Den Ouden, LaurenSuo, ChaoAlbertella, LucyGreenwood, Lisa-MarieLee, Rico S.C.Fontenelle, LeonardoParkes, LindenTiego, JegganChamberlain, Samuel RRichardson, Karyn E.Segrave, RebeccaYucel, Murat2024-03-282024-03-282158-3188http://hdl.handle.net/1885/316388Compulsivity is a poorly understood transdiagnostic construct thought to underlie multiple disorders, including obsessive-compulsive disorder, addictions, and binge eating. Our current understanding of the causes of compulsive behavior remains primarily based on investigations into specific diagnostic categories or findings relying on one or two laboratory measures to explain complex phenotypic variance. This proof-of-concept study drew on a heterogeneous sample of community-based individuals (N = 45; 18–45 years; 25 female) exhibiting compulsive behavioral patterns in alcohol use, eating, cleaning, checking, or symmetry. Data-driven statistical modeling of multidimensional markers was utilized to identify homogeneous subtypes that were independent of traditional clinical phenomenology. Markers were based on well-defined measures of affective processing and included psychological assessment of compulsivity, behavioral avoidance, and stress, neurocognitive assessment of reward vs. punishment learning, and biological assessment of the cortisol awakening response. The neurobiological validity of the subtypes was assessed using functional magnetic resonance imaging. Statistical modeling identified three stable, distinct subtypes of compulsivity and affective processing, which we labeled “Compulsive Non-Avoidant”, “Compulsive Reactive” and “Compulsive Stressed”. They differed meaningfully on validation measures of mood, intolerance of uncertainty, and urgency. Most importantly, subtypes captured neurobiological variance on amygdala-based resting-state functional connectivity, suggesting they were valid representations of underlying neurobiology and highlighting the relevance of emotion-related brain networks in compulsive behavior. Although independent larger samples are needed to confirm the stability of subtypes, these data offer an integrated understanding of how different systems may interact in compulsive behavior and provide new considerations for guiding tailored intervention decisions.RSCL is funded by a National Health and Medical Research Council project grant (#APP1162031). JT was supported by National Health and Medical Research Council (NHMRC) project grants 1050504 and 1146292. SC receives honoraria from Elsevier for journal editorial responsibilities. LFF was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; grant # 302526/2018-8, Rio de Janeiro, RJ, Brazil), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ; grant # CNE E-26/203.052/2017, Rio de Janeiro, RJ, Brazil), the David Winston Turner Endowment Fund (Melbourne, VIC, Australia), and intramural grants from D’Or Institute for Research and Education (IDOR, Rio de Janeiro, RJ, Brazil). LP was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number K99MH127296 anda 2020 NARSAD YoungInvestigator Grant from the Brain & Behavior Research Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. KR is supported by the Wilson Foundation and David Winston Turner Endowment Fund. RS is funded by the David Winston Turner Endowment Fund and has received funding from Monash University, NHMRC, the Wilson Foundation, and not-for-profit bodies such as Beyond Blue, nib Foundation, and the Sir Edward Dunlop Medical Research Foundation. MY has received funding from Monash University, and Australian Government funding bodies such as the National Health and Medical Research Council (NHMRC; including Fellowship #APP1117188), the Australian Research Council (ARC), Australian Defense Science and Technology (DST), and the Department of Industry, Innovation and Science (DIIS). He has also received philanthropic donations from the David Winston Turner Endowment Fund, Wilson Foundation, as well as payment from law firms in relation to court, expert witness, and/ or expert review reports.application/pdfen-AU© The Author(s) 2021http://creativecommons.org/licenses/by/4.0/202210.1038/s41398-021-01773-12022-11-13Creative Commons Attribution 4.0 International License