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High-dose ondansetron reduces activation of interoceptive and sensorimotor brain regions

Stern, Emily R; Shahab, Rebbia; Grimaldi, Stephanie J; Leibu, Evan; Murrough, James W; Fleysher, Lazar; Parides, Michael K; Coffey, Barbara J; Burdick, Katherine E; Goodman, Wayne K
Several psychiatric disorders involve abnormalities of interoception and associated neural circuitry centered on the insula. The development of interventions modulating interoceptive circuits could lead to novel treatment approaches for these disorders. The 5-HT3 receptor antagonist ondansetron is a good candidate for the modulation of interoceptive circuits, as 5-HT3 receptors are located abundantly on sensory pathways and ondansetron has shown some clinical utility in disorders characterized by sensory and interoceptive abnormalities. The present study tested the ability of three different doses of ondansetron to engage neural regions involved in interoception to determine the drug's utility as a therapeutic agent to target circuit abnormalities in patients. Fifty-three healthy subjects were randomized to receive a single 8-mg (n = 18), 16-mg (n = 17), or 24-mg (n = 18) dose of ondansetron and placebo before MRI scanning on separate days. Subjects performed an fMRI task previously shown to engage interoceptive circuitry in which they viewed videos depicting body movements/sensation and control videos. The results revealed a highly significant relationship between dosage and activation in bilateral insula, somatosensory and premotor regions, cingulate cortex, and temporal cortex for control but not body-focused videos. These effects were driven by a robust reduction in activation for ondansetron compared to placebo for the 24-mg group, with weaker effects for the 16-mg and 8-mg groups. In conclusion, high-dose ondansetron reduces activation of several areas important for interoception, including insula and sensorimotor cortical regions. This study reveals the potential utility of this drug in modulating hyperactivity in these regions in patients.
PMID: 30116006
ISSN: 1740-634x
CID: 3241462

Cognitive Neuroscience of Obsessive-Compulsive Disorder

Bragdon, Laura B; Eng, Goi Khia; Recchia, Nicolette; Collins, Katherine A; Stern, Emily R
Cognitive neuroscientific research has the ability to yield important insights into the complex neurobiological processes underlying obsessive-compulsive disorder (OCD). This article provides an updated review of neuroimaging studies in seven neurocognitive domains. Findings from the literature are discussed in the context of obsessive-compulsive phenomenology and treatment. Expanding our knowledge of the neural mechanisms involved in OCD could help optimize treatment outcomes and guide the development of novel interventions.
PMID: 36740355
ISSN: 1558-3147
CID: 5420682

Imbalance between default mode and sensorimotor connectivity is associated with perseverative thinking in obsessive-compulsive disorder

Stern, Emily R; Eng, Goi Khia; De Nadai, Alessandro S; Iosifescu, Dan V; Tobe, Russell H; Collins, Katherine A
Obsessive-compulsive disorder (OCD) is highly heterogeneous. Although perseverative negative thinking (PT) is a feature of OCD, little is known about its neural mechanisms or relationship to clinical heterogeneity in the disorder. In a sample of 85 OCD patients, we investigated the relationships between self-reported PT, clinical symptom subtypes, and resting-state functional connectivity measures of local and global connectivity. Results indicated that PT scores were highly variable within the OCD sample, with greater PT relating to higher severity of the "unacceptable thoughts" symptom dimension. PT was positively related to local connectivity in subgenual anterior cingulate cortex (ACC), pregenual ACC, and the temporal poles-areas that are part of, or closely linked to, the default mode network (DMN)-and negatively related to local connectivity in sensorimotor cortex. While the majority of patients showed higher local connectivity strengths in sensorimotor compared to DMN regions, OCD patients with higher PT scores had less of an imbalance between sensorimotor and DMN connectivity than those with lower PT scores, with healthy controls exhibiting an intermediate pattern. Clinically, this imbalance was related to both the "unacceptable thoughts" and "symmetry/not-just-right-experiences" symptom dimensions, but in opposite directions. These effects remained significant after accounting for variance related to psychiatric comorbidity and medication use in the OCD sample, and no significant relationships were found between PT and global connectivity. These data indicate that PT is related to symptom and neural variability in OCD. Future work may wish to target this circuity when developing personalized interventions for patients with these symptoms.
PMID: 35022398
ISSN: 2158-3188
CID: 5118862

The buildup of an urge in obsessive-compulsive disorder: Behavioral and neuroimaging correlates

Stern, Emily R; Brown, Carina; Ludlow, Molly; Shahab, Rebbia; Collins, Katherine; Lieval, Alexis; Tobe, Russell H; Iosifescu, Dan V; Burdick, Katherine E; Fleysher, Lazar
Obsessive-compulsive disorder (OCD) is highly heterogeneous. While obsessions often involve fear of harm, many patients report uncomfortable sensations and/or urges that drive repetitive behaviors in the absence of a specific fear. Prior work suggests that urges in OCD may be similar to everyday "urges-for-action" (UFA) such as the urge to blink, swallow, or scratch, but very little work has investigated the pathophysiology underlying urges in OCD. In the current study, we used an urge-to-blink approach to model sensory-based urges that could be experimentally elicited and compared across patients and controls using the same task stimuli. OCD patients and controls suppressed eye blinking over a period of 60 s, alternating with free blinking blocks, while brain activity was measured using functional magnetic resonance imaging. OCD patients showed significantly increased activation in several regions during the early phase of eyeblink suppression (first 30 s), including mid-cingulate, insula, striatum, parietal cortex, and occipital cortex, with lingering group differences in parietal and occipital regions during late eyeblink suppression (last 30 s). There were no differences in brain activation during free blinking blocks, and no conditions where OCD patients showed reduced activation compared to controls. In an exploratory analysis of blink counts performed in a subset of subjects, OCD patients were less successful than controls in suppressing blinks. These data indicate that OCD patients exhibit altered brain function and behavior when experiencing and suppressing the urge to blink, raising the possibility that the disorder is associated with a general abnormality in the UFA system that could ultimately be targeted by future treatments.
PMID: 31916668
ISSN: 1097-0193
CID: 4257542

Identifying subgroups of urge suppression in Obsessive-Compulsive Disorder using machine learning

Eng, Goi Khia; De Nadai, Alessandro S; Collins, Katherine A; Recchia, Nicolette; Tobe, Russell H; Bragdon, Laura B; Stern, Emily R
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

Functional neural mechanisms of sensory phenomena in obsessive-compulsive disorder

Brown, Carina; Shahab, Rebbia; Collins, Katherine; Fleysher, Lazar; Goodman, Wayne K; Burdick, Katherine E; Stern, Emily R
Sensory phenomena (SP) are aversive or uncomfortable sensations that accompany and/or drive repetitive behaviors in obsessive-compulsive disorder (OCD). Although SP are associated with significant distress and may respond less well to standard treatments than harm-related obsessions, little is known about their underlying neurobiology. The present study used functional magnetic resonance imaging (fMRI) to measure brain functioning related to severity of SP during a "body-focused" videos task designed to elicit activation in sensorimotor brain regions. Regression analysis examined the relationship between severity of SP and activation during task using permutation analysis, cluster-level corrected for multiple comparisons (family-wise error rate p < 0.05). The distribution of SP severity was not significantly different from normal, with both high- and low-severity scores represented in the OCD sample. Severity of SP was not correlated with other clinical symptoms in OCD including general anxiety, depression, or harm avoidance. When viewing body-focused videos, patients with greater severity of SP showed increased activity in the mid-posterior insula, a relationship that remained significant when controlling for other clinical symptoms, medication status, and comorbidities. At uncorrected thresholds, SP severity was also positively related to somatosensory, mid orbitofrontal, and lateral prefrontal cortical activity. These data suggest that SP in OCD are dissociable from other symptoms in the disorder and related to hyperactivation of the insula. Future work examining neural mechanisms of SP across different disorders (tics, trichotillomania) as well as with other imaging modalities will be needed to further understand the neurobiology of these impairing symptoms.
PMID: 30508745
ISSN: 1879-1379
CID: 3520582

Randomized Controlled Trial of the Effects of High-Dose Ondansetron on Clinical Symptoms and Brain Connectivity in Obsessive-Compulsive and Tic Disorders

Stern, Emily R; Collins, Katherine A; Bragdon, Laura B; Eng, Goi Khia; Recchia, Nicolette; Coffey, Barbara J; Leibu, Evan; Murrough, James W; Tobe, Russell H; Iosifescu, Dan V; Burdick, Katherine E; Goodman, Wayne K
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

Dzinalija, Nadza; Vriend, Chris; Waller, Lea; Simpson, H Blair; Ivanov, Iliyan; Agarwal, Sri Mahavir; Alonso, Pino; Backhausen, Lea L; Balachander, Srinivas; Broekhuizen, Aniek; Castelo-Branco, Miguel; Costa, Ana Daniela; Cui, Hailun; Denys, Damiaan; Duarte, Isabel Catarina; Eng, Goi Khia; Erk, Susanne; Fitzsimmons, Sophie M D D; Ipser, Jonathan; Jaspers-Fayer, Fern; de Joode, Niels T; Kim, Minah; Koch, Kathrin; Kwon, Jun Soo; van Leeuwen, Wieke; Lochner, Christine; van Marle, Hein J F; Martinez-Zalacain, Ignacio; Menchon, Jose M; Morgado, Pedro; Narayanaswamy, Janardhanan C; Olivier, Ian S; Picó-Pérez, Maria; Postma, Tjardo S; Rodriguez-Manrique, Daniela; Roessner, Veit; Rus-Oswald, Oana Georgiana; Shivakumar, Venkataram; Soriano-Mas, Carles; Stern, Emily R; Stewart, S Evelyn; van der Straten, Anouk L; Sun, Bomin; Thomopoulos, Sophia I; Veltman, Dick J; Vetter, Nora C; Visser, Henny; Voon, Valerie; Walter, Henrik; van der Werf, Ysbrand D; van Wingen, Guido; ,; Stein, Dan J; Thompson, Paul M; Veer, Ilya M; van den Heuvel, Odile A
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

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

Kim, Bo-Gyeom; Kim, Gakyung; Abe, Yoshinari; Alonso, Pino; Ameis, Stephanie; Anticevic, Alan; Arnold, Paul D; Balachander, Srinivas; Banaj, Nerisa; Bargalló, Nuria; Batistuzzo, Marcelo C; Benedetti, Francesco; Bertolín, Sara; Beucke, Jan Carl; Bollettini, Irene; Brem, Silvia; Brennan, Brian P; Buitelaar, Jan K; Calvo, Rosa; Castelo-Branco, Miguel; Cheng, Yuqi; Chhatkuli, Ritu Bhusal; Ciullo, Valentina; Coelho, Ana; Couto, Beatriz; Dallaspezia, Sara; Ely, Benjamin A; Ferreira, Sónia; Fontaine, Martine; Fouche, Jean-Paul; Grazioplene, Rachael; Gruner, Patricia; Hagen, Kristen; Hansen, Bjarne; Hanna, Gregory L; Hirano, Yoshiyuki; Höxter, Marcelo Q; Hough, Morgan; Hu, Hao; Huyser, Chaim; Ikuta, Toshikazu; Jahanshad, Neda; James, Anthony; Jaspers-Fayer, Fern; Kasprzak, Selina; Kathmann, Norbert; Kaufmann, Christian; Kim, Minah; Koch, Kathrin; Kvale, Gerd; Kwon, Jun Soo; Lazaro, Luisa; Lee, Junhee; Lochner, Christine; Lu, Jin; Manrique, Daniela Rodriguez; Martínez-Zalacaín, Ignacio; Masuda, Yoshitada; Matsumoto, Koji; Maziero, Maria Paula; Menchón, Jose M; Minuzzi, Luciano; Moreira, Pedro Silva; Morgado, Pedro; Narayanaswamy, Janardhanan C; Narumoto, Jin; Ortiz, Ana E; Ota, Junko; Pariente, Jose C; Perriello, Chris; Picó-Pérez, Maria; Pittenger, Christopher; Poletti, Sara; Real, Eva; Reddy, Y C Janardhan; van Rooij, Daan; Sakai, Yuki; Sato, João Ricardo; Segalas, Cinto; Shavitt, Roseli G; Shen, Zonglin; Shimizu, Eiji; Shivakumar, Venkataram; Soreni, Noam; Soriano-Mas, Carles; Sousa, Nuno; Sousa, Mafalda Machado; Spalletta, Gianfranco; Stern, Emily R; Stewart, S Evelyn; Szeszko, Philip R; Thomas, Rajat; Thomopoulos, Sophia I; Vecchio, Daniela; Venkatasubramanian, Ganesan; Vriend, Chris; Walitza, Susanne; Wang, Zhen; Watanabe, Anri; Wolters, Lidewij; Xu, Jian; Yamada, Kei; Yun, Je-Yeon; Zarei, Mojtaba; Zhao, Qing; Zhu, Xi; ,; Thompson, Paul M; Bruin, Willem B; van Wingen, Guido A; Piras, Federica; Piras, Fabrizio; Stein, Dan J; van den Heuvel, Odile A; Simpson, Helen Blair; Marsh, Rachel; Cha, Jiook
PMID: 38454086
ISSN: 1476-5578
CID: 5694752

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

Kim, Bo-Gyeom; Kim, Gakyung; Abe, Yoshinari; Alonso, Pino; Ameis, Stephanie; Anticevic, Alan; Arnold, Paul D; Balachander, Srinivas; Banaj, Nerisa; Bargalló, Nuria; Batistuzzo, Marcelo C; Benedetti, Francesco; Bertolín, Sara; Beucke, Jan Carl; Bollettini, Irene; Brem, Silvia; Brennan, Brian P; Buitelaar, Jan K; Calvo, Rosa; Castelo-Branco, Miguel; Cheng, Yuqi; Chhatkuli, Ritu Bhusal; Ciullo, Valentina; Coelho, Ana; Couto, Beatriz; Dallaspezia, Sara; Ely, Benjamin A; Ferreira, Sónia; Fontaine, Martine; Fouche, Jean-Paul; Grazioplene, Rachael; Gruner, Patricia; Hagen, Kristen; Hansen, Bjarne; Hanna, Gregory L; Hirano, Yoshiyuki; Höxter, Marcelo Q; Hough, Morgan; Hu, Hao; Huyser, Chaim; Ikuta, Toshikazu; Jahanshad, Neda; James, Anthony; Jaspers-Fayer, Fern; Kasprzak, Selina; Kathmann, Norbert; Kaufmann, Christian; Kim, Minah; Koch, Kathrin; Kvale, Gerd; Kwon, Jun Soo; Lazaro, Luisa; Lee, Junhee; Lochner, Christine; Lu, Jin; Manrique, Daniela Rodriguez; Martínez-Zalacaín, Ignacio; Masuda, Yoshitada; Matsumoto, Koji; Maziero, Maria Paula; Menchón, Jose M; Minuzzi, Luciano; Moreira, Pedro Silva; Morgado, Pedro; Narayanaswamy, Janardhanan C; Narumoto, Jin; Ortiz, Ana E; Ota, Junko; Pariente, Jose C; Perriello, Chris; Picó-Pérez, Maria; Pittenger, Christopher; Poletti, Sara; Real, Eva; Reddy, Y C Janardhan; van Rooij, Daan; Sakai, Yuki; Sato, João Ricardo; Segalas, Cinto; Shavitt, Roseli G; Shen, Zonglin; Shimizu, Eiji; Shivakumar, Venkataram; Soriano-Mas, Carles; Sousa, Nuno; Sousa, Mafalda Machado; Spalletta, Gianfranco; Stern, Emily R; Stewart, S Evelyn; Szeszko, Philip R; Thomas, Rajat; Thomopoulos, Sophia I; Vecchio, Daniela; Venkatasubramanian, Ganesan; Vriend, Chris; Walitza, Susanne; Wang, Zhen; Watanabe, Anri; Wolters, Lidewij; Xu, Jian; Yamada, Kei; Yun, Je-Yeon; Zarei, Mojtaba; Zhao, Qing; Zhu, Xi; ,; Thompson, Paul M; Bruin, Willem B; van Wingen, Guido A; Piras, Federica; Piras, Fabrizio; Stein, Dan J; van den Heuvel, Odile A; Simpson, Helen Blair; Marsh, Rachel; Cha, Jiook
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