White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

EEG alpha band functional connectivity reveals distinct cortical dynamics for overt and covert emotional face processing.

Current knowledge regarding how the focus of our attention during face processing influences neural responses largely comes from neuroimaging studies reporting on regional brain activations. The present study was designed to add novel insights to this research by studying how attention can differentially impact the way cortical regions interact during emotional face processing. High-density electroencephalogram was recorded in a sample of fifty-two healthy participants during an emotional face processing task. The task required participants to either attend to the expressions (i.e., overt processing) or attend to a perceptual distractor, which rendered the expressions task-irrelevant (i.e., covert processing). Functional connectivity in the alpha band was estimated in source space and modeled using graph theory to quantify whole-brain integration and segregation. Results revealed that overt processing of facial expressions is linked to reduced cortical segregation and increased cortical integration, this latter specifically for negative expressions of fear and sadness. Furthermore, we observed increased communication efficiency during overt processing of negative expressions between the core and the extended face processing systems. Overall, these findings reveal that attention makes the interaction among the nodes involved in face processing more efficient, also uncovering a connectivity signature of the prioritized processing mechanism of negative expressions, that is an increased cross-communication within the nodes of the face processing network.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Right Prefrontal Cortical Thickness Is Associated With Response to Cognitive-Behavioral Therapy in Children With Obsessive-Compulsive Disorder.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is considered a first-line treatment for obsessive-compulsive disorder (OCD) in pediatric and adult populations. Nevertheless, some patients show partial or null response. The identification of predictors of CBT response may improve clinical management of patients with OCD. Here, we aimed to identify structural magnetic resonance imaging (MRI) predictors of CBT response in 2 large series of children and adults with OCD from the worldwide ENIGMA-OCD consortium. METHOD: Data from 16 datasets from 13 international sites were included in the study. We assessed which variations in baseline cortical thickness, cortical surface area, and subcortical volume predicted response to CBT (percentage of baseline to post-treatment symptom reduction) in 2 samples totaling 168 children and adolescents (age range 5-17.5 years) and 318 adult patients (age range 18-63 years) with OCD. Mixed linear models with random intercept were used to account for potential cross-site differences in imaging values. RESULTS: Significant results were observed exclusively in the pediatric sample. Right prefrontal cortex thickness was positively associated with the percentage of CBT response. In a post hoc analysis, we observed that the specific changes accounting for this relationship were a higher thickness of the frontal pole and the rostral middle frontal gyrus. We observed no significant effects of age, sex, or medication on our findings. CONCLUSION: Higher cortical thickness in specific right prefrontal cortex regions may be important for CBT response in children with OCD. Our findings suggest that the right prefrontal cortex plays a relevant role in the mechanisms of action of CBT in children.

An fMRI study of cognitive planning before and after symptom provocation in pediatric obsessive-compulsive disorder.

BACKGROUND: Pediatric obsessive-compulsive disorder (OCD) has been associated with poorer planning in laboratory, school and home settings. It is unclear whether this impairment is a standalone cognitive issue or the result of OCD symptoms. No study has examined the influence of provoked distress on planning performance and neural correlates in pediatric OCD. METHODS: Before and after a symptom provocation task, youth with OCD (n = 23; 9 boys; mean age ± standard deviation 15.1 ± 2.6 years) and matched healthy controls (n = 23) completed the Tower of London task during functional MRI scanning. RESULTS: During planning, participants with OCD recruited the left superior frontal gyrus to a greater extent than healthy controls after symptom provocation (group × time point interaction; t 44 = 5.22, p < 0.001). In a seeded, region of interest-constrained, functional connectivity analysis, we identified greater connectivity between the left superior frontal gyrus and the right middle frontal gyrus, left precuneus and left inferior parietal lobule in participants with OCD than healthy controls. We also identified greater connectivity between the right amygdala and right medial frontal gyrus in patients with OCD than healthy controls, but only before symptom provocation. LIMITATIONS: The fixed-order design of the study and the number of participants taking medication (n = 20) should be noted. CONCLUSION: Participants with OCD demonstrated greater amygdalar-cortical connectivity before symptom provocation, while sustaining greater recruitment and connectivity of task-related planning areas throughout the task. These results suggest that brain activity and connectivity is altered after symptom provocation, in the absence of impaired planning performance.

Associations of medication with subcortical morphology across the lifespan in OCD: Results from the international ENIGMA Consortium.

BACKGROUND: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. METHODS: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. RESULTS: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31). CONCLUSIONS: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

Spatiotemporal Dynamics of Covert vs. Overt Emotional Face Processing in Dysphoria.

People at risk of developing clinical depression exhibit attentional biases for emotional faces. To clarify whether such effects occur at an early, automatic, or at a late, deliberate processing stage of emotional processing, the present study used high-density electroencephalography during both covert and overt processing of sad, fearful, happy, and neutral expressions in healthy participants with high dysphoria (n = 16) and with low dysphoria (n = 19). A state-of-the-art non-parametric permutation-based statistical approach was then used to explore the effects of emotion, attentional task demands, and group. Behaviorally, participants responded faster and more accurately when overtly categorizing happy faces and they were slower and less accurate when categorizing sad and fearful faces, independent of the dysphoria group. Electrophysiologically, in an early time-window (N170: 140-180 ms), there was a significant main effect for the dysphoria group, with greater negative voltage for the high vs. low dysphoria group over the left-sided temporo-occipital scalp. Furthermore, there was a significant group by emotional interaction, with the high dysphoria group displaying greater negative amplitude N170 for happy than fearful faces. Attentional task demands did not influence such early effects. In contrast, in an intermediate time-window (EPN: 200-400 ms) and in a late time-window (LPP: 500-750 ms) there were no significant main effects nor interactions involving the dysphoria Group. The LPP results paralleled the behavioral results, with greater LPP voltages for sad and fearful relative to happy faces only in the overt task, but similarly so in the two dysphoria groups. This study provides novel evidence that alterations in face processing in dysphoric individuals can be seen at the early stages of face perception, as indexed by the N170, although not in the form of a typical pattern of mood-congruent attentional bias. In contrast, intermediate (EPN) and late (LPP) stages of emotional face processing appear unaffected by dysphoria. Importantly, the early dysphoria effect appears to be independent of the top-down allocation of attention, further supporting the idea that dysphoria may influence a stage of automatic emotional appraisal. It is proposed that it may be a consequence of a shift from holistic to feature-based processing of facial expressions, or may be due to the influence of negative schemas acting as a negative context for emotional facial processing.

The thalamus and its subnuclei-a gateway to obsessive-compulsive disorder.

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

Spatiotemporal Dynamics of Covert Versus Overt Processing of Happy, Fearful and Sad Facial Expressions.

Behavioral and electrophysiological correlates of the influence of task demands on the processing of happy, sad, and fearful expressions were investigated in a within-subjects study that compared a perceptual distraction condition with task-irrelevant faces (e.g., covert emotion task) to an emotion task-relevant categorization condition (e.g., overt emotion task). A state-of-the-art non-parametric mass univariate analysis method was used to address the limitations of previous studies. Behaviorally, participants responded faster to overtly categorized happy faces and were slower and less accurate to categorize sad and fearful faces; there were no behavioral differences in the covert task. Event-related potential (ERP) responses to the emotional expressions included the N170 (140-180 ms), which was enhanced by emotion irrespective of task, with happy and sad expressions eliciting greater amplitudes than neutral expressions. EPN (200-400 ms) amplitude was modulated by task, with greater voltages in the overt condition, and by emotion, however, there was no interaction of emotion and task. ERP activity was modulated by emotion as a function of task only at a late processing stage, which included the LPP (500-800 ms), with fearful and sad faces showing greater amplitude enhancements than happy faces. This study reveals that affective content does not necessarily require attention in the early stages of face processing, supporting recent evidence that the core and extended parts of the face processing system act in parallel, rather than serially. The role of voluntary attention starts at an intermediate stage, and fully modulates the response to emotional content in the final stage of processing.

Structural neuroimaging biomarkers for obsessive-compulsive disorder in the ENIGMA-OCD consortium: medication matters.

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker.

Mapping Cortical and Subcortical Asymmetry in Obsessive-Compulsive Disorder: Findings From the ENIGMA Consortium.

BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD. METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.

Neurocognitive risk markers in pediatric obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) has complex genetic underpinnings, particularly in its early-onset form, which places siblings at a 10-fold increased risk of developing the disorder. Examination for neurocognitive markers preceding pediatric OCD onset has not been conducted, although markers have been identified in adult OCD. This study compared neurocognition across groups of OCD-affected youth (n = 87), unaffected siblings of those with early-onset OCD (n = 67), and healthy controls (HC; n = 79). METHODS: A total of 233 participants aged 6-18 years old completed standardized neurocognitive tests of cognitive flexibility, decision making, planning, response inhibition, spatial working memory, attention, recognition nonverbal memory, and intelligence. They were administered the Anxiety Disorders Interview Schedule-Parent version (ADIS-P) and completed self-report anxiety and OCD questionnaires. Linear mixed-effects models tested for differences between groups, adjusting for age, gender, IQ, state anxiety, and ethnicity, and accounting for random effects of family membership. RESULTS: OCD-affected youth and unaffected siblings performed significantly worse on planning in comparison to HCs (Cohen's d = 0.74; 95% CI = [0.11, 1.36]; Cohen's d = 0.75; 95% CI = [0.12, 1.38], respectively; omnibus group effect p = .007). No other significant between-group differences were identified. CONCLUSIONS: Neurocognitive performance differences between groups identified planning as a preexisting trait marker of pediatric OCD, while no other domain presented as a marker of pediatric OCD. This differs from adult OCD, which is associated with broader cognitive impairments. Investigating longitudinal trajectories and predictive significance of neurocognition in those affected by, and at risk for, early-onset OCD is warranted. Ideally, this will enhance individualized risk stratification and inform future prevention and early intervention strategies.

Neural correlates of symptom provocation in pediatric obsessive-compulsive disorder.

OBSESSIVE-COMPULSIVE DISORDER: (OCD)-affected adults and children exhibit three to four symptom dimensions with distinct but overlapping neural correlates. No symptom provocation behavioural or imaging study has examined all symptom dimensions in a pediatric OCD sample. METHOD: Clinically diagnosed pediatric OCD-affected participants (n = 25) as well as age, gender and Tanner pubertal stage-matched healthy controls (HCs; n = 24) (total sample: mean age = 14.77 ±â€¯2.93 years; age range = 9-18 years; 35% male) viewed alternating blocks of OCD symptom provocation (Contamination, Bad Thoughts, and Just Right symptom dimensions), Fear, Neutral and Rest (i.e. fixation) conditions during functional magnetic resonance imaging. A region-of-interest analysis used seeds based upon results of an adult OCD meta-analysis RESULTS: OCD participants found OCD symptom-related stimuli bothersome, particularly when compared to controls in the "Just Right" symptom dimension. Pediatric OCD patients exhibited greater recruitment of the left superior temporal gyrus (STG) than healthy controls during combined symptom provocation versus neutral conditions. CONCLUSION: Findings suggest involvement of the temporal poles rather than in classic cortico-striatal-thalamico-cortical circuits in pediatric OCD during symptom provocation.

A case-control study of sleep disturbances in pediatric obsessive-compulsive disorder.

BACKGROUND: Sleep disturbances, including delayed sleep phase disorder (DSPD) and disorders of sleep initiation and maintenance (DIMS), have repeatedly been identified in adult obsessive-compulsive disorder (OCD). These disturbances have not been well-characterized objectively in pediatric OCD. METHODS: Thirty OCD-affected youth (8-18 yrs, 40% male) and 30 age and gender-matched healthy controls (HCs) completed the Sleep Disturbances Scale for Children (SDSC), and one week of continuous actigraphy with concurrent sleep diary documentation. A subsample completed the Children's Sleep Hygiene Scale (CSHS) and Sleep Attitudes and Beliefs Scale (SABS). RESULTS: Seventy-two percent of OCD participants reported sleep disturbances versus 15% of HC participants (p < 0.001). Convergent actigraphy results suggested DIMS but not DSPD were common. DISCUSSION: The parents of OCD-affected children seem to be successfully controlling bedtimes, preventing circadian rhythm system disruptions. OCD status does adversely impact, however, the perisleep arousal system. These results have important clinical implications, suggesting sleep problems may be best managed through direct treatment of OCD symptoms. It is recommended that all pediatric OCD patients be screened for sleep disturbances to inform treatment plan development.

Prevalence of Acute-Onset Subtypes in Pediatric Obsessive-Compulsive Disorder.

BACKGROUND: Pediatric obsessive-compulsive disorder (OCD) is a common, debilitating illness. When childhood OCD symptom onset is described as acute and severe, diagnostic criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) should be considered. However, the frequency and differentiating features of these putative syndromes within pediatric OCD remain poorly understood. OBJECTIVES: To determine the prevalence and characteristics of those meeting PANDAS and/or PANS criteria within pediatric OCD, as determined by parent report and clinician interview. METHODS: Consecutive youth presenting to a subspecialty pediatric OCD clinic were rigorously assessed through the Anxiety Disorders Interview Schedule for DSM-IV, the Children's Yale-Brown Obsessive-Compulsive Scale, and through self- and parent-report measures, including a medical questionnaire. Strict diagnostic criteria for PANDAS and PANS were applied to determine prevalence rates, and comparative analyses were performed between subgroups. RESULTS: Among 136 youth with a lifetime OCD diagnosis, 5% (n = 7; 95% adjusted Wald interval: 1%-10%) met proposed criteria for PANDAS and/or PANS, of whom two met PANDAS criteria, four met PANS criteria, and one met criteria for both. Those in the PANDAS/PANS subgroup were more likely to have autoimmune illness, less likely to report symmetry factor symptoms, and had greater OCD-related family impairment during their worst OCD episode. CONCLUSION: A small yet significant percentage of pediatric OCD outpatients met criteria for PANDAS and/or PANS, justifying routine screening and attention to related characteristics during assessment and management. Longitudinal studies of these putative subtypes are warranted.

Electrophysiology of blunted emotional bias in psychopathic personality.

Diminished emotional capacity is a core characteristic of psychopathic personality. We examined behavioral and electrophysiological differences in attentional bias to emotional material in 34 healthy individuals rated high or low in psychopathic traits using the short form of the Psychopathic Personality Inventory-Revised (18 high-trait, 16 low-trait). While performing an emotional Stroop task, high-trait participants displayed reduced emotional modulation of the late positive potential (LPP, 400-600 ms), and early anterior positivity (EAP, 200-300 ms) amplitudes. Results suggest blunted bias to affective content in psychopathic personality, characterized by diminished early capture to emotional salience (EAP) and dampened cognitive emotional processing (LPP).

Single-trial EEG-fMRI coupling of the emotional auditory early posterior negativity.

Event-related potential (ERP) studies in the visual domain often report an emotion-evoked early posterior negativity (EPN). Studies in the auditory domain have recently shown a similar component. Little source localization has been done on the visual EPN, and no source localization has been done on the auditory EPN. The aim of the current study was to identify the neural generators of the auditory EPN using EEG-fMRI single-trial coupling. Data were recorded from 19 subjects who completed three auditory choice reaction tasks: (1) a control task using neutral tones; (2) a prosodic emotion task involving the categorization of syllables; and (3) a semantic emotion task involving the categorization of words. The waveforms of the emotion tasks diverged from the neutral task over parietal scalp during a very early time window (132-156 ms) and later during a more traditional EPN time window (252-392 ms). In the EEG-fMRI analyses, the variance of the voltage in the earlier time window was correlated with activity in the medial prefrontal cortex, but only in the word task. In the EEG-fMRI analyses of the traditional EPN time window both emotional tasks covaried with activity in the left superior parietal lobule. Our results support previous parietal cortex source localization findings for the visual EPN, and suggest enhanced selective attention to emotional stimuli during the EPN time window.