Don't worry, it won't be fine. Contributions of worry and anxious arousal to startle responses and event-related potentials in threat anticipation.

A widely shared framework suggests that anxiety maps onto two dimensions: anxious apprehension and anxious arousal. Previous research linked individual differences in these dimensions to differential neural response patterns in neuropsychological, imaging, and physiological studies. Differential effects of the anxiety dimensions might contribute to inconsistencies in prior studies that examined neural processes underlying anxiety, such as hypersensitivity to unpredictable threat. We investigated the association between trait worry (as a key component of anxious apprehension), anxious arousal, and the neural processing of anticipated threat. From a large online community sample (N = 1,603), we invited 136 participants with converging and diverging worry and anxious arousal profiles into the laboratory. Participants underwent the NPU-threat test with alternating phases of unpredictable threat, predictable threat, and safety, while physiological responses (startle reflex and startle probe locked event-related potential components N1 and P3) were recorded. Worry was associated with increased startle responses to unpredictable threat and increased attentional allocation (P3) to startle probes in predictable threat anticipation. Anxious arousal was associated with increased startle and N1 in unpredictable threat anticipation. These results suggest that trait variations in the anxiety dimensions shape the dynamics of neural processing of threat. Specifically, trait worry seems to simultaneously increase automatic defensive preparation during unpredictable threat and increase attentional responding to threat-irrelevant stimuli during predictable threat anticipation. The current study highlights the utility of anxiety dimensions to understand how physiological responses during threat anticipation are altered in anxiety and supports that worry is associated with hypersensitivity to unpredictable, aversive contexts.

Unrealistic pessimism and obsessive-compulsive symptoms during the COVID-19 pandemic: Two longitudinal studies.

OBJECTIVE: Unrealistic pessimism (UP) is an aspect of overestimation of threat (OET) that has been associated with obsessive-compulsive disorder/symptoms (OCD/OCS). During the COVID-19 pandemic, UP may have played an important role in the course of OCD. To investigate the relationship, we conducted two longitudinal studies assuming that higher UP predicts an increase in OCS. METHOD: In Study 1, we investigated UP in the general population (N = 1,184) at the start of the pandemic asking about overall vulnerability to infection with SARS-CoV-2 and UP regarding infection and outcome of severe illness. Further, OCS status (OCS+/-) was assessed at the start of the pandemic and 3 months later. In Study 2, we investigated UP in individuals with OCD (N = 268) regarding the likelihood of getting infected, recovering, or dying from an infection with SARS-CoV-2 at the start of the pandemic and re-assessed OCS 3 months later. RESULTS: In Study 1, UP was higher in the OCS+ compared to the OCS- group, and estimates of a higher overall vulnerability for an infection predicted a decrease in OCS over time. UP regarding severe illness predicted an increase in symptoms over time. In Study 2, UP was found for a recovery and death after an infection with SARS-CoV-2, but not for infection itself. CONCLUSIONS: Exaggeration of one's personal vulnerability rather than OET per se seems pivotal in OCD, with UP being associated with OCD/OCS+ as well as a more negative course of symptomatology over the pandemic in a nonclinical sample. PRACTITIONER POINTS: Unrealistic optimism, a bias common in healthy individuals, is thought to be a coping mechanism promoting well-being in the face of danger or uncertainty. The current study extends findings that its inversion, unrealistic pessimism, may play an important role in obsessive-compulsive disorder and may also be involved in the development of the disorder. This study highlights the importance that prevention programs during a pandemic should include targeting unrealistic pessimism.

Error-related brain activity as a transdiagnostic endophenotype for obsessive-compulsive disorder, anxiety and substance use disorder.

BACKGROUND: Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed. METHODS: The error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27). RESULTS: Increased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes. CONCLUSIONS: Alterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control.

Schizotypy and smooth pursuit eye movements as potential endophenotypes of obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto-striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM. Here, we examined a large sample of n = 168 patients with OCD, n = 93 unaffected first-degree relatives and n = 171 healthy control subjects to investigate whether elevated levels of schizotypy and SPEM deficits represent potential endophenotypes of OCD. We applied a SPEM task with high demands on predictive pursuit that is more sensitive to assess executive dysfunctions than a standard task with continuous visual feedback, as episodes of target blanking put increased demands on basal ganglia and prefrontal involvement. Additionally, we examined the relation between schizotypy and SPEM performance in OCD patients and their relatives. Results indicate that OCD patients and unaffected relatives do not show deficient performance in either standard or predictive SPEM. Yet, both patients and relatives exhibited elevated levels of schizotypy, and schizotypy was significantly correlated with velocity gain during standard trials in unmedicated and depression-free OCD patients. These findings highlight the role of schizotypy as a candidate endophenotype of OCD and add to the growing evidence for predisposing personality traits in OCD. Furthermore, intact gain may represent a key characteristic that distinguishes the OCD and schizophrenia patient populations.

Performance monitoring in obsessive-compulsive undergraduates: Effects of task difficulty.

Both obsessive-compulsive disorder and subclinical obsessive-compulsive (OC) symptoms seem to be associated with hyperactive error-related brain activity. The current study examined performance monitoring in subjects with subclinical OC symptoms using a new task with different levels of difficulty. Nineteen subjects with high and 18 subjects with low OC characteristics performed a random dot cinematogram (RDC) task with three levels of difficulty. The high and low OC groups did not differ in error-related negativity (ERN), correct-related negativity (CRN) and performance irrespective of task difficulty. The amplitude of the ERN decreased with increasing difficulty whereas the magnitude of CRN did not vary. ERN and CRN approached in size and topography with increasing difficulty, which suggests that errors and correct responses are processed more similarly. These results add to a growing number of studies that fail to replicate hyperactive performance monitoring in individuals with OC symptoms in task with higher difficulty or requiring learning. Together with these findings our results suggest that the relationship between OC symptoms and performance monitoring may be sensitive to type of task and task characteristics and cannot be observed in a RDC that differs from typically used tasks in difficulty and the amount of response-conflict.

Performance monitoring in obsessive-compulsive disorder: a temporo-spatial principal component analysis.

Hyperactive performance monitoring is a robust finding in obsessive-compulsive disorder (OCD). Patients show increased amplitudes of the error-related negativity (ERN) and correct-related negativity (CRN). Recently, two temporo-spatial factors were shown to contribute to both ERPs in healthy individuals. In the present study, it was investigated whether the factor structure underlying ERN and CRN is similar in OCD and which factors differ between groups. A principal component analysis (PCA) was employed to investigate the temporo-spatial factor structure of ERN and CRN. Twenty-six OCD patients and 26 healthy controls conducted a flanker task. EEG data were analyzed as conventional ERP components and as factor scores derived from temporo-spatial PCA. ERP results showed expected increases in ERN and CRN amplitudes in OCD patients. For both groups, the PCA confirmed the assumed factor structure of a central and a fronto-parietal factor contributing to ERN and CRN. Factor scores of both factors were differently affected by response correctness in OCD. Alterations in factor scores indicate increased activity in both an outcome-independent monitoring process and an error-sensitive process, contributing to overactive performance monitoring in OCD.

Show me the Money: the impact of actual rewards and losses on the feedback negativity.

The feedback negativity (FN) is an event-related potential component which is typically conceptualized as a negativity in response to losses that is absent in response to gains. However, there is also evidence that variation in the FN reflects the neural response to gains. The present study sought to explore these possibilities by manipulating the context in which loss and gain feedback was presented in a straightforward gambling task. In half the blocks, participants could win or lose money (Value condition), and in half the blocks, participants could not win or lose any money (No Value condition). The degree to which losses and gains were differentiated from one another (i.e., the ΔFN) was greater in the Value condition than in the No Value condition. Furthermore, though the responses to loss feedback and gain feedback were each enhanced in the Value condition relative to the No-Value condition, the effect of the monetary manipulation was substantially larger for the positivity to gains than the negativity to losses. This is consistent with the notion that the FN might reflect two independent processes, but that variation in the FN depends more upon the response to rewards than losses.

Overactive performance monitoring in obsessive-compulsive disorder is independent of symptom expression.

Overactive performance monitoring has been consistently reported in obsessive-compulsive disorder (OCD). OCD is a clinically heterogeneous disorder and is characterized by several symptom dimensions that may have partially distinct neural correlates. We examined whether performance-monitoring alterations are related to symptom severity and symptom dimensions. Electrocortical correlates of performance monitoring were assessed in 72 OCD patients and 72 matched healthy comparison participants during a flanker task. Amplitudes of the error- and correct-related negativity as well as delta and theta power were used to quantify performance-monitoring activity, and a composite measure was derived using factor analysis. Symptom dimension scores were obtained from the Yale-Brown Obsessive Compulsive Scale symptom checklist. OCD patients showed increased electrocortical responses associated with correct and erroneous responses compared to healthy comparison participants. In patients, no correlations were obtained between performance monitoring and global symptom severity as well as lifetime symptom dimension scores. Only a statistical trend was found that higher symmetry/hoarding scores were associated with reduced performance-monitoring activity. For present symptom dimensions scores, an association with rituals/superstitious symptoms was obtained such that higher scores were associated with greater performance-monitoring activity. However, for both dimensions, subjects with low scores or high scores on each dimension were characterized by overactive performance monitoring compared to healthy controls. Overactive brain processes during performance monitoring are a neural correlate of OCD that is independent of global symptom severity and can be observed for all symptom dimensions. This supports the notion of overactive performance monitoring being a candidate endophenotype for OCD.

Heart rate and heart rate variability in obsessive-compulsive disorder: Evidence from patients and unaffected first-degree relatives.

Altered heart rate (HR) and heart rate variability (HRV) are common observations in psychiatric disorders. Yet, few studies have examined these cardiac measures in obsessive-compulsive disorder (OCD). The current study aimed to investigate HR and HRV, indexed by the root mean square of successive differences (RMSSD) and further time domain indices, as putative biological characteristics of OCD. Electrocardiogram was recorded during a five-minute resting state. Group differences between patients with OCD (n = 96), healthy participants (n = 112), and unaffected first-degree relatives of patients with OCD (n = 47) were analyzed. As potential moderators of group differences, we examined the influence of age and medication, respectively. As results indicated, patients with OCD showed higher HR and lower HRV compared to healthy participants. These group differences were not moderated by age. Importantly, subgroup analyses showed that only medicated patients displayed lower HRV compared to healthy individuals, while HR alterations were evident in unmedicated patients. Regarding unaffected first-degree relatives, group differences in HRV remained at trend level. Further, an age-moderated group differentiation showed that higher HRV distinguished relatives from healthy individuals in young adulthood, whereas at higher age lower HRV was indicative of relatives. Both the role of familial risk and medication in HRV alterations need further elucidation. Pending future studies, alterations in HR and potentially HRV might serve as useful indices to characterize the pathophysiology of OCD.

The association of dispositional anxiety with the NoGo N2 under relaxation instruction vs. speed/accuracy instruction.

Prior research suggests that cognitive control, indicated by NoGo N2 amplitudes in Go/NoGo tasks, is associated with dispositional anxiety. This negative association tends to be reduced in anxiety-enhancing experimental conditions. However, anxiety-reducing conditions have not yet been investigated systematically. Thus, the present study compares the effect of a relaxation instruction with the conventional speed/accuracy instruction in a Go/NoGo task on the correlation of the NoGo N2 with two subconstructs of dispositional anxiety, namely anxious apprehension and anxious arousal. As the test of differences between correlations needs considerable statistical power, the present study was included into the multi-lab CoScience Project. The hypotheses, manipulation checks, and the main path of pre-processing and statistical analysis were preregistered. Complete data sets of 777 participants were available for data analysis. Preregistered general linear models revealed that the different instructions of the task (speed/accuracy vs. relaxation) had no effect on the association between dispositional anxiety and the NoGo N2 amplitude in general. This result was supported by Cooperative-Forking-Path analysis. In contrast, a preregistered latent growth model with categorical variables revealed that anxious arousal was a negative predictor of the NoGo N2 intercept and a positive predictor of the NoGo N2 slope. Non-preregistered growth models, allowing for correlations of anxious apprehension with anxious arousal, revealed that higher anxious apprehension scores were associated with more negative NoGo N2 amplitudes with increased relaxation. Results are discussed in the context of the compensatory error monitoring hypothesis and the revised Reinforcement Sensitivity Theory.

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.

Associations of neural error-processing with symptoms and traits in a dimensional sample recruited across the obsessive-compulsive spectrum.

The error-related negativity (ERN), a neural response to errors, has been associated with several forms of psychopathology and assumed to represent a neural risk marker for obsessive-compulsive disorder (OCD) and anxiety disorders. Yet, it is still unknown which specific symptoms or traits best explain ERN variation. This study investigated performance-monitoring in participants (N = 100) recruited across a spectrum of obsessive-compulsive characteristics (n = 26 patients with OCD; n = 74 healthy participants including n = 24 with low, n = 24 with medium, and n = 26 with high OC-characteristics). Several compulsivity- and anxiety-associated characteristics were assessed and submitted to exploratory principal axis factor analysis. Associations of raw measures and derived factors with ERN and correct-related negativity (CRN) were examined. Patients with OCD showed increased ERN amplitudes compared to healthy participants. The ERN was associated with a variety of traits related to anxiety and negative affect. Factor analysis results revealed a most prominent association of the ERN with a composite measure of anxiety and neuroticism, whereas the CRN was specifically associated with compulsivity. Results support differential associations for the ERN and CRN and demonstrate that a dimensional recruitment approach and use of composite measures can improve our understanding of characteristics underlying variation in neural performance monitoring.

Registered replication report of the construct validity of the error-related negativity (ERN): A multi-site study of task-specific ERN correlations with internalizing and externalizing symptoms.

Intact cognitive control is critical for goal-directed behavior and is widely studied using the error-related negativity (ERN). A common assumption in such studies is that ERNs recorded during different experimental paradigms reflect the same construct or functionally equivalent processes and that ERN is functionally distinct from other error-monitoring event-related brain potentials (ERPs; error positivity [Pe]), other neurophysiological indices of cognitive control (N2), and even other theoretically unrelated indices (visual N1). The present registered report represents a replication-plus-extension study of the psychometric validity of cognitive control ERPs and evaluated the convergent and divergent validity of ERN, Pe, N2, and visual N1 recorded during flanker, Stroop, and Go/no-go tasks. Data from 182 participants were collected from two study sites, and ERP psychometric reliability and validity were evaluated. Findings supported replication of convergent and divergent validity of ERN, Pe, and ΔPe (error minus correct)-these ERPs correlated more with themselves across tasks than with other ERPs measured during the same task. Convergent validity of ΔERN across tasks was not replicated, despite high internal consistency. ERN strongly correlated with N2 at levels similar or higher than those in support of convergent validity for other ERPs, and the present study failed to provide evidence of divergent validity for ERN and Pe from N2 or N1. ERN and ΔERN were unrelated to internalizing or externalizing symptoms. Findings underscore the importance of considering the psychometric validity of ERPs, as it provides a foundation for interpreting and comparing ERPs across tasks and studies.

A rare scare: The role of intolerance of uncertainty in startle responses and event-related potentials in anticipation of unpredictable threat.

Intolerance of uncertainty (IU) represents a transdiagnostic risk factor for internalizing psychopathology. However, little is known regarding its psychophysiological correlates. IU is thought to render individuals hypersensitive to threatening events, even if the occurrence probability is low. To test this, we recruited 90 students who completed two NPU-threat tests separating temporal unpredictability from probabilistic unpredictability (i.e., probability of occurrence): First, a NPU version in which the timing of threat (i.e., shock) was either predictable or unpredictable but the shock probability was 100 % in each trial. Second, a probabilistic NPU version in which the timing of the shock was also either predictable or unpredictable, but the shock probability was 33 % in each trial. Startle reflex, event-related potentials N1 and P3 locked to auditory startle probes, and anxiety ratings were analyzed. As expected, temporally unpredictable threat modulated startle, N1, and anxiety ratings. IU predicted increased startle to lower shock probability, regardless of the temporal predictability. No evidence emerged for IU affecting N1 or P3. However, IU predicted anxiety ratings to threat conditions regardless of temporal or probabilistic predictability. Individual differences in IU shape startle responses to eventual threat: IU increases automatic defensive responding to unpredictable and potentially threatening situations if the threat probability is low. Individuals with higher IU may tend to "err on the side of caution" with a mismatch between physiological preparation and threat probability, such that the effects of IU are particularly observable in low threat probability conditions.

Disentangling the effects of trait and state worry on error-related brain activity: Results from a randomized controlled trial using worry manipulations.

Enhanced amplitudes of the error-related negativity (ERN) have been suggested to be a transdiagnostic neural risk marker for internalizing psychopathology. Previous studies propose worry to be an underlying mechanism driving the association between enhanced ERN and anxiety. The present preregistered study focused on disentangling possible effects of trait and state worry on the ERN by utilizing a cross sectional observational and a longitudinal randomized controlled experimental design. To this end, we examined the ERN of n = 90 students during a flanker task (T0), which were then randomly assigned to one of three groups (worry induction, worry reduction, passive control group). Following the intervention, participants performed another flanker task (T1) to determine potential alterations of their ERN. Manipulation checks revealed that compared to the control group, state worry increased in the induction but also in the reduction group. ERN amplitudes did not vary as a function of state worry. An association of trait worry with larger ERN amplitudes was only observed in females. Furthermore, we found larger ERN amplitudes in participants with a current or lifetime diagnosis of internalizing disorders. In summary, our findings suggest that the ERN seems to be insensitive to variations in state worry, but that an elevated ERN is associated with the trait-like tendency to worry and internalizing psychopathology, which is consistent with the notion that the ERN likely represents a trait-like neural risk associated with anxiety.

Early hypervigilance and later avoidance: Event-related potentials track the processing of threatening stimuli in anxiety.

Avoidance behavior is a core symptom of anxiety disorders that may hinder adaptation. Anxiety disorders are heterogeneous and previous research suggests to decompose anxiety into two dimensions: anxious apprehension and anxious arousal. How these two dimensions are associated with avoidance of and exposure to threatening stimuli, as well as their accompanying neural processes, is barely understood. We examined threat processing using event-related potentials (N1, LPP) from 134 individuals considering the influence of anxiety dimensions. During a two-phase picture-viewing task the participants watched neutral and threatening pictures, which they were instructed to either avoid or attend to during repeated presentations. Results showed that threatening compared to neutral pictures were associated with increased attention allocation (N1) and in-depth processing (LPP), modulated by task-instructions (lower during avoidance). Further, increased anxious apprehension was associated with heightened automatic attention (increased N1), followed by reduced LPP amplitudes for threatening pictures suggesting reduced in-depth processing. During re-exposure, threatening pictures were associated with increased in-depth processing, with no difference between previously avoided and maintained pictures. Together, these results illustrate that avoidance and high anxious apprehension seem to lead to similar neural changes in the processing of aversive images that may conflict with long-term adaptation.

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.

Error-Related Brain Activity in Patients With Obsessive-Compulsive Disorder and Unaffected First-Degree Relatives: Evidence for Protective Patterns.

Background: Indicators of increased error monitoring are associated with obsessive-compulsive disorder (OCD), as shown in electroencephalography and functional magnetic resonance imaging studies. As most studies used strictly controlled samples (excluding comorbidity and medication), it remains open whether these findings extend to naturalistic settings. Thus, we assessed error-related brain activity in a large, naturalistic OCD sample. We also explored which activity patterns might qualify as vulnerability endophenotypes or protective factors for the disorder. To this aim, a sample of unaffected first-degree relatives of patients with OCD was also included. Methods: Participants (84 patients with OCD, 99 healthy control participants, and 37 unaffected first-degree relatives of patients with OCD) completed a flanker task while blood oxygen level-dependent responses were measured with functional magnetic resonance imaging. Aberrant error-related brain activity in patients and relatives was identified. Results: Patients with OCD showed increased error-related activity in the supplementary motor area and within the default mode network, specifically in the precuneus and postcentral gyrus. Unaffected first-degree relatives showed increased error-related activity in the bilateral inferior frontal gyrus. Conclusions: Increased supplementary motor area and default mode network activity in patients with OCD replicates previous studies and might indicate excessive error signals and increased self-referential error processing. Increased activity of the inferior frontal gyrus in relatives may reflect increased inhibition. Impaired response inhibition in OCD has been demonstrated in several studies and might contribute to impairments in suppressing compulsive actions. Thus, increased inferior frontal gyrus activity in the unaffected relatives of patients with OCD may have contributed to protection from symptom development.

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.