Diffusion imaging studies of white matter integrity in bipolar disorder

Abstract

Diffusion tensor imaging (DTI) is a neuroimaging technique with a potential to elucidate white matter integrity. Recently, it has been used in the field of psychiatry to further understand the pathophysiology of major diseases, including bipolar disorder (BD). This review sought to focus on existing DTI findings on white matter organization in BD.

In the last decade, several efforts have been made in order to detect possible biomarkers of bipolar disorder (BD) and recent advances in neuroimaging research have pointed out the putative role of white matter (Arnone et al. 2008; Doron & Gazzaniga 2008). In this regard, structural magnetic resonance imaging (MRI) studies described diffuse cortical and callosal white matter pathology in BD patients (Adler et al. 2006; Kempton et al. 2008; Vita et al. 2009), suggesting the presence of altered intra- and inter-hemispheric connectivity (Atmaca et al. 2007; Bellani et al. 2009a, b). A relatively recent application of MRI is the diffusion tensor imaging (DTI), a non-invasive imaging technique that measures the motion of water molecules in brain tissue and provides information about the microstructural coherence of white matter (Basser & Jones 2002). Water diffusion within the neural tissue is impeded by a myelin sheath, axonal density and thickness, and cellular structures. The degree of water molecule diffusion can be quantified by the apparent diffusion coefficient (ADC), and the fibre tract directionality can be evaluated indirectly by fractional anisotropy (FA; Beaulieu, 2002). ADC and FA may be considered as good markers of white matter microstructure organization. In particular, low FA values indicate probable damage to axonal membrane, de-/dys-myelination or reduced amount of intra-axonal structures, whereas high ADC measures are found when water diffusion is unimpeded, e.g. in ventricles or demyelinated white matter (Beaulieu & Allen, 1994). Several DTI data on BD have been published so far, showing some white matter abnormalities (Brambilla et al. 2009a). Most studies (see Table 1) reported reduced FA and/or elevated ADC values compared to healthy controls involving specific brain regions such as prefrontal, parietal, temporal and occipital lobes, internal capsule, uncinate fasciculus, superior longitudinal fasciculus and corpus callosum (for extensive review see Bellani et al. 2009a, b; Heng et al. 2010). However, the effect of mood states on white matter integrity is often not taken into account (Adler et al. 2004; Bruno et al. 2008; Mahon et al. 2009) or patients with different clinical states are just studied together (Beyer et al. 2005; Versace et al. 2008; Wang et al. 2008a, b; Barnea-Goraly et al. 2009). In this regard, patients suffering from different bipolar episode may be characterized by specific DTI ‘signature’. Anyway, till date, few studies have been conducted on patients with homogeneous mood state. In euthymia, FA is usually increased in the genu of corpus callosum, internal capsule, anterior thalamic radiation and uncinate fasciculus (Haznedar et al. 2005; Yurgelun-Todd et al. 2007; Sussmann et al. 2009; Wessa et al. 2009; Zanetti et al. 2009), whereas in bipolar depression lower FA has been shown in the genu of the corpus callosum and in corona radiata (Regenold et al. 2006; Chaddock et al. 2009; Benedetti et al. 2011). Not surprisingly, in mixed samples higher and lower FA values were found in different brain regions (Beyer et al. 2005; Wang et al. 2008a, b; Barnea-Goraly et al. 2009).

Table 1. DTI studies in bipolar disorder

ADC, apparent diffusion coefficient; FA, fractional anisotropy; BD, bipolar disorder; HC, healthy controls.

The impact of mood stabilizers on white matter connectivity in BD should also be considered, particularly lithium and quetiapine, which have been suggested to potentially induce myelination processes (Bearden et al. 2008; Zhang et al. 2008; Brambilla et al. 2009b; Tondo & Baldessarini, 2009). However, a recent DTI study did not find any lithium effect on DTI measures in patients suffering from BD (Benedetti et al. 2011).

In summary, the DTI literature on BD suggests loss of white matter network connectivity as a possible phenomenon of the disease, particularly including altered fronto-occipital, superior longitudinal fasciculus and callosal connections (Wang et al. 2008a; Barnea-Goraly et al. 2009; Chaddock et al. 2009). However, diffusion-imaging studies in BD are mostly limited by heterogeneity and relatively small size of the samples. Moreover, the impact of some clinical variables on white matter coherence such as mood states and mood stabilizer administration still needs to be fully elucidated. In this perspective, future DTI studies are expected to further investigate whether abnormal white matter may represent a trait or a mood state biomarker of BD, potentially being preserved by psychotropic drugs such as lithium.