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Mol Psychiatry. 2016 Sep;21(9):1194-201. doi: 10.1038/mp.2016.5. Epub 2016 Feb 23.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

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University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Statistics, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Psychology, Temple University, Philadelphia, PA, USA.
Alpert Medical School, Brown University, Providence, RI, USA.
Department of Psychiatry and Behavioral Neuroscience, Wayne State University, Detroit, MI, USA.
University Hospitals Case Medical Center/Case Western Reserve University, Cleveland, OH, USA.
Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
The Research Institute at Nationwide Children's Hospital, The Ohio State University, College of Medicine, Columbus, OH, USA.
Department of Child Psychiatry, New York University School of Medicine, New York, NY, USA.
Pediatric Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, USA.
Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.


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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