Abstract
Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.
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Acknowledgements
This work was supported by the National Institute of Mental Health Grants 2R01 MH73953 (Dr Boris Birmaher and Dr Mary L Phillips, University of Pittsburgh), 2R01 MH73816 (Dr Scott Holland, Children’s Hospital Medical Center), 2R01 MH73967 (Dr Robert Findling, Case Western Reserve University), 2R01 MH73801(Dr Mary Fristad, Ohio State University), and the Pittsburgh Foundation (Mary L Phillips). The funding agency was not involved in the design and conduct of the study, the collection, management, analysis or interpretation of the data, or the preparation, review or approval of the manuscript. We would like to acknowledge Richard White, Gary Ciuffetelli, Eric Rodriguez and Christine Demeter for their contributions to the study.
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Bertocci, Bebko, Olino, Fournier, Iyengar, Horwitz, Axelson, Holland, Schirda, Versace, Almeida, Perlman, Diwadkar, Travis, Bonar, Gill and Forbes have no financial interests or potential conflict of interest. Dr Findling receives or has received research support, acted as a consultant and/or served on a speaker's bureau for Alcobra, American Academy of Child & Adolescent Psychiatry, American Physician Institute, American Psychiatric Press, AstraZeneca, Bracket, Bristol-Myers Squibb, CogCubed, Cognition Group, Coronado Biosciences, Dana Foundation, Elsevier, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson and Johnson, Jubilant Clinsys, KemPharm, Lilly, Lundbeck, Merck, NIH, Neurim, Novartis, Noven, Otsuka, Oxford University Press, Pfizer, Physicians Postgraduate Press, Purdue, Rhodes Pharmaceuticals, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Transcept Pharmaceuticals, Tris, Validus, and WebMD. Dr Frazier has received federal funding or research support from, acted as a consultant to, received travel support from and/or received a speaker’s honorarium from the Cole family research fund, the Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Kugona LLC, Shire Development, Bristol-Myers Squibb, National Institutes of Health and the Brain and Behavior Research Foundation. Dr Arnold has received research funding from Curemark, Forest, Lilly, Neuropharm, Novartis, Noven, Shire, Supernus, and YoungLiving (as well as NIH and Autism Speaks) and has consulted with or been on advisory boards for Arbor, Gowlings, Ironshore, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Roche, Seaside Therapeutics, Sigma Tau, Shire, Tris Pharma, and Waypoint and received travel support from Noven. Dr Youngstrom has consulted with Pearson, Lundbeck and Otsuka about assessment, as well as having grant support from the NIH. Dr Fristad receives royalties from Guilford Press, APPI, CFPSI and is a consultant to Physicians Postgraduate Press and Western Psychological Services. Dr Birmaher receives royalties from for publications from Random House (New hope for children and teens with bipolar disorder) and Lippincott Williams & Wilkins (Treating Child and Adolescent Depression). He is employed by the University of Pittsburgh and the University of Pittsburgh Medical Center and receives research funding from NIMH. Dr Kowatch is a consultant for Forest Pharmaceutical and the REACH Foundation. He is employed by the Ohio State Wexner Medical Center. Dr Sunshine receives research support from Siemens Healthcare, Dr Phillips is a consultant for Roche.
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Bertocci, M., Bebko, G., Versace, A. et al. Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth. Mol Psychiatry 21, 1194–1201 (2016). https://doi.org/10.1038/mp.2016.5
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DOI: https://doi.org/10.1038/mp.2016.5
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