Shape analysis of subcortical structures in obsessive-compulsive disorder and the relationship with comorbid anxiety, depression, and medication use: A meta-analysis by the OCD Brain Imaging Consortium.

OBJECTIVE: Neuroimaging studies of obsessive-compulsive disorder (OCD) patients have highlighted the important role of deep gray matter structures. Less work has however focused on subcortical shape in OCD patients. METHODS: Here we pooled brain MRI scans from 412 OCD patients and 368 controls to perform a meta-analysis utilizing the ENIGMA-Shape protocol. In addition, we investigated modulating effects of medication status, comorbid anxiety or depression, and disease duration on subcortical shape. RESULTS: There was no significant difference in shape thickness or surface area between OCD patients and healthy controls. For the subgroup analyses, OCD patients with comorbid depression or anxiety had lower thickness of the hippocampus and caudate nucleus and higher thickness of the putamen and pallidum compared to controls. OCD patients with comorbid depression had lower shape surface area in the thalamus, caudate nucleus, putamen, hippocampus, and nucleus accumbens and higher shape surface area in the pallidum. OCD patients with comorbid anxiety had lower shape surface area in the putamen and the left caudate nucleus and higher shape surface area in the pallidum and the right caudate nucleus. Further, OCD patients on medication had lower shape thickness of the putamen, thalamus, and hippocampus and higher thickness of the pallidum and caudate nucleus, as well as lower shape surface area in the hippocampus and amygdala and higher surface area in the putamen, pallidum, and caudate nucleus compared to controls. There were no significant differences between OCD patients without co-morbid anxiety and/or depression and healthy controls on shape measures. In addition, there were also no significant differences between OCD patients not using medication and healthy controls. CONCLUSIONS: The findings here are partly consistent with prior work on brain volumes in OCD, insofar as they emphasize that alterations in subcortical brain morphology are associated with comorbidity and medication status. Further work is needed to understand the biological processes contributing to subcortical shape.

Disentangling Within- and Between-Person Effects During Response Inhibition in Obsessive-Compulsive Disorder.

Background: Obsessive-compulsive disorder (OCD) has been related to worse performance, abnormal brain activity, and functional connectivity during response inhibition. Whether these findings are indications of stable traits that contribute to the development of the disorder, or whether they are a result of the state severity of obsessions and anxiety, remains unclear since previous research mainly has employed cross-sectional designs. The present study aimed to assess longitudinal between- and within-person relationships between symptoms, task performance, right inferior frontal gyrus brain activation, and connectivity between the right amygdala and the right pre-supplementary motor area in 29 OCD patients before and after concentrated exposure and response prevention treatment. Method: Patients received exposure and response prevention delivered during 4 consecutive days, following the Bergen 4-day Treatment format. Patients performed a Stop Signal Task during 3T functional Magnetic Resonance Imaging the day before treatment, as well as 1 week and 3 months after treatment completion. Multilevel models were used to analyze disaggregated within- and between-person effects over time. Independent variables were scores on the symptom severity scales for OCD, anxiety, depression, and state distress during scanning. Dependent variables were reaction time for go trials, stop signal response time, task-related brain activation and connectivity. Results: A positive between-person effect was found for obsessive-compulsive, anxiety, and depressive symptom severity on go trial reaction time, indicating that patients with higher symptom scores on average respond slower during accurate go trials. We also found no significant between- or within-person relations between symptom severity and task-related activation or fronto-limbic connectivity. Conclusions: The between-person findings may point toward a general association between slower processing speed and symptom severity in OCD. Longitudinal studies should disaggregate between- and within-person effects to better understand variation over time.

Effects of Bergen 4-Day Treatment on Resting-State Graph Features in Obsessive-Compulsive Disorder.

BACKGROUND: Exposure and response prevention is an effective treatment for obsessive-compulsive disorder (OCD), but it is unclear how symptom reduction is related to changes in the brain. We aimed to determine the effects of a 4-day concentrated exposure and response prevention program (Bergen 4-day treatment) on the static and dynamic functional connectome in patients with OCD. METHODS: Thirty-four patients with OCD (25 unmedicated) underwent resting-state functional magnetic resonance imaging the day before the Bergen 4-day treatment, and 28 (21 unmedicated) were rescanned after 1 week. Twenty-eight healthy control subjects were also scanned for baseline comparisons and 19 of them were rescanned after 1 week. Static and dynamic graph measures were quantified to determine network topology at the global, subnetwork, and regional levels (including efficiency, clustering, between-subnetwork connectivity, and node flexibility in module allegiance). The Yale-Brown Obsessive Compulsive Scale was used to measure symptom severity. RESULTS: Twenty-four patients (86%) responded to treatment. We found significant group × time effects in frontoparietal-limbic connectivity (ηp2 = 0.19, p = .03) and flexibility of the right subgenual anterior cingulate cortex (ηp2 = 0.18, p = .03), where, in both cases, unmedicated patients showed significant decreases while healthy control subjects showed no significant changes. Healthy control subjects showed increases in global and subnetwork efficiency and clustering coefficient, particularly in the somatomotor subnetwork. CONCLUSIONS: Concentrated exposure and response prevention in unmedicated patients with OCD leads to decreased connectivity between the frontoparietal and limbic subnetworks and less flexibility of the connectivity of the subgenual anterior cingulate cortex, suggesting a more independent and stable network topology. This may represent less limbic interference on cognitive control subnetworks after treatment.

Static and dynamic network properties of the repetitive transcranial magnetic stimulation target predict changes in emotion regulation in obsessive-compulsive disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique to treat psychiatric disorders, such as obsessive-compulsive disorder (OCD). However, the rTMS response varies across subjects. OBJECTIVE/HYPOTHESIS: We hypothesize that baseline network properties of the rTMS target may help understand this variation and predict response. METHODS: Excitatory rTMS to the dorsolateral prefrontal cortex (dlPFC) was applied in 19 unmedicated OCD patients, while inhibitory dlPFC-rTMS was applied in 17 healthy controls. The vertex was used as an active control target (19 patients, 18 controls). The rTMS response was operationalized as the individual change in state distress rating during an emotion regulation task. At baseline, subjects underwent resting-state functional MRI. The brain network was constructed by calculating wavelet coherence between regional activity of regions in the Brainnetome atlas. Local and integrative static connectivity and the dynamic network role of the target were calculated. Baseline target region network features were non-parametrically correlated to rTMS response. RESULTS: In the dlPFC-stimulated patients, greater local connectivity (Kendall's Tau = -0.415, p = 0.013) and less promiscuous role of the target (Kendall's Tau = 0.389, p = 0.025) at baseline were related to greater distress reduction after excitatory rTMS. There were no significant associations in healthy subjects nor in the active control stimulated patients. CONCLUSIONS: Pre-treatment network topological indices predict rTMS-induced emotional response changes in OCD, such that greater baseline resting-state local connectivity and less temporal integration of the target region imply greater stimulation effects. These results may lead the way towards personalized neuromodulation in OCD.

Stable inhibition-related inferior frontal hypoactivation and fronto-limbic hyperconnectivity in obsessive-compulsive disorder after concentrated exposure therapy.

Response inhibition has previously been suggested as an endophenotype for obsessive-compulsive disorder (OCD), evidenced by studies showing worse task performance, and altered task-related activation and connectivity. However, it's unclear if these measures change following treatment. In this study, 31 OCD patients and 28 healthy controls performed a stop signal task during 3 T functional magnetic resonance imaging before treatment, while 24 OCD patients and 17 healthy controls were rescanned one week and three months after concentrated exposure and response prevention over four consecutive days using Bergen 4-Day Format. To study changes over time we performed a longitudinal analysis on stop signal reaction time and task-related activation and amygdala connectivity during successful and failed inhibition. Results showed that there was no group difference in task performance. Before treatment, OCD patients compared to controls showed less inhibition-related activation in the right inferior frontal gyrus, and increased functional connectivity between the right amygdala and the right inferior frontal gyrus and pre-supplementary motor area. During error-processing, OCD patients versus controls showed less activation in the pre-SMA before treatment. These group differences did not change after treatment. Pre-treatment task performance, brain activation, and connectivity were unrelated to the degree of symptom improvement after treatment. In conclusion, inferior frontal gyrus hypoactivation and increased fronto-limbic connectivity are likely trait markers of OCD that remain after effective exposure therapy.

The Effect of High-Frequency Repetitive Transcranial Magnetic Stimulation on Emotion Processing, Reappraisal, and Craving in Alcohol Use Disorder Patients and Healthy Controls: A Functional Magnetic Resonance Imaging Study.

Impaired cognitive-motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the (cognitive) regulation of emotional and motivational states, such as in regulation of craving or negative emotions that may lead to relapse in alcohol use. These cognitive-motivational functions, including emotion regulation, are a target in cognitive behavioral therapy and may possibly be improved by neurostimulation techniques. The present between-subjects, single-blind study assesses the effects of sham-controlled high-frequency neuronavigated repetitive transcranial magnetic stimulation (10 Hz) of the right dorsolateral prefrontal cortex (dlPFC) on several aspects relevant for emotion regulation (emotion processing and reappraisal abilities) and related brain activity, as well as self-reported craving in a sample of alcohol use disorder patients (AUD; n = 39) and healthy controls (HC; n = 36). During the emotion reappraisal task, participants were instructed to either attend or reappraise their emotions related to the negative, positive, neutral, and alcohol-related images, after which they rated their experienced emotions. We found that repetitive transcranial magnetic stimulation (rTMS) reduces self-reported experienced emotions in response to positive and negative images in AUD patients, whereas experienced emotions were increased in response to neutral and positive images in HCs. In the functional magnetic resonance imaging (fMRI) analyses, we found that rTMS reduces right dlPFC activity during appraisal of affective images relative to sham stimulation only in AUD patients. We could not confirm our hypotheses regarding the effect of rTMS craving levels, or on reappraisal related brain function, since no significant effects of rTMS on craving or reappraisal related brain function were found. These findings imply that rTMS can reduce the emotional impact of images as reflected in blood oxygenation level-dependent (BOLD) response, especially in AUD patients. Future studies should replicate and expand the current study, for instance, by assessing the effect of multiple stimulation sessions on both explicit and implicit emotion regulation paradigms and craving, and assess the effect of rTMS within subgroups with specific addiction-relevant image preferences. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815.

Emotion Processing, Reappraisal, and Craving in Alcohol Dependence: A Functional Magnetic Resonance Imaging Study.

Alcohol dependence has long been related to impaired emotion regulation-including reappraisal-but little is known about the performance and associated neural activity of alcohol-dependent patients (ADPs) on an emotion reappraisal task. This study, therefore, compares reappraisal of negative, positive, neutral, and alcohol-related images at a behavioral and neural level between ADPs and healthy controls (HCs). Thirty-nine ADPs and 39 age-, gender-, and education-matched HCs performed an emotion reappraisal task during functional magnetic resonance imaging (fMRI), and craving was measured before and after the reappraisal task. During the emotion reappraisal task, participants were instructed to either attend or reappraise positive, negative, neutral, or alcohol-related images, and to indicate their experienced emotion on a visual analogue scale (VAS). Both ADPs and HCs completed the emotion reappraisal task successfully, showing significant differences in self-reported experienced emotion after attending versus reappraising visual stimuli and in brain activity in emotion processing/reappraisal relevant areas. ADPs were not impaired in cognitive reappraisal at a behavioral or neural level relative to HCs, nor did ADPs indicate any difference in self-reported emotion while attending emotional images. However, ADPs were different from HC in emotion processing: ADPs revealed a blunted response in the (posterior) insula, precuneus, operculum, and superior temporal gyrus while attending emotional images compared neutral images compared to HCs, and in ADPs, higher baseline craving levels were associated with a less blunted response to alcohol-related images than in HCs. These results reveal that ADPs do not show impaired reappraisal abilities when instructed, although future studies should assess voluntary reappraisal abilities in alcohol-dependent patients. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815.

Error Processing and Inhibitory Control in Obsessive-Compulsive Disorder: A Meta-analysis Using Statistical Parametric Maps.

BACKGROUND: Error processing and inhibitory control enable the adjustment of behaviors to meet task demands. Functional magnetic resonance imaging studies report brain activation abnormalities in patients with obsessive-compulsive disorder (OCD) during both processes. However, conclusions are limited by inconsistencies in the literature and small sample sizes. Therefore, the aim here was to perform a meta-analysis of the existing literature using unthresholded statistical maps from previous studies. METHODS: A voxelwise seed-based d mapping meta-analysis was performed using t-maps from studies comparing patients with OCD and healthy control subjects (HCs) during error processing and inhibitory control. For the error processing analysis, 239 patients with OCD (120 male; 79 medicated) and 229 HCs (129 male) were included, while the inhibitory control analysis included 245 patients with OCD (120 male; 91 medicated) and 239 HCs (135 male). RESULTS: Patients with OCD, relative to HCs, showed longer inhibitory control reaction time (standardized mean difference = 0.20, p = .03, 95% confidence interval = 0.016, 0.393) and more inhibitory control errors (standardized mean difference = 0.22, p = .02, 95% confidence interval = 0.039, 0.399). In the brain, patients showed hyperactivation in the bilateral dorsal anterior cingulate cortex, supplementary motor area, and pre-supplementary motor area as well as right anterior insula/frontal operculum and anterior lateral prefrontal cortex during error processing but showed hypoactivation during inhibitory control in the rostral and ventral anterior cingulate cortices and bilateral thalamus/caudate, as well as the right anterior insula/frontal operculum, supramarginal gyrus, and medial orbitofrontal cortex (all seed-based d mapping z value >2, p < .001). CONCLUSIONS: A hyperactive error processing mechanism in conjunction with impairments in implementing inhibitory control may underlie deficits in stopping unwanted compulsive behaviors in the disorder.

Emotion Regulation in Obsessive-Compulsive Disorder, Unaffected Siblings, and Unrelated Healthy Control Participants.

BACKGROUND: Functional neuroimaging endophenotypes of obsessive-compulsive disorder (OCD) have been suggested during executive tasks. The purpose of this study was to investigate whether behavioral and neural responses during emotion processing and regulation also represent an endophenotype of OCD. METHODS: Forty-three unmedicated adult OCD patients, 19 of their unaffected siblings, and 38 healthy control participants underwent 3T functional magnetic resonance imaging during an emotion regulation task including neutral, fear-inducing, and OCD-related visual stimuli. Stimuli were processed during natural appraisal and during cognitive reappraisal, and distress ratings were collected after each picture. We performed between-group comparisons on task behavior and brain activation in regions of interest during emotion provocation and regulation. RESULTS: Siblings reported similar distress as healthy control participants during provocation, and significantly less than patients. There was no significant three-group difference in activation during fear provocation or regulation. Three-group comparisons showed that patients had higher amygdala and dorsomedial prefrontal cortex activation during OCD-related emotion provocation and regulation, respectively, while siblings were intermediate between patients and control participants but not significantly different from either. Siblings showed higher left temporo-occipital activation (compared with both healthy control participants and patients) and higher frontolimbic connectivity (compared with patients) during OCD-related regulation. CONCLUSIONS: Unaffected siblings do not show the same distress and amygdala activation during emotional provocation as OCD patients. Siblings show distinct activation in a temporo-occipital region, possibly related to compensatory cognitive control. This suggests that emotion regulation is not a strong endophenotype for OCD. When replicated, this contributes to our understanding of familial risk and resilience for OCD.

Cognitive control networks in OCD: A resting-state connectivity study in unmedicated patients with obsessive-compulsive disorder and their unaffected relatives.

OBJECTIVES: Executive network deficits are putative neurocognitive endophenotypes for obsessive-compulsive disorder (OCD). Yet, unlike alterations in fronto-striatal and limbic connectivity, connectivity in the fronto-parietal (FPN) and cingulo-opercular (CON) networks involved in cognitive control has received little attention. METHODS: The coherence of FPN, CON and fronto-limbic networks was investigated in 39 unmedicated OCD patients, 16 of their unaffected siblings and 36 healthy controls using resting-state functional-connectivity MRI and a seed-based analysis approach. RESULTS: FPN and CON connectivity was similar for patients and controls. Siblings showed higher connectivity than patients within the CON, and between the CON and FPN compared to patients and controls (trend level). In OCD patients, but not in siblings, fronto-limbic hyperconnectivity was present compared to controls. In contrast to our expectations, no group differences in resting-state connectivity of the cognitive control networks were observed between OCD patients and controls. CONCLUSIONS: The increased within- and between-network connectivity in siblings, but not in patients, could indicate a mechanism of increased cognitive control that may act as a protective mechanism. None of the observed network alterations can be considered an endophenotype for OCD since differences were present in either patients or siblings, but not in both groups.