorbid IQ that i table over time in patient with chronic chizophrenia (Smith et al., 1998).

4 254 C. Panteli et al. / Schizophrenia Reearch 37 (1999) Table 1 Subject characteritic Group n Age NART IQ Sex Age of onet Length of Length of (SE) (SE) M:F of illne (SE) illne (SE) admiion (SE) Schizophrenia All : (1.56) (2.10) (0.83) (1.44) (1.66) High IQ : (2.15) (1.42) (1.33) (2.13) (2.49) Low IQ : (2.56) (2.41) (1.12) (2.25) (2.54) Frontal Lobe : leion patient (4.03) (2.71) Control ubject : (4.03) (2.06) Patient with chizophrenia coring le than ten patient had a mean NART IQ core of 87.1 (SE= correct word on the NART were further teted 2.4; range: 65 99) and a mean WAIS-R IQ of 73.5 uing the Schonell Graded Word Reading Tet (SE=2.3; range: 61 87). The age range in thee (Schonell, 1942), which provided more accurate patient wa year (mean=48.4; SE=2.6). aement at lower IQ level. The mean etimated IQ (NART IQ) wa 98.2 (SE=2.1; range: Frontal lobe patient ). Current IQ of the ample wa alo Data for the patient with frontal lobe leion aeed in 32 of the patient with chizophrenia (n=22) have been decribed previouly (Owen uing the WAIS-R ( Wechler Adult Intelligence et al., 1990; Panteli et al., 1997) and are included Scale, Revied) ( Wechler, 1981). The core here for direct comparion. Briefly, thee patient ranged from 61 to 109 (mean 80.8; SE=2.0) had undergone unilateral or bilateral frontal lobe uggeting that there had been ignificant intellec- urgery at the Maudley Hopital Neurourgical tual decline within the ample, conitent with Unit, London. Reaon for urgery included previou finding in a imilar patient group anterior communicating aneurym clipping, (Nelon et al., 1990). meningioma or other tumour, arterio-venou mal- A the patient with chizophrenia had a low formation removal. Patient with computeried mean IQ in comparion with the frontal leion tomography (CT ) can evidence of ubcortical patient and normal control, the 51 patient with damage were excluded. The patient were teted, chizophrenia were divided into two group having on average, 38 month potoperatively (median= high and low NART IQ core. Thi wa achieved 24 month, range: month). Fifteen were on uing a median plit of the NART IQ core for anticonvulant medication at the time of teting. the 47 patient with chizophrenia for whom thee data were available. In order to match patient Control ubject with chizophrenia and thoe with frontal leion A ingle group of normal control ubject (n= effectively, only the 24 patient in the high IQ 18) wa elected to match the two patient group group (NART IQ core >100) were ued for the for age and NART etimated IQ. The control comparion tudy. In thi group the mean NART group wa elected from a pool of volunteer from IQ core wa (SE=1.4; range: ) and the North-Eat Age Reearch panel in Newcatlethe mean WAIS-R core wa 87.2 (SE=2.3; range: upon-tyne ); all thee patient cored above 25 on the The ummary characteritic for the three group Mini Mental State Examination (MMSE) are hown in Table 1. One-way ANOVA revealed ( Foltein et al., 1975). The age range in thi no ignificant difference between the high IQ ubgroup wa year (mean=48.2, SE=2.2). chizophrenia patient and the frontal leion The 23 (20 male, 3 female) low IQ chizophrenia patient or normal control for ex (x2=4.33, df=

5 C. Panteli et al. / Schizophrenia Reearch 37 (1999) , NS), age [F(2,61)=1.26, NS], or NART IQ etimate [ F(2,60)=2.08, NS] Procedure (a) (b) (c) (d) Attentional et-hifting tak (ID/ED tak) In thi tak (Downe et al., 1989; Owen et al., 1991) each ubject wa required to learn a erie of dicrimination in which one of two timulu dimenion ( purple-filled hape or white line) wa relevant and the other wa not, uing feedback provided automatically by the computer. Four boxe were preented on the computer creen, two of which contained different exemplar of one of the dimenion, either hape or line (ee Fig. 1). Initially, patient were given a imple imultaneou dicrimination (SD) in which ubject had to identify which exemplar wa correct. A repone reulted in an auditory tone, together with viual feedback which informed the ubject if their repone wa correct; either the word CORRECT in green letter or the word WRONG in red would appear on the creen. The ame feedback wa ued for each of the ubequent tage. After 1.5 the creen cleared and there wa an inter-trial interval of 1 before the timuli were again preented but at different location. Following eight conecutive correct repone the tak moved on to the next et-hifting tage. Following the initial SD tage, the remaining eight tage were a follow. In the econd tage (SDR) the previouly incorrect choice became the correct one (i.e. the contingencie were revered). At the third tage (C_D) the econd dimenion ( purple hape) wa introduced with one exemplar of each dimenion paired together to form a compound timulu in two of the repone boxe. To ucceed, a ubject had to continue to repond to the correct exemplar of the previou tage. For thi and ubequent tage, exemplar of different dimenion were paired in a peudo-random fah- (e) Fig. 1. (a) Simple Dicrimination (SD) and Reveral (SDR). (b) Compound Dicrimination, with exemplar eparated (C_D). (c) Compound Dicrimination with overlapping exemplar (CD) and Reveral (CDR). (d) Intradimenional Shift (IDS) and Reveral (IDR). (e) Extradimenional Shift (EDS) and Reveral (EDR).

6 256 C. Panteli et al. / Schizophrenia Reearch 37 (1999) ion o that all four combination were ued Attrition rate. Subject were initially However, no more than three trial with the ame compared in term of the proportion of ubject pairing were allowed. The timuli for the fourth in each group reaching criterion at each tage of tage (CD) and ubequent tage were alo compound, the tet (Fig. 2). The aociation between the but the two exemplar from the different performance of the different group were analyed dimenion were uperimpoed, with the white line uing a likelihood ratio analyi, which i ueful alway in the foreground. The contingencie were with mall cell frequencie ( Kullback, 1959; again unchanged from the previou two tage. A Robbin, 1977). The tatitic i termed 2i and i reveral then occurred at the fifth tage (CDR). ditributed a chi-quare (x2). New exemplar for both dimenion were introduced A eparate analyi wa performed in order to at the ixth tage, the intra-dimenional hift compare the non-cumulative proportion of each (IDS), but the relevant dimenion for a correct ubject group reaching criterion at each learning repone wa unchanged from tage 1 (i.e. if line tage. That i, thi analyi compared the actual were the correct dimenion in tage 1, line continued number of ubject who failed at each individual to be correct). Thi wa followed by a further tage, a oppoed to a cumulative core. reveral at the eventh tage (IDR). In the next tage, the extra-dimenional hift ( EDS), new Trial-to-criterion and number of exemplar were again introduced, and ubject error. Further analye of group difference in were now required to repond to the previouly performance were undertaken by an examination irrelevant dimenion (e.g. hape rather than line). of the number of trial required to reach criterion In the final tage there wa again a reveral ( EDR) at each tage. The group were compared uing a o that repone to the previouly irrelevant exemplar erie of one-way ANOVA, with Bonferroni cor- of the new dimenion wa required for a rection to minimie Type I error. Thi analyi correct repone. The main meaure of performance wa undertaken in two way: (1) all the ubject on thi tak wa the tage uccefully who had tarted the tak in each group were attained. Performance indice on the et-hifting included in the comparion at each tage of tak compried meaure of the proportion of learning. For thoe ubject who did not complete patient reaching criterion at each tage, trial to all nine level due to failure at an earlier tage, the criterion and number of error at each tage. number of trial wa inerted a 50. That i, it wa aumed that the ubject would have failed all Symptom rating ubequent level and would have ued up all 50 The Mancheter Scale ( Krawiecka et al., 1977) of the available trial; ( 2) only thoe ubject who wa ued to ae pychopathology. A new item reached criterion at that tage were included in the of bradyphrenia (lowne of thought) wa opera- analyi, that i, only thoe ubject who uccefully tionally defined (ee Appendix A). Pychopathology completed the tak within the 50 trial allowed rating were made by one of the inveti- (i.e. thi analyi wa conditional on paing). gator ( TREB), who wa trained in uing the cale, Thi conditional comparion provide a meaure and who wa blind to the neuropychological of tak performance for a ubgroup of patient aement. who paed that tage a oppoed to examining performance of all ubject regardle of their 2.3. Data analyi pa fail tatu. The econd et of analye, uing only thoe ubject who paed that learning tage, Comparion of patient with chizophrenia, wa conducted in order to determine whether there frontal patient and healthy control were qualitative difference between the performance In order to match ubject appropriately acro of the three group when all ubject were the three group, in thi ection of the analye the 23 low IQ patient with chizophrenia were excluded. paing the tet at that level. The three group were alo compared on the bai of the number of error produced at each

7 C. Panteli et al. / Schizophrenia Reearch 37 (1999) (a) (b) Fig. 2. (a) Percentage of ubject reaching criterion at each learning tage. (b) Non-cumulative attrition rate for each learning tage.

8 258 C. Panteli et al. / Schizophrenia Reearch 37 (1999) learning tage. In a imilar manner to the data for 3. Reult number of trial, a erie of one-way ANOVA wa firt conducted on the data for all patient 3.1. Comparion of patient with chizophrenia, regardle of their pa fail tatu at that leaning frontal patient and healthy control tage; a econd et of ANOVA wa performed to compare only thoe ubject paing that learning Attrition rate: cumulative (Fig. 2a) tage ( conditional analyi). Again, Bonferroni Significant group difference emerged at the IDS correction were applied where appropriate. and IDR tage ( IDS: 2i=14.32, df=2, p<0.001; IDR: 2i=21.07, df=2, p< ) and the EDS Comparion of high and low IQ patient with and EDR tage (2i=23.15, df=2, p= ). chizophrenia Further invetigation revealed that the effect wa The data for thi ection of the reult were due to an increaed number of failure in the analyed in the ame way a previouly. The one way ANOVA were performed by comparing the two group of patient with chizophrenia. patient with chizophrenia, a compared with the other two group at the IDS and EDS tage (chizophrenia v control: IDS: 2i=13.50, df=1, p<0.0005; IDR: 2i=18.87, df=1, p<0.0005; EDS and EDR: 2i=23.13, df=1, p<0.0005), a well a Comparion of ymptom rating cale core with tak performance greater failure of the frontal patient in comparion In order to conduct a more detailed examination with the control ubject at the EDS tage (2i= of the patient with chizophrenia, all 51 patient 9.61, df=1, p<0.005). were grouped according to their performance on the et-hifting tak. Patient were divided into a Attrition rate: non-cumulative (Fig. 2b) number of group, determined by their performance When examined non-cumulatively, ignificant on the et-hifting tak (ee Reult ection). group difference were found at the IDS ( IDS Score on the Mancheter Scale were compared (2i=15.729, df=2, p<0.0005), IDR (2i=8.149, acro the group. In accordance with Liddle df=2, p<0.05) and EDS (2i=8.493, df=2, p= model of three yndrome of chizophrenia 0.01) tage. Further analyi comparing each (Liddle, 1987b), compoite core for negative, patient group with the normal ubject revealed poitive and diorganiation yndrome were calculated that, at the intra-dimenional hift tage thi wa from the Mancheter Scale individual item due to a ignificant attrition of patient with chizo- core for each patient (Johntone et al., 1984; phrenia ( IDS: 2i=9.97, df=1, p<0.005; IDR: 2i= Appendix A). A clinical rating of bradyphrenia 5.36, df=1, p=0.05), while there wa no attrition wa examined a a eparate item. in frontal patient or control ubject at thee The chizophrenia group were compared with tage. At the EDS tage, both chizophrenic and regard to pychopathology uing a erie of oneway frontal group were ignificantly different to con- ANOVA. Where appropriate, pot hoc trol (chizophrenia v control: 2i=6.69, df=1, Student t-tet were conducted to etablih the p=0.01; frontal v control: 2i=6.36, df=1, p= nature of the difference. Previou invetigation of 0.01). chizophrenic yndrome core ha found an aociation between negative ymptom and impair Trial to criterion (Fig. 3a) ment on tet of frontal lobe functioning (Liddle Uing the firt method of analyi, that i includ- and Morri, 1991). In accordance with thee find- ing all ubject regardle of whether they had ing, it wa propoed that ubject who performed paed or failed, there wa a ignificant main effect imilarly to thoe with frontal leion would have of group [MANOVA, F(2,59)=16.30, more negative ymptom than the other group. p< ], a ignificant group by hift inter- In order to tet thi hypothei, a priori contrat action [ Wilk l=0.394, F(16,104)=3.86, were ued in the one-way ANOVA comparing the p<0.0005] and a ignificant main effect of hift group on negative ymptomatology. [ Wilk l=0.275, F( 8,52)=17.10, p< ].

9 C. Panteli et al. / Schizophrenia Reearch 37 (1999) (a) (b) Fig. 3. (a) Trial to criterion for thoe ubject paing each learning tage. (b) Error at each learning tage.

10 260 C. Panteli et al. / Schizophrenia Reearch 37 (1999) Pot-hoc tet howed that the chizophrenic group lar, no difference were een at IDS, EDS or EDR needed ignificantly more trial to reach criterion level of learning. than both the other group at the SD [F(2,59)= 11.31, p<0.0001], SDR [ F( 2,59)=9.86, 3.2. Comparion of high v low IQ group p<0.0002], IDS [ F(2,59)=8.05, p<0.001], EDS [ F(2,59)=9.59, p<0.0002] and EDR [ F(2,59)= Attrition rate (Fig. 4) 16.40, p< ] tage. At the EDS tage the Comparion of the high and low IQ ubgroup patient with frontal leion were alo ignificantly of patient with chizophrenia revealed a ignifi- different from the normal control and the patient cant difference in cumulative attrition rate only with chizophrenia. by the EDR tage of learning (2i=4.34, df=1, Uing the conditional method of analyi, only p<0.05). There were no difference in non-cumulaubject paing the particular tage were examined tive failure rate between the two group. ( Fig. 3a). The patient with chizophrenia needed ignificantly more trial to reach criterion than Trial to criterion both the frontal leioned patient and control at Analyi of the number of trial to reach crite- the SD learning tage [ F( 2,59)=11.31, p<0.0001], rion between the two group over all tage of the the SDR tage [ F(2,59)=9.86, p<0.0005] and the hift tak revealed a ignificant difference between IDR tage [ F( 2,43)=8.58, p<0.001]. In addition, the two group [ F( 1,45)=5.42, p<0.05], a ignifithe patient with chizophrenia took more trial cant effect of hift [ Wilk l=0.132, F(8,38)= to reach criterion than the control group but not 31.30, p<0.0005] but no group by tage interaction the frontal group at the CDR tage [F(2,53)= [ Wilk l= , F( 8,38)=1.263, NS]. Pot-hoc 5.46, p<0.01]. analyi revealed that there wa a ignificant difference cumulatively at the C_D tage of learning [ F( 1,45)=9.38, p<0.005]. Uing the noncumulative method of analyi of trial for each Number of error (Fig. 3b) of thee group (i.e. patient failing a particular There wa a ignificant difference in the number tage were excluded in the analyi of the ubeof error produced between the group at the SDR quent tage), the low IQ group needed more trial tage [ F(2,58)=3.94, p<0.05], IDS tage to reach criterion at the C_D learning tage com- [ F(2,53)=9.41, p=0.0005] and at the IDR tage pared with the high IQ patient [ F(1,43)=6.55, [ F(2,46)=8.84, p=0.001]. Pot-hoc tet revealed p=0.01]. Further, even for thoe patient paing that thi wa due to ignificantly greater error by the C_D tage, the lower IQ group required more the patient with chizophrenia in comparion with trial to reach criterion than the higher IQ group the control at the SDR tage; while patient with [ F( 1,40)=10.29, p<0.005]. chizophrenia made ignificantly more error than both the other group at the IDS and IDR tage Number of error Patient with frontal leion did not differ from The increaed difficulty in performance at the control for the number of error. C_D tage wa alo reflected in a ignificantly When error were analyed for thoe ubject increaed number of error in the low IQ group paing a particular learning tage, ignificant [ F( 1,43)=5.14, p<0.05]. Analyi of only thoe difference were found at the SDR tage patient paing the C_D tage confirmed that the [ F(2,58)=3.94, p<0.05], which wa due to ig- low IQ group produced more error to reach nificantly greater error in the chizophrenic group criterion at that tage [F( 1,40)=10.57, p<0.005]. compared with the normal group. At the IDR tage, patient with chizophrenia paing thi 3.3. Comparion of ymptom rating cale core tage made ignificantly more error than both the with tak performance frontal leion patient and the control group [ F(2,43)=5.65, p<0.01]. There were no differ- The above reult demontrated that the patient ence in error core at the other tage, in particu- with chizophrenia howed ignificant difficulty at

11 C. Panteli et al. / Schizophrenia Reearch 37 (1999) Fig. 4. Set-hifting in high v low IQ chizophrenia group. the IDS, IDR and EDS tage of learning. Patient patient paing all tage did not differ from thoe with chizophrenia were therefore divided into the failing at IDS or EDS; therefore, the patient following group: (i) thoe who failed prior to failing at thee et-hifting tage of the tak were reaching the IDS tage (n=10); (ii) thoe who compared with thoe completing the tak failed at IDS (n=13); (iii) patient failing at IDR uccefully. (n=9); (iv) patient failing at EDS (n=11); and A one-way ANOVA with a priori contrat (v) thoe who completed the tak (n=7). A the howed that patient who failed at EDS had group who completed the tak had ignificantly ignificantly higher negative ymptom core than higher NART IQ core than the other group the other three group [t(23.9)=2.80, p=0.01]. [ F(4,42)=4.27, p=0.005], the main comparion Patient failing at EDS alo had ignificantly higher examined the firt four group a they did not negative ymptom in comparion with thoe differ on the IQ meaure [ F(3,36)=1.48, NS]. patient paing all tage of the tak [t(16)=2.35, However, pot-hoc analyi revealed that the p<0.05]. Comparion of the four group revealed

12 262 C. Panteli et al. / Schizophrenia Reearch 37 (1999) that patient failing at the IDS tage had ignifi- the CD (r = 0.32, p<0.05) and EDR cantly lower core on the bradyphrenia item (r = 0.29, p<0.05) tage of the tak. Therefore, [t(37)= 2.21, p<0.05]. the effect of medication do not explain the deficit in performance on the tak. Length of illne wa 3.4. Correlational analye aociated with poorer performance at the earliet tage (SD: r =0.28, p<0.05; and SDR: r =0.35, For the normal group, there were no ignificant p<0.05) of the tak, while hopitaliation hitory aociation between NART IQ etimate and wa not aociated with performance. either error or trial at any tage of the tak. In With repect to the ymptom of chizophrenia, contrat, the chizophrenic group howed moder- error at the SDR tage were aociated with ate and ignificant correlation at the C_D greater negative ymptom (r =0.82, p<0.05), (r = 0.40, p<0.01) and IDS (r = 0.34, while poorer performance at the CD and CDR p<0.05) tage. The frontal group only howed a tage were aociated with greater ymptom of ignificant poitive correlation between IDR trial diorganiation (r =0.31 and 0.30, repectively, and IQ (r =0.67, p<0.05), indicating that higher p<0.05). Alo, higher core for bradyphrenia NART IQ wa aociated with a greater number were predictive of poorer performance at the C_D of trial. The normal ubject howed ignificant and CDR level (r =0.34 and 0.33, repectively, correlation between age and performance at the p<0.05). No relationhip wa found between the EDS tage of learning (r =0.52, p<0.05). The variou performance meaure and the poitive other group did not how any correlation with ymptom of chizophrenia. age or NART IQ. Further, for the control ubject, older age wa aociated with greater number of total error (r =0.572, p<0.05) ummed over all 4. Dicuion tage, while older age wa aociated with lower EDID level achieved in the frontal group The reult of thi tudy, comparing patient (r = 0.569, p<0.01). In contrat, for the patient with chizophrenia with both frontal leion with chizophrenia, tage of the tak achieved wa patient and matched control ubject, how triking difference in the profile of the two patient correlated with NART IQ (r =0.355, p=0.01), which wa conitent with the earlier analye. group on the et-hifting paradigm. While ignificantly In order to examine the influence of illne and more ubject in both patient group failed treatment factor on performance, correlational at the extra-dimenional ( EDS) tage of the tak analye were examined for the patient with compared with control, by far the majority of chizophrenia. Doage of medication, expreed a patient with chronic chizophrenia were unable milligram equivalent of chlorpromazine, wa ignificantly to reach criterion by the earlier intra-dimenional aociated with age (r = 0.545, hift (IDS) and reveral (IDR) tage of learning. p<0.0005) and illne hitory ( length of illne, Analyi of trial and error data revealed that r = 0.495, p<0.0005; length of current admi- patient with chizophrenia required more trial to ion, r = 0.409, p<0.005; total length of all reach criterion than the frontal patient and con- hopitaliation: r = 0.468, p=0.001). Thee trol at the imple dicrimination and reveral (SD, correlation were not ignificant after covarying SDR) and at intra-dimenional ( IDS), and extra- for age. Thu, older patient with chizophrenia dimenional ( EDS and EDR) tage of learning. having longer illne hitorie were receiving lower In addition, the patient with chizophrenia pro- doe of medication. There wa a trend for patient duced more error at the intra-dimenional ( IDS with negative ymptom to be on lower doe of and IDR) tage than the other group. A broadly medication (r = 0.244, p<0.1), while there wa imilar pattern wa found when data were analyed excluding ubject who failed that particular learn- ing tage, uggeting that even thoe chizophrenia patient who were able to achieve criterion at the no relationhip between medication doage and bradyphrenia (r =0.02, NS). Higher doe of med- ication were aociated with better performance at

13 C. Panteli et al. / Schizophrenia Reearch 37 (1999) IDS tage had ignificant difficulty in hifting at one explanation for the extremely poor perforthee level. mance of ome chizophrenia patient on the Such difference in performance between WCST i that they have failed to grap the mot patient with chizophrenia and thoe with frontal baic conceptual requirement of the tak. Thi lobe leion would ugget that different underlying view i upported by ome of the recent literature cognitive deficit are reponible for tak failure. regarding training patient with chizophrenia on Failure at the intra-dimenional learning tage, the WCST. Many author have found that and ignificant difficulty even in thoe who were patient performance doe not improve on the ucceful, indicate a profound impairment in the tet following intruction (Goldberg et al., 1987; ability of patient with chronic chizophrenia to Stu et al., 1983; Schneider and Aarnow, 1987). generalie a dicrimination learned for a particular The preent reult indicate that while et-hiftet of exemplar to another et from the ame ing tak, like the WCST, are ueful in aeing abtract category. Patient with chizophrenia were the ability to make extra-dimenional hift they able to learn or acquire et, a indicated by their may be le appropriate a a meaure of et-hifting relatively intact performance during the early ability in patient with chizophrenia who have a learning tage, however, the learning of et at the more general difficulty in etablihing et. If CD tage wa not generalied to the IDS when the patient are unable to attain even one orting type of timuli preented were altered. Thu, thee category the tak become merely a binary dicrimpatient were unable to generalie learning which ination between thoe who can grap the requiremay be due to fundamentally inadequate conceptument of the orting tet and thoe who cannot, aliation. Thi i conitent with other obervation rather than a detailed decription of et-hifting in the literature which have uggeted that a pribehaviour. Thu, failure on the WCST may not mary cognitive deficit in chizophrenia i the failure be due to a pecific deficit in inhibiting previou to utilie previouly acquired information to influexperience but may in ome patient be attributable ence current perception ( Hemley, 1987, 1994). to a fundamental impairment in concept Many tudie have reported that patient with formation. chizophrenia achieve fewer orting categorie on Elliott et al. (1995) ued a modified verion of the WCST than normal control and ome have the et-hifting tak to tet a ample of younger, hown that patient are o impaired at the tak community-baed patient with chizophrenia. By that they achieve only one or even no orting categorie. Thi performance deficit ha been contrat to the preent tudy, they found that the attributed to a failure to inhibit the previouly greatet attrition rate wa at the EDS tage, with relevant orting category reflected by an increae very few patient failing at the intra-dimenional in pereverative error ( Fey, 1951; Stu et al., hift. Additionally, the chizophrenia patient in 1983). Thee deficit have been conidered a charto that hown by frontal leion patient on the their tudy howed tuck in et behaviour imilar acteritic of frontal lobe damage and, on the computeried et-hifting tak, would how up a ame tak (Owen et al., 1993). The dicrepant a failure to hift attentional et at the extraoverall everity and chronicity of illne between reult may be accounted for by difference in the dimenional hift tage (i.e. thee tak require hifting between dimenion/categorie, rather the two ample. The patient with chizophrenia than evaluating the ability to hift within category). ued in the current tudy had been hopitalied for The preent reult indicate that only a mall an average of 18 year and, a uch, repreent a proportion of thee patient with chizophrenia everely diabled ample. Thi extreme chronicity behave imilarly to frontal leion patient and of illne i likely to be reflected in the clinical diplay thi tuck-in-et behaviour when preentation of the ample; although Elliott and attempting the EDS tage. The majority of our colleague do not report ymptom data in their patient do not reach the EDS level a they are patient, the reult from the preent tudy indicate unable to learn et in the previou tage. Thu, that ymptomatological difference are aociated

14 264 C. Panteli et al. / Schizophrenia Reearch 37 (1999) with variation in performance on the et-hifting reult of our tudy indicate that the et-hifting tak (ee below). deficit cannot be explained in thi way. Thu, Severity and chronicity of illne may impact on patient and control were matched for NART IQ, tak performance in two way. Firt, it may be and MMSE core for the matched patient with preumed that patient who become chronic are, chizophrenia were within the normal range. by definition, more everely affected by chizophrenia Further, lower IQ ubject with chizophrenia perhave from the outet and therefore would alway formed in a qualitatively imilar manner to the performed more poorly on the et-hifting higher IQ patient. A een in Fig. 4 the perfor- tak. A uch, impaired performance at early tage mance of patient with high IQ core i hifted to of the illne would be predictive of a more chronic the right indicating uperior overall performance coure. With reference to the preent tudy thi although the profile of attrition between thee two would imply that the patient would alway have IQ group wa imilar. Thee data are in accord hown impairment at the intra-dimenional hift with the finding of a recent tudy in which a mall level. Second, chronicity of illne may relate to ample of chizophrenia patient with preerved the number of neural ytem that have been intellectual function were found to have pecific progreively compromied by the dieae proce. deficit on a verion of the ID/ED et-hifting tak Succeful completion of the et-hifting tak ( Elliott et al., 1998). require a number of different executive and The performance profile of the patient with memory procee (for example: attention, inhibi- chizophrenia reveal a gradual rate of attrition tion, repone election), which need to work interactively acro the nine learning tage, a well a the for the tak to be completed uccefully udden attrition oberved at intra- and extra- and may each be uberved by eparate neural dimenional tage. Previou reearch uing thi ytem, a dicued elewhere (Panteli and computeried et-hift paradigm ha hown that Brewer, 1995, 1996). Thu, while Elliott et al. neurological patient, with frontal damage or di- (1995) found a dicrete executive impairment, the order of the baal ganglia (including Parkinon preent tudy dicovered a more evere and generalied dieae and multi-ytem atrophy), a well a youn- cognitive deficit, perhap reflecting the larger ger patient with chizophrenia and thoe with number of neural ytem that have been compromied. unipolar depreion drop out ubtantially at the Thi wa alo uggeted by the profound extra-dimenional learning tage, but there i very deficit oberved on a range of other tak of little ubject attrition at the IDS tage ( Downe executive function hown by patient derived from et al., 1989; Owen et al., 1992; Elliott et al., 1995; the ame cohort a the preent tudy ( Panteli Robbin et al., 1994; Purcell et al., 1997). In et al., 1997). In our patient group, there wa no addition, Parkinonian and frontal leion patient relationhip found between et-hifting ability and who were able to achieve a particular hift were length of hopitaliation, age, illne duration or conitently able to pa the reveral form of thi period of hopitaliation. Interetingly, in a firtepiode hift. In the preent invetigation, many patient tudy by Hutton et al. ( 1998), patient with chizophrenia were unable to complete the had relatively preerved performance on a imilar intra-dimenional reveral hift ( IDR) depite et-hifting tak, while there wa ome evidence having uccefully achieved criterion at the preceding for deterioration on thi tak after 12 month IDS tage. Thi wa not oberved at extrafor (Joyce et al., 1998). Longitudinal tudie of thi dimenional reveral hift ( EDR), which wa kind over longer period are neceary adequately paed by all thoe patient who uccefully com- to examine the relationhip of neurocognitive defi- pleted EDS. A poible explanation for thi failure cit to illne chronicity. at IDR may be that thoe patient who paed at While there i debate about the preence of IDS but went on to fail at IDR did not achieve a pecific neuropychological impairment that are true intra-dimenional hift and therefore were not explained by a generalied cognitive decline unable to manipulate the newly learned rule in (Nelon et al., 1990; Barber et al., 1996), the order to ucceed at the reveral level. Thi explana-

15 C. Panteli et al. / Schizophrenia Reearch 37 (1999) tion i upported by the data howing that the involved. It i apparent from our tudy that, while number of error at IDS wa ignificantly higher the mot evere deficit occur at the intra- and for patient with chizophrenia who paed the extra-dimenional hift tage, there are alo IDS tage than for the normal control and frontal difficultie in reveral learning. Dia et al. (1996a), leion ubject, uggeting that patient with in their tudy of marmoet howed that ethifting, chizophrenia had ome difficulty in fully undertanding pecifically extra-dimenional hift, wa the new rule. aociated with leion of the DLPFC, while failure An alternative explanation for the failure of in reveral learning occurred after leion of patient to achieve criterion at IDR i that there the orbitofrontal cortex. Recent finding of greater i a pecific difficulty for thee patient in undertaking deficit on reveral tage of the ID/ED paradigm a reveral hift. The data for trial and in thoe frontotemporal dementia patient having error core revealed that patient with chizophrenia more elective OFC involvement alo upport thee had difficulty at the SDR tage and that concluion ( Rahman et al., 1998). Thi would both the chizophrenia and the frontal group committed ugget the poible involvement of thee area more error at CDR than the normal and their baal ganglia connection in chizo- control. Thi reult i conitent with that found phrenia. While there i good evidence for involve- by Elliott et al. ( 1995) who alo found an increaed ment of DLPFC in chizophrenia ( Weinberger number of error produced at the SDR tage by et al., 1986), few tudie have pecifically addreed comparion with SD. OFC function though there i increaing evidence Specific impairment of thi kind, in the ability for it involvement (e.g., Brewer et al., 1996). to perform an intra-dimenional hift have not From the reult of the preent tudy, it might been identified in other group of patient, except be predicted that an inability to generalie a rule in the advanced tage of ome dementing illnee. from one ituation to another imilar, yet altered Patient early on in the coure of Huntington etting, would impair patient ability to generalie dieae ( HD) and Alzheimer dieae generally do what they had learned. Thu, kill learned in one not demontrate uch an impairment at the IDS etting, uch a a ward, may not necearily be tage. However, later in the coure of thee condi- carried into a community etting. Thi ugget tion, patient are unable to perform the earlier that rehabilitation intervention would benefit by tage of the tak, although thi i in the context evaluating the preence and everity of uch deficit of more generalied neuropathological change in their patient and developing appropriate trate- and a range of other neuropychological deficit gie for remediation, a ha been undertaken in a (Sahakian et al., 1990; Lange et al., 1995; Lawrence few recent tudie (Green et al., 1990, 1992; et al., 1996). The comparion with HD i more Delahunty et al., 1993; Morice and Delahunty, 1996). relevant here, a the tudie indicate a progreion of impairment in et-hifting ability, with a profound deficit in extra-dimenional hifting during the early tage, but with dramatic increae in pereveration during the reveral phae of the tak in more evere form of the illne (Lange et al., 1995; Lawrence et al., 1996). Lawrence et al. (1996) have argued that thi i conitent with current undertanding of neuropathological progreion in the caudate of HD patient and for involvement of the doro-lateral prefrontal cortex (DLPFC ) and orbitofrontal cortex (OFC) and their caudate connection, with the latter (i.e. OFC) being implicated later in the hitory of the illne a the more ventral caudate area become 4.1. Relationhip of et-hifting ability to the ymptom of chizophrenia There wa a trong correlation between negative ymptom and performance at the SDR learning tage, indicating that greater everity of negative ymptom in chizophrenia wa predictive of poorer performance at the earliet tage of the et-hifting tak. Thi ugget that patient with prominent negative ymptom were more likely to have difficulty in undertanding the requirement of the et-hifting tak. Alternatively, the amotiva-

16 266 C. Panteli et al. / Schizophrenia Reearch 37 (1999) tion and apathy aociated with thee ymptom contingencie. Rather, they acted impulively (a may influence their ability to participate. alo oberved on Tower of London tak Panteli In term of the ymptomatological difference et al., 1997; Hutton et al., 1998) and/or were between patient failing at different learning tage, unable to inhibit their inappropriate repone. patient who failed at EDS had higher level of Thi would alo be conitent with the oberved negative ymptomatology, which are characteritic aociation between poor performance jut prior ymptom of chronically hopitalied patient, to the IDS tage and high core for the diorganiation uch a thoe in the preent tudy (Nelon et al., yndrome. Patient with the latter ymptom 1990). Further, thoe chizophrenia patient who have been characteried a howing greater intruion performed more like the frontal leion patient of inappropriate cognition or of inapproperformed were characteried by the preence of negative priate behaviour (McGrath, 1991). Deficit of ymptom, including flat affect and poverty of impule control and the inability to inhibit peech. Thi finding i conitent with previouly inappropriate repone have been linked to leion reported aociation between the negative ymptom in orbitofrontal area (for dicuion: Panteli and of chizophrenia and performance on tet Brewer, 1995, 1996). enitive to frontal lobe leion, uch a the WCST Thu, in the preent tudy ignificant difference (Addington et al., 1991; Liddle, 1987a; Liddle and in et-hifting performance were aociated with Morri, 1991; Brown and White, 1992; Norman pecific ymptomatological profile, which may et al., 1997; Berman et al., 1997; for dicuion, implicate different underlying neural ytem, a ee Panteli et al., 1992; Elliott and Sahakian, ha been previouly uggeted (Liddle, 1987a; 1995). It hould be noted that few previou tudie Liddle and Morri, 1991; Liddle et al., 1992; have pecifically invetigated the relationhip Norman et al., 1997). between neuropychological domain and ymptom-baed yndrome uing a priori hypothei 4.2. Concluion teting. In the tudie by Norman et al. ( 1997) and Berman et al. (1997) the negative ymptom The preent reult indicate that there i a ubgroup (pychomotor poverty yndrome) were aociated of patient with ignificant negative ymp- with WCST performance, which i conitent with tom who exhibit ome imilar performance deficit our finding of a relationhip between impaired to patient with frontal leion, namely, failure to extra-dimenional et-hifting and negative ymp- perform an extra-dimenional hift. However, the tom. It i relevant here that deficit in the ability major deficit oberved in thi chronically hopitali- to hift attentional et to previouly irrelevant ed group of patient occur at an earlier ethifting timuli (extra-dimenional hifting) have been tage, which require an intra-dimenional aociated with abnormalitie of the doro-lateral hift. Thi reflect a failure to learn et and to prefrontal cortex (DLPFC) ( Weinberger et al., generalie what wa previouly learned when novel 1986) (Panteli and Brewer, 1995, 1996; Dia et al., material i preented, even when the rule remain 1996a,b) and the negative ymptom of chizophrenia unchanged. Further, failure at thi tage wa aoregion have been linked to hypofrontality of thi ciated with a tendency to act quickly in an impul- (e.g. Liddle et al., 1992; Rodriguez et al., ive manner, uggeting a failure of appropriate 1997). inhibitory mechanim to monitor performance. In the preent invetigation, patient who failed Poor performance at the early tage of the tak at IDS had lower core on the clinical meaure wa alo aociated with the ymptom of the of bradyphrenia than thoe failing at other tage diorganiation yndrome, which ha been linked of the tak, indicating that thee patient were to failure of inhibitory mechanim. Thi fater. Given that they failed at thi relatively differential pattern of performance and of relation- imple level of the tak, it i likely that they acted hip to the different yndrome of chizophrenia quickly but inaccurately. Thi ugget that they upport the notion of eparate underlying patho- were not paying ufficient attention to the tak phyiological mechanim, involving eparate fron-