A role for white matter abnormalities in the pathophysiology of bipolar disorder

Abstract

Bipolar disorder is a chronically disabling psychiatric disorder characterized by manic states that is often interspersed with periods of depression whose neurobiology remains largely unknown. There is, however, increasing evidence that white matter (WM) abnormalities may play an important role in the neurobiology of the disorder. In this review we critically evaluate evidence for WM abnormalities in bipolar disorder obtained from neuroimaging, neuropathological, and genetic research. Increased rates of white matter hyperintensities, regional volumetric abnormalities, abnormal water diffusion along prefrontal-subcortical tracts, fewer oligodendrocytes in prefrontal WM, and alterations in the expression of myelin- and oligodendrocyte-related genes are among the most consistent findings. Abnormalities converge in the prefrontal WM and, in particular, tracts that connect prefrontal regions and subcortical gray matter structures known to be involved in emotion. Taken together, the evidence supports and clarifies a model of BD that involves disconnectivity in regions implicated in emotion generation and regulation.

Figure 1. Major white matter tracts

The approximate location of major white matter tracts, represented by the center of each tract (the “mean FA skeleton” [Jones et al., 2006]). A mean FA skeleton has been colored and labeled and is shown overlaid on the FA-weighted average brain template, both available in Tract Based Spatial Statistics (TBSS; Jones et al., 2006). Labeled/colored tracts have been found to be altered in BD, although not necessarily at the location represented in this figure (individual studies are provided in the figure key). (A) red = corpus callosum: Frazier et al., 2007; Yurgelun-Todd et al., 2007; Wang et al., 2008b; Barnea-Goraly et al., 2009; Sussman et al., 2009; (B) magenta = frontal occipital fasciculus: Bruno et al., 2008; Chaddock et al., 2009; Zanetti et al., (in press); (C) yellow = uncinate fasciculus: Houenou et al., 2007; McIntosh et al., 2008; Versace et al., 2008; Sussmann et al., 2009; Wang et al., 2009; Zanetti et al. (in press); (D) orange = pontine crossing tract: Mahon et al., 2009; (E) green = cingulum bundle: Barnea-Goraly et al., 2009; Frazier et al., 2007; Wang et al., 2008a; (F) brown = inferior longitudinal fasciculus: Barnea-Goraly et al., 2009; Bruno et al., 2008; Chaddock et al., 2009; Zanetti et al., (in press); (G) blue = thalamic radiations/corticospinal/corticopontine tracts: Frazier et al., 2007; Mahon et al., 2009; Wessa et al., 2009; Zanetti et al., (in press); (H) cyan = superior longitudinal fasciculus: Chaddock et al., 2009; Mahon et al., 2009; Zanetti et al., (in press); (I) black = fornix: Barnea-Goraly et al., 2009; white = miscellaneous tracts/ unspecified.

Figure 2. Schematic representation of networks proposed to be disrupted in BD1

Proposed model of disrupted white matter tracts in the neurobiology of bipolar disorder. Disruption along frontocortical-striatal-thalamic-frontocortical circuits may lead to abnormal processing of emotional information and deficient emotion regulation. Disruption along tracts (e.g., the uncinate fasciculus) that connect regions involved in automatic emotion regulation, such as the medial orbital frontal cortex and the amygdala/hippocampus, may result in extreme mood states. Errors in processing anywhere along a circuit may be propagated through disruptions within both top-down (emotion regulation) and bottom-up (emotion generation/perception) systems. Evidence for disruption along major tracts within these circuits has been reported (see text and Table 3); however, future research is required to define these abnormal tracts more specifically and to determine which sub-circuits are affected. In particular, research conducted to date in BD does not allow for a reliable distinction between cortico-striatal tract disruption and thalamic-frontal tract disruption, although this distinction is likely to be important in our understanding of BD pathophysiology. Note that not all connections between regions are shown in the figure. Abbreviations: DLPFC = dorsolateral prefrontal cortex; sgACC = subgenual anterior cingulate cortex; OFC = orbital frontal cortex; GP= globus pallidus; VP = ventral pallidum ¹ Adapted from Haldane & Frangou, 2004; Phillips et al., 2008; Soares & Mann, 1997; Strakowski et al., 2005; Vawter et al., 2000.