Integrated Reward-Circadian Rhythm Model of First Onset of Bipolar Spectrum Disorders in Adolescence

7. Project Summary/Abstract
Adolescence is an “age of risk” for the emergence of first onset of bipolar spectrum disorders (BSD). Despite
their prevalence and public health significance, major unanswered questions exist regarding the mechanisms
involved in vulnerability to BSDs. BSDs are associated with hypersensitivity to reward and elevated reward-
related brain function. However, research has not yet tested whether chronically high reward responsivity (RR)
or increases in RR development during adolescence, beyond baseline RR, predicts first onset of BSD. A
separate literature documents circadian rhythm disruption in BSDs, and social rhythm disruption (SRD) can
trigger BSD episodes. Yet, research has not tested whether baseline circadian dysregulation, chronic social
and circadian rhythm disruptions, or increases in these rhythm disruptions during adolescence predict onset of
BSD. Further, circadian and reward approaches to BSDs mostly have proceeded in parallel. However, we and
others have proposed integrated reward-circadian models of BSDs based on evidence the two systems
influence each other and interact to affect mood functioning. When dysregulated, reward and circadian system
signaling may combine to form a positive feedback loop, whereby dysregulation in one system exacerbates
dysregulation in the other. This proposal is the first systematic test of a novel, integrated reward-circadian
model for first onset of BSD. We will use an innovative biobehavioral high-risk design to examine bidirectional
relationships between multiple indices and domains (monetary, social) of RR and multiple indices of social and
circadian rhythms and their joint prediction of first onset of BSD and increases in bipolar symptoms. Three
hundred twenty 14-16 year old participants (Ps) will complete a prospective 3-year longitudinal study. Ps with
no prior BSD will be selected along the entire dimension of self-reported RR, with oversampling at the high tail
of the dimension in order to increase the likelihood of BSD onsets. At Times 1-6, every 6 months, Ps will
complete assessments of reward-relevant and SRD life events and self-report and diagnostic assessments of
bipolar symptoms and episodes. Yearly, at Times 1, 3, and 5, Ps also will complete self-report measures of
circadian chronotype (morningness-eveningness) and social rhythm regularity, a salivary dim light melatonin
onset (DLMO) procedure to assess circadian phase, self-report, behavioral, and neural (fMRI) assessments of
monetary and social RR, and a 7-day EMA period. During each EMA period, Ps will complete continuous
measures of sleep/wake and activity (actigraphy) and 3 within-day (morning, afternoon, evening) measures of
life events coded for reward-relevance and SRD, monetary and social reward responsivity, positive and
negative affect, and hypo/manic and depressive symptoms. The fMRI scan and DLMO procedure will occur on
the day before the start of each EMA period, excluding weekends. This proposal is an innovative integration of
research on reward and circadian signaling in understanding first onset of BSD in adolescence. It has the
potential to facilitate reward and social/circadian rhythm interventions to treat, and ideally prevent, BSD.

Grant Number: 5R01MH126911-05
NIH Institute/Center: NIH
Principal Investigator: LAUREN ALLOY