From markers to mechanisms: A multimodal investigation of structural markers of vulnerability and disease progression in affective disorders

Affective disorders, such as bipolar disorder and major depressive disorder, are complex and severe mental illnesses characterized by mood episodes. These disorders present significant challenges to diagnosis and treatment due to their complex nature and the interplay of genetic, environmental, and biological factors. Recent advances in magnetic resonance imaging have identified structural brain changes associated with these disorders, holding promise for early detection and targeted intervention. This dissertation examined structural magnetic resonance imaging brain markers of vulnerability and disease progression in bipolar disorder and major depressive disorder. Study I conducted cross-sectional analyses to investigate common gray matter volume changes in a group of individuals at risk for and another group diagnosed with bipolar disorder, compared to a group of healthy controls. Results showed larger putamen volumes in both individuals at risk and with manifest disease, suggesting that putamen enlargement might be a vulnerability marker for bipolar disorder. This neuroanatomical vulnerability may precede the onset of the disorder and persist throughout its course. Study II employed longitudinal analyses to assess gray matter volume changes in a group of patients with bipolar disorder, who experienced depressive or manic episodes over a two-year follow-up interval, in comparison to a group of patients without episodes and a group of healthy controls. Results showed volume increases in the right exterior cerebellum in patients with multiple depressive episodes during the two-year interval, which correlated with elevated baseline levels of C-reactive protein, a marker of systemic inflammation. Conversely, patients without an episode during the two-year interval, particularly those with a longer history of manic episodes before the baseline assessment, exhibited volume decreases in the same area, compared to healthy controls. These findings suggest that volume increases during depressive episodes might reflect neuroinflammatory processes, followed by volume decreases during periods of remission, potentially as a result of synaptic pruning induced by previous episodes. These findings highlight the potential role of the cerebellum in the disease progression in bipolar disorder associated with recurrent mood episodes. Study III examined longitudinal gray matter volume changes in a group of patients with major depressive disorder in response to stressful life events over a two-year interval, particularly those with recurrent depressive episodes and a history of childhood maltreatment, compared to a group of healthy controls. Results showed volume increases in the middle frontal, precentral, and postcentral gyri in these patients, which correlated with elevated baseline C-reactive protein levels, potentially suggesting maladaptive neuroinflammatory responses to stress. In contrast, healthy controls showed volume decreases in these areas, potentially representing adaptive neural compensations. These findings underscore the potential role of the middle frontal, precentral, and postcentral gyri in vulnerability and disease progression in major depressive disorder associated with recurrent depressive episodes, particularly concerning predisposing factors such as childhood maltreatment. These findings highlight the importance of a multimodal, longitudinal approach to assessing neuroanatomical correlates of disease trajectories in affective disorders. By moving beyond traditional case-control cross-sectional designs, this work provides a nuanced understanding of how episodes, environmental factors, and inflammatory processes collectively impact brain structure across disease trajectories. Future research should continue to refine these dynamics through detailed subgroup analyses and multiple assessment points to ultimately improve diagnostic, preventive, and therapeutic strategies.