Integrated Neurobiology of Bipolar Disorder

Abstract

From a neurobiological perspective there is no such thing as bipolar disorder. Rather, it is almost certainly the case that many somewhat similar, but subtly different, pathological conditions produce a disease state that we currently diagnose as bipolarity. This heterogeneity – reflected in the lack of synergy between our current diagnostic schema and our rapidly advancing scientific understanding of the condition – limits attempts to articulate an integrated perspective on bipolar disorder. However, despite these challenges, scientific findings in recent years are beginning to offer a provisional “unified field theory” of the disease. This theory sees bipolar disorder as a suite of related neurodevelopmental conditions with interconnected functional abnormalities that often appear early in life and worsen over time. In addition to accelerated loss of volume in brain areas known to be essential for mood regulation and cognitive function, consistent findings have emerged at a cellular level, providing evidence that bipolar disorder is reliably associated with dysregulation of glial–neuronal interactions. Among these glial elements are microglia – the brain’s primary immune elements, which appear to be overactive in the context of bipolarity. Multiple studies now indicate that inflammation is also increased in the periphery of the body in both the depressive and manic phases of the illness, with at least some return to normality in the euthymic state. These findings are consistent with changes in the hypothalamic–pituitary–adrenal axis, which are known to drive inflammatory activation. In summary, the very fact that no single gene, pathway, or brain abnormality is likely to ever account for the condition is itself an extremely important first step in better articulating an integrated perspective on both its ontological status and pathogenesis. Whether this perspective will translate into the discovery of innumerable more homogeneous forms of bipolarity is one of the great questions facing the field and one that is likely to have profound treatment implications, given that fact that such a discovery would greatly increase our ability to individualize – and by extension, enhance – treatment.

Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes

“…However, other work has shown a significant correlation between gene expression in blood and brain that includes many genes related to schizophrenia [15]. There is accumulating evidence that altered immunological functioning and immune system activation may be associated with states of depression [25] as well as mania [26]; these functions also appear to be generally disrupted in the pathophysiology of BD [27,28]. Lithium has been shown to decrease cyclooxygenase-2 and prostaglandin activity, and this mechanism has been proposed as a contributor to its therapeutic action in BD [29].…”

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

“…Clinical observations in bipolar patients show that repeated episodes or residual symptoms enhance the risk of future recurrences (De Dios et al, 2012), while aggravating deterioration and volumetric changes of brain tissue (Strakowski et al, 2002;Moorhead et al, 2007;Lim et al, 2013). Recent studies have even shown that neuropsychological deficits may persist during euthymic state, corroborating the idea of a continuous aggressive inflammatory environment (for a review on neurobiology of BD, see Maletic and Raison, 2014). The enhanced risk of developing comorbidities, as long as the disorder progresses, would be supported by microgliainduced cell death, as proposed in our hypothesis.…”

Relationship altered between functional T1ρ and BOLD signals in bipolar disorder

“…However, there were also two regions that had a stronger relationship between these imaging modalities in the bipolar versus healthy control group (i.e., coupling was enhanced), the left temporal pole and left inferior temporal gyrus. Many of these regions have been previously implicated by functional imaging studies as having a role in bipolar disorder (Cerullo, Adler, Delbello, & Strakowski, 2009; Gruber, Rogowska, & Yurgelun‐Todd, 2004; Keener & Phillips, 2007; Maletic & Raison, 2014; Strakowski et al., 2011; Townsend et al., 2012; Whitton, Treadway, & Pizzagalli, 2015; Yoshimura et al., 2014), which suggests that the altered relationship between fT1ρ and BOLD is related to the illness. For instance, numerous studies have shown that functional activity in the striatum is altered in bipolar disorder during the completion of reward tasks (Caseras, Lawrence, Murphy, Wise, & Phillips, 2013; Whitton et al., 2015; Yip, Worhunsky, Rogers, & Goodwin, 2014) and reduced during fear perception tasks (Killgore, Gruber, & Yurgelun‐Todd, 2008).…”