DESCRIPTION (provided by applicant): The onset of bipolar disorder typically occurs during adolescence, the age when maturation of orbitofrontal cortical (OFC) connectivity with limbic structures including the amygdala (AMY) typically becomes established. Adolescents and young adults with and at risk for developing bipolar disorder exhibit abnormalities in OFC and AMY function, chemistry, and connectivity. Adolescents with a familial risk for developing bipolar disorder commonly initially present with deficits in attention, and are thus often initially prescribed a psychostimulant medication (i.e., amphetamine, AMPH). Although the effects of psychostimulant exposure on pathological brain changes associated with bipolar disorder are not known, a growing body of evidence suggests that long-term psychostimulant exposure may precipitate mood symptoms, and accelerate the onset of bipolar illness. Moreover, rodent studies have found that repeated stimulant exposure leads to a progressive and enduring increase in behavioral activation (i.e., sensitization) which is associated with dendritic atrophy n the OFC and alterations in amygdala activity, suggesting that stimulants may contribute to reductions in OFC- AMY structural and functional connectivity observed in bipolar adolescents. Translational evidence also suggests that increasing dietary omega-3 fatty acids during brain development promotes cortical maturation and increases neuronal resilience to excitoxicity as well as AMPH-induced behavioral sensitization in rodents. Clinical studies have found that bipolar disorder is associated with omega-3 fatty acid deficits and neuronal atrophy in postmortem OFC, and red blood cell membrane omega-3 fatty acid deficits which precede and/or coincide with the initial onset of mania. With these considerations in mind, the primary hypothesis guiding this proposal is that youth with a familial risk for developing bipolar disorder and who are expressing symptoms of ADHD have an increased vulnerability for impaired OFC-AMY connectivity when exposed to psychostimulants, which initially manifests as behavioral activation, and ultimately, mania. Moreover, we predict that lower omega-3 fatty acid biostatus will be associated with greater decreases in OFC-AMY structural and functional connectivity in psychostimulant-treated high-risk adolescents. To test these hypotheses, we propose to conduct the first controlled prospective surveillance trial to examine the effects of candidate ris factors (i.e., having a first-degree relative with bipolar disorder, DSM-5 ADHD, chronic psychostimulant exposure) and moderating protective factors (i.e., omega-3 fatty acid biostatus) on OFC-AMY functional and structural connectivity using multimodal neuroimaging techniques (fMRI, DTI,1H MRS). To achieve this objective, we will recruit a total of 240 medication-free adolescent (ages 13-17 years old) ADHD patients (n=120 `high-risk' and n=60 `low-risk') and 60 healthy comparison subjects. High-risk ADHD patients will be randomized to placebo (n=60) or psychostimulant medication (MAS-XR)(n=60) for 12 weeks, and low-risk ADHD patients will receive open-label MAS-XR for 12 weeks. All subjects will receive neuroimaging scans at baseline and Week 12.

PUBLIC HEALTH RELEVANCE: Adolescents with bipolar disorder frequently exhibit omega-3 fatty acid deficits and initially present with symptoms of inattention, agitation and hyperactivity which are commonly treated with psychostimulants. However, psychostimulant exposure in conjunction with low omega-3 fatty acid biostatus may accelerate the onset of mood symptoms in adolescents with a familial risk for developing bipolar disorder. This proposal will use multimodal neuroimaging techniques to prospectively investigate the effects of psychostimulant exposure on pathological brain changes in adolescents with ADHD and a familial risk for developing bipolar disorder and determine whether omega-3 fatty acid biostatus moderates these effects.