Reduced Orbitofrontal-Striatal Activity on a Reversal Learning Task in Obsessive-Compulsive Disorder

ORIGINAL ARTICLE Reduced Orbitofrontal-Striatal Activity on a Reversal Learning Task in Obsessive-Compulsive Disorder

Peter L. Remijnse, MD; Marjan M. A. Nielen, PhD; Anton J. L. M. van Balkom, MD, PhD; Danie¨lle C. Cath, MD, PhD; Patricia van Oppen, PhD; Harry B. M. Uylings, PhD; Dick J. Veltman, MD, PhD

Context: The orbitofrontal cortex (OFC)–striatal cir- sponses relative to control subjects but showed ad- cuit, which is important for motivational behavior, is as- equate behavior on receipt of punishment and with re- sumed to be involved in the pathophysiology of obsessive- gard to affective switching. On reward outcome, patients compulsive disorder (OCD) according to current showed decreased responsiveness in right medial and lat- neurobiological models of this disorder. However, the en- eral OFC as well as in the right caudate nucleus (border gagement of this neural loop in OCD has not been tested zone ventral striatum) when compared with controls. Dur- directly in a cognitive activation imaging paradigm so far. ing affective switching, patients recruited the left posterior OFC, bilateral insular cortex, bilateral dorsolateral, Objective: To determine whether the OFC and the ven- and bilateral anterior prefrontal cortex to a lesser extent tral striatum show abnormal neural activity in OCD dur- than control subjects. No areas were found for which pa- ing cognitive challenge. tients exhibited increased activity relative to controls, and no differential activations were observed for punish- Design: A reversal learning task was employed in 20 pa- ment in a direct group comparison. tients with OCD who were not receiving medication and 27 healthy controls during an event-related functional Conclusions: These data show behavioral impairments magnetic resonance imaging experiment using a scan- accompanied by aberrant OFC-striatal and dorsal pre- ning sequence sensitive to OFC signal. This design al- frontal activity in OCD on a reversal learning task that lowed investigation of the neural correlates of reward and addresses this circuit’s function. These findings not only punishment receipt as well as of “affective switching,” confirm previous reports of dorsal prefrontal dysfunc- ie, altering behavior on reversing reinforcement contin- tion in OCD but also provide evidence for the involve- gencies. ment of the OFC-striatal loop in the pathophysiology of OCD. Results: Patients with OCD exhibited an impaired task end result reflected by a reduced number of correct re- Arch Gen Psychiatry. 2006;63:1225-1236

HE ORBITOFRONTAL COR- relevant stimulus on an object discrimi- tex (OFC) and the ventral nation reversal task.8,9 In a subsequent ex- striatum constitute the periment, a double dissociation in the pre- main components of 1 of a frontal cortex was observed: deficits on series of parallel, segre- affective switching but intact perfor- gated neural loops, which were first de- mance on attentional (extradimensional) Author Affiliations: T 1,2 scribed by Alexander et al. The func- switching were found in OFC-lesioned Departments of Psychiatry tional roles of these areas have been marmosets, whereas the opposite was (Drs Remijnse, Nielen, investigated extensively in both non- true for dorsolateral prefrontal cortex van Balkom, Cath, van Oppen, 10 and Veltman) and Anatomy human primates and humans. Electro- (DLPFC)–ablated animals. (Dr Uylings), VU University physiological studies in monkeys have In humans, research on the function of Medical Center, Amsterdam, the demonstrated that OFC neurons code the the OFC has focused primarily on rever- Netherlands; Graduate School context-dependent positive or negative sal learning and decision-making.11 Hu- of Neurosciences, Amsterdam reinforcement value of sensory stimuli3-6 man lesion studies have corroborated ani- (Drs Remijnse and Uylings); and register the rapid reversal of such mal experiments with respect to the Outpatient Academic Clinic for stimulus-reinforcement associations,3,7 disruption of reversal learning in OFC- Anxiety Disorders, GGZ which is important for motivational be- damaged patients12 and found a dissocia- Buitenamstel, Amsterdam 6 (Drs van Balkom, Cath, havior. Orbitofrontal involvement in re- tion in affective switching for patients with van Oppen, and Veltman); and versal learning (also termed affective OFC damage and those with DLPFC dam- 13,14 Netherlands Institute for Brain switching) had previously been shown in age. In addition, neuroimaging stud- Research, KNAW, Amsterdam OFC-ablated macaques, who exhibited ies in healthy subjects have repeatedly (Dr Uylings). perseverant responding to the previously shown the involvement of the OFC in the

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1225

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 processing of reward and punishment stimuli, either from was shown to recruit OFC and striatal regions in healthy a sensory quality15,16 or from an abstract (monetary) na- controls,53 data of which were also used in the present ture.17,18 Moreover, neuroimaging studies using reversal study. Since functional magnetic resonance imaging of learning paradigms have reported OFC activity during the OFC is notoriously difficult because of signal drop- affective switching.19,20 out,25,54 we applied a scanning sequence specifically sen- As stated earlier, the OFC is connected with the ven- sitive to OFC signal.55 Based on the previously reviewed tral sector of the caudate nucleus and these structures data on OFC-striatal function together with its pro- conjointly form a frontal-striatal circuit.1,2,6 Indeed, neu- posed role in the pathophysiology of OCD, we hypoth- roimaging studies have also demonstrated the ventral stria- esized that patients would show impaired performance tum to be engaged in reward processing21,22 and in affec- during the reversal learning task compared with control tive switching.23-25 Thus, the OFC and the ventral part subjects. Moreover, we expected that this would be ac- of the striatum are presumed to be crucial in an organ- companied by abnormal OFC-striatal activity during pro- ism’s processing of reward and punishment and in the cessing of reward, punishment, and affective switching. ability to alter behavior on changing stimulus- reinforcement contingencies, ie, in affective switching. METHODS Recent neurobiological models of obsessive- compulsive disorder (OCD) have stressed the role of dysfunctional OFC-striatal circuitry in the pathogenesis of SUBJECTS this disorder26-29 based on several observations. First, from a phenomenological point of view, reward and punish- Twenty patients with OCD (14 women; mean age, 34 years; range, 19-54 years) and 27 healthy controls (19 women; mean ment perception appear to be abnormal in OCD; ie, pa- age, 32 years; range, 22-53 years) participated in this study. Pa- tients with OCD give the impressions of having an on- tients were recruited from the outpatient clinic for anxiety dis- going error sensation (“something is wrong”) when orders and by advertisements on the internet. Diagnoses were experiencing obsessions27 and of feeling insufficiently re- established by experienced clinicians with the Structured Clini- lieved by compulsive behavior that serves a rewarding cal Interview for DSM-IV Axis I disorders.56 Exclusion criteria goal.27,29 Moreover, the rigid behavior exhibited by pa- were the presence of alcohol or substance abuse and major in- tients with OCD that appears insensitive to reinforcing ternal or neurological disorders. The following comorbid dis- signals can be thought of as reflecting an inability to per- orders were diagnosed with the Structured Clinical Interview form affective switching. Second, neuropsychological tasks for DSM-IV Axis I disorders: major depressive disorder (n=7), that specifically address OFC function have shown im- dysthymia (n=4), social phobia (n=3), generalized anxiety disorder (n=3), panic disorder (n=2), agoraphobia (n=1), and paired performance in patients with OCD compared with 30,31 32,33 posttraumatic stress disorder (n=1). Moreover, comorbid healthy controls (but see other resources ). Third, Tourette disorder was clinically diagnosed in 2 patients, whereas structural and functional neuroimaging studies have re- 5 patients were diagnosed with “pure” OCD. At the time of the peatedly shown abnormalities associated with these brain study, all patients and control subjects were free of psycho- areas in OCD, although these findings have not been uni- tropic medication for at least 2 weeks and, in case of fluox- form: ie, increased34 or decreased35 OFC volumes and en- etine or antipsychotic medication, for at least 1 month. More- larged,35 normal,36 or diminished37 striatal volumes in mor- over, no patients were currently involved in a cognitive phometric studies in addition to either increased38,39 or behavioral therapy program. All participants gave written in- decreased40 activity in the OFC and hypoactivity41 or hy- formed consent and the study was approved by the ethical re- peractivity38,42 in the caudate nucleus during resting- view board of the VU University Medical Center (Amsterdam, the Netherlands). state imaging. Similarly, symptom provocation studies 43 To assess symptom characteristics and severity scores, the in OCD have demonstrated increased OFC activity next Yale-Brown Obsessive Compulsive Scale57 was administered (pa- 43,44 45 to both increased and decreased caudate activity. Fi- tients only), whereas the Padua Inventory–Revised58,59 was used nally, selective serotonin reuptake inhibitors and dopa- to measure participants’ obsessive-compulsive characteristics mine antagonists appear to be efficacious in OCD,46,47 and (both groups). One patient with OCD had obsessions only and intact transmission of serotonin (5-hydroxytrypta- 1 had compulsions only, and symptoms were mainly related mine) and dopamine has been associated with normal to the obsessions/checking (n=15) and symmetry/ordering OFC functioning48 and reward processing in the ventral (n=5) dimensions.60 To rate the presence and severity of de- 49 pressive symptoms in both groups, we used the Beck Depres- striatum, respectively. 61 62 Thus, several lines of research have indicated that OFC- sion Inventory, the 21-item Hamilton Depression Rating Scale, and the 10-item Montgomery-Asberg Depression Rating Scale.63 striatal dysfunction is a key factor in the pathogenesis of Because of logistic problems, 3 patients failed to be inter- OCD and may be the neural substrate of abnormal reviewed with the Hamilton Depression Rating Scale and Mont- ward, punishment, and affective switching processing in gomery-Asberg Depression Rating Scale, and 2 patients did not OCD. Although other parts of frontal-striatal circuitry, complete the Beck Depression Inventory and Padua Inventory– in particular anterior cingulate cortex, have been tar- Revised. geted before using cognitive neuroimaging paradigms in 50-52 OCD, the OFC-striatal loop has not been challenged REVERSAL LEARNING TASK directly so far. In the present study, we addressed this AND EXPERIMENTAL PROCEDURE issue by employing a reversal learning task in an event- related, functional magnetic resonance imaging experi- We used a self-paced, probabilistic reversal learning task with ment. This paradigm enabled assessment of reward and an affectively neutral baseline (Figure 1) that has been de- punishment processing as well as affective switching and scribed in detail elsewhere.53 In brief, each trial in the experi-

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1226

∗ CR

175 Total 4350

(Choice)

∗ BL

Choice Made

(Choice)

∗ PENS

–80 Tie Correct Total 4270 Bus Incorrect (Choice)

∗ CR

175 Total 4445

(Choice)

∗ PRE

–200 Reversal Total 4245

(Choice)

∗ FRE

–150 Bus Correct Total 4095 Tie Incorrect (Choice)

∗ CR

225 Total 4320

Figure 1. The reversal learning task. This example (consecutive trials are running from top left to bottom right) shows all events of interest. Two stimuli are presented to subjects on each trial, ie, cartoons of a bus and a tie in experimental trials and cartoons of a car and a pair of trousers on baseline trials. In experimental trials, either stimulus is correct and positive or negative feedback is given in the form of points immediately after a subject’s choice as well as the total number of points accumulated up to that trial. In baseline trials, subjects were instructed in advance which of the 2 stimuli to select and neutral feedback is given after a subject’s choice (Choice Made). After 6 to 10 correct responses, a reversal occurs without the subject’s knowledge. CR indicates correct response; BL, baseline trial; PENS, probabilistic error with no shift; PRE, preceding reversal error; FRE, final reversal error.

mental task consisted of 2 stimuli, ie, cartoons of a bus and a response (CR). A correct response that was probabilistically given tie, which were presented at either side of a screen with ran- negative feedback could either lead to a shift in stimulus se- domized locations for 3000 milliseconds maximally. Subjects lection (probabilistic error with shift [PES]) or not lead to such selected either stimulus by pressing the left or right button on a shift (probabilistic error with no shift [PENS]). False re- a button box. On a correct response, either positive or nega- sponses (spontaneous errors [SEs]) were always given negative feedback was given based on an 80:20 ratio, consisting of tive feedback. Criterion for reversal was reached after 6 to 10 gaining or losing a random amount of 80 to 250 points. A cor- correct responses (randomized). Immediately after reversal (un- rect response with a reward outcome was defined as a correct known to the subject), a false response (according to the new

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1227

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 criterion) not leading to a shift to the new correct stimulus was DATA ANALYSIS designated a preceding reversal error (PRE), and the last false response prior to a shift a final reversal error (FRE). Each trial ended with a 2000-millisecond display of both the number of Demographic and behavioral data were analyzed using SPSS points won or lost in that trial and the number of accumulated software (version 11.5 for Windows; SPSS Inc, Chicago, Ill). points in the task up to that trial followed by a fixation cross For our behavioral analysis, the following outcome variables for 1000 milliseconds. The main task instruction was to strive were assessed in both groups: the average number of CR, to obtain a maximum number of points; subjects were not en- PENS, FRE, PRE, PES, and SE events and the average num- couraged to respond as quickly as possible. After the scanning ber of points accumulated by the end of the task. A 1-way session, participants received a payment in euros equal to the analysis of variance with group (OCD vs controls) as the total number of accumulated points during the task divided between-subject factor and event type as the within-subject by 1000. factor was performed to assess performance differences An affectively neutral baseline (BL) task consisting of 2 dif- between groups. ferent equivalent stimuli (cartoons of a car and a pair of trou- Imaging analysis was done using SPM2 (Statistical Para- sers) was presented in between experimental trials, and re- metric Mapping; Wellcome Department of Cognitive Neurol- sponses in this task were given neutral feedback. Subjects were ogy, London, United Kingdom). Images were reoriented, slice- instructed in advance which of the 2 BL stimuli to select. The timed, and realigned to the first volume. The mean image was scanning session ended after 400 trials (including the BL task) coregistered with the whole-brain EPI volume, and images were and lasted approximately 25 minutes. normalized to a SPM T2* template (using 12 linear param- Immediately after the scanning procedure, a 5-item OC ques- eters and a set of nonlinear cosine basis functions). Spatial tionnaire was administered in the patient group to assess the smoothing was performed using a 6-mm full-width-at-half- degree and severity of OC symptoms during the task. This ques- maximum gaussian kernel with the aim of increasing sensitiv- tionnaire consisted of 3 items related to obsessions (assessing ity for small activation foci, particularly in the OFC, even though their time-consuming, task-interfering, and anxiety- larger filters may be more efficient for noise reduction. Statis- provocative properties) and 2 items related to compulsions (as- tical analysis was carried out in the context of the general lin- sessing the time spent on mental compulsions and the urge to ear model, in which each event was modeled using a ␦ func- perform compulsive behavior), all of which were rated on a tion convolved with the canonical hemodynamic response 5-point scale. To familiarize participants with the concept of function. The following events were modeled to the onset of probabilistic errors, subjects performed a brief version of the the feedback presentation, as defined previously: (1) baseline reversal learning task that did not contain reversal stages prior events (BLs), (2) correct responses with a reward outcome (CRs), to scanning. (3) probabilistic errors with no following shift (PENSs), (4) preceding reversal errors, ie, false responses after reversal not leading to a shift (PREs), and (5) final reversal errors, ie, the last false response after reversal prior to a shift (FREs). Two events IMAGING PROCEDURE were modeled as events of no interest: (6) spontaneous errors (SEs), and (7) probabilistic errors with a following shift (PESs). Imaging data were collected using a 1.5-T Sonata magnetic reso- Movement parameters were also included in the model as re- nance system (Siemens, Erlangen, Germany) with a standard gressors of no interest. circularly polarized head coil. Task stimuli were generated by The following contrasts were computed: (1) CRs minus BLs a Pentium PC and projected on a screen behind the subject’s to assess the main effect of reward, (2) (PENSs plus PREs plus head at the end of the scanner table. This screen was visible FREs) minus BLs to assess the main effect of all punishment for the subject through a mirror mounted above the subject’s events, and (3) FREs minus (PENSs plus PREs) to subtract pun- head. Two magnet-compatible response boxes were used to re- ishment events not leading to a shift from punishment events cord the subject’s responses. To reduce motion artifacts, the prior to a shift, ie, to isolate affective switching. subject’s head was immobilized using foam pads. Contrasts were first performed at single subject level. These T2*-weighted echo-planar images (EPI) with blood oxy- were then entered into a second level (random effects) analy- genation level–dependent (BOLD) contrast were acquired. A sis by calculating 1-sample t tests on each individual’s contrast customized EPI sequence sensitive to OFC signal was used.55 images for contrasts 1 through 3. Group main effects for each This sequence included an additional gradient pulse that was contrast were analyzed with 1-way analysis of variance. We per- applied between excitation and readout, with a duration of 1 formed conjunction analyses for our events of interest to iden- millisecond and amplitude of –1.3 mT/m in the slice direc- tify regions showing consistent activations across groups and tion. This gradient pulse resulted in enhanced signal intensity group interaction effects by using a statistical parametric map in the OFC at the expense of a slight decrease in signal inten- of the minimum t statistic over the relevant orthogonal con- sity acquired in other brain regions characterized by a homo- trasts.64 The P values of the ensuing regional effects were ad- geneous magnetic field. The acquisition plane was tilted par- justed for the whole-brain search volume using the false dis- allel to the air/tissue interface of the OFC for each subject covery rate method implemented in SPM2.65 A significant effect (between 0° and 15° from the anterior-posterior commissure (PϽ.05) suggests that one or both contrasts were significant line in our subject groups). Using this sequence with a repeti- at a corrected level against the null hypothesis of no effect in tion time of 2.18 seconds and an echo time of 45 milliseconds, either contrast. After statistical testing, inclusive masking was we obtained 35 slices (3ϫ3–mm in-plane resolution; 2.5-mm used to ensure that both contrasts contributed substantially to slice thickness; matrix size, 64ϫ64). The scanner automati- the overall effect.66 In the patient group, additional correlation cally discarded the first 2 measurements in each session be- analyses were performed between BOLD responses on re- fore the task started. Scanning was manually halted after the ward, punishment, and affective switching and OC and de- task had ended. Furthermore, a whole-brain EPI scan for each pression severity scores. Results for main effects and correla- subject was acquired using the same sequence (40-43 slices per tion analyses are similarly reported at PϽ.05 and are false scan, 3 measurements in total) as well as a structural scan us- discovery rate–corrected unless indicated otherwise. Localiza- ing a 3D coronal T1-weighted sequence (voxel size, 1ϫ1ϫ1.5 tion of group results was expressed in MNI (Montreal Neuro- mm; 160 sections). logical Institute) coordinates.67

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1228

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Demographic and Clinical Characteristics of OCD Table 2. Behavioral Data on the Reversal Learning Task: and Control Groups Average Numbers for Each Event Type in OCD and Control Groups Patients With OCD Controls P Group؋Event Characteristic (n = 20) (n = 27) Value Patients Type ANOVA With OCD, Controls, Sex, F/M, No. 14/6 19/8 .97* Mean (SD), Mean (SD), F Value P Age, mean (SD), y 34 (10.8) 32 (7.7) .58† Event Type No. (n = 20) No. (n = 27) (df = 1.45)Value Handedness, R/L, No. 16/4 23/4 .64* Baseline 47 (3.0) 47 (3.5) 0.36 .55 Education score, mean (SD) 7.8 (2.3) 8.6 (1.4) .28§ Correct responses 209 (26) 224 (17) 5.96 Ͻ.02 (range 1-10)‡ Probabilistic errors 22 (7.8) 19 (7.7) 1.36 .25 Duration of illness, mean (SD), y 20.8 (14.1) with no shift Medication naı¨ve patients, No. 7 Final reversal errors 15 (7.3) 17 (5.8) 1.44 .24 Patients with previous CBT, No. 10 Preceding reversal 17 (11.2) 16 (9.4) 0.02 .89 Total Y-BOCS severity score, 20.8 (5.4) errors mean (SD) (range, 11-29) Spontaneous errors 74 (41.5) 55 (23.1) 3.95 .05 Padua-IR score, mean (SD) 56.8 (26.6) 11.5 (10.4)࿣ Ͻ.001† Probabilistic errors 19.3 (7.9) 21.4 (8.2) 0.78 .38 BDI score, mean (SD) 17.0 (8.5) 1.7 (2.6)࿣ Ͻ.001† with shift Accumulated points 10 073 (9709) 15 524 (5998) 5.63 Ͻ.03 HDRS score, mean (SD) 11.7 (4.3) 0.4 (1.0)¶ Ͻ.001† by end of task MADRS score, mean (SD) 13.6 (8.0) 0.6 (0.9)¶ Ͻ.001† Acquired scans 707.2 (36.0) 679.1 (25.8) 9.7 Ͻ.004 Postscan 5-item OC 3.0 (3.4) over RLT questionnaire score, mean (SD) (range 0-20) Abbreviations: ANOVA, analysis of variance; OCD, obsessive-compulsive disorder; RLT, reversal learning task. Abbreviations: BDI, Beck Depression Inventory; CBT, cognitive behavioral therapy; HDRS, Hamilton Depression Rating Scale; L, left; MADRS, Montgomery-Asberg Depression Rating Scale; OCD, obsessive-compulsive disorder; Padua-IR, Padua Inventory–Revised; R, right; Y-BOCS, Yale-Brown Obsessive Compulsive Scale. eral OFC, right DLPFC, right superior parietal cortex, *␹2 Test. bilateral occipital cortex, bilateral caudate nucleus, and †Independent samples t test. ‡A score of 1 denotes primary school unfinished; 10 denotes university left ventral pallidum/nucleus accumbens. Patients with graduated. OCD did not show activations at our a priori signifi- §Mann-Whitney U test. cance level. However, at PϽ.001 uncorrected, increased ࿣Assessed in 18 patients with OCD. ¶Assessed in 17 patients with OCD. BOLD responses were found in the right DLPFC, right inferior parietal cortex, and bilateral occipital cortex (see Figure 2 for an example of individual results at the level of the OFC together with each subject’s mean RESULTS EPI). Conjunction analyses demonstrated greater reward-associated activity in the right medial and lateral DATA OFC, bilateral occipital cortex, and right caudate nucleus (border zone ventral striatum) in controls rela- Table 1 summarizes demographic and clinical charac- tive to the OCD group (Figure 3). No areas were teristics for both groups. The OCD group displayed sig- found showing hyperactivity for patients compared nificantly higher OCD severity scores in addition to sig- with controls. nificantly increased depressive symptom ratings compared with the control group. Table 2 lists behavioral data from PUNISHMENT the reversal learning task. Patients with OCD were found to have a significantly lower average number of points When contrasting all punishment events with baseline accumulated by the end of the task as well as a signifi- events ([PREsϩ PENSsϩ FREs]−BLs), controls cantly reduced number of CRs and an increased num- showed activity in the right medial and lateral OFC, ber of SEs that was borderline significant. In the patient right insular cortex, and bilateral occipital cortex. In group, no significant correlations were found between contrast, patients demonstrated inferior parietal the average number of points obtained and the number cortex activity. At an uncorrected significance level of of CRs on the one hand and depression severity mea- PϽ.001, additional areas were found activated in the sures (PϾ.30 for all), OCD severity ratings (PϾ.10 for OCD group, ie, in the right anterior PFC, right all), or scores from the 5-item postscan OC question- DLPFC, right insular cortex, and right occipital naire (PϾ.16 for both) on the other. Imaging results for cortex. Conjunction analyses did not reveal significant main effects of reward, punishment, and affective switch- group differences for punishment-associated brain ing in both groups as well as conjunction analyses are activity. An additional analysis subtracting baseline listed in Table 3. events from punishment events not leading to a shift ([PREsϩ PENSs]−BLs) showed the same REWARD main effects in both groups as the contrast ([PREsϩPENSsϩFREs]−BLs), albeit with the excep- In controls, reward processing (CRs−BLs) was associ- tion of right insular activity and at a slightly lower ated with increased activity in the right medial and lat- threshold (PϽ.001 uncorrected). Again, a conjunction

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1229

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 3. Brain Regions Showing Main Effects for Reward, Punishment, and Affective Switching in Patients With OCD and Control Subjects and for the Conjunction of Main Effects and Group Interaction Effects*

Conjunction of Main Effects OCD Group (n = 20) Control Group (n = 27) and Group Interaction Effects

MNI MNI MNI Coordinates Coordinates Coordinates z Cluster z Cluster z Cluster Area L/R xyzValue Size† xyzValue Size† xyzValue‡ Size† Reward (CRs − BLs) OCD vs controls No significant effects Controls vs OCD

Lateral OFC R 36 54 −12 4.37 21 36 51 −12 4.35 1 Medial OFC R 15 36 −15 4.16 13 15 36 −15 4.49 1 Dorsolateral PFC R 45 42 −18 3.65§ 3 45 42 21 3.70 10 Parietal superior R 30 −63 48 3.77 17 Parietal inferior R 27 −63 45 4.01§ 20 Occipital cortex R 33 −93 0 4.18§ 50 36 −93 −9 5.76 173 36 −93 −12 4.79 5 L −24 −99 −12 3.53§ 6 −33 −96 −12 4.41 31 −36 −93 −3 4.04 1 Caudate nucleus R 6 18 6 4.43 49 6 18 3 4.49 1 L −6 15 6 3.73 49 Ventral pallidum/ L −12 6 −9 3.76 3 nucleus accumbens (Punishment ([PREs ؉ PENSs ؉ FREs] − BLs OCD vs controls No significant effects Lateral OFC R 33 54 −12 5.45 48 Controls vs OCD Medial OFC R 18 42 −15 3.74 7 No significant effects Anterior PFC R 39 51 −3 4.31§ 20 Dorsolateral PFC R 45 39 27 3.94§ 42 Insular cortex R 33 21 −3 4.33§ 26 30 24 −12 4.04 16 Parietal inferior R 27 −63 45 4.77 29 Occipital cortex R 36 −96 0 4.30§ 9 33 −93 −9 5.00 122 L −33 −96 −12 3.78 4 ([Affective Switching (FREs − [PREs ؉ PENSs OCD vs controls No significant effects Controls vs OCD

Lateral OFC R 30 51 −15 3.61§ 4 Posterior OFC L −18 18 −15 3.70§ 8 −18 18 −15 4.15 1 Anterior PFC R 30 54 15 3.38§ 4 36 51 9 4.71 136 36 54 −3 4.53 2 L −30 51 6 3.31§ 3 −30 60 9 3.85§ 29 −31 60 6 4.38 2 Dorsolateral PFC R 33 45 33 5.09 136 33 45 33 5.45 5 L −45 36 27 3.46§ 3 −42 33 42 4.17 9 −42 33 42 4.71 1 Insular cortex R 33 18 6 3.95§ 4 33 18 6 4.53 75 36 27 3 3.79 ࿣ 1 L −33 21 9 4.99 70 −33 21 6 5.37 12 Anterior cingulate 0 30 33 3.69§ 15

Abbreviations: BLs, baseline events; CRs, correct responses; FREs, final reversal errors; L, left; MNI, Montreal Neurological Institute; OCD, obsessive- compulsive disorder; OFC, orbitofrontal cortex; PENSs, probabilistic errors with no shift; PFC, prefrontal cortex; PREs, preceding reversal errors; R, right. *All results at PϽ.05 false discovery rate–corrected unless indicated otherwise. †Number of voxels. ‡ z Values refer to the effect for the combination of main effects and group interaction effect. §PϽ.001 uncorrected. ࿣PϽ.06 FDR corrected.

analysis did not reveal significant groupϫtask differ- FREs−[PREsϩPENSs]). In controls, this contrast re- ences. vealed activity in the left posterior OFC, bilateral anterior PFC, bilateral DLPFC, bilateral insula, and anterior AFFECTIVE SWITCHING cingulate cortex. No significant activations were found in the patient group at PϽ.05 corrected. However, at To assess the main effect of affective switching, PϽ.001 uncorrected, activity was observed in the right punishment events not leading to a shift were sub- lateral OFC, bilateral anterior PFC, left DLPFC, and right tracted from punishment events prior to a shift (ie, insular cortex. Conjunction analyses showed increased

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1230

RL RL

L L

R R B PPB B CCB

RL RL

L L Figure 2. Examples of mean echo-planar images (coronal and axial slices) acquired with the orbitofrontal cortex (OFC)–sensitive sequence (A) in a 27-year-old female patient (P) and a 28-year-old female control subject (C) and of their main effects for reward (correct responses−baseline trials) superimposed on each subject’s individual normalized structural magnetic resonance imaging scan (B). All slices were at the same level of the OFC; crosshairs were at x=24, y=42, z=−15. L indicates left; R, right.

A B B

RL R L

C C R

Figure 3. Conjunction analysis of overall main effect for reward and interaction effect of controls vs patients with obsessive-compulsive disorder (OCD) for reward superimposed on coronal, transaxial, and sagittal slices from a canonical (MNI [Montreal Neurological Institute] compatible) T1 image as supplied by SPM2 (Statistical Parametric Mapping; Wellcome Department of Cognitive Neurology, London, United Kingdom). Increased blood oxygenation level–dependent responses are shown for control subjects compared with patients with OCD in the right caudate nucleus (A) (border zone ventral striatum encircled; x=6, y=18, z=3); right medial orbitofrontal cortex (OFC) (B) (encircled; x=15, y=36, z=−15); and right lateral OFC (C) (encircled; x=36, y=51, z=−12). The mask is set at P=.05 for purposes of illustration. L indicates left; R, right.

BOLD responses in the left posterior OFC, bilateral an- CORRELATION ANALYSES terior PFC, bilateral DLPFC, and bilateral insular cortex (right-sided at borderline significance level [PϽ.06]) In patients, no significant correlations were found for controls vs patients with OCD (Figure 4). The op- between BOLD responses during reward, punishment, posite contrast did not reveal significant differences. or affective switching on the one hand and symptom

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1231

B C

R L R L

R D

Figure 4. Conjunction analysis of overall main effect for affective switching and interaction effect of controls vs patients with obsessive-compulsive disorder (OCD) for affective switching, superimposed on sagittal, coronal, and transaxial slices from a canonical (MNI [Montreal Neurological Institute] compatible) T1 image as supplied by SPM2 (Statistical Parametric Mapping; Wellcome Department of Cognitive Neurology, London, United Kingdom). Enhanced blood oxygenation level–dependent responses are shown for control subjects relative to patients with OCD in the left posterior orbitofrontal cortex (A) (encircled; x=−18, y=18, z=−15); right anterior prefrontal cortex (B) (encircled; x=36, y=54, z=−3); right dorsolateral prefrontal cortex (C) (encircled; x=33, y=45, z=33); and left anterior insular cortex (D) (encircled; x=−33, y=21, z=6). The mask is set at P=.05 for purposes of illustration. Significant effects in structures B, C, and D were found bilaterally (not shown in this figure). L indicates left; R, right.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1232

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 severity ratings on the other (Hamilton Depression Rat- ity is not likely to explain decreased task-associated activity ing Scale, Montgomery-Asberg Depression Rating Scale, as observed in our patients with OCD, however. First, OFC- and Beck Depression Inventory for depression; Yale- striatal hypoactivity was found only for reward and affec- Brown Obsessive Compulsive Scale and Padua Inventory– tive switching but not for punishment; second, the con- Revised for OCD). Nor did we find significant correla- trast assessing affective switching compares 2 different tions between 3 contrasts of interest and performance punishment events and does not include baseline activ- scores. ity, ruling out ceiling effects as a possible explanation. It is interesting that task-induced hypoactivity in brain regions associated with resting-state hyperactivity has been COMMENT reported before in OCD because Rauch and cowork- ers68,69 demonstrated decreased striatal responsiveness in To our knowledge, the present functional magnetic reso- OCD during implicit learning, in both a positron emis- nance imaging study is the first to investigate orbitofron- sion tomography and a functional magnetic resonance im- tal function in OCD employing a reversal learning task. aging design. Taken together, these findings suggest that This paradigm allowed the investigation of reward and OFC-striatal dysfunction in OCD is associated with in- punishment processing as well as affective switching, ie, creased resting-state activity together with decreased re- the alteration of behavior by switching to new associa- sponsiveness on cognitive challenge. Future research may tions after a reversal of stimulus-reinforcement contin- address this issue by combining resting-state and cogni- gencies. Moreover, these effects were assessed with the tive activation paradigms within a single session. aid of a scanning sequence specifically sensitive to OFC Current neurobiological models of OCD emphasize signal.55 As was hypothesized, patients showed im- the involvement of the OFC-striatal circuit in the patho- paired overall task performance reflected by a signifi- genesis of this disorder,26-28 although the exact nature of cantly lower number of accumulated points by the end this dysfunction is insufficiently clear. As outlined pre- of the task. This was found to be associated with a smaller viously, this neural loop is associated with motivational number of correct responses (CRs) as well as a greater behavior, in particular processing of reward and punish- number of spontaneous errors (SEs). Our findings of im- ment, and rapid reversal of stimulus-reinforcement as- paired overall performance are in accordance with sociations. Consequently, dysfunctional OFC-striatal cir- some,30,31 but not all,32,33 previous neuropsychological stud- cuitry in OCD may be the neural substrate of deficient ies using tasks addressing OFC function in OCD. These modulation of emotional information with subsequent discrepant results may be explained by major differ- ineffective behavioral adaptation being core features of ences in task implementation (ie, object alternation, de- this disorder.27,29 The present findings of reward- cision-making, olfactory discrimination, and reversal associated activity in the right OFC and ventral caudate learning tasks), medication status, and patient inclu- in healthy controls but not in patients with OCD appear sion criteria. However, compared with these previous stud- to be in line with these models. With respect to affective ies, the current paradigm provides direct support for the switching, patients showed less activity in the left pos- hypothesis of OFC dysfunction in patients with OCD not terior OFC compared with control subjects. Interest- receiving medication by showing abnormal neural re- ingly, the posterior region of OFC has been found to be sponsiveness during cognitive challenge. associated with reversal learning impairments in a Imaging results showed differential activity between recent study of subjects with left-lateralized OFC/ groups in the OFC-striatal circuit, among other areas, dur- ventromedial brain lesions.13 The posterior OFC is part ing reward processing and affective switching. Specifi- of a paralimbic circuit encompassing, among other areas, cally, patients with OCD recruited the right medial and insular and cingulate cortices.70,71 The functional rela- lateral OFC as well as the right caudate nucleus (border tionship between these structures may explain func- zone ventral striatum) to a lesser extent than controls dur- tional abnormalities in anterior cingulate and insula during reward processing. During affective switching, pa- ing affective switching in OCD, although only the latter tients showed decreased activity compared with con- region was found to be hypoactive in our study. Al- trols in the left posterior OFC in addition to the bilateral though speculative, the observed OFC-striatal deficien- insula, bilateral anterior PFC, and bilateral DLPFC. It can cies in OCD on reward and affective switching may be be argued that comorbid depression may have con- the neural correlates of a failure of compulsive behavior founded these between-group differences. However, we to alleviate obsession-caused anxiety and cognitive- found no significant correlations between task-induced behavioral inflexibility despite changing reinforcing sig- brain activity and depression severity ratings in pa- nals in the environment, respectively.27 Clearly, this hy- tients. Moreover, post hoc analyses performed after ex- pothesis is in need of further empirical testing. cluding patients with OCD with comorbid depression re- In addition to these paralimbic regions, we found de- vealed similar group differences for reward and affective creased activation in OCD during affective switching for switching (data not shown). brain areas that are normally involved in “executive” func- The finding of lower task-induced activity of the OFC- tions, ie, the bilateral DLPFC and anterior prefrontal cor- striatal circuit in the present study is remarkable because tex. In a recent article, we reported the engagement of a wealth of data have demonstrated increased perfusion these structures in affective switching and concluded that and glucose uptake in these regions in resting-state neu- this may reflect cognitive set switching per se as well as roimaging designs in OCD,38,39,42 although conflicting re- inhibitory control.53 The involvement of these regions has sults have also been reported.40 Enhanced baseline activ- been reported during decision-making in another re-

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1233

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 cent study,72 suggesting that these areas support the com- implies the need for a replication of the present results putational aspects not only of affective switching but also with a different task known to validly probe the OFC in of decision-making. Our finding of diminished activa- OCD. Second, effect sizes for reward- and punishment- tions in paralimbic and executive brain structures dur- associated activity were only modest, in particular for in- ing affective switching in OCD points to an impairment teraction effects. Given our fairly robust sample size, the of both emotional and cognitive aspects in reversal learn- most likely explanation is that OFC signal is difficult to ing in this disorder. Inadequate functioning of dorsal and capture, even with a specifically tailored sequence. Third, ventral prefrontal-striatal loops is in agreement with patho- mean symptom severity in our OCD group was only mild physiological models of OCD focusing on an altered bal- to moderate (mean Yale-Brown Obsessive Compulsive ance between inhibitory (dorsolateral) and excitatory Scale score, 20.8), and our sample was clinically heter- (ventromedial) frontal-striatal circuits.1,26,28 ogeneous, despite evidence that different neuronal Contrary to expectation, conjunction analyses failed mechanisms may underlie various OCD subdimen- to show group differences for punishment events in the sions.42 The current findings may therefore possibly re- present study despite clear-cut differences in group main flect a diluted effect that is specific to one of the OCD effects because right medial and lateral OFC activity was symptom dimensions. seen in controls but not in patients, whereas the oppo- In conclusion, the present study has shown that ab- site was true for right inferior parietal activity. Previous normal OFC-striatal activity is associated with impaired cognitive activation paradigms during functional neu- performance during an OFC-sensitive reversal learning roimaging using response conflict tasks have associated task in OCD, consistent with a proposed role for this cir- OCD with increased anterior cingulate cortex activity both cuit in the pathogenesis of this disorder. Future re- on errors50,73 and during correct responses encompass- search will need to further specify the significance of ab- ing high-conflict situations.50,51,74 These results corrobo- errant activity in these structures on reward and affective rated the notion that OCD is characterized by a dysfunc- switching processing in relation to OCD symptoms. tional error recognition system that has its origin in aberrant anterior cingulate cortex and OFC activity.75 It Submitted for Publication: June 9, 2005; final revision is assumed that this is the neural substrate of the con- received February 17, 2006; accepted February 28, 2006. tinual sense in patients with OCD that something is Correspondence: Peter L. Remijnse, MD, Department of wrong.27,29,50,73,74 Discrepant results between these stud- Nuclear Medicine and PET Research, VU University Medi- ies and the present experiment may be explained by dif- cal Center, PO Box 7057, 1007 MB Amsterdam, the Neth- ferent methods of error sensation induction, ie, external erlands ([email protected]). negative feedback in our reversal learning task vs inter- Financial Disclosure: None reported. nally generated error detection in response conflict Funding/Support: This work was supported by a TOP tasks.50,73 grant (No. 912-02-050) from the Dutch Organization for It is interesting that our finding of OFC hypoactivity Scientific Research (NWO). for reward but not for punishment processing in OCD Acknowledgment: We thank Joost P. A. Kuijer, PhD, for may be related to recent data from a tryptophan deple- his technical support. tion study in healthy volunteers.76 These authors showed that lowering serotonergic transmission altered the processing of reward but not of punishment-related infor- REFERENCES mation during a decision-making task, implying that serotonin selectively modulates reward processing, most likely 1. Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical cir- 6 cuits: parallel substrates for motor, oculomotor, “prefrontal’’ and “limbic’’ functions. mediated by the OFC. These findings suggest that OFC Prog Brain Res. 1990;85:119-146. hypoactivity during reward processing in subjects with 2. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally seg- OCD is due to abnormal serotonin (5-hydroxytrypta- regated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986; mine) transmitter function, in accordance with the com- 9:357-381. monly assumed role of brain serotonergic systems in the 3. Thorpe SJ, Rolls ET, Maddison S. The orbitofrontal cortex: neuronal activity in 77 the behaving monkey. Exp Brain Res. 1983;49:93-115. pathophysiology of OCD. 4. Critchley HD, Rolls ET. Hunger and satiety modify the responses of olfactory and In contrast to the presumed serotonergic regulation visual neurons in the primate orbitofrontal cortex. J Neurophysiol. 1996;75: of OFC function, dopaminergic activity is intimately as- 1673-1686. sociated with normal basal ganglia function, including 5. Tremblay L, Schultz W. Relative reward preference in primate orbitofrontal cortex. 22,49 Nature. 1999;398:704-708. reward processing in the ventral striatum. In the con- 6. Rolls ET. The orbitofrontal cortex and reward. Cereb Cortex. 2000;10:284-294. text of our finding of reward-related ventral striatal hy- 7. Rolls ET, Critchley HD, Mason R, Wakeman EA. Orbitofrontal cortex neurons: poresponsiveness in OCD, it is of interest that recent single role in olfactory and visual association learning. J Neurophysiol. 1996;75:1970- photon emission computed tomography ligand studies 1981. reported abnormal dopamine transporter density and D2 8. Iversen SD, Mishkin M. Perseverative interference in monkeys following selec- 78,79 tive lesions of the inferior prefrontal convexity. Exp Brain Res. 1970;11: receptor binding in the basal ganglia in OCD. Fur- 376-386. ther research to clarify the relationship between OCD and 9. Jones B, Mishkin M. Limbic lesions and the problem of stimulus-reinforcement dopamine dysfunction is obviously warranted. associations. Exp Neurol. 1972;36:362-377. The present study is not without limitations. First, we 10. Dias R, Robbins TW, Roberts AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature. 1996;380:69-72. used a new reversal learning task that, although em- 11. Clark L, Cools R, Robbins TW. The neuropsychology of ventral prefrontal cor- 53 ployed successfully in a group of healthy volunteers, tex: decision-making and reversal learning. Brain Cogn. 2004;55:41-53. has not been validated before in subjects with OCD. This 12. Rolls ET, Hornak J, Wade D, McGrath J. Emotion-related learning in patients with

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1234

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 social and emotional changes associated with frontal lobe damage. J Neurol Neu- 37. Robinson D, Wu H, Munne RA, Ashtari M, Alvir JM, Lerner G, Koreen A, Cole K, rosurg Psychiatry. 1994;57:1518-1524. Bogerts B. Reduced caudate nucleus volume in obsessive-compulsive disorder. 13. Fellows LK, Farah MJ. Ventromedial frontal cortex mediates affective shifting in Arch Gen Psychiatry. 1995;52:393-398. humans: evidence from a reversal learning paradigm. Brain. 2003;126:1830- 38. Baxter LR Jr, Schwartz JM, Mazziotta JC, Phelps ME, Pahl JJ, Guze BH, Fair- 1837. banks L. Cerebral glucose metabolic rates in nondepressed patients with obsessive- 14. Hornak J, O’Doherty J, Bramham J, Rolls ET, Morris RG, Bullock PR, Polkey CE. compulsive disorder. Am J Psychiatry. 1988;145:1560-1563. Reward-related reversal learning after surgical excisions in orbito-frontal or dor- 39. Lacerda AL, Dalgalarrondo P, Caetano D, Camargo EE, Etchebehere EC, Soares solateral prefrontal cortex in humans. J Cogn Neurosci. 2004;16:463-478. JC. Elevated thalamic and prefrontal regional cerebral blood flow in obsessive- 15. Zald DH, Lee JT, Fluegel KW, Pardo JV. Aversive gustatory stimulation activates compulsive disorder: a SPECT study. Psychiatry Res. 2003;123:125-134. limbic circuits in humans. Brain. 1998;121:1143-1154. 40. Busatto GF, Zamignani DR, Buchpiguel CA, Garrido GE, Glabus MF, Rocha ET, 16. Francis S, Rolls ET, Bowtell R, McGlone F, O’Doherty J, Browning A, Clare S, Maia AF, Rosario-Campos MC, Campi Castro C, Furuie SS, Gutierrez MA, McGuire Smith E. The representation of pleasant touch in the brain and its relationship PK, Miguel EC. A voxel-based investigation of regional cerebral blood flow ab- with taste and olfactory areas. Neuroreport. 1999;10:453-459. normalities in obsessive-compulsive disorder using single photon emission com- 17. O’Doherty J, Kringelbach ML, Rolls ET, Hornak J, Andrews C. Abstract reward puted tomography (SPECT). Psychiatry Res. 2000;99:15-27. and punishment representations in the human orbitofrontal cortex. Nat Neurosci. 41. Rubin RT, Villanueva-Meyer J, Ananth J, Trajmar PG, Mena I. Regional xenon 2001;4:95-102. 133 cerebral blood flow and cerebral technetium 99m HMPAO uptake in un- 18. Elliott R, Newman JL, Longe OA, Deakin JF. Differential response patterns in the medicated patients with obsessive-compulsive disorder and matched normal con- striatum and orbitofrontal cortex to financial reward in humans: a parametric func- trol subjects: determination by high-resolution single-photon emission com- tional magnetic resonance imaging study. J Neurosci. 2003;23:303-307. puted tomography. Arch Gen Psychiatry. 1992;49:695-702. 19. O’Doherty J, Critchley H, Deichmann R, Dolan RJ. Dissociating valence of out- 42. Saxena S, Brody AL, Maidment KM, Smith EC, Zohrabi N, Katz E, Baker SK, Bax- come from behavioral control in human orbital and ventral prefrontal cortices. ter LR Jr. Cerebral glucose metabolism in obsessive-compulsive hoarding. Am J Neurosci. 2003;23:7931-7939. J Psychiatry. 2004;161:1038-1048. 20. Kringelbach ML, Rolls ET. Neural correlates of rapid reversal learning in a simple 43. Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN, Ken- model of human social interaction. Neuroimage. 2003;20:1371-1383. drick AD, Davis TL, Jiang A, Cohen MS, Stern CE, Belliveau JW, Baer L, O’Sullivan 21. Delgado MR, Nystrom LE, Fissell C, Noll DC, Fiez JA. Tracking the hemody- RL, Savage CR, Jenike MA, Rosen BR. Functional magnetic resonance imaging namic responses to reward and punishment in the striatum. J Neurophysiol. 2000; of symptom provocation in obsessive-compulsive disorder. Arch Gen Psychiatry. 84:3072-3077. 1996;53:595-606. 22. Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks 44. Rauch SL, Jenike MA, Alpert NM, Baer L, Breiter HCR, Savage CR, Fischman AJ. DJ, Bench CJ, Grasby PM. Evidence for striatal dopamine release during a video Regional cerebral blood flow measured during symptom provocation in obsessive- game. Nature. 1998;393:266-268. compulsive disorder using oxygen 15-labeled carbon dioxide and positron emis- 23. Divac I, Rosvold E, Szwarcbart MK. Behavioral effects of selective ablation of sion tomography. Arch Gen Psychiatry. 1994;51:62-70. the caudate nucleus. J Comp Physiol Psychol. 1967;63:184-190. 45. van den Heuvel OA, Veltman DJ, Groenewegen HJ, Dolan RJ, Cath DC, Boellaard 24. Rogers RD, Andrews TC, Grasby PM, Brooks DJ, Robbins TW. Contrasting cor- R, Mesina CT, van Balkom AJLM, van Oppen P, Witter MP, Lammertsma AA, tical and subcortical activations produced by attentional-set shifting and rever- van Dyck R. Amygdala activity in obsessive-compulsive disorder with contami- sal learning in humans. J Cogn Neurosci. 2000;12:142-162. nation fear: a study with oxygen-15 water positron emission tomography. Psy- 25. Cools R, Clark L, Owen AM, Robbins TW. Defining the neural mechanisms of chiatry Res. 2004;132:225-237. probabilistic reversal learning using event-related functional magnetic reso- 46. Zohar J, Westenberg HG. Anxiety disorders: a review of tricyclic antidepres- nance imaging. J Neurosci. 2002;22:4563-4567. sants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl. 26. Saxena S, Brody AL, Schwartz JM, Baxter LR. Neuroimaging and frontal- 2000;403:39-49. subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl. 47. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, 1998;173(suppl 35):26-37. placebo-controlled study of risperdone addition in serotonin reuptake inhibitor- 27. Schwartz JM. A role for volition and attention in the generation of new brain cir- refractory obsessive-compulsive disorder. Arch Gen Psychiatry. 2000;57: cuitry: toward a neurobiology of mental force. J Consciousness Studies. 1999; 794-801. 6:115-142. 48. Rogers RD, Blackshaw AJ, Middleton HC, Matthews K, Hawtin K, Crowley C, Hop- 28. Baxter LR Jr, Clark EC, Iqbal M, Ackermann RF. Cortical-subcortical systems in wood A, Wallace C, Deakin JFW, Sahakian BJ, Robbins TW. Tryptophan deple- the mediation of obsessive-compulsive disorder. In: Lichter DG, Cummings JL, tion impairs stimulus-reward learning while methylphenidate disrupts atten- eds. Frontal-Subcortical Circuits in Psychiatric and Neurological Disorders. New tional control in healthy young adults: implications for the monoaminergic basis York, NY: Guilford Publications, Inc; 2001:207-230. of impulsive behaviour. Psychopharmacology (Berl). 1999;146:482-491. 29. Aouizerate B, Guehl D, Cuny E, Rougier A, Bioulac B, Tignol J, Burbaud P. Patho- 49. Schultz W. Predictive reward signal of dopamine neurons. J Neurophysiol. 1998; physiology of obsessive-compulsive disorder: a necessary link between phe- 80:1-27. nomenology, neuropsychology, imagery and physiology. Prog Neurobiol. 2004; 50. Ursu S, Stenger VA, Shear MK, Jones MR, Carter CS. Overactive action moni- 72:195-221. toring in obsessive-compulsive disorder: evidence from functional magnetic reso- 30. Abbruzzese M, Ferri S, Scarone S. The selective breakdown of frontal functions nance imaging. Psychol Sci. 2003;14:347-353. in patients with obsessive-compulsive disorder and in patients with schizophre- 51. Maltby N, Tolin DF, Worhunsky P, O’Keefe TM, Kiehl KA. Dysfunctional action nia: a double dissociation experimental finding. Neuropsychologia. 1997;35: monitoring hyperactivates frontal-striatal circuits in obsessive-compulsive dis- 907-912. order: an event-related fMRI study. Neuroimage. 2005;24:495-503. 31. Cavedini P, Riboldi G, D’Annucci A, Belotti P, Cisima M, Bellodi L. Decision- 52. Fitzgerald KD, Welsh RC, Gehring WJ, Abelson JL, Himle JA, Liberzon I, Taylor making heterogeneity in obsessive-compulsive disorder: ventromedial prefron- SF. Error-related hyperactivity of the anterior cingulate cortex in obsessive- tal cortex function predicts different treatment outcomes. Neuropsychologia. 2002; compulsive disorder. Biol Psychiatry. 2005;57:287-294. 40:205-211. 53. Remijnse PL, Nielen MMA, Uylings HBM, Veltman DJ. Neural correlates of a re- 32. Hermesh H, Zohar J, Weizman A, Voet H, Gross-Isseroff R. Orbitofrontal cortex versal learning task with an affectively neutral baseline; an event-related fMRI dysfunction in obsessive-compulsive disorder? II. Olfactory quality discrimina- study. Neuroimage. 2005;26:609-618. tion in obsessive-compulsive disorder. Eur Neuropsychopharmacol. 1999; 54. Kringelbach ML, Rolls ET. The functional neuroanatomy of the human orbito- 9:415-420. frontal cortex: evidence from neuroimaging and neuropsychology. Prog Neurobiol. 33. Nielen MMA, Veltman DJ, de Jong R, Mulder G, den Boer JA. Decision making per- 2004;72:341-372. formance in obsessive compulsive disorder. J Affect Disord. 2002;69:257-260. 55. Deichmann R, Gottfried JA, Hutton C, Turner R. Optimized EPI for fMRI studies 34. Kim JJ, Lee MC, Kim J, Kim IY, Kim SI, Han MH, Chang KH, Kwon JS. Grey mat- of the orbitofrontal cortex. Neuroimage. 2003;19:430-441. ter abnormalities in obsessive-compulsive disorder. Br J Psychiatry. 2001; 56. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for 179:330-334. DSM-IV Axis I Disorders, Patient Edition (SCID-1/P, Version 2.0). New York, NY: 35. Pujol J, Soriano-Mas C, Alonso P, Cardoner N, Menchon JM, Deus J, Vallejo J. Biometrics Research Dept; 1996. Mapping structural brain alterations in obsessive-compulsive disorder. Arch Gen 57. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Psychiatry. 2004;61:720-730. Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale, I: de- 36. Aylward EH, Harris GJ, Hoehn-Saric R, Barta PE, Machlin SR, Pearlson GD. velopment, use, and reliability. Arch Gen Psychiatry. 1989;46:1006-1011. Normal caudate nucleus in obsessive-compulsive disorder assessed by quanti- 58. Sanavio E. Obsessions and compulsions: the Padua Inventory. Behav Res Ther. tative neuroimaging. Arch Gen Psychiatry. 1996;53:577-584. 1988;26:169-177.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1235

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 59. van Oppen P, Hoekstra RJ, Emmelkamp PMG. The structure of obsessive com- 70. Augustine JR. Circuitry and functional aspects of the insular lobe in primates pulsive disorders. Behav Res Ther. 1995;33:15-23. including humans. Brain Res Brain Res Rev. 1996;22:229-244. 60. Mataix-Cols D, Rosario-Campos MC, Leckman JF. A multidimensional 71. Mesulam MM. Paralimbic (mesocortical) areas. In: Mesulam MM, ed. Prin- model of obsessive-compulsive disorder. Am J Psychiatry. 2005;162: ciples of Behavioral and Cognitive Neurology. 2nd ed. New York, NY: Oxford Uni- 228-238. versity Press; 2000:49-54. 61. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measur- 72. Cohen MX, Heller AS, Ranganath C. Functional connectivity with anterior cingu- ing depression. Arch Gen Psychiatry. 1961;4:561-571. late and orbitofrontal cortices during decision-making. Brain Res Cogn Brain Res. 62. Hamilton M. Development of a rating scale of primary depressive illness. Br J 2005;23:61-70. Soc Clin Psychol. 1967;6:278-296. 73. Gehring WJ, Himle J, Nisenson LG. Action-monitoring dysfunction in obsessive- 63. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to compulsive disorder. Psychol Sci. 2000;11:1-6. change. Br J Psychiatry. 1979;134:382-389. 74. van der Wee NJA, Ramsey NF, Jansma JM, Denys DA, van Megen HJGM, 64. Friston KJ, Holmes AP, Price CJ, Buchel C, Worsley KJ. Multisubject fMRI stud- Westenberg HMG, Kahn RS. Spatial working memory deficits in obsessive- ies and conjunction analyses. Neuroimage. 1999;10:385-396. compulsive disorder are associated with excessive engagement of the medial 65. Genovese CR, Lazar NA, Nichols T. Thresholding of statistical maps in func- frontal cortex. Neuroimage. 2003;20:2271-2280. tional neuroimaging using the false discovery rate. Neuroimage. 2002;15: 75. Pitman RK. A cybernetic model of obsessive-compulsive psychopathology. Compr 870-878. Psychiatry. 1987;28:334-343. 66. Friston KJ, Penny WD, Glaser DE. Conjunction revisited. Neuroimage. 2005;25: 76. Rogers RD, Tunbridge EM, Bhagwagar Z, Drevets WC, Sahakian BJ, Carter CS. 661-667. Tryptophan depletion alters the decision-making of healthy volunteers through al- 67. Brett M, Johnsrude IS, Owen AM. The problem of functional localization in the tered processing of reward cues. Neuropsychopharmacology. 2003;28:153-162. human brain. Nat Rev Neurosci. 2002;3:243-249. 77. Baumgarten HG, Grozdanovic Z. Role of serotonin in obsessive-compulsive 68. Rauch SL, Savage CR, Alpert NM, Dougherty D, Kendrick A, Curran T, Brown disorder. Br J Psychiatry Suppl. 1998;173(suppl 35):13-20. HD, Manzo P, Fischman AJ, Jenike MA. Probing striatal function in obsessive- 78. van der Wee NJ, Stevens H, Hardeman JA, Mandl RC, Denys DA, van Megen HJ, compulsive disorder: a PET study of implicit sequence learning. J Neuropsy- Kahn RS, Westenberg HM. Enhanced dopamine transporter density in psychotropic- chiatry Clin Neurosci. 1997;9:568-573. naive patients with obsessive-compulsive disorder shown by [123I]␤-CIT SPECT. 69. Rauch SL, Whalen PJ, Curran T, Shin LM, Coffey BJ, Savage CR, McInerney SC, Am J Psychiatry. 2004;161:2201-2206. Baer L, Jenike MA. Probing striato-thalamic function in obsessive-compulsive 79. Denys D, van der Wee N, Janssen J, de Geus F, Westenberg HGM. Low level of

disorder and Tourette syndrome using neuroimaging methods. Adv Neurol. 2001; dopaminergic D2 receptor binding in obsessive-compulsive disorder. Biol 85:207-224. Psychiatry. 2004;55:1041-1045.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 1236