Neural markers of risk and resilience in youth mood disorders

Bipolar disorder and major depressive disorder result in significant psychosocial and economic burdens for individuals and society. Thus, it is imperative to understand the etiology of these mood disorders to better detect, treat, and prevent them from persisting through a lifetime. Further, early onset of bipolar disorder and major depressive disorder may involve impairments related to reward and emotion processing and may initially present similarly with respect to clinical symptoms leading to misdiagnosis and mismatched treatment. Elucidating reliable and early biological markers that can distinguish these disorders could mitigate diagnostic confusion and prevent treatment-emergent complications and poor outcomes. A promising avenue to understand the etiologies of these disorders may emerge from understanding the neural underpinnings of reward and emotion, especially as it relates to risk for and resilience from developing lifelong mood disorders. In this dissertation, I examine specific brain markers that characterize risk for or resilience from the development of these major mood disorders. Healthy youth with at least one parent diagnosed with bipolar disorder or major depressive disorders were followed for approximately 4.5 years and any psychiatric symptoms and diagnoses were noted. Using fMRI, I examined whether neural correlates of emotion (Chapter 2) and reward processing (Chapter 3) at baseline could distinguish youth at familial risk for bipolar disorder from youth at familial risk for major depressive disorder and youth without any personal or family psychopathology. I also investigated whether brain function at baseline could predict subsequent resilience versus mood and other psychiatric symptom development at follow-up (Chapter 4). During positive emotion processing, youth at familial risk for bipolar disorder showed reduced putamen activation, and decreased connectivity between the putamen and cingulate cortex compared to youth at familial risk for major depressive disorder and healthy controls. Decreased connectivity between the putamen and posterior cingulate cortex was associated with subsequent peer problems and higher risk of conversion. During reward processing, youth at familial risk for bipolar disorder had decreased thalamus activation and decreased connectivity of the thalamus to executive control regions compared to youth at familial risk for major depressive disorder and healthy controls. Decreased thalamic connectivity was associated with increased impulsivity at baseline and reduced prosocial behavior at follow-up. Lastly, youth who did not convert to psychopathology exhibited functional activation and connectivity of visual, frontal, and limbic regions that could reflect neural networks that support adaptive emotion processing strategies. Overall, these findings suggest that potential neural markers of risk to mood disorders include aberrant activation and connectivity of limbic, subcortical, and frontal regions and that a subset of these youth at familial risk for mood disorders may have compensatory increases in connectivity that could be neuroprotective and represent resilience biomarkers within emotion processing networks. Identifying biomarkers of risk and resilience in bipolar disorder and major depressive disorder holds promise for the development of novel early interventions that mitigate the negative consequences of early neural vulnerabilities that may be associated with the onset and progression of mood symptoms. These biomarkers may also point to key targets for prevention, leveraging the intrinsic capacities of these youth to show compensatory increases in network connectivity in the context of their gene-by-environment exposure to parental psychopathology

Advisor: Williams Leanne M.
Carrión Victor G.
Obradović Jelena (Education professor)
Raymond Jennifer L.