Distinguishing Remitted Bipolar Disorder from Remitted Unipolar Depression in Pre-adolescent Children: A Neural Reward Processing Perspective

Abstract

Bipolar disorder (BD) and unipolar depression (UD) are two severe mood disorders, with BD often misdiagnosed as UD. Given their severity and high rates of misdiagnosis, it is of paramount importance to understand the psychological and neurobiological mechanisms underlying these disorders to enhance our ability to diagnose, treat, and prevent them effectively. Many neuroimaging studies have shown that mood disorders are associated with abnormal reward-related responses, particularly in the ventral striatum (VS). Yet, the link between mood disorders and reward-related responses in other regions remains inconclusive, thus limiting our understanding of the pathophysiology of mood disorders. To provide insights into the neurobiological underpinnings of reward processing dysfunction in mood disorders, two studies were conducted. Study 1 (Chapter 2) is a coordinate-based meta-analysis of 41 whole-brain neuroimaging studies encompassing reward-related responses from a total of 794 patients with major depressive disorder (MDD), and 803 healthy controls (HC). It aims to address inconsistencies in the literature by synthesizing the literature quantitatively. The findings of Study 1 indicate that MDD is associated with opposing abnormalities in the reward circuit: hypo-responses in the VS and hyper-responses in the orbitofrontal cortex (OFC). These findings provide a foundation for Study 2 (Chapter 3) and help to reconceptualize our understanding of reward processing abnormalities in UD by suggesting a role for dysregulated corticostriatal connectivity. Study 2 is the first fMRI study to employ region-of-interest (VS and OFC), whole-brain, activation, connectivity, and network analyses to examine the similarities and differences in reward-related brain activation patterns between 46 children with remitted bipolar I disorder, 48 children with remitted MDD, and 46 HC. The results of Study 2 revealed differential connectivity in corticostriatal circuitry during reward processing among BD, UD, and HC in pre-adolescence. Specifically, BD exhibited increases in OFC-VS connectivity during anticipation of larger reward, whereas UD and HC showed no changes in OFC-VS connectivity across anticipation conditions ranging from large loss to large reward. Furthermore, BD and UD generally showed more abnormal whole-brain responses to reward anticipation in accordance with the valence of the stimuli than HC. These findings suggest that pre-adolescents with BD and UD exhibit reward processing dysfunction during reward anticipation relative to HC even outside of acute periods of illness. Taken together, the dissertation provides novel insight into the nature of reward processing abnormalities in mood disorders in pre-adolescence. As early onset BD or UD often is associated with long treatment delays and a persistently pernicious illness course, this dissertation may aid efforts to ensure early accurate diagnosis, which may improve our ability to intervene with appropriate treatments and result in a more benign prognosis and course of illness over the lifespan.