Faculty Bibliography
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91
Randomized Controlled Trial of the Effects of High-Dose Ondansetron on Clinical Symptoms and Brain Connectivity in Obsessive-Compulsive and Tic Disorders
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.
PMID: 39876680
ISSN: 1535-7228
CID: 5780852
Negative valence in Obsessive-Compulsive Disorder: A worldwide mega-analysis of task-based functional neuroimaging data of the ENIGMA-OCD consortium
OBJECTIVE:Obsessive-compulsive disorder (OCD) is associated with altered brain function related to processing of negative emotions. To investigate neural correlates of negative valence in OCD, we pooled fMRI data of 633 individuals with OCD and 453 healthy controls from 16 studies using different negatively-valenced tasks across the ENIGMA-OCD Working-Group. METHODS:Participant data were processed uniformly using HALFpipe, to extract voxelwise participant-level statistical images of one common first-level contrast: negative vs. neutral stimuli. In pre-registered analyses, parameter estimates were entered into Bayesian multilevel models to examine whole-brain and regional effects of OCD and its clinically relevant features - symptom severity, age of onset, and medication status. RESULTS:We provided a proof-of-concept that participant-level data can be combined across several task paradigms and observed one common task activation pattern across individuals with OCD and controls that encompasses fronto-limbic and visual areas implicated in negative valence. Compared to controls, individuals with OCD showed very strong evidence of weaker activation of the bilateral occipital cortex (P+<0.001) and adjacent visual processing regions during negative valence processing that was related to greater OCD severity, late-onset of disease and an unmedicated status. Individuals with OCD also showed stronger activation in the orbitofrontal, subgenual anterior cingulate and ventromedial prefrontal cortex (all P+<0.1) that was related to greater OCD severity and late onset. CONCLUSION/CONCLUSIONS:In the first mega-analysis of this kind, we replicate previous findings of stronger ventral prefrontal activation in OCD during negative valence processing and highlight the lateral occipital cortex as an important region implicated in altered negative valence processing.
PMID: 39725297
ISSN: 1873-2402
CID: 5767792
Identifying subgroups of urge suppression in Obsessive-Compulsive Disorder using machine learning
Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous. While predominant models suggest fear and harm prevention drive compulsions, many patients also experience uncomfortable sensory-based urges ("sensory phenomena") that may be associated with heightened interoceptive sensitivity. Using an urge-to-blink eyeblink suppression paradigm to model sensory-based urges, we previously found that OCD patients as a group had more eyeblink suppression failures and greater activation of sensorimotor-interoceptive regions than controls. However, conventional approaches assuming OCD homogeneity may obscure important within-group variability, impeding precision treatment development. This study investigated the heterogeneity of urge suppression failure in OCD and examined relationships with clinical characteristics and neural activation. Eighty-two patients with OCD and 38 controls underwent an fMRI task presenting 60-s blocks of eyeblink suppression alternating with free-blinking blocks. Latent profile analysis identified OCD subgroups based on number of erroneous blinks during suppression. Subgroups were compared on behavior, clinical characteristics, and brain activation during task. Three patient subgroups were identified. Despite similar overall OCD severity, the subgroup with the most erroneous eyeblinks had the highest sensory phenomena severity, interoceptive sensitivity, and subjective urge intensity. Compared to other subgroups, this subgroup exhibited more neural activity in somatosensory and interoceptive regions during the early phase (first 30 s) of blink suppression and reduced activity in the middle frontal gyrus during the late phase (second 30 s) as the suppression period elapsed. Heterogeneity of urge suppression in OCD was associated with clinical characteristics and brain function. Our results reveal potential treatment targets that could inform personalized medicine.
PMID: 39004004
ISSN: 1879-1379
CID: 5687252
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.
PMID: 38326559
ISSN: 1476-5578
CID: 5632312
Correction: White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group
PMID: 38454086
ISSN: 1476-5578
CID: 5694752
Sensory over-responsivity and orbitofrontal cortex connectivity in obsessive-compulsive disorder
BACKGROUND:Sensory over-responsivity (SOR) in obsessive-compulsive disorder (OCD) is associated with illness severity and functional impairment. However, the neural substrates of SOR in OCD have not yet been directly probed. METHODS:We examined resting-state global functional connectivity markers of SOR in 119 adults with OCD utilizing the CONN-fMRI Functional Connectivity Toolbox for SPM (v21a). We quantified SOR with the sensory sensitivity and sensory avoiding subscales of the Adult and Adolescent Sensory Profile (AASP). We also measured: OCD severity, with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Obsessive-Compulsive Inventory-Revised (OCI-R); sensory phenomena with the Sensory Phenomena Scale (SPS); general anxiety, with the Beck Anxiety Inventory (BAI); and depressive symptomatology, with Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR). RESULTS:There was a significant positive relationship of SOR with global connectivity in anterior and medial OFC (Brodmann's area 11, k = 154, x = 14, y = 62, z = -18, whole-brain corrected at FWE p < 0.05). LIMITATIONS/CONCLUSIONS:Future investigations should explore neural responses to sensory stimulation tasks in OCD and compare findings with those obtained in other conditions also characterized by high SOR, such as autism spectrum disorder. CONCLUSIONS:This study implicates OFC functional connectivity as a neurobiological mechanism of SOR in OCD and suggests that the substrates of SOR in OCD may be dissociable from both that of other symptoms in OCD, and SOR in other disorders. With replication and extension, the finding may be leveraged to develop and refine treatments for OCD and investigate the pathophysiology of SOR in other conditions.
PMID: 38382815
ISSN: 1573-2517
CID: 5634382
The Human Affectome
Over the last decades, the interdisciplinary field of the affective sciences has seen proliferation rather than integration of theoretical perspectives. This is due to differences in metaphysical and mechanistic assumptions about human affective phenomena (what they are and how they work) which, shaped by academic motivations and values, have determined the affective constructs and operationalizations. An assumption on the purpose of affective phenomena can be used as a teleological principle to guide the construction of a common set of metaphysical and mechanistic assumptions-a framework for human affective research. In this capstone paper for the special issue "Towards an Integrated Understanding of the Human Affectome", we gather the tiered purpose of human affective phenomena to synthesize assumptions that account for human affective phenomena collectively. This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.
PMID: 37925091
ISSN: 1873-7528
CID: 5607222
Correction: The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium
PMID: 37582859
ISSN: 1476-5578
CID: 5619162
Associations Between Suicidality and Interoception in Obsessive-Compulsive Disorder
BACKGROUND/UNASSIGNED:Individuals with obsessive-compulsive disorder (OCD) are at increased risk for suicide. One potential risk factor is interoceptive sensibility (IS), which is one's subjective experience of bodily sensations. The current study examined the relationship between IS and current suicidal ideation and lifetime history of suicide attempt, controlling for relevant covariates. METHODS/UNASSIGNED:= 145) were a clinical sample of individuals with OCD from the New York City area. A clinical rater administered a diagnostic interview and an OCD severity assessment, and participants completed questionnaires about demographics, IS, and suicidality. RESULTS/UNASSIGNED:Current suicidal ideation was associated with reduced trusting of the body, and lifetime history of suicide attempt was related to greater general awareness of sensation. These associations remained significant after controlling for covariates. CONCLUSIONS/UNASSIGNED:These results suggest that specific facets of IS may be associated with specific domains of suicidality. Decreased body trusting may represent a feeling of disconnection from the body that facilitates desire for death. Increased noticing of bodily sensations may lead to greater mental pain, which could interact with deficits in emotion regulation to increase risk for suicide attempt. Further research on the relationships between IS and suicidality in OCD is warranted.
PMCID:10610034
PMID: 37901053
ISSN: 2211-3649
CID: 5736422
Failures of Urge Suppression in Obsessive-Compulsive Disorder: Behavioral Modeling Using a Blink Suppression Task
Many individuals with obsessive-compulsive disorder (OCD) report sensory-based urges (e.g. 'not-just-right experiences') in addition to, or instead of, concrete fear-based obsessions. These sensations may be comparable to normative "urges-for-action" (UFA), such as the urge to blink. While research has identified altered functioning of brain regions related to UFA in OCD, little is known about behavioral patterns of urge suppression in the disorder. Using an urge-to-blink task as a model for sensory-based urges, this study compared failures of urge suppression between OCD patients and controls by measuring eyeblinks during 60-second blocks of instructed blink suppression. Cox shared frailty models estimated the hazard of first blinks during each 60-second block and recurrent blinks following each initial erroneous blink. OCD patients demonstrated a higher hazard of first and recurrent blinks compared to controls, suggesting greater difficulty resisting repetitive sensory-based urges. Within OCD, relationships between task outcomes and symptom severity were inconsistent. Findings provide support for a deficit in delaying initial urge-induced actions and terminating subsequent actions in OCD, which is not clearly related to clinical heterogeneity. Elucidating the nature of behavioral resistance to urges is relevant for informing conceptualizations of obsessive-compulsive psychopathology and optimizing treatment outcomes.
PMCID:10373599
PMID: 37521712
ISSN: 2211-3649
CID: 5545172
