Although bipolar I disorder is a dynamic condition expressing a wide range of affective, cognitive and
neurovegetative symptoms, it is defined by the occurrence of mania. Mania typically first emerges in
adolescence and young adulthood, and it is a strongly predictive phenotype. Moreover, the early course of
bipolar I disorder is progressive, as euthymic periods shorten over time. Additionally, bipolar I disorder is
strongly familial with heritability rates approaching 85%. A family history of bipolar I disorder increases risk
for mania as well as a number of other psychiatric conditions, including suicidal behaviors and reward
hypersensitivity. Together, these characteristics suggest that bipolar I disorder results from an inherited
failure during adolescence to develop healthy neural systems that modulate mood and behavioral activation.
Complicating the inherited risk is that people with a family history of bipolar disorder also report higher rates
of early life adversity than the general population. Early life adversity is associated with lifelong elevated
rates of depression, anxiety and substance use disorders, impaired risk-reward processing, and suicide.
Consequently, during development individuals with a familial risk for bipolar I disorder may be exposed to a
dual risk, i.e. an inherited vulnerability and environmental early-life stress. How these risks interact to impact
brain development and subsequent outcomes in these individuals is not known.
Mood and risk-reward behaviors are managed by intersecting ventral prefrontal networks. These
networks undergo substantial development in the transition from adolescence to young adulthood (when
bipolar I disorder emerges) in which maturation of prefrontal networks leads to adaptive adult emotional
regulation and risk-reward processing. Abnormalities in these networks are commonly described in both
bipolar disorder and in response to early life adversity, with many shared characteristics. With these
considerations in mind, we hypothesize that heritability for bipolar I disorder interacts with early life adversity
to synergistically disrupt healthy ventral prefrontal network development during adolescence, underlying a
cumulative increased risk for developing mania and other conditions more common in bipolar families. To
test this hypothesis, over a four-year interval we will assess trajectories in ventral prefrontal network
connectivity in youth at-familial-risk for bipolar I disorder compared to those without this risk, and the
interaction with or without early life trauma, to determine whether these risks cumulatively lead to increasing
emergence of: 1) mood symptoms and syndromes, 2) substance misuse, 3) suicidal behaviors, and 4)
approach motivation hypersensitivity. These results can inform future approaches to prevent illness onset
and progression in individuals at risk for or early in the course of bipolar disorder.