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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

Relationships between interoceptive sensibility and resting-state functional connectivity of the insula in obsessive-compulsive disorder

Eng, Goi Khia; Collins, Katherine A; Brown, Carina; Ludlow, Molly; Tobe, Russell H; Iosifescu, Dan V; Stern, Emily R
Patients with obsessive-compulsive disorder (OCD) exhibit abnormality in their subjective perception of internal sensation, a process known as interoceptive sensibility (IS), as well as altered functioning of the insula, a key neural structure for interoception. We investigated the multivariate structure of IS in 77 OCD patients and 53 controls and examined associations of IS with resting-state functional connectivity (FC) of the insula within the OCD group. For each group, principal component analysis was performed on 8 subscales of the Multidimensional Assessment of Interoceptive Awareness assessing putatively "adaptive" and "maladaptive" aspects of IS. Associations between IS components and insula FC in the OCD group were evaluated using seed regions placed in each of 3 subdivisions of the insula (posterior, anterior dorsal, and anterior ventral). Behaviorally, controls showed a 2-component solution broadly categorized into "adaptive" and "maladaptive" IS, while OCD patients exhibited a 3-component solution. The general tendency to notice or be aware of sensation loaded onto an "adaptive" IS component in controls but loaded onto both "adaptive" and "maladaptive" IS components in OCD. Within OCD, insula FC was differentially associated with distinct aspects of IS, identifying network connections that could serve as future targets for the modulation of IS in OCD.
PMID: 35257146
ISSN: 1460-2199
CID: 5183432

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

Dimensions of interoception in obsessive-compulsive disorder

Eng, Goi Khia; Collins, Katherine A; Brown, Carina; Ludlow, Molly; Tobe, Russell H; Iosifescu, Dan V; Stern, Emily R
Interoceptive sensibility (IS) refers to the subjective experience of perceiving and being aware of one's internal body sensations, and is typically evaluated using self-report questionnaires or confidence ratings. Here we evaluated IS in 81 patients with OCD and 76 controls using the Multidimensional Scale of Interoceptive Awareness (MAIA), which contains 8 subscales assessing adaptive and maladaptive responses to sensation. Compared to controls, OCD patients showed hyperawareness of body sensations. Patients also demonstrated a more maladaptive profile of IS characterized by greater distraction from and worry about unpleasant sensations, and reduced tendency to experience the body as safe and trustworthy. These findings were independent of medication status and comorbidities in the patient group. Correlational analyses showed that subscales of the MAIA were differentially associated with OCD symptom dimensions. These findings indicate that patients with OCD show abnormality of IS that is independent of confounding factors related to medication and comorbidities and associated with different OCD symptom dimensions. Future work would benefit from examining neural correlates of these effects and evaluating whether dimensions of IS are impacted by treatments for the disorder.
PMID: 33194538
ISSN: 2211-3649
CID: 4671322

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

Sensory over-responsivity and orbitofrontal cortex connectivity in obsessive-compulsive disorder

Collins, Katherine A; Recchia, Nicolette; Eng, Goi Khia; Harvey, Jeanmarie; Tobe, Russell H; Stern, Emily R
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

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

The Human Affectome

Schiller, Daniela; Yu, Alessandra N C; Alia-Klein, Nelly; Becker, Susanne; Cromwell, Howard C; Dolcos, Florin; Eslinger, Paul J; Frewen, Paul; Kemp, Andrew H; Pace-Schott, Edward F; Raber, Jacob; Silton, Rebecca L; Stefanova, Elka; Williams, Justin H G; Abe, Nobuhito; Aghajani, Moji; Albrecht, Franziska; Alexander, Rebecca; Anders, Silke; Aragón, Oriana R; Arias, Juan A; Arzy, Shahar; Aue, Tatjana; Baez, Sandra; Balconi, Michela; Ballarini, Tommaso; Bannister, Scott; Banta, Marlissa C; Barrett, Karen Caplovitz; Belzung, Catherine; Bensafi, Moustafa; Booij, Linda; Bookwala, Jamila; Boulanger-Bertolus, Julie; Boutros, Sydney Weber; Bräscher, Anne-Kathrin; Bruno, Antonio; Busatto, Geraldo; Bylsma, Lauren M; Caldwell-Harris, Catherine; Chan, Raymond C K; Cherbuin, Nicolas; Chiarella, Julian; Cipresso, Pietro; Critchley, Hugo; Croote, Denise E; Demaree, Heath A; Denson, Thomas F; Depue, Brendan; Derntl, Birgit; Dickson, Joanne M; Dolcos, Sanda; Drach-Zahavy, Anat; Dubljević, Olga; Eerola, Tuomas; Ellingsen, Dan-Mikael; Fairfield, Beth; Ferdenzi, Camille; Friedman, Bruce H; Fu, Cynthia H Y; Gatt, Justine M; deGelder, Beatrice; Gendolla, Guido H E; Gilam, Gadi; Goldblatt, Hadass; Gooding, Anne Elizabeth Kotynski; Gosseries, Olivia; Hamm, Alfons O; Hanson, Jamie L; Hendler, Talma; Herbert, Cornelia; Hofmann, Stefan G; Ibanez, Agustin; Joffily, Mateus; Jovanovic, Tanja; Kahrilas, Ian J; Kangas, Maria; Katsumi, Yuta; Kensinger, Elizabeth; Kirby, Lauren A J; Koncz, Rebecca; Koster, Ernst H W; Kozlowska, Kasia; Krach, Sören; Kret, Mariska E; Krippl, Martin; Kusi-Mensah, Kwabena; Ladouceur, Cecile D; Laureys, Steven; Lawrence, Alistair; Li, Chiang-Shan R; Liddell, Belinda J; Lidhar, Navdeep K; Lowry, Christopher A; Magee, Kelsey; Marin, Marie-France; Mariotti, Veronica; Martin, Loren J; Marusak, Hilary A; Mayer, Annalina V; Merner, Amanda R; Minnier, Jessica; Moll, Jorge; Morrison, Robert G; Moore, Matthew; Mouly, Anne-Marie; Mueller, Sven C; Mühlberger, Andreas; Murphy, Nora A; Muscatello, Maria Rosaria Anna; Musser, Erica D; Newton, Tamara L; Noll-Hussong, Michael; Norrholm, Seth Davin; Northoff, Georg; Nusslock, Robin; Okon-Singer, Hadas; Olino, Thomas M; Ortner, Catherine; Owolabi, Mayowa; Padulo, Caterina; Palermo, Romina; Palumbo, Rocco; Palumbo, Sara; Papadelis, Christos; Pegna, Alan J; Pellegrini, Silvia; Peltonen, Kirsi; Penninx, Brenda W J H; Pietrini, Pietro; Pinna, Graziano; Lobo, Rosario Pintos; Polnaszek, Kelly L; Polyakova, Maryna; Rabinak, Christine; HeleneRichter, S; Richter, Thalia; Riva, Giuseppe; Rizzo, Amelia; Robinson, Jennifer L; Rosa, Pedro; Sachdev, Perminder S; Sato, Wataru; Schroeter, Matthias L; Schweizer, Susanne; Shiban, Youssef; Siddharthan, Advaith; Siedlecka, Ewa; Smith, Robert C; Soreq, Hermona; Spangler, Derek P; Stern, Emily R; Styliadis, Charis; Sullivan, Gavin B; Swain, James E; Urben, Sébastien; Van den Stock, Jan; Vander Kooij, Michael A; van Overveld, Mark; Van Rheenen, Tamsyn E; VanElzakker, Michael B; Ventura-Bort, Carlos; Verona, Edelyn; Volk, Tyler; Wang, Yi; Weingast, Leah T; Weymar, Mathias; Williams, Claire; Willis, Megan L; Yamashita, Paula; Zahn, Roland; Zupan, Barbra; Lowe, Leroy; Gabriela, Gan; Charlotte F, Huggins; Leonie, Loeffler
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

Bruin, Willem B; Abe, Yoshinari; Alonso, Pino; Anticevic, Alan; Backhausen, Lea L; Balachander, Srinivas; Bargallo, Nuria; Batistuzzo, Marcelo C; Benedetti, Francesco; Bertolin Triquell, Sara; Brem, Silvia; Calesella, Federico; Couto, Beatriz; Denys, Damiaan A J P; Echevarria, Marco A N; Eng, Goi Khia; Ferreira, Sónia; Feusner, Jamie D; Grazioplene, Rachael G; Gruner, Patricia; Guo, Joyce Y; Hagen, Kristen; Hansen, Bjarne; Hirano, Yoshiyuki; Hoexter, Marcelo Q; Jahanshad, Neda; Jaspers-Fayer, Fern; Kasprzak, Selina; Kim, Minah; Koch, Kathrin; Bin Kwak, Yoo; Kwon, Jun Soo; Lazaro, Luisa; Li, Chiang-Shan R; Lochner, Christine; Marsh, Rachel; Martínez-Zalacaín, Ignacio; Menchon, Jose M; Moreira, Pedro S; Morgado, Pedro; Nakagawa, Akiko; Nakao, Tomohiro; Narayanaswamy, Janardhanan C; Nurmi, Erika L; Zorrilla, Jose C Pariente; Piacentini, John; Picó-Pérez, Maria; Piras, Fabrizio; Piras, Federica; Pittenger, Christopher; Reddy, Janardhan Y C; Rodriguez-Manrique, Daniela; Sakai, Yuki; Shimizu, Eiji; Shivakumar, Venkataram; Simpson, Blair H; Soriano-Mas, Carles; Sousa, Nuno; Spalletta, Gianfranco; Stern, Emily R; Evelyn Stewart, S; Szeszko, Philip R; Tang, Jinsong; Thomopoulos, Sophia I; Thorsen, Anders L; Yoshida, Tokiko; Tomiyama, Hirofumi; Vai, Benedetta; Veer, Ilya M; Venkatasubramanian, Ganesan; Vetter, Nora C; Vriend, Chris; Walitza, Susanne; Waller, Lea; Wang, Zhen; Watanabe, Anri; Wolff, Nicole; Yun, Je-Yeon; Zhao, Qing; van Leeuwen, Wieke A; van Marle, Hein J F; van de Mortel, Laurens A; van der Straten, Anouk; van der Werf, Ysbrand D; ,; Thompson, Paul M; Stein, Dan J; van den Heuvel, Odile A; van Wingen, Guido A
PMID: 37582859
ISSN: 1476-5578
CID: 5619162