title: Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.
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.
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Bertocci
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bebko
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Versace
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Fournier
authors.affiliation: Department of Statistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Iyengar
authors.affiliation: Department of Psychology, Temple University, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Olino
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bonar
authors.affiliation: Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: J R C
authors.initials: JR
authors.lastname: Almeida
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Perlman
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Schirda
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Travis
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Gill
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, Wayne State University, Detroit, MI, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Diwadkar
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Forbes
authors.affiliation: University Hospitals Case Medical Center/Case Western Reserve University, Cleveland, OH, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Sunshine
authors.affiliation: Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Holland
authors.affiliation: The Research Institute at Nationwide Children's Hospital, The Ohio State University, College of Medicine, Columbus, OH, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Kowatch
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Birmaher
authors.affiliation: The Research Institute at Nationwide Children's Hospital, The Ohio State University, College of Medicine, Columbus, OH, USA.
authors.forename: D
authors.initials: D
authors.lastname: Axelson
authors.affiliation: Department of Child Psychiatry, New York University School of Medicine, New York, NY, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Horwitz
authors.affiliation: Pediatric Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Frazier
authors.affiliation: Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Arnold
authors.affiliation: Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Fristad
authors.affiliation: Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Youngstrom
authors.affiliation: University Hospitals Case Medical Center/Case Western Reserve University, Cleveland, OH, USA.|Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Findling
authors.affiliation: University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Phillips
mesh_terms: D000293:Adolescent; D000342:Affective Symptoms / Q000235:genetics / Q000503:physiopathology*; D001714:Bipolar Disorder / Q000175:diagnosis; D001921:Brain / Q000503:physiopathology; D002648:Child; D004644:Emotions / Q000502:physiology; D005260:Female; D005544:Forecasting / Q000379:methods; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010290:Parents / Q000523:psychology; D011569:Psychiatric Status Rating Scales; D012201:Reward; D016896:Treatment Outcome; D066127:White Matter / Q000503:physiopathology*