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 free-viewing matrix task: A reliable measure of attention allocation in psychopathology.

Aberrant attention allocation has been implicated in the etiology and maintenance of a range of psychopathologies. However, three decades of research, relying primarily on manual response-time tasks, have been challenged on the grounds of poor reliability of its attention bias indices. Here, in a large, multisite, international study we provide reliability information for a new eye-tracking-based measure of attention allocation and its relation to psychopathology and age. Data from 1567 participants, across a wide range of psychiatric diagnoses and ages, were aggregated from nine sites around the world. Of these, 213 participants also provided retest data. Acceptable overall internal consistency and test-retest reliability were observed among adult participants (Cronbach's alpha = 0.86 and r(213) = 0.89, respectively), as well as across all examined psychopathologies. Youth demonstrated lower internal consistency scores (Cronbach's alpha = 0.65). Finally, the percent dwell time index derived from the task statistically differentiated between healthy participants and participants diagnosed with social anxiety disorder, major depression, and post-traumatic stress disorder. These results potentially address a long-standing reliability crisis in this research field. Aberrant attention allocation patterns in a variety of psychiatric disorders may be targeted with the hope of affecting symptoms. The attention allocation index derived from the matrix task offers reliable means to measure such cognitive target engagement in clinical contexts.

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.

Affective evaluation of errors and neural error processing in obsessive-compulsive disorder.

Even though overactive error monitoring, indexed by enhanced amplitudes of the error-related negativity (ERN), is a potential biomarker for obsessive-compulsive disorder (OCD), the mechanisms underlying clinical variations in ERN amplitude remain unknown. To investigate whether ERN enhancement in OCD results from altered error evaluation, we examined the trial-wise valence evaluation of errors and its relation to the ERN in 28 patients with OCD and 28 healthy individuals. Electroencephalogram was recorded during an affective priming paradigm in which responses in a go/no-go task were followed by valence-based word categorization. Results indicated that errors were followed by faster categorization of negative than positive words, confirming that negative valence is assigned to errors. This affective priming effect was reduced in patients with OCD, while go/no-go performance was comparable between groups. Notably, this reduction amplified with increasing symptom severity. These results suggest attenuated affective error evaluation in OCD, possibly resulting from interfering effects of anxiety. There was no evidence for a trial-level association between valence evaluation and ERN, implying that ERN amplitude does not reflect valence assignment to errors. Consequently, altered error monitoring in OCD may involve alterations in possibly distinct processes, with weaker assignment of negative valence to errors being one of them.

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.

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.

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.

Non-invasive brain stimulation modulates neural correlates of performance monitoring in patients with obsessive-compulsive disorder.

Overactive performance monitoring, as reflected by enhanced neural responses to errors (the error-related negativity, ERN), is considered a biomarker for obsessive-compulsive disorder (OCD) and may be a promising target for novel treatment approaches. Prior research suggests that non-invasive brain stimulation with transcranial direct current stimulation (tDCS) may reduce the ERN in healthy individuals, yet no study has investigated its efficacy in attenuating the ERN in OCD. In this preregistered, randomized, sham-controlled, crossover study, we investigated effects of tDCS on performance monitoring in patients with OCD (n = 28) and healthy individuals (n = 28). Cathodal and sham tDCS was applied over the presupplementary motor area (pre-SMA) in two sessions, each followed by electroencephalogram recording during a flanker task. Cathodal tDCS reduced the ERN amplitude compared to sham tDCS, albeit this effect was only marginally significant (p = .052; mean difference: 0.86 µV). Additionally, cathodal tDCS reduced the correct-response negativity and increased the error positivity. These neural modulations were not accompanied by behavioral changes. Moreover, we found no evidence that the tDCS effect was more pronounced in the patient group. In summary, our findings indicate that tDCS over the pre-SMA modulates neural correlates of performance monitoring across groups. Therefore, this study represents a valuable starting point for future research to determine whether repeated tDCS application induces a more pronounced ERN attenuation and normalizes aberrant performance monitoring in the long term, thereby potentially alleviating obsessive-compulsive symptoms and providing a psychophysiological intervention strategy for individuals who do not benefit sufficiently from existing interventions.

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.

Event-related potential studies of emotion regulation: A review of recent progress and future directions.

Event-related potentials (ERPs) bring many strengths to the study of emotion regulation, including: direct measurement of neural activity, high temporal resolution, affordability and suitability to a wide range of participants. Research using ERPs to study emotion regulation began approximately two decades ago, but has grown exponentially over the last 10 years. Here, we highlight progress in this body of work throughout the past decade, as well as emerging themes, novel approaches and paradigms that will likely shape the field in the coming years. While standardized picture sets are still the most commonly used stimuli in these studies, new types of stimuli (e.g., mental imagery, autobiographical memories) have become increasingly common throughout the past decade, with the potential for improved ecological validity. Cognitive reappraisal is still seen by many as the gold standard of emotion regulation, yet mixed findings suggest that its utility might be better understood by taking into account the type of stimuli and context to which it is applied. Moreover, other emotion regulation techniques, particularly for the upregulation of positive emotion (e.g., savoring), have been relatively unexamined in the ERP literature to-date, as have associations between controlled, lab-based measures of emotion generation and regulation in everyday life (e.g., as assessed using ambulatory techniques). In sum, the past decade has seen progress in a more granular understanding of emotion regulation, with ongoing and future work aimed at increasing understanding of the boundary conditions of emotion regulation; novel techniques and emotion regulation's application to everyday life.

Depression reduces neural correlates of reward salience with increasing effort over the course of the progressive ratio task.

BACKGROUND: Depressive disorders have been associated with altered effort-cost decision making (ECDM) in behavioral investigations, such as a decreased willingness to expend effort for reward attainment. However, little is known about neural mechanisms implicated in altered ECDM. METHODS: The study investigates neural correlates of reward attainment during a progressive ratio task in participants with a current depressive disorder (n = 65) and never-depressed healthy individuals (n = 44). On each trial, participants completed an increasing number of button presses to attain a fixed monetary reward, indicated by an auditory reward signal. Participants could decide to quit the task anytime (breakpoint). EEG was recorded during the task and P300 amplitudes were examined in response to the auditory signal of reward attainment. RESULTS: There was no difference in breakpoint, as both groups completed comparable numbers of button presses. In contrast, results from mixed-effects models of trial-level ERP responses indicated depression-related effects on P300 amplitudes over the course of the task. Generally, the reward-locked P300 increased with ascending effort expenditure; however, compared to healthy participants, individuals with current depression were characterized by an attenuated trajectory of the reward-locked P300, pointing towards decreased reactivity to reward attainment with increasing effort. LIMITATIONS: Sample size and reward magnitude were possibly not large enough to detect differences in breakpoint. CONCLUSIONS: The results of the current study demonstrate that the investigation of reward-related P300 trajectory may represent an informative novel addition to the progressive ratio task, which could help shed light on depression-related alterations in motivation and ECDM.

Reduced electrocortical responses to pleasant pictures in depression: A brief report on time-domain and time-frequency delta analyses.

BACKGROUND: The late positive potential (LPP) to pleasant content is an electrocortical indicator of blunted emotional reactivity in depression. A reduced time-frequency delta power has never been investigated in clinical samples. The present study examined time-frequency delta in depression and at investigated whether the combination of time-domain and time-frequency data would explain additional variance in the depression status. METHODS: The study was a secondary analysis of data collected during a passive viewing task of pleasant and neutral pictures in a community-based sample of 75 participants with a current depressive disorder and 42 controls. A time-frequency analysis on event-related changes within delta frequency band was conducted. RESULTS: Cluster-based statistics revealed a centro-parietal increase in delta power to pleasant relative to neutral pictures in the control group but not within the depression group. Moreover, a fronto-centro-parietal reduction in delta power to pleasant pictures emerged in depression relative to controls. Both a smaller LPP and delta power to pleasant pictures were related to depression status. The combination of LPP and delta power explained a greater amount of variance compared to the model where LPP was entered as the only predictor of depression status. CONCLUSIONS: These data suggest that delta power might be a promising electrocortical correlate of the hypoactivation of the approach-related motivational system in depression. Additionally, a blunted delta and LPP might reflect unique processes related to depression. A combination of these measures can be leveraged together to enhance clinical utility and to shed light on the underlying mechanisms associated with depression.

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.

In the Face of Potential Harm: The Predictive Validity of Neural Correlates of Performance Monitoring for Perceived Risk, Stress, and Internalizing Psychopathology During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic is a major life stressor posing serious threats not only to physical but also to mental health. To better understand mechanisms of vulnerability and identify individuals at risk for psychopathological symptoms in response to stressors is critical for prevention and intervention. The error-related negativity (ERN) has been discussed as a neural risk marker for psychopathology, and this study examined its predictive validity for perceived risk, stress, and psychopathological symptoms during the COVID-19 pandemic. METHODS: A total of 113 individuals who had participated as healthy control participants in previous electroencephalography studies (2014-2019) completed a follow-up online survey during the first COVID-19 wave in Germany. Associations of pre-pandemic ERN and correct-response negativity (CRN) with perceived risk regarding COVID-19 infection, stress, and internalizing symptoms during the pandemic were examined using mediation models. RESULTS: Pre-pandemic ERN and CRN were associated with increased perceived risk regarding a COVID-19 infection. Via this perceived risk, the ERN and CRN were associated with increased stress during the pandemic. Furthermore, risk perception and stress mediated indirect effects of ERN and CRN on internalizing psychopathology, including anxiety, depression, and obsessive-compulsive symptoms, while controlling for the effects of pre-pandemic symptom levels. CONCLUSIONS: In summary, heightened pre-pandemic performance monitoring showed indirect associations with increases in psychopathological symptoms during the first COVID-19 wave via effects on perceived COVID-19 risk and stress. These results further strengthen the notion of performance monitoring event-related potentials as transdiagnostic neural risk markers and highlight the relevance of stress as a catalyst for symptom development.

Polygenic risk for obsessive-compulsive disorder (OCD) predicts brain response during working memory task in OCD, unaffected relatives, and healthy controls.

Alterations in frontal and parietal neural activations during working memory task performance have been suggested as a candidate endophenotype of obsessive-compulsive disorder (OCD) in studies involving first-degree relatives. However, the direct link between genetic risk for OCD and neuro-functional alterations during working memory performance has not been investigated to date. Thus, the aim of the current functional magnetic resonance imaging (fMRI) study was to test the direct association between polygenic risk for OCD and neural activity during the performance of a numeric n-back task with four working memory load conditions in 128 participants, including patients with OCD, unaffected first-degree relatives of OCD patients, and healthy controls. Behavioral results show a significant performance deficit at high working memory load in both patients with OCD and first-degree relatives (p < 0.05). A whole-brain analysis of the fMRI data indicated decreased neural activity in bilateral inferior parietal lobule and dorsolateral prefrontal cortex in both patients and relatives. Most importantly, OCD polygenic risk scores predicted neural activity in orbitofrontal cortex. Results indicate that genetic risk for OCD can partly explain alterations in brain response during working memory performance, supporting the notion of a neuro-functional endophenotype for OCD.

Feeling bad about being wrong: Affective evaluation of performed actions and its trial-by-trial relation to autonomic arousal.

Research on action monitoring and error processing has begun to consider the role of emotion, motivation, and peripheral autonomic arousal. To date, little is known about the specific nature of evaluative processing during action monitoring and its interaction with autonomic arousal. This study aimed to replicate and extend previous findings on affective action evaluation and to examine trial-level associations between action evaluation and autonomic arousal. Thirty participants performed an affective priming paradigm, consisting of a go/no-go task with an embedded word categorization task, while skin conductance response (SCR) was recorded. After each motor response in the go/no-go task, participants categorized an affective word as positive or negative. Using mixed-effects modeling, we replicated previous evidence of action-based affective priming, in that false alarms in the go/no-go task were followed by faster and more accurate categorization of negative compared with positive words, whereas hits were followed by faster categorization of positive compared with negative words. We found no evidence for a trial-level association between this priming effect and SCR. Instead, errors increased SCR and its magnitude predicted post-error slowing (PES) on a trial-by-trial level, in line with an orienting account of PES. Our findings support the notion that valence values are assigned to own performed actions, with incorrect actions being evaluated as negative events and correct actions as positive events. Our results further suggest that this valence evaluation might operate independently of arousal-related processes during action monitoring, indicating that these processes might serve different roles in promoting adaptive behavior. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Neural responses to reward and pleasant pictures prospectively predict remission from depression.

Reduced neural responses to reward and pleasant stimuli-indicators of anhedonia and reduced emotional reactivity, respectively-have been reported among individuals with depressive disorders. The current study examined whether these neural measures could prospectively predict the course of depression among a community-based sample of 83 participants diagnosed with a depressive disorder. At initial assessment, participants performed both a guessing task to elicit the reward positivity (RewP) and a picture viewing paradigm with neutral and pleasant pictures to measure the late positive potential (LPP)-both event-related brain potentials (ERPs) independently related to diagnosis of depression. After approximately 9 months, 53 of those participants returned to the lab for a clinical assessment of current symptoms and course of disorder during the follow-up period. We found a more intact (i.e., larger) RewP and LPP at baseline among participants who achieved an episode of full remission from depression at any point during the follow-up period. In multiple logistic regression models, the RewP and LPP were both independent predictors of remission status; moreover, the RewP, but not the LPP, remained a significant predictor after accounting for other clinical variables that predicted remission. These data provide initial evidence for the clinical utility of ERPs from reward and picture viewing tasks within depressed individuals to predict disease course prospectively, which could be further leveraged to improve intervention approaches and parse the heterogeneity of depression. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Ventral striatal activation during reward differs between major depression with and without impaired mood reactivity.

BACKGROUND: Recent efforts to classify subtypes of major depressive disorder marked by different psychophysiological indicators have identified blunted reward-related brain activation in gambling tasks as a characteristic linked specifically to depressed participants with impaired mood reactivity. METHODS: The current study compared individuals diagnosed with current depressive disorder (n = 26) with healthy controls (n = 24) regarding brain responses to gain and loss trials in an fMRI version of the "Doors" choice-feedback task. Study aims were to examine reward-related brain activation in relation to depression, depressive subtypes, and course of depression. RESULTS: Across the sample, participants showed a significant response to gain versus loss in left and right ventral striatum as well as medial and left lateral prefrontal cortex. Relative to controls, participants with current depression were characterized by blunted reactivity in left ventral striatum. Furthermore, activation in the left ventral striatum differentiated subgroups of depression with and without impaired mood reactivity. Finally, left striatal hypoactivation to reward predicted remission when controlling for current depressive symptomatology, albeit at a trend level. CONCLUSIONS: Blunted reward-related activation in the left ventral striatum might be useful as a marker for depression subtype and may have the potential to predict future course of depression.