ARTICLE IN PRESS

2                                     J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx

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10                                          J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx
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  1. 1. + MODEL ARTICLE IN PRESS Schizophrenia Research xx (2006) xxx – xxx www.elsevier.com/locate/schres Deficit in schizophrenia to recruit the striatum in implicit learning: A functional magnetic resonance imaging investigation Jeffrey P. Reiss a,b,⁎, Darren W. Campbell a,b , William D. Leslie a,c , Martin P. Paulus a,d , Lawrence N. Ryner a,e , Joseph O. Polimeni a,b , Brendon J. Foot a,b , Jitender Sareen a,b a Psychiatric Neuroimaging Research Program, University of Manitoba, Winnipeg, Manitoba, Canada b Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba, Canada c Departments of Radiology and Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada d Laboratory of Biological Dynamics and Theoretical Medicine, Department of Psychiatry, University of California, San Diego, USA e National Research Council, Institute for Biodiagnostics, Winnipeg, Manitoba, Canada Received 30 November 2005; received in revised form 6 April 2006; accepted 10 April 2006 Abstract In schizophrenia, explicit learning deficits have been well established although it is less clear whether these patients have deficits in implicit learning (IL). IL is thought to depend on intact striatal functioning. This study examined the hypothesis that schizophrenia patients show deficient recruitment of striatal activation during an IL paradigm, relative to performance-matched healthy comparison subjects. Ten subjects with schizophrenia on atypical antipsychotic medication and 10 age, gender, education, and performance matched healthy comparison subjects underwent fMRI while performing an IL task. On the basis of whole-brain and striatal region-of-interest analyses, we found a relative lack of striatal activation in schizophrenia patients. This result is consistent with convergent evidence of striatal dysfunction in schizophrenia. © 2006 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Implicit learning; Procedural learning; Striatum; Caudate; fMRI 1. Introduction et al., 2004), findings are less consistent in regard to implicit learning (IL) deficits. Most studies report intact IL While there is general acceptance of there being in schizophrenia (Bazin et al., 1996; Bazin and Perruchet, explicit learning deficits in schizophrenia (Fioravanti et al., 1996; Clare et al., 1993; Danion et al., 2001; Dominey and 2005; Green et al., 1997, 2000; Heinrichs and Zakzanis, Georgieff, 1997; Gopal, 1997; Granholm et al., 1993; 1998; Lussier and Stip, 2001; Saykin et al., 1994) and in Gras-Vincendon et al., 1994; Kazes et al., 1999; Keri et al., biological relatives of schizophrenia patients (Sponheim 2000; Kern et al., 1997; Ninomiya et al., 1998; Schmand et al., 1992a,b; Sponheim et al., 2004; Wexler et al., 1997; ⁎ Corresponding author. Room PZ203, 771 Bannatyne Avenue, Woonings et al., 2002), though a minority suggests that IL Winnipeg, Manitoba, Canada R3E 3N4. Tel.: +1 204 787 7202; fax: +1 is impaired (Bressi et al., 1998; Giménez et al., 2003; 204 787 7480. Goldberg et al., 1990; Green et al., 1997; Kumari et al., E-mail address: jpreiss@cc.umanitoba.ca (J.P. Reiss). 2002; Randolph et al., 1993; Schwartz et al., 2003). One 0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.04.027 SCHRES-02788; No of Pages 11
  2. 2. ARTICLE IN PRESS 2 J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx reason for this discrepancy may relate to the specific type cation-naïve patients have been reported to have extra- of IL being studied such as priming, visuomotor, and pyramidal symptoms, suggesting intrinsic striatal problem solving tasks. Sequence learning tasks appear dysfunction (Caligiuri and Lohr, 1997; Chatterjee et al., most likely to reveal deficient learning in schizophrenia 1995; Cortese, 2001; Puri et al., 1999). Further, Granholm (Bressi et al., 1998; Green et al., 1997; Kumari et al., 2002; et al. (1993) demonstrated that the severity of tardive Schwartz et al., 2003). Consequently, implicit sequence dyskinesia in schizophrenia was associated with both learning may be dependent on a particular neural substrate shortened caudate T2 relaxation times and decreased IL. that is impaired in schizophrenia. More recently, Giménez et al. (2003) found an inverse It is also possible that the periodically observed IL correlation between caudate metabolism (NAA/Cho deficits may relate to the effect of dopamine antagonist ratio) and IL in schizophrenia. antipsychotic medication rather than the underlying illness. There has been one fMRI investigation to date that has Impaired IL has been reported in healthy participants evaluated IL in participants with schizophrenia (Kumari administered haloperidol (Kumari et al., 1997; Peretti et al., et al., 2002). In this study, using a serial reaction time task, 1997), and chlorpromazine (Danion et al., 1992), with six healthy controls demonstrated significantly greater enhanced IL occurring with the dopamine agonist, amphet- activations in the striatum, thalamus, precuneus, and sen- amine (Kumari et al., 1997). Investigations have demon- sorimotor regions than the six schizophrenia participants strated largely intact IL in schizophrenia with patients who were taking typical antipsychotic medication. Impor- taking atypical antipsychotic medication, but impaired IL tantly, while the controls demonstrated robust evidence of with the older, typical class of antipsychotic medication IL, the patients did not whatsoever. This marked dis- (Paquet et al., 2004; Schérer et al., 2004; Stevens et al., crepancy in task performance limits the interpretation of 2002). Moreover, IL has improved in schizophrenia neural activation differences (Rauch et al., 2001) because patients after being switched to an atypical antipsychotic it can be argued that the two groups were not engaged in (Purdon et al., 2000). the same cognitive processes while undergoing fMRI, i.e. Appropriate functioning of the striatum and its connec- the controls were learning but the patients were not. ted neural substrates are thought to be critical for adequate Given these discrepant findings on IL in schizophre- performance in IL tasks (Curran, 1998). Individuals with nia, the current study evaluates the neural basis of an striatal pathology, such as in Huntington's (Knopman and implicit sequence learning task in schizophrenia partici- Nissen, 1991; Willingham and Koroshetz, 1993) and pants taking atypical antipsychotics and who demonstrat- Parkinson's disease (Doyon et al., 1997; Pascual-Leone ed equivalent learning to controls. We chose to utilize a et al., 1993), demonstrate impaired IL. Functional imaging sequence learning task, as this type of IL has been the studies have reported striatal activation in participants most likely to reveal differential performance in patients who displayed IL (Grafton et al., 1995; Peigneux et al., with schizophrenia as compared to healthy controls 2000; Martis et al., 2004; Rauch et al., 1995, 1997a,b, (Bressi et al., 1998; Green et al., 1997; Kumari et al., 1998), and a recent paper has further consolidated this 2002; Schwartz et al., 2003). In addition to a whole-brain relationship with the use of a control group (Reiss et al., exploratory analysis, we conducted an a priori region of 2005). Other motor-associated areas have been correlated interest analysis of the striatum, given its pivotal role in IL with IL including primary motor cortex, premotor cortex, and postulated role in schizophrenia. We hypothesized supplementary motor area and the cerebellum (Grafton that the schizophrenia group would demonstrate less et al., 1992, 1995; Jueptner et al., 1997). More perceptually striatal activation than the control group, despite similar oriented areas have also been associated with IL such as behavioral performance on the IL task. parietal and temporal cortices, as well as the hippocampus (Curran, 1998; Schendan et al., 2003), though all these 2. Materials and methods areas are less consistently reported than the striatum. Typical antipsychotics bind to striatal dopamine recep- 2.1. Participant selection tors thereby potentially impairing IL, whereas atypical antipsychotics have much less effect on the striatum (Blin, We examined 20 right-handed (Oldfield, 1971) volun- 1999; Chiodo and Bunney, 1983; Grace, 1992; Kapur teers, 10 with schizophrenia, and 10 age, gender, and et al., 1995; Kapur, 1998). Yet there is reason to suspect education matched healthy controls, through outpatient striatal abnormalities exist in schizophrenia itself. Struc- clinic contacts and poster advertisements. Task perfor- tural imaging studies with medication-naïve patients have mance was comparable between the two groups (Table 1), reported striatal abnormalities (Corson et al., 1999; Gur and so no participant selection actions were needed. The et al., 1998; Lang et al., 1999, 2001). Moreover, medi- study and all procedures were conducted with the approval
  3. 3. ARTICLE IN PRESS J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx 3 of the University of Manitoba and National Research an asterisk. A 25-trial practice run was followed by two Council, Institute for Biodiagnostics, research ethics 312-trial runs (each lasting 6.25 min). Each run consisted of boards. All participants provided signed, informed consent. alternating blocks of random (R) and IL conditions brack- eted by a 19.2-second cross-hair fixation block. In the IL 2.2. Sample characteristics condition, the stimuli followed a 12-item sequence (posi- tion: 1-2-1-4-2-3-4-1-3-2-4-3) that repeated six times. In Administration of the MINI International Diagnostic the R condition, 24 trials were pseudo-randomly presented Interview version 5.0 (Sheehan et al., 1998) for DSM-IV with no immediately repeated locations. No signs were (American Psychiatric Association, 1994) confirmed that given to distinguish between R and IL blocks. For each all clinical participants had a diagnosis of schizophrenia participant, a median reaction time (RT) score was calcu- with no co-morbid conditions. Clinical participants were lated for each condition, R and IL, and an IL reaction time assessed with the Positive and Negative Syndrome Scale advantage (RTa) score [100 ⁎ (R - IL) /R]. RT estimates for Schizophrenia (PANSS) (Kay et al., 1987) which were based on correct trial responses. provided a total, as well as subscale scores for positive, negative, and general psychopathology symptoms. 2.4. Debriefing Schizophrenia illness duration ranged from 3 to 41 years (mean and SD in Table 1). All schizophrenia Following the scan, participants were informed of and participants were on stable doses of atypical antipsychotic asked to reproduce the repeating sequence by making 15 medication, which were converted to chlorpromazine key presses (Martis et al., 2004; Rauch et al., 1997b). The equivalent doses (Woods, 2002) (see Table 1). Partici- longest string that matched the 12-item implicit sequence pants with schizophrenia did not differ significantly from estimated the degree of explicit learning. Scores ≥ 7 were healthy controls on age, gender, or education (Table 1). categorized as explicit learning (see Martis et al., 2004). 2.3. Task 2.5. MRI acquisition We used the serial reaction time (SRT) task (Martis Images were acquired on a General Electric 1.5 Tesla et al., 2004, Rauch et al., 1997a,b) for which MRI-com- MRI system with a clinical transmit/receive head coil. patible eye-pieces displayed an asterisk in one of four Anatomical scans for each individual used a T1-weighted horizontally arranged boxes for 1.0 s, followed by a 0.2 fast spin-echo sequence (TR/TE/FOV = 400/8 ms/25 cm, second empty-boxes interval. Using separate fingers, parti- 2 mm slice thickness) for a 2 × 1 × 1 mm voxel image. cipants pressed one of four keys in immediate response to Functional MRI data used a single-shot gradient–recalled- Table 1 Sociodemographic, clinical status, and behavioral performance of the participants Schizophrenia (n = 10) Control (n = 10) t(18) p Grand mean mean (SD) mean (SD) (n = 20) Sociodemographics Gender: female/male 1/9 1/9 – – 2/18 Age (years) 29.1 (9.4) 26.1 (7.1) 0.80 .43 27.6 (8.3) Education (years) 12.8 (2.5) 13.4 (2.4) −0.54 .59 13.1 (2.4) Clinical measures Medication dosage (chlorpromazine equivalents mg/d) 330 (180) n/a PANSS 69.0 (8.2)a n/a Illness duration (years) 11.5 (12) n/a Serial reaction time task behavior performance Reaction time (ms)b Random 415.5 (77.0) 411.7 (53.9) −0.13 .90 413.6 (64.7) Implicit learning 398.7 (75.6) 389.7 (55.3) −0.31 .76 394.2 (64.6) Reaction time advantage (%)c 4.1 (2.9) 5.4 (4.7) −0.75 .46 4.8 (3.9) Error rates 4.9 (4.1) 2.9 (1.9) −1.4 .19 3.9 (3.3) Explicit learning scores 3.7 (0.7) 4.3 (1.3) 1.3 .22 4.0 (1.1) n = 9; bReaction time based on the mean of median reaction times in milliseconds with the SD in brackets; c% RT advantage = 100 ⁎ (baseline RT − implicit a RT)/ baseline RT.
  4. 4. ARTICLE IN PRESS 4 J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx echo echo planar imaging sequence with TR/TE/flip and group differences in IL-related BOLD responses angle/FOV = 2400/60 ms/45°/25 cm. Approximately 80% (group by condition interactions). ANOVA cluster aver- of the brain was imaged using 23 contiguous axial slices ages were imported into SPSS for descriptive statistic and and 3.9 mm isotropic voxels excluding the most superior simple effect analyses. To supplement these analyses, we and inferior brain regions. In each experimental run, tested for degree of IL-related (RTa) BOLD responses 172 volumes were acquired (344 volumes in total). within each group as well as RTa by group interactions. All areas of activation are reported in Montreal Neurological 2.6. fMRI individual analyses Institute coordinates with positive values as right, anterior, and superior. For each IL-related activation cluster iden- Image analyses were performed with Analysis of tified, we tested for correlations between BOLD responses Functional NeuroImages (AFNI) software (Cox, 1996). and PANSS scores and medication dosage. The fMRI data were slice time-corrected. Functional vol- umes were co-registered to the volume that minimized 3. Results translation and rotation relative to all other volumes. The first 3 volumes were excluded to allow for equilibrium of 3.1. Task performance the MRI signal. One additional volume (out of 344) with visually detectable movement (0.3 degrees of pitch ro- Schizophrenia patients and controls did not differ on tation and 0.4 mm) was excluded in one person with mean RT or RTa (Table 1). Each group showed faster schizophrenia. Run 2 was concatenated to Run 1. The mean RT during the IL condition compared to the random block design time-series was convolved to account for the condition [schizophrenia, t(9) = 4.5, p b .001, and controls, hemodynamic response function. Multiple regression an- t(9) = 3.6, p b .006]. Total error rates (commissions and alysis included nine regressors: 2 convolved IL and R omissions) and mean explicit learning estimates did not condition regressors, 3 head-motion covariates (i.e., roll, differ between groups (Table 1). There was no correlation pitch, and yaw), 2 slope regressors (1 per Run), and between symptom severity, i.e. PANSS total and subscale 2 intercept (fixation cross-hair blocks) regressors (1 per scores, and task performance measures, i.e. RTa and per- Run). The beta coefficient for each condition (IL and R) cent correct (all p valuesN .70). As well, medication dos- was divided by the mean fixation cross-hair coefficient to age was not correlated with task performance RTa scores, estimate percent blood oxygen level dependent (BOLD) p N .70, or percent correct, p N .35. signal change for each condition (Cohen and DuBois, 1999). Beta values represent partial signal change when 3.2. Common IL vs. R BOLD responses simultaneously also taking into account the baseline, linear drift, and movement nuisance regressors. To account for Three brain regions were identified showing greater anatomical variations, an 8 mm full-width half-maximum BOLD response to IL trials compared to R trials in both Gaussian filter was applied. Data were transformed into groups (Table 2). Post hoc simple effect analyses the Montreal Neurological Institute (MNI) coordinates. 2.7. Alpha control criteria Table 2 Brain regions showing greater blood oxygen level dependent (BOLD) responses to the IL minus R condition in both groups (common For the whole brain analyses, Monte Carlo simula- condition effect) tions estimated that a voxel-wise probability of p b 0.02 Brain region BA x y z Vol. F Mn IL - R and a minimum cluster volume of 640 μl would main- (μl) (1,18) tain an overall p b 0.05. For the striatum (defined via the HC Sz AFNI software atlas) Region of Interest (ROI) analyses, L middle 22 − 50 − 34 3 2432 16.0 0.11⁎ 0.09⁎ a more liberal criterion was used. ROI Monte Carlo temporal simulations estimated that a voxel-wise probability of R superior 38 38 4 −14 1856 18.7 0.15⁎ 0.18⁎ p b 0.04 and a minimum cluster volume of 448 μl would temporal L inferior 47 − 38 20 −8 1344 20.3 0.08⁎ 0.12⁎ maintain an overall p b 0.05. frontal 2.8. fMRI between- and within-group analyses BA = Brodman Area, x, y, z = Montreal Neurological Institute coordinates of maximally activated voxel, Vol. = volume, L = left, R = right, Mn IL − R = mean difference of implicit learning minus A 2 × 2 repeated measures ANOVAwas used to identify random condition % BOLD scores. ⁎ = Significantly different from common IL-related BOLD responses (condition effect) zero, p b 05.
  5. 5. ARTICLE IN PRESS J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx 5 Table 3 (Table 3b). For the schizophrenia group, these regions Brain regions showing group differences in blood oxygen level did not differ significantly in the IL vs. R contrast. dependent (BOLD) responses to the IL minus R contrast (group by condition interaction effect) 3.5. Striatal region of interest group differences Brain region BA x y z F Vol. Mn IL − R (1,18) (μl) HC Sz The left caudate showed a significant group-by-task condition interaction in BOLD response (Table 4a and a. Group by condition interactions L medial 8 − 6 38 46 14.0 1792 0.11⁎ − 0.08⁎ Fig. 1a). Simple effect post hoc analyses determined that frontal the control group exhibited significantly higher BOLD R/L 2 − 6 17 16.3 1280 0.13⁎ − 0.13⁎ responses to the IL condition than the R condition, while thalamus the schizophrenia group exhibited a non-significant de- (includes crease to the IL compared to the R condition (Table 4a). L caudate) L precentral 6 − 42 − 7 43 20.9 1088 0.06⁎ − 0.09⁎ This region partially overlaps with the thalamic/caudate R superior 41 59 −26 12 19.7 704 0.10⁎ − 0.04 region identified in the whole brain interaction analysis. temporal The control group showed a significantly greater BOLD L culmen 30 − 6 −46 3 16.4 640 0.12⁎ − 0.10⁎ response to the IL vs. R contrast in a second caudate region L posterior 30 − 14 −63 10 22.7 640 0.10⁎ − 0.10 (Table 4b and Fig. 1b). This region showed no significant cingulate R cingulate 24 14 − 3 43 12.3 640 0.07⁎ − 0.08⁎ difference among the schizophrenia group (Table 4b). In R precentral 4 38 −20 42 12.8 640 0.09⁎ − 0.08⁎ these two regions, the control group showed greater absolute BOLD responses to the IL condition (p b .01) as b. Group-specific condition effect well as greater IL vs. R relative BOLD responses (Fig. 1). L cuneus 19 − 2 −85 35 1280 16.9 0.21⁎ 0.06 R caudate 22 −47 15 832 13.9 0.10⁎ 0.06 tail 3.6. Region of interest RTa-BOLD associations BA = Brodman area, x, y, z = Montreal Neurological Institute coordinates of maximally activated voxel, IL = implicit learning, R = In the voxel-by-voxel ROI analysis, among the control random condition, Vol. = volume, L = left, R = right, Mn IL − R = mean group, degree of IL was associated with greater activation difference of IL minus R % BOLD scores. ROI = region of interest in the left striatum (volume = 1088 μL), r = .87, p b .001, analysis, ⁎ = significantly different from zero, p b .05. with the maximum intensity voxel located in the left putamen (x = −18, y = 12, z = −4, t(8) = 3.1, pb .02). In the confirmed that each group separately exhibited a voxel-by-voxel ROI analyses for the schizophrenia group significant BOLD response in these three brain regions. only a trend level cluster was identified (overall p b .1). For this trend level cluster, degree of IL was associated 3.3. Group differences in IL vs. R BOLD responses with greater average cluster BOLD response within the left caudate (volume = 512 μL), r = .71, p b .03, with the Eight brain regions were identified showing significant maximum intensity voxel at the MNI coordinates of x = group-by-task condition BOLD responses (Table 3a). −14, y = 11, z = 9 (t(8) = 2.6, p b .05). Simple effect post hoc analyses determined that the con- trol group exhibited significantly higher BOLD responses Table 4 to the IL condition than the R condition in all eight regions Striatal region of interest group differences in blood oxygen level (Table 3a). In contrast, the schizophrenia group exhibited dependent (BOLD) responses to the IL minus R condition lower BOLD responses to the IL condition than the R BA x y z Vol. F (1,18) Mn IL − R condition in these regions with significant decreases in six (μl) of the eight regions (Table 3a). Note the thalamic cluster HC Sz of differential activation included the left caudate. a. Group by condition interaction L caudate − 10 −6 17 448 8.5 0.12⁎ − 0.06 3.4. Other control group activations in IL vs R BOLD b. Group-specific condition effect responses L caudate − 14 11 18 512 8.0 0.11⁎ 0.04 Whole brain repeated measures ANOVA identified BA = Brodman area, x, y, z = Montreal Neurological Institute coordinates of maximally activated voxel, IL = implicit learning, R = two additional regions that showed a significant random condition, Vol. = volume, L = left, R = right, Mn IL − R = mean BOLD response in the control group for the IL vs. R difference of IL minus R condition % BOLD scores. ROI = region of contrast, namely the left cuneus and the right caudate tail interest analysis, ⁎ = significantly different from zero, p b .05.
  6. 6. ARTICLE IN PRESS 6 J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx Fig. 1. Group differences in blood oxygen level dependent (BOLD) responses to the implicit learning (IL) condition compared to the random (R) condition in the striatum region-of-interest analyses. The group by condition interaction is labeled “a” and the control-specific condition effect is labeled “b”. The 95% confidence intervals in the bar charts reveal a significant IL minus R (IL − R) effect for the control group (HC) and a non- significant IL effect for the schizophrenia group (Sz). 3.7. Other within-group RTa-BOLD associations action cluster was found that largely overlaps with the left ACC cluster associated with greater IL in the schizophre- In the whole brain analysis, among the control group no nia group. Thus, the positive association between degree clusters of activation were associated with the degree of IL. of IL and left ACC BOLD response is unique to the In contrast, among the schizophrenia group, degree of IL schizophrenia group. was associated with BOLD responses in two regions: the left dorsolateral prefrontal cortex (DLPFC, volume = 3.9. Schizophrenia symptom severity and medication 1216 μL), r= .95, p b .001, and the left anterior cingulate dosage correlations to BOLD responses cortex (ACC, volume= 832 μL), r= .84, p b .002. More specifically, degree of IL was associated with greater Schizophrenia symptom severity estimates (PANSS BOLD responses in the left DLPFC (BA 10) with the total and subscale scores) were not correlated with any maximum intensity voxel at the MNI coordinates of x = of the BOLD responses in the patient group, p N .20. −34, y= 43, z =20 (t(8)= 3.0, pb .02), and the left ACC (BA Similarly, medication dosage was not correlated to any 24,33) with the maximum intensity voxel at the MNI of the BOLD responses, p N .15. coordinates of x =−2, y = 14, z= 23 (t(8) =3.4, p b .01). 4. Discussion 3.8. RTa-BOLD interactions This investigation found that schizophrenia patients Interactions between degree of IL (RTa scores) and show reduced striatal activation relative to performance- group were tested using both the whole brain and ROI matched healthy comparison subjects during an IL task, analyses criteria. No significant clusters were identified. which supports our hypothesis of deficient recruitment of However, a borderline significant (overall p b .1) inter- the striatum.
  7. 7. ARTICLE IN PRESS J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx 7 The controls demonstrated a distributed neural network Our patients were taking only atypical antipsychotic of IL-related activation, invoking frontostriatal circuits, medication, with the expectation of them demonstrating multiple temporal lobe areas, and motor cortices, all areas intact IL. Consistent with this assumption, a recent previously reported with this type of task (Grafton et al., neuroimaging study involving IL in schizophrenia (Paquet 1995; Peigneux et al., 2000; Rauch et al., 1995, 1998; et al., 2004) used SPECT to assess the effects of two Schendan et al., 2003; Thomas et al., 2004). In contrast, the antipsychotic drugs on IL and striatal dopamine (D2) schizophrenia participants, despite equivalent behavioural receptor occupancy. The patients receiving haloperidol, a performance, recruited fewer brain regions, restricted to typical antipsychotic, demonstrated impaired IL, whereas the middle and superior temporal, and inferior frontal those receiving olanzapine, an atypical antipsychotic, per- cortices. Of particular note, participants with schizophre- formed equivalently to controls. Additionally, in the nia failed to activate the striatum to the same degree as haloperidol-treated patients significant correlations were controls, this area being considered a pivotal part of the IL found between IL deficits and striatal D2 receptor occu- neural network (Doyon et al., 1997; Peigneux et al., 2000; pancy. Similarly, the greater striatal D2 binding of Rauch et al., 1997a,b; Reiss et al., 2005; Willingham and risperidone relative to other atypical antipsychotics has Koroshetz, 1993). This functional neuroimaging finding been forwarded as the explanation for impaired IL on complements previous evidence of striatal abnormalities risperidone-treated patients in studies also involving in schizophrenia, as summarized in the Introduction. Not- olanzapine (Purdon et al., 2003) and clozapine (Schérer withstanding, the striatal region-of-interest RTa correlation et al., 2004). It is unknown if our participants with analysis trend-level result in the schizophrenia group is schizophrenia had significant striatal D2 blockade or to suggestive of some degree of striatal recruitment in task what extent this might contribute to the observed relative performance in schizophrenia. Moreover, the schizophre- decreased striatal activation. Moreover, the present investi- nia whole-brain RTa correlation analysis results are pos- gation cannot directly address whether IL is intact in sibly reflective of this group having their IL performance schizophrenia per se or behaviorally normalized by the mediated through non-striatal regions (ACC and DLPFC). usage of atypical antipsychotic medication. Taken together, in both healthy controls and especially in In an evoked potential investigation of colour patterns, schizophrenia subjects, IL task performance is not ex- Hsieh et al. (2004) recently reported IL deficits in clusively dependent on striatal involvement. schizophrenia which were correlated with less gating of The finding of the schizophrenia group invoking the the P50 component. Abnormal P50 evoked potentials ACC and DLPFC in relation to improving task perfor- have also been reported in both Parkinson's (Teo et al., mance is intriguing. Both the ACC (Kumari et al., 2002; 1997) and Huntington's (Uc et al., 2003) diseases, both Peigneux et al., 2000; Rauch et al., 1997b) and the DLPFC degenerative disorders of striatal pathology. These fin- (Grafton et al., 1995; Schendan et al., 2003) have been dings are consistent with an overall linkage between IL, associated with the conduct of implicit sequence tasks. striatal function, and schizophrenia as reported in this Additionally, Snitz et al. (2005) recently demonstrated study. hypoactivation of the DLPFC and ACC in unmedicated The findings of the current study contrast with those first-episode patients doing a cognitive task designed to of Kumari et al. (2002), the only other fMRI study of dissociate the two regions. After 4 weeks of treatment with IL in schizophrenia to our knowledge. However, our atypical antipsychotics, a subset of these patients was study involved a larger sample and was comprised of rescanned and demonstrated increased/normalized acti- patients taking only atypical antipsychotics, whereas in vation of the ACC, but not of the DLPFC. However, the earlier study all patients were on typical anti- Honey et al. (1999) reported increased ACC/supplemen- psychotics. Conceivably, the Kumari et al. (2002) tary motor area and DLPFC activation in a working findings may reflect an effect of typical antipsychotics memory task when patients were switched from typical (as opposed to being an effect of illness) in that the antipsychotic medications to risperidone. Moreover, it has schizophrenia participants performing a similar implicit been shown that both clozapine (Lahti et al., 2004) and sequence-learning paradigm demonstrated minimal olanzapine (Lahti et al., 2005) enhance ACC regional neural activation. However, an equally plausible ex- cerebral blood flow when given to medication-free pa- planation would be that their schizophrenia group tients. Hence, our schizophrenia group demonstrated showed no behavioural evidence of IL. The authors normal behavioural performance which was conceivably acknowledged these points as well making the partially mediated through the ACC and DLPFC, and in recommendation that further fMRI studies be done in turn this effect may have been enabled by atypical anti- participants receiving atypical antipsychotic drugs, psychotic medication. such as the present one.
  8. 8. ARTICLE IN PRESS 8 J.P. Reiss et al. / Schizophrenia Research xx (2006) xxx–xxx The present study may shed light on the divergent In conclusion, we found a relative lack of striatal literature on IL in schizophrenia. Most, but not all studies activation in schizophrenia patients on atypical antipsy- report intact IL in schizophrenia, with sequence learning chotic medication during an implicit sequence-learning studies being the type most likely to yield differential task, despite similar behavioral performance to healthy behavioural performance. The present investigation pro- controls. This result is consistent with convergent evi- duced results that are suggestive of a neural inefficiency dence of striatal dysfunction in schizophrenia. in schizophrenia during implicit sequence learning. Despite equivalent behavioural performance, the schizo- Acknowledgments phrenia group did not invoke an as distributed network as the controls, and in particular failed to equally recruit the Grant support was provided by the Health Sciences striatum. This proposed neural inefficiency might ac- Centre and the St. Boniface Hospital Research Founda- count for findings of intact IL in those studies where task tions. The authors thank Brenda Stoesz, Stephen Hassard, demands are relatively modest (as perhaps in the present Michael McIntyre, Kristina Malisza, Patrick Stroman, study), but result in impaired IL when the sequencing Wolfgang Richter, Corinne LeBlanc, and Deanna Braun task demands exceed the capability of the deficient for their contributions. neural network. Another aspect of the discrepancies regarding IL References findings in schizophrenia is the heterogeneity of the schizophrenia groups between studies and of the illness American Psychiatric Association, 1994. 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