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.

Introduction

Bipolar disorder (BD) is a serious affective illness that affects approximately 1.5% of the population (Angst, 1998, Narrow et al., 2002) and remains a leading worldwide cause of disability, morbidity, and mortality from suicide (Goodwin et al., 2007, Murray and Lopez, 1996). The disease is characterized by a recurrent and episodic course involving disturbances of mood, sleep, behavior, perception, and cognition (Goodwin et al., 2007). Bipolar disorder has a spectrum presentation, with major subtypes of bipolar I and bipolar II, seemingly falling along a continuum of severity. According to current diagnostic categorization, patients with bipolar I disorder experience full mania, marked by symptoms of elated or irritable mood, reduced need for sleep, increased goal-directed activity, rapid speech, flight of ideas, and increased energy (DSM-IV, 1994). Additionally, in approximately 50% of bipolar I cases (DSM-IV, 1994), acute episodes are characterized by concurrent symptoms of psychosis, including auditory/visual hallucinations, and delusions that are typically focused around mood-congruent themes (i.e. religious preoccupations or manic beliefs in one's own supernatural powers). Bipolar II patients have milder symptoms of mania which, by definition, do not involve psychosis, are typically shorter in duration, and do not significantly interfere with daily functioning. Both bipolar I and bipolar II subtypes experience intermittent major depressive episodes with sad mood, suicidal ideation, and changes in appetite, sleep, and energy, often interfering significantly with psychosocial functioning (DSM-IV, 1994). The notable heterogeneity in the clinical phenotype, including multiple subtypes (bipolar I, bipolar II) and several characteristics that are present only in a subgroup of patients (i.e. psychosis, cognitive impairment), complicate the attempts to elucidate the underlying pathophysiology of the illness.

Although the exact etiologies of BD remain unknown, data from post-mortem, genetic, computed tomography (CT), positron emission tomography (PET), and magnetic resonance (MR) imaging studies provide evidence that brain abnormalities contribute to the disorder. The cause and significance of these abnormalities remain somewhat speculative, and findings are often contradictory. Recent models of BD (Adler et al., 2006b, Green et al., 2007, Lyoo et al., 2006, Phillips et al., 2003b, Phillips et al., 2008, Soares and Mann, 1997, Strakowski et al., 2005), however, suggest that the sometimes inconsistent and even contradictory findings involving abnormal brain anatomy, structure, and function may be understood within a framework of emotional dysregulation in circuits involving frontal cortical and limbic structures (Mayberg, 1997). Several influential accounts of BD have suggested that the interplay between phylogenetically new cortical and phylogenetically old limbic regions is compromised in patients with BD and may be responsible for the core symptoms of the disease (Drevets et al., 1997, Mayberg et al., 1999, Strakowski et al., 2005). Dysregulation of various nodes in the limbic system may produce affective symptoms, including depression and mania. Limbic system structures include the amygdala, hippocampus and parahippocampal gyrus, ventral striatum, insula, anterior cingulate (ACC), and orbitofrontal cortex (OFC) (Mesulam and Geula, 1988, Öngür and Price, 2000). The system is thought to reflect an evolutionary advance critical in the development of a distinctly mammalian CNS (MacLean, 1990). The structures are involved in response to or appraisal of threat (amygdala), the integration of autonomic, affectively valenced information and behavioral “scripts,” especially as they relate to anticipated social outcome (ventral prefrontal cortex), autonomic processing, and affective and conflict monitoring (subgenual and dorsal cingulate). Because of reciprocal connectivity between these areas it is likely that both “top-down” and “bottom-up” dysfunction exists and brings about both the emotional dysregulation that characterizes the illness as well as the concomitant neurocognitive impairment that is common in BD.

The majority of brain research in bipolar disorder has focused on the gray matter (GM). This is likely due to the fact that the white matter (WM), comprised of fiber tracts interconnecting cortical and subcortical GM, has been much more difficult to visualize and quantify than GM (see Fig. 1). Alterations in WM tissue would likely have significant implications for the functioning of the brain as a whole, as it is the WM which serves as the circuitry and connective wiring of the brain. With the advent of techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) that allow for better quantification and characterization of the WM, it has become possible to move toward a connectivity-based model of brain abnormality that both supports and clarifies cortico-limbic models of emotional dysregulation.