Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response.

Obsessive-compulsive disorder (OCD) is a prevalent mental disorder affecting ~2-3% of the population. This disorder involves genetic and, possibly, epigenetic risk factors. The dynamic nature of epigenetics also presents a promising avenue for identifying biomarkers associated with symptom severity, clinical progression, and treatment response in OCD. We, therefore, conducted a comprehensive case-control investigation using Illumina MethylationEPIC BeadChip, encompassing 185 OCD patients and 199 controls recruited from two distinct sites in Germany. Rigorous clinical assessments were performed by trained raters employing the Structured Clinical Interview for DSM-IV (SCID-I). We performed a robust two-step epigenome-wide association study that led to the identification of 305 differentially methylated CpG positions. Next, we validated these findings by pinpointing the optimal set of CpGs that could effectively classify individuals into their respective groups. This approach identified a subset comprising 12 CpGs that overlapped with the 305 CpGs identified in our EWAS. These 12 CpGs are close to or in genes associated with the sweet-compulsive brain hypothesis which proposes that aberrant dopaminergic transmission in the striatum may impair insulin signaling sensitivity among OCD patients. We replicated three of the 12 CpGs signals from a recent independent study conducted on the Han Chinese population, underscoring also the cross-cultural relevance of our findings. In conclusion, our study further supports the involvement of epigenetic mechanisms in the pathogenesis of OCD. By elucidating the underlying molecular alterations associated with OCD, our study contributes to advancing our understanding of this complex disorder and may ultimately improve clinical outcomes for affected individuals.

Effectiveness of Individual Cognitive-Behavioral Therapy and Predictors of Outcome in Adult Patients with Obsessive-Compulsive Disorder.

INTRODUCTION: Cognitive-behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) has proven its efficacy in randomized controlled trials (RCTs). OBJECTIVE: To test generalizability to routine care settings, we conducted an effectiveness study to provide naturalistic outcome data and their predictors. METHODS: Pre-post changes in symptoms and impairment as well as response rates were determined in a naturalistic OCD sample (intention-to-treat, ITT, n = 393). Patients received individual CBT for OCD adopting an exposure-based, non-manualized treatment format. Linear and logistic regression analyses were applied to identify associations of sociodemographic and clinical variables with symptom change. RESULTS: Effect size in ITT patients amounted to d = 1.47 in primary outcome (Yale-Brown Obsessive-Compulsive Scale, Y-BOCS). Remission rates were 46.3% (ITT), 52.0% (completers), and 18.2% (non-completers). The rates of treatment response without remission, no change, and deterioration in the ITT sample were 13.2, 38, and 3%, respectively. Initial symptom severity, comorbid personality disorder, and unemployment were associated with a poorer outcome, and previous medication with a better outcome. Comorbid depressive and anxiety disorders as well as other clinical or sociodemographic variables showed no effects on symptom change. CONCLUSIONS: Outcomes in this large observational trial in a naturalistic setting correspond to available RCT findings suggesting that CBT for OCD should be strongly recommended for dissemination in routine care. Targets for further research include early prediction of non-response and development of alternative treatment strategies for patients who respond insufficiently.

Mechanisms of exposure and response prevention in obsessive-compulsive disorder: effects of habituation and expectancy violation on short-term outcome in cognitive behavioral therapy.

BACKGROUND: Exposure and response prevention is effective and recommended as the first choice for treating obsessive-compulsive disorders (OCD). Its mechanisms of action are rarely studied, but two major theories make distinct assumptions: while the emotional processing theory assumes that treatment effects are associated with habituation within and between exposure sessions, the inhibitory learning approach highlights the acquisition of additional associations, implying alternative mechanisms like expectancy violation. The present study aimed to investigate whether process variables derived from both theories predict short-term outcome. METHOD: In a university outpatient unit, 110 patients (63 female) with OCD received manual-based cognitive-behavioral therapy with high standardization of the first two exposure sessions. Specifically, therapists repeated the first exposure session identically and assessed subjective units of distress as well as expectancy ratings in the course of exposure sessions. Based on these data, individual scores for habituation and distress-related expectancy violation were calculated and used for prediction of both percentage change on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and remission status after 20 therapy sessions. RESULTS: In a multiple regression model for percentage change, within-session habituation during the first exposure was a significant predictor, while in a logistic regression predicting remission status, distress-related expectancy violation during the first exposure revealed significance. A path model further supported these findings. CONCLUSIONS: The results represent first evidence for distress-related expectancy violation and confirm preliminary findings for habituation, suggesting that both processes contribute to treatment benefits of exposure in OCD, and both mechanisms appear to be independent.

Systematic evaluation of the 'efficacy-effectiveness gap' in the treatment of depression with venlafaxine and duloxetine.

OBJECTIVE: Evidence of larger drug effects in highly standardized studies (efficacy) compared to clinical routine (effectiveness) is discussed as efficacy-effectiveness gap. This study aimed to quantify effect size differences of RCTs and non-RCTs in the treatment of depression with venlafaxine and duloxetine and to identify effect modifying predictors. METHODS: A comprehensive systematic review and meta-analysis was conducted, including all prospective trials, which evaluated the treatment effects of duloxetine or venlafaxine in patients with depression. The primary outcome was the pre-post effect size after acute therapy, which were compared between RCTs and non-RCTs. Moreover, an exploratory analysis of predictors in a mixed meta-regression model within an information-theoretic approach was performed. RESULTS: 171 RCTs and 74 non-RCTs were included. The pre-post effect size differed significantly between RCTs and non-RCTs (-3.04 vs. -2.62, Δ = 0.41, p = 0.012, high heterogeneity). Study characteristics were very similar between RCTs and non-RCTs. Most important variables to predict effect sizes were 'depression severity', 'dose' and 'number of participants'. CONCLUSION: Despite differences in effect sizes between RCTs and non-RCTs, study design is not clearly an important predictor for the effect sizes. Our results question the common assumption that non-RCTs are generally better suited to describe a drug's effectiveness in clinical practice than RCTs. Future studies and their reporting should put more emphasis on the description of external validity, in order to allow better assessments of clinical relevance.

Identifying CBT non-response among OCD outpatients: A machine-learning approach.

Objectives: Machine learning models predicting treatment outcomes for individual patients may yield high clinical utility. However, few studies tested the utility of easy to acquire and low-cost sociodemographic and clinical data. In previous work, we reported significant predictions still insufficient for immediate clinical use in a sample with broad diagnostic spectrum. We here examined whether predictions will improve in a diagnostically more homogeneous yet large and naturalistic obsessive-compulsive disorder (OCD) sample. Methods: We used sociodemographic and clinical data routinely acquired during CBT treatment of n = 533 OCD subjects in a specialized outpatient clinic. Results: Remission was predicted with 65% (p = 0.001) balanced accuracy on unseen data for the best model. Higher OCD symptom severity predicted non-remission, while higher age of onset of first OCD symptoms and higher socioeconomic status predicted remission. For dimensional change, prediction achieved r = 0.31 (p = 0.001) between predicted and actual values. Conclusions: The comparison with our previous work suggests that predictions within a diagnostically homogeneous sample, here OCD, are not per se superior to a more diverse sample including several diagnostic groups. Using refined psychological predictors associated with disorder etiology and maintenance or adding further data modalities as neuroimaging or ecological momentary assessments are promising in order to further increase prediction accuracy.

Differential roles of the frontal and parietal cortices in the control of saccades.

Although externally as well as internally-guided eye movements allow us to flexibly explore the visual environment, their differential neural mechanisms remain elusive. A better understanding of these neural mechanisms will help us to understand the control of action and to elucidate the nature of cognitive deficits in certain psychiatric populations (e.g., schizophrenia) that show increased latencies in volitional but not visually-guided saccades. Both the superior precentral sulcus (sPCS) and the intraparietal sulcus (IPS) are implicated in the control of eye movements. However, it remains unknown what differential contributions the two areas make to the programming of visually-guided and internally-guided saccades. In this study we tested the hypotheses that sPCS and IPS distinctly encode internally-guided saccades and visually-guided saccades. We scanned subjects with fMRI while they generated visually-guided and internally-guided delayed saccades. We used multi-voxel pattern analysis to test whether patterns of cue related, preparatory and saccade related activation could be used to predict the direction of the planned eye movement. Results indicate that patterns in the human sPCS predicted internally-guided saccades but not visually-guided saccades in all trial periods and patterns in the IPS predicted internally-guided saccades and visually-guided saccades equally well. The results support the hypothesis that the human sPCS and IPS make distinct contributions to the control of volitional eye movements.

Impaired volitional saccade control: first evidence for a new candidate endophenotype in obsessive-compulsive disorder.

Recent research suggests that patients with obsessive-compulsive disorder (OCD) have deficits in the volitional control of saccades. Specific evidence comes from increased latencies of saccadic eye movements when they were volitionally executed but not when they were visually guided. The present study sought to test whether this deviance represents a cognitive endophenotype. To this end, first-degree relatives of OCD patients as genetic risk carriers were compared with OCD patients and healthy controls without a family history of OCD. Furthermore, as volitional response generation comprises selection and initiation of the required response, the study also sought to specify the cognitive mechanisms underlying impaired volitional response generation. Twenty-two unaffected first-degree relatives of OCD patients, 22 unmedicated OCD patients, and 22 healthy comparison subjects performed two types of volitional saccade tasks measuring response selection or only response initiation, respectively. Visually guided saccades were used as a control condition. Our results showed that unaffected first-degree relatives and OCD patients were significantly slowed compared to healthy comparison subjects in volitional response selection. Patients and relatives did not differ from each other. There was no group difference in the visually guided control condition. Taken together, the study provides first evidence that dysfunctional volitional response selection is a candidate endophenotype for OCD.

Lack of speeded disengagement from facial expressions of disgust in remitted major depressive disorder: Evidence from an eye-movement study.

Acute major depression is characterized by specific abnormalities in the way emotional material is attended to. In late stages of stimulus processing, clinically depressed and dysphoric individuals show difficulties to disengage attention from emotionally negative material. It is unclear, however, whether aberrant disengagement is a transitory attentional phenomenon tied to depressive symptoms, or whether it constitutes a more stable disposition that outlast the symptomatic episode. To address this issue, the current study examined 39 currently euthymic individuals previously affected by major depression (RMD) and 40 healthy control participants reporting no lifetime psychopathology (ND). We used a gaze-contingent eye tracking paradigm designed to separately assess the attentional components of engagement and disengagement when viewing facial expressions of sadness, disgust and happiness. Never-depressed healthy participants, but not remitted euthymic individuals, showed speeded disengagement from facial expressions of disgust. We propose that the lack of this distinct acceleration in previously depressed but fully remitted individuals might reflect an attentional disposition that carries over to euthymic phases of the disease. On the other hand, a tendency to disengage quickly from areas in the visual field that convey social disdain could potentially act as a protective, possibly mood-stabilizing bias in resilient individuals.

Predicting heterogeneous treatment effects of an Internet-based depression intervention for patients with chronic back pain: Secondary analysis of two randomized controlled trials.

Background: Depression is highly prevalent among individuals with chronic back pain. Internet-based interventions can be effective in treating and preventing depression in this patient group, but it is unclear who benefits most from this intervention format. Method: In an analysis of two randomized trials (N = 504), we explored ways to predict heterogeneous treatment effects of an Internet-based depression intervention for patients with chronic back pain. Univariate treatment-moderator interactions were explored in a first step. Multilevel model-based recursive partitioning was then applied to develop a decision tree model predicting individualized treatment benefits. Results: The average effect on depressive symptoms was d = -0.43 (95 % CI: -0.68 to -0.17; 9 weeks; PHQ-9). Using univariate models, only back pain medication intake was detected as an effect moderator, predicting higher effects. More complex interactions were found using recursive partitioning, resulting in a final decision tree with six terminal nodes. The model explained a large amount of variation (bootstrap-bias-corrected R2 = 45 %), with predicted subgroup-conditional effects ranging from di = 0.24 to -1.31. External validation in a pilot trial among patients on sick leave (N = 76; R2 = 33 %) pointed to the transportability of the model. Conclusions: The studied intervention is effective in reducing depressive symptoms, but not among all chronic back pain patients. Predictions of the multivariate tree learning model suggest a pattern in which patients with moderate depression and relatively low pain self-efficacy benefit most, while no benefits arise when patients' self-efficacy is already high. If corroborated in further studies, the developed tree algorithm could serve as a practical decision-making tool.

Response selection in prosaccades, antisaccades, and other volitional saccades.

Saccades made to the opposite side of a visual stimulus (antisaccades) and to central cues (simple volitional saccades) both require active response selection but whether the mechanisms of response selection differ between these tasks is unclear. Response selection can be assessed by increasing the number of response alternatives: this leads to increased reaction times when response selection is more demanding. We compared the reaction times of prosaccades, antisaccades, saccades cued by a central arrow, and saccades cued by a central number, in blocks of either two or six possible responses. In the two-response blocks, reaction times were fastest for prosaccades and antisaccades, and slowest for arrow-cued and number-cued saccades. Increasing response alternatives from two to six caused a paradoxical reduction in reaction times of prosaccades, had no effect on arrow-cued saccades, and led to a large increase in reaction times of number-cued saccades. For antisaccade reaction times, the effect of increasing response alternatives was intermediate, greater than that for arrow-cued saccades but less than that for number-cued saccades. We suggest that this pattern of results may reflect two components of saccadic processing: (a) response triggering, which is more rapid with a peripheral stimulus as in the prosaccade and antisaccade tasks and (b) response selection, which is more demanding for the antisaccade and number-cued saccade tasks, and more automatic when there is direct stimulus-response mapping as with prosaccades, or over-learned symbols as with arrow-cued saccades.

Neural correlates of emotional reactivity predict response to cognitive-behavioral therapy in obsessive-compulsive disorder.

BACKGROUND: Examining predictive biomarkers to identify individuals who will likely benefit from a specific treatment is important for the development of targeted interventions. The late positive potential (LPP) is a neural marker of attention and elaborated stimulus processing, and increased LPP responses to negative stimuli are characteristic of pathological anxiety. The present study investigated whether LPP reactivity would prospectively predict response to cognitive-behavioral therapy (CBT), the first-line treatment for obsessive-compulsive disorder (OCD). METHODS: To this end, the LPP in response to negative as compared to neutral pictures was examined in 45 patients with OCD, who underwent CBT in a naturalistic outpatient setting. LPP amplitudes were used as predictors of symptom reduction after CBT. RESULTS: We found that higher LPP amplitudes to negative relative to neutral stimuli were predictive of lower self-reported OCD symptoms after completion of CBT, controlling for pre-treatment symptoms. Further, LPP reactivity was negatively correlated with self-reported habitual use of suppression in everyday life. LIMITATIONS: Some participants had already begun treatment at the time of study participation. Overall, results need further replication in larger samples and standardized therapy settings. CONCLUSIONS: The current findings suggest that patients with increased emotional reactivity benefit more from CBT, possibly through less avoidance of anxiety-provoking stimuli during exposure with response prevention, a crucial component in CBT for OCD. Although its clinical utility still needs to be evaluated further, the LPP constitutes a promising candidate as a prognostic marker for CBT response in OCD.

Impaired differential learning of fear versus safety signs in obsessive-compulsive disorder.

Pavlovian learning mechanisms are of great importance both for models of psychiatric disorders and treatment approaches, but understudied in obsessive-compulsive disorder (OCD). Using an established Pavlovian fear conditioning and reversal procedure, we studied skin conductance responses in 41 patients with OCD and in 32 matched healthy control participants. Within both groups, fear acquisition and reversal effects were evident. When comparing groups, patients showed impaired differential learning of threatening and safe stimuli, consistent with previous research. In contrast to prior findings, differential learning impairments were restricted to fear acquisition, and not observed in the reversal stage of the experiment. As previous and present fear reversal experiments in OCD differed in the use of color coding to facilitate stimulus discrimination, the studies converge to suggest that differential learning of threatening versus safe stimuli is impaired in OCD, but manifests itself differently depending on the difficulty of the association to be learned. When supported by the addition of color, patients with OCD previously appeared to acquire an association early but failed to reverse it according to changed contingencies. In absence of such color coding of stimuli, our data suggest that patients with OCD already show differential learning impairments during fear acquisition, which may relate to findings of altered coping with uncertainty previously observed in OCD. Impaired differential learning of threatening versus safe stimuli should be studied further in OCD, in order to determine whether impairments in differential learning predict treatment outcomes in patients, and whether they are etiologically relevant for OCD.

Error-related activity of the sensorimotor network contributes to the prediction of response to cognitive-behavioral therapy in obsessive-compulsive disorder.

BACKGROUND: Although cognitive behavioral therapy is a highly effective treatment for obsessive-compulsive disorder (OCD), yielding large symptom reductions on the group level, individual treatment response varies considerably. Identification of treatment response predictors may provide important information for maximizing individual treatment response and thus achieving efficient treatment resource allocation. Here, we investigated the predictive value of previously identified biomarkers of OCD, namely the error-related activity of the supplementary motor area (SMA) and the sensorimotor network (SMN, postcentral gyrus/precuneus). METHODS: Seventy-two participants with a primary diagnosis of OCD underwent functional magnetic resonance imaging (fMRI) scanning while performing a flanker task prior to receiving routine-care CBT. RESULTS: Error-related BOLD response of the SMN significantly contributed to the prediction of treatment response beyond the variance accounted for by clinical and sociodemographic variables. Stronger error-related SMN activity at baseline was associated with a higher likelihood of treatment response. CONCLUSIONS: The present results illustrate that the inclusion of error-related SMN activity can significantly increase treatment response prediction quality in OCD. Stronger error-related activity of the SMN may reflect the ability to activate symptom-relevant processing networks and may thus facilitate response to exposure-based CBT interventions.

Hypermethylation of the oxytocin receptor gene (OXTR) in obsessive-compulsive disorder: further evidence for a biomarker of disease and treatment response.

Obsessive-compulsive disorder (OCD) has recently been linked to increased methylation levels in the oxytocin receptor (OXTR) gene, and OXTR hypermethylation has predicted a worse treatment response to cognitive-behavioural therapy (CBT). Furthermore, OCD is associated with childhood trauma and stressful life events, which have both been shown to affect OXTR methylation. Here, we aimed to replicate findings of increased OXTR methylation as a predictor of disease and worse treatment response in an independent sample that received treatment within the public health care system. In addition, we aimed to extend previous findings by examining associations between OXTR hypermethylation, environmental stressors, OCD diagnosis, and treatment response. Methylation levels at two CpGs within OXTR exon III were compared between n = 181 OCD patients and n = 199 healthy controls using linear regression analysis. In a subsample of OCD patients (n = 98) with documented treatment data, we examined associations between methylation and treatment response to CBT. Childhood adversity and stressful life events were assessed using Childhood Trauma Questionnaire and Life Experience Survey, respectively. OCD patients exhibited significant hypermethylation at CpG site cg04523291 compared to controls, and increased methylation was associated with impaired treatment response. Moreover, hypermethylation at cg04523291 was associated with stressful life events in OCD patients, and with childhood adversity in controls. Yet, there were no significant mediation effects. In conclusion, we replicated the association between OXTR hypermethylation and OCD in the largest sample, so far. Furthermore, our findings support the role of OXTR methylation as a promising biomarker for treatment response in OCD.

Distinct neural correlates for volitional generation and inhibition of saccades.

The antisaccade task has proven highly useful in basic and clinical neuroscience, and the neural structures involved are well documented. However, the cognitive and neural mechanisms that mediate task performance are not yet understood. An event-related fMRI study was designed to dissociate the neural correlates of two putative key functions, volitional saccade generation and inhibition of reflexive saccades, and to investigate their interaction. Nineteen healthy volunteers performed a task that required (a) to initiate saccades volitionally, either with or without a simultaneous demand to inhibit a reflexive saccade; and (b) to inhibit a reflexive saccade, either with or without a simultaneous demand to initiate a saccade volitionally. Analysis of blood oxygen level-dependent signal changes confirmed a major role of the frontal eye fields and the supplementary eye fields in volitional saccade generation. Inhibition-related activation of a specific fronto-parietal network was highly consistent with previous evidence involved in inhibitory processes. Unexpectedly, there was little evidence of specific brain activation during combined generation and inhibition demands, suggesting that the neural processing of generation and inhibition in antisaccades is independent to a large extent.

Long-Term Stability of Benefits of Cognitive Behavioral Therapy for Obsessive Compulsive Disorder Depends on Symptom Remission During Treatment.

Background: Cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD) and may afford stable long-term improvements. It is not clear, however, how stability or symptom recurrence can be predicted at the time of termination of CBT. Method: In a 1-year follow-up intention-to-treat study with 120 OCD patients receiving individual CBT at a university outpatient unit, we investigated the predictive value of international consensus criteria for response only (Y-BOCS score reduction by at least 35%) and remission status (Y-BOCS score ≤ 12). Secondly, we applied receiver-operating characteristic (ROC) curves in order to find an optimal cut-off score to classify for deterioration and for sustained gains. Results: Response only at post-treatment increased the likelihood of deterioration at follow-up compared to remission at an odds ratio of 8.8. Moreover, ROC curves indicated that a post-treatment score of ≥ 13 differentiated optimally between patients with and without symptom deterioration at follow-up assessment. The optimal cut-off score to classify for any sustained gains (response, remission, or both) at follow-up relative to baseline was 12. Importantly, previous findings of generally high long-term symptom stability after treatment in OCD could be replicated. Conclusion: The findings highlight the clinical importance of reaching remission during CBT, and suggest that a recently published expert consensus for defining remission has high utility.

Dwelling on verbal but not pictorial threat cues: An eye-tracking study with adult survivors of childhood interpersonal violence.

OBJECTIVE: Previous studies have found evidence of an attentional bias for trauma-related stimuli in posttraumatic stress disorder (PTSD) using eye-tracking (ET) technlogy. However, it is unclear whether findings for PTSD after traumatic events in adulthood can be transferred to PTSD after interpersonal trauma in childhood. The latter is often accompanied by more complex symptom features, including, for example, affective dysregulation and has not yet been studied using ET. The aim of this study was to explore which components of attention are biased in adult victims of childhood trauma with PTSD compared to those without PTSD. METHOD: Female participants with (n = 27) or without (n = 27) PTSD who had experienced interpersonal violence in childhood or adolescence watched different trauma-related stimuli (Experiment 1: words, Experiment 2: facial expressions). We analyzed whether trauma-related stimuli were primarily detected (vigilance bias) and/or dwelled on longer (maintenance bias) compared to stimuli of other emotional qualities. RESULTS: For trauma-related words, there was evidence of a maintenance bias but not of a vigilance bias. For trauma-related facial expressions, there was no evidence of any bias. CONCLUSIONS: At present, an attentional bias to trauma-related stimuli cannot be considered as robust in PTSD following trauma in childhood compared to that of PTSD following trauma in adulthood. The findings are discussed with respect to difficulties attributing effects specifically to PTSD in this highly comorbid though understudied population. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Response switching in schizophrenia patients and healthy subjects: effects of the inter-response interval.

Schizophrenia patients show impaired saccadic response switching, pointing to action control deficits at the level of response selection. Previous studies on healthy subjects suggested that response switch effects might decrease if the prior response is longer ago, reflecting a slow dissipation of the response program persisting from the previous trial. The present study aimed at directly investigating whether response switch effects in schizophrenia patients and healthy subjects depend on the inter-response interval (IRI). Effects of response switching on pro- and antisaccade performance were analyzed in 19 schizophrenia patients and 19 healthy controls at 3 different IRIs (2,500, 3,000, 4,000 ms). Response switch effects of healthy subjects did not vary with the IRI, suggesting that the previous response program persists as long as no contrary response program is activated. In schizophrenia, response switch deficits were replicated at an IRI of 3,000 ms, whereas at IRIs of 2,500 and 4,000 ms, effects of response switching did not significantly differ from healthy subjects. This might suggest that there is a specific IRI range particularly sensitive to response switch deficits in schizophrenia. However, effects of response switching at different IRIs remain to be consolidated.

Decomposing the neural correlates of antisaccade eye movements using event-related FMRI.

The antisaccade task is a model of the conflict between an unwanted reflexive response (which must be inhibited) and a complex volitional response (which must be generated). The present experiment aimed to investigate separately the neural correlates of these cognitive components using a delayed saccade paradigm to dissociate saccade inhibition from generation. Seventeen healthy volunteers completed event-related functional magnetic resonance imaging at 1.5 T during saccades to and away from a peripheral visual target (prosaccades and antisaccades, respectively). Saccades were requested in response to an auditory go signal on average 12 s after peripheral target appearance. It was found that the right supramarginal gyrus showed significantly greater activation during the inhibition phase than the generation phase of the paradigm for both antisaccade and prosaccade trials, suggesting a role in saccade inhibition or stimulus detection. On the other hand, the right lateral frontal eye field and bilateral intraparietal sulcus showed evidence of selective involvement in antisaccade generation. Ventrolateral and dorsolateral prefrontal cortices showed comparable levels of activation in both phases of the task. These areas likely fulfill a more general supervisory role in the volitional control of eye movements, such as stimulus appraisal, task set, and decision making.