ReviewA role for white matter abnormalities in the pathophysiology of bipolar disorder
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.
Section snippets
Models of BD
An abnormal relationship between the cortex and limbic structures as a basis for mood dysregulation was proposed by Mayberg (1997) as a general, adaptable framework for unipolar depression. Many recent reviews of neuroanatomical findings in BD suggest that this framework is useful for conceptualizing BD as well (Adler et al., 2006b, Bearden et al., 2001, Green et al., 2007, Haldane and Frangou, 2004, Lyoo et al., 2006, Phillips et al., 2003b, Phillips et al., 2008, Savitz and Drevets, 2009,
White matter hyperintensities
An increased number and/or severity of white matter hyperintensities (WMH), which are hyper-intense bright spots that may be detected in T2-weighted and fluid-attenuated inversion recovery (FLAIR) MR images, is one of the most consistently reported abnormalities in bipolar disorder (Ahn et al., 2004, Altshuler et al., 1995, Aylward et al., 1994, de Asis et al., 2006, Dupont et al., 1990, Dupont et al., 1995, Figiel et al., 1991, Gulseren et al., 2006, Kempton et al., 2008, Lloyd et al., 2009,
Neuropathological evidence
Relatively few neuropathological studies have been conducted in BD, yet the results indicate that cytoarchitectural and neurochemical abnormalities are present in this disorder (Connor et al., 2009, Harrison, 2002, Rajkowska, 2002). As is the case for neuroimaging studies, neuropathological studies have tended to focus on GM and have not investigated the WM to the same extent. Of particular relevance for WM investigation is the study of oligodendrocytes and myelin, although few studies have
Genetic evidence
There is no doubt that the genetic underpinnings of BD are likely to be immensely complex. Twin studies have estimated the concordance rate for monozygotic twin pairs to be approximately 43%, whereas the rate for dizygotic twins appears to be approximately 6% (Kieseppä et al., 2003). van der Schot et al. (2009) found that WM deficits in BD appear to be genetically mediated, whereas this was not found to be the case for GM deficits. Data from microarray and genetic linkage studies suggest that
Summary and integration with existing models
Evidence for altered WM metabolism and compromised WM coherence and organization, in addition to a wealth of evidence suggesting functional disconnection in BD, indicates that WM connectivity is likely to be an important component in the pathophysiology of this disorder. In general, models of BD and SCZ have moved beyond discrete lesion-based proposals to models based on circuit-wide dysfunction, and WM investigation is an essential facet of this more recent focus. The lack of consistent gross
Conclusions and future directions
Long neglected due to the limited feasibility of examining such tissue in vivo, researchers are increasingly turning to WM examination as a means of more fully understanding the neurological underpinnings of bipolar disorder. Imaging, genetic, and neuropathological evidence suggest that abnormalities in WM tissue play an important role in BD pathophysiology and phenomenology. In particular, theoretical and empirical research suggests a model of BD in which the connections within and between
Acknowledgements
This work was supported in part by grants from the Stanley Foundation and the NSLIJ Research Institute General Clinical Research Center (M01 RR018535).
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