Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Blumberg, Hilary

Abstract

Bipolar depression is associated with profound suffering and disability, and increased risk for suicide thoughts and behaviors. Key in understanding its complexities is its characterization in relation to other mood states of bipolar disorder (BD) as well as the depression of major depressive disorder (MDD). Adolescents and young adults often present to clinicians with symptoms of depression; however, there are no symptoms known currently to reliably distinguish whether the symptoms are resulting from BD or MDD. This can lead to misdiagnosis, improper treatments, and disease worsening. Study of functional brain system connectivity provide insights into identifying markers of depression in BD to distinguish it from other mood states of BD, as well as the depression of MDD. Despite the importance of elucidating the pathophysiology of depression of BD and generating more effective detection and treatment strategies, there is minimal literature on the use of functional neuroimaging to study depression in BD, and particularly when studied in comparison to other mood states of BD, or in direct comparison to depression in MDD. An especially important gap in the literature, is that it is scarce on studies conducted in adolescents and young adults. Their study is critically important as investigations close to disorder onset can provide information key to early intervention and prevention strategies that can improve prognosis. Prior functional neuroimaging research publications on bipolar depression focused on region of interest activation and functional connectivity, and showed converging support for the involvement of frontal systems that subserve emotion regulation. However, in this nascent field, it is important not to have premature closure on brain regions that may be of importance. Additionally, the identification of “hubs” of abnormalities, that may be important contributors to brain dysfunction, could be critical for the generation of more targeted detection and intervention approaches. Thus, for the work of this thesis, a graph theory-based methodology, Intrinsic Connectivity Distribution (ICD), was used to investigate “hubs” of dysconnectivity in adolescents and young adults in both within- and across-disorder designs. In my introduction, I summarized the clinical correlates of BD and MDD, as well as particular clinical and behavioral characterizations during the adolescent and young adult period. In my second chapter, I contextualized the current state of the field of the functional neuroanatomy of bipolar depression relating to state- and trait-related features of BD in adolescents and young adults in a critical review. My third chapter utilized ICD to directly compare whole-brain functional connectivity disturbances across adolescents and young adults with BD in current depressed, elevated, or euthymic states to a healthy control group which addressed a gap in the literature I identified in my second chapter, of scarce functional connectivity studies across mood states of BD in adolescents and young adults. Based on my results identifying key dysconnectivity in bipolar depression, in my fourth chapter, I compared bipolar depressed and healthy control groups to adolescents and young adults with MDD, currently in a depressed state, to investigate distinguishing or similar factors of depressions. In my fifth chapter, I look towards future directions of this work including the necessity for multimodal study to better understand the structural underpinnings of the observed functional dysconnectivity and brain-based interventions which may be able to utilize these findings to inform clinical strategies. These investigations shed new light on the early emerging functional neuroanatomical features of bipolar depression. Compared to adolescents and young adults in other mood states of BD and healthy controls, bipolar depressed participants exhibited bilateral, and interhemispheric frontotemporal dysconnectivity, identifying the prefrontal cortex (PFC) and lenticular nucleus (LN) as “hubs” of whole-brain disturbances, some of which are areas less well-studied in BD research. When compared to the depression of MDD, left-sided frontal, insular, and medial temporal dysconnectivity appeared to be transdiagnostic features of depression; bipolar depression was distinguished by its additional, and more extreme, disturbances in right-sided PFC and basal ganglia whole-brain dysconnectivity. Thus, interhemispheric and bilateral disturbances in functional neuroanatomy may be a key distinguishing feature of bipolar depression in adolescents and young adults. These findings taken together underscore the relevance of bipolar depression during the adolescent and young adult epoch and provide ample support for future study of these functional neuroanatomical underpinnings as potential targets for early detection, intervention, and prevention.

Download

Share

COinS