Faculty Bibliography

Atypical interoception is a transdiagnostic feature of psychiatric illness. Interoceptive alterations have been demonstrated in both obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). However, the nature and direction of differences between patients and controls have been inconsistent, and interoception has not been directly compared between OCD and MDD in the same study. The current study addressed this gap by comparing OCD patients, MDD patients, and healthy controls (HCs) on three different facets of interoception: accuracy (IAcc; objective ability to detect bodily sensations), confidence in interoceptive ability (self-reported ability to detect bodily sensations accurately), and one dimension of interoceptive sensibility (IS; self-reported tendency to notice bodily sensation). Measures of IAcc and confidence were derived from responses in a heartbeat tracking task, whereas IS was measured with the Multidimensional Assessment of Interoceptive Awareness (MAIA) Noticing subscale. There were no differences between the groups in IAcc. Individuals with OCD displayed lower confidence in their interoceptive ability relative to both HC and MDD, although the pairwise effects did not survive multiple comparison-correction. Lower confidence was also nominally associated with greater obsessive-compulsive symptom severity. Both OCD patients and MDD patients exhibited significantly elevated IS compared to HCs, however, IS did not differ between patient groups. Exploratory analyses suggested a positive association between IAcc and confidence in interoceptive ability within OCD patients, while no associations between IAcc and confidence were found in MDD or HCs. These findings provide preliminary evidence for shared and potentially unique alterations of interoception in OCD and MDD.

Studies of brain morphology in mental illness often focus on a few neuroimaging phenotypes. Here we present a comprehensive morphological characterization in obsessive-compulsive disorder (OCD) in a large sample (2255 OCD, 2264 controls) using nine cortical and four subcortical phenotypes, including several not previously examined in OCD, among them a subcortical structural similarity network phenotype developed here. Spatially distinct regional alterations emerged across structural phenotypes: cortical curvature alterations in default mode and frontoparietal networks, increased structural similarity network node degree in sensorimotor regions, widespread volume reductions associated with medication use, and localized subcortical shape alterations. In brain-behavior predictive models, curvature phenotypes showed the strongest associations with clinical features. Cortical alterations, especially in structural similarity networks, were associated with specific gene expression patterns, implicating dysregulation of excitatory neurons. RNA-sequencing data from tissue collected during functional neurosurgery revealed that genes downregulated in the dorsolateral prefrontal cortex in OCD contributed to the gene expression patterns linked to cortical alterations. Previously reported differentially expressed genes from postmortem brain studies of OCD also contributed. These findings support the importance of a comprehensive approach to characterizing brain morphology and suggest that cortical curvature and structural similarity alterations reflect key pathophysiological processes in OCD.

Functional magnetic resonance imaging studies have reported disruptions in functional connectivity within brain networks, known as connectomes. Researchers have tested connectomes to see whether they serve as biomarkers for various psychiatric conditions. This meta-analysis aims to evaluate the diagnostic test accuracy of predictive models of connectomes derived from resting-state fMRI in diagnosing obsessive-compulsive disorder. A systematic review and meta-analysis were conducted on previous studies assessing the sensitivity, specificity, and accuracy of connectome-based diagnostic models in obsessive-compulsive disorder and healthy controls. Eight studies were identified, comprising 563 individuals with obsessive-compulsive disorder and 564 healthy controls. The results revealed robust diagnostic performance with a pooled sensitivity of 0.827 (95% CI: 0.779-0.867) and specificity of 0.794 (95% CI: 0.759-0.826). Connectome-based diagnostic models demonstrated excellent clinical utility, with an area under the curve of 87% (95% CI: 84%-90%), and significant predictive power as indicated by positive (4.15) and negative (0.21) likelihood ratios, as well as strong diagnostic odds ratio of 18.69 (95% CI: 11.84-29.49). The results highlight the potential of functional connectome-based predictive modeling as a robust tool for accurately diagnosing obsessive-compulsive disorder, with possibility of future implications for early diagnosis, monitoring treatment-related changes, involving in decision modeling, and understanding the biological mechanisms underlying obsessive-compulsive disorder.

Adolescence represents a critical neurodevelopmental period of high vulnerability to the onset of psychiatric conditions. Altered processing of uncertain reward outcomes likely contributes to this vulnerability, yet remains poorly understood. Addressing this knowledge gap, we sought to use the fMRI Reward Flanker Task, originally developed by our group, to examine neural responses to uncertain rewards and their clinical associations. To fully capture clinical correlates, we recruited adolescents with mood and anxiety symptoms ranging from low to high severity, including healthy controls (HC). Participants were 84 psychotropic-medication-free adolescents (15.3 ± 2.1 years; 62% female; 17 HC); all completed diagnostic and dimensional symptom assessments. Neuroimaging data were preprocessed using Human Connectome Project pipelines. Analyses examined participant-level neural responses to uncertain reward expectancy and attainment, adjusted for age, sex, and multiple comparisons. Across the whole sample, uncertain versus certain cues activated the default network and suppressed the fronto-parietal control network. Neural responses during expectancy to uncertain reward were intermediate between responses to certain reward and non-reward stimuli. Outcome attainment following uncertain cues activated stronger neural responses in reward and salience regions compared to reward cues. Anhedonia severity correlated with default network activation during uncertain outcome attainment. Anxiety severity correlated with blunted striatal responses during uncertain vs. certain non-reward expectancy. Exploratory group comparisons revealed that adolescents with mood and anxiety symptoms versus HC showed blunted striatal responses during uncertain versus non-reward expectancy and hyperactivation in visual and default network areas during attainment following uncertain cues. Together, these findings support the role of uncertain reward processing in adolescent mood and anxiety psychopathology.

Alterations in cortical morphology have consistently been reported in obsessive-compulsive disorder (OCD). However, the microstructural properties of the cortex in OCD, including intracortical myelination, remain far less explored. The contrast between signal intensity in gray and subjacent white matter from T1-weighted magnetic resonance imaging (MRI), i.e. the gray/white matter contrast (GWC), is linked to intracortical myelination and may offer novel insights into the cortical microstructure of OCD. Here, we compared multivariate patterns of GWC defined from an independent component analysis between 454 adults with OCD and 394 healthy controls from eight international sites. To contextualize GWC results with the macrostructure of gray matter in OCD, we also investigated the association between GWC and each individual's similarity with the pattern of gray matter morphology derived from ENIGMA-OCD using the Regional Vulnerability Index (RVI). Finally, we investigated the association of GWC with demographic and clinical characteristics of participants with OCD. Individuals with OCD showed significantly higher GWC in occipital and frontal regions relative to healthy controls. Moreover, OCD individuals had elevated OCD RVI, and individuals with a higher OCD RVI showed widespread higher GWC across the cortex. Finally, sexual/religious symptoms in OCD individuals were associated with higher GWC in frontal regions. In conclusion, we present new evidence of cortical microstructural alterations in OCD, with microstructural alterations relating to both the gray matter macrostructure and the clinical presentation of the disorder.

BACKGROUND:Although subtle differences in cortico-striato-thalamo-cortical (CTSC) circuit structure and function are critical to the current understanding of the neurocircuitry in obsessive-compulsive disorder (OCD), emerging evidence suggests that the cerebellum may also be involved. However, much of this evidence comes from studies with small samples and notable methodological heterogeneity. METHODS:We conducted a mega-analysis of individual participant data on cerebellar sub-regional volumes, comparing individuals with OCD and healthy controls (HC) from the ENIGMA-OCD Working Group. 3D T1-weighted volumetric structural brain magnetic resonance imaging (MRI) scans from 1,954 individuals with OCD and 2,091 HC across 22 sites (40 datasets) were processed using the ACAPULCO (Automatic Cerebellum Anatomical Parcellation using U-Net Locally Constrained Optimization) pipeline to extract cerebellar parcellations. We harmonized the volume measures across sites using the ComBat algorithm. Multiple linear regression models were fitted to estimate group differences separately within the pediatric (<12 years), adolescent (12-18 years), and adult (from 18 years) samples, adjusting for age, gender, and intracranial volume (ICV). RESULTS:= 0.036). None of the comparisons between children or adolescents with OCD versus HC remained statistically significant after FDR correction. In all three age groups, cerebellar (subregional) volumes were significantly moderated by medication status. CONCLUSIONS:We report novel findings implicating specific cerebellar sub-regions across developmental stages of OCD, and the key impact of medication status. Further research on the functional significance of these findings may offer new translational leads.

OBJECTIVE/UNASSIGNED:Obsessive-compulsive disorder (OCD) is a chronic condition in which impaired inhibitory control and excessive error monitoring may contribute to the maintenance of obsessions and compulsions. This mega-analysis investigates neural activation during response inhibition and error processing using adult and pediatric data from the ENIGMA-OCD consortium and the ABCD study. METHODS/UNASSIGNED:Individual participant data was uniformly processed using HALFpipe to extract statistical maps for response inhibition and error processing contrasts. Bayesian multilevel models were used to assess regional and whole-brain effects of OCD, with additional analyses examining the association between the OCD clinical profile and task-related activation. RESULTS/UNASSIGNED:Across inhibitory control tasks, both individuals with OCD and control participants showed robust activation in regions implicated in response inhibition and error processing. During response inhibition, compared to controls, adults with OCD showed stronger somatomotor cortex activation, while children with OCD showed stronger occipital cortex activation. Children with likely OCD from the ABCD cohort showed reduced activity in the frontoparietal network in the anterior insula/frontal operculum region. During error processing, relative to controls, adults with OCD showed weaker activation in fronto-striatal regions, while children with OCD showed stronger activation in frontoparietal and attention networks. Greater OCD symptom severity was associated with weaker task-related activation in adults and stronger activation in children during response inhibition. CONCLUSION/UNASSIGNED:Case-control differences in brain activation during inhibitory control varied by age group and task contrast. Symptom severity emerged as the main clinical correlate of activation during inhibition, suggesting that inhibitory control deficits in OCD may be both state-dependent and developmentally specific.

Obsessive-compulsive disorder (OCD) is chronic and impairing. While OCD often involves fear of harm or bad events, many patients experience "sensory phenomena," which are aversive sensory experiences that drive repetitive behaviors regardless of specific fears. Standard treatments do not effectively address sensory phenomena, and novel approaches are needed. Transcranial magnetic stimulation (TMS) is a safe and non-invasive neuromodulation technique increasingly used in psychiatric disorders, including OCD. This work presents a data-driven approach to identifying TMS brain targets for modulating sensory urges in OCD incorporating both behavioral and clinical criteria (Study 1) for a proof-of-concept investigation (Study 2). Study 1 included 69 individuals with OCD and 23 controls who completed an urges-for-action fMRI task involving instructed eyeblink suppression as an experimental model for sensory-based urges. Data-driven conjunction analysis revealed several brain regions, including the right postcentral gyrus, that were associated with more blink suppression failure (behavioral), more severe sensory phenomena (clinical), and were hyperactivated in OCD patients compared to controls. Study 2 administered single-session inhibitory TMS on 4 returning OCD patients using individualized targets within the postcentral gyrus identified from Study 1. Compared to sham, inhibitory TMS delivered to individualized postcentral gyrus targets resulted in fewer blink suppression failures, reduced activation in the target (postcentral gyrus) and key urge-related areas (insula, mid-cingulate), and greater reduction in self-reported urge to engage in OCD-related compulsions, with medium to large effect sizes. These findings demonstrate the potential of utilizing data-driven approaches incorporating behavioral and clinical criteria to target hard-to-treat sensory phenomena in OCD.

Up to half of individuals with depression do not respond to first-line treatments, possibly due to a lack of treatment interventions informed by neurobiology. A novel therapeutic approach for depression has recently emerged from translational work targeting aberrant activity of ventral tegmental area (VTA) dopamine neurons via modulation of the KCNQ voltage-gated potassium channels. In this study, individuals with major depressive disorder (MDD) with elevated anhedonia were randomized to five weeks of the KCNQ channel opener, ezogabine (up to 900 mg/day) or placebo. Participants completed functional MRI during a monetary anticipation task and resting-state at baseline and at end-of-treatment. The clinical results were reported previously. Here, we examined VTA activity during monetary anticipation and resting-state functional connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway) and ventral striatum (mesolimbic pathway) at baseline and end-of-treatment. Results indicated a significant drug-by-time interaction in VTA activation during anticipation (F_(1,34) = 4.36, p = 0.044), where VTA activation was reduced from pre-to-post ezogabine, compared to placebo. Mesocortical functional connectivity was also higher in depressed participants at baseline compared to a healthy control group (t₍₅₆₎ = 2.68, p = 0.01) and associated with VTA hyper-activity during task-based functional MRI at baseline (R = 0.352, p = 0.033). Mesocortical connectivity was also reduced from pre-to-post ezogabine, compared to placebo (significant drug-by-time interaction, F_(1,33) = 4.317, p = 0.046). Together this translational work is consistent with preclinical findings highlighting VTA hyper-activity in depression, and suggesting a mechanism of action for KCNQ channel openers in normalizing this hyper-activity in individuals with both depression and anhedonia.

OBJECTIVE/UNASSIGNED:receptor antagonist ondansetron. The present study employed an experimental medicine approach to test the effects of 4 weeks of high-dose ondansetron compared to placebo on SP severity and brain connectivity in a cohort of individuals with OCD and/or Tourette's disorder. METHODS/UNASSIGNED:Of 51 participants who completed the study, 27 were assigned to receive 24 mg/day of ondansetron and 24 to receive placebo. Analyses examined changes in SP severity and, for participants with OCD, overall OCD severity from baseline to final visit. Functional MRI data were collected at both visits for analysis of intrinsic functional connectivity metrics characterizing global correlation (reflecting area "hubness") and local correlation (reflecting near-neighbor coherence). RESULTS/UNASSIGNED:There were no significant differences between ondansetron and placebo in the reduction of SP or overall OCD severity in the full sample. In a subsample of participants with OCD taking concomitant serotonin reuptake inhibitors (SRIs), ondansetron was associated with a significant decrease in overall OCD severity and global connectivity of the medial sensorimotor cortex compared with placebo. Longitudinal reductions in SP severity were related to decreases in right sensorimotor hubness in both groups, and to brainstem local coherence only in participants taking ondansetron. CONCLUSIONS/UNASSIGNED:There was no effect of high-dose ondansetron on SP. However, when used as an augmentation to SRIs, ondansetron reduced overall OCD severity, which may be related to changes in the "hubness" of the sensorimotor cortex. Ondansetron's ability to modulate brainstem connectivity may underlie its variable effectiveness in reducing SP.