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. Reference Arnone, McIntosh, Chandra and Ebmeier2008; Doron & Gazzaniga Reference Doron and Gazzaniga2008). In this regard, structural magnetic resonance imaging (MRI) studies described diffuse cortical and callosal white matter pathology in BD patients (Adler et al. Reference Adler, Del Bello and Strakowski2006; Kempton et al. Reference Kempton, Geddes, Ettinger, Williams and Grasby2008; Vita et al. Reference Vita, De Peri and Sacchetti2009), suggesting the presence of altered intra- and inter-hemispheric connectivity (Atmaca et al. Reference Atmaca, Ozdemir and Yildirim2007; Bellani et al. Reference Bellani, Marzi and Brambilla2009a, Reference Bellani, Yeh, Tansella, Balestrieri, Soares and Brambillab). 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 Reference Basser and Jones2002). 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, Reference Beaulieu2002). 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, Reference Beaulieu and Allen1994). Several DTI data on BD have been published so far, showing some white matter abnormalities (Brambilla et al. Reference Brambilla, Bellani, Yeh, Soares and Tansella2009a). 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. Reference Bellani, Marzi and Brambilla2009a, b; Heng et al. Reference Heng, Song and Sim2010). However, the effect of mood states on white matter integrity is often not taken into account (Adler et al. Reference Adler, Holland, Schmithorst, Wilke, Weiss, Pan and Strakowski2004; Bruno et al. Reference Bruno, Cercignani and Ron2008; Mahon et al. Reference Mahon, Wu, Malhotra, Burdick, De Rosse, Ardekani and Szeszko2009) or patients with different clinical states are just studied together (Beyer et al. Reference Beyer, Taylor, MacFall, Kuchibhatla, Payne, Provenzale, Cassidy and Krishnan2005; Versace et al. Reference Versace, Almeida, Hassel, Walsh, Novelli, Klein, Kupfer and Phillips2008; Wang et al. Reference Wang, Kalmar, Edmiston, Chepenik, Bhagwagar, Spencer, Pittman, Jackowski, Papademetris, Constable and Blumberg2008a, Reference Wang, Jackowski, Kalmar, Chepenik, Tie, Qiu, Gong, Pittman, Jones, Shah, Spencer, Papademetris, Constable and Blumbergb; Barnea-Goraly et al. Reference Barnea-Goraly, Chang, Karchemskiy, Howe and Reiss2009). 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. Reference Haznedar, Roversi, Pallanti, Baldini-Rossi, Schnur, Licalzi, Tang, Hof, Hollander and Buchsbaum2005; Yurgelun-Todd et al. Reference Yurgelun-Todd, Silveri, Gruber, Rohan and Pimentel2007; Sussmann et al. Reference Sussmann, Lymer, McKirdy, Moorhead, Maniega, Job, Hall, Bastin, Johnstone, Lawrie and McIntosh2009; Wessa et al. Reference Wessa, Houenou, Leboyer, Chanraud, Poupon, Martinot and Paillère-Martinot2009; Zanetti et al. Reference Zanetti, Jackowski, Versace, Almeida, Hassel, Duran, Busatto, Kupfer and Phillips2009), whereas in bipolar depression lower FA has been shown in the genu of the corpus callosum and in corona radiata (Regenold et al. Reference Regenold, D'Agostino, Ramesh, Hasnain, Roys and Gullapalli2006; Chaddock et al. Reference Chaddock, Barker, Marshall, Schulze, Hall, Fern, Walshe, Bramon, Chitnis, Murray and McDonald2009; Benedetti et al. Reference Benedetti, Yeh, Bellani, Radaelli, Nicoletti, Poletti, Falini, Dallaspezia, Colombo, Scotti, Smeraldi, Soares and Brambilla2011). Not surprisingly, in mixed samples higher and lower FA values were found in different brain regions (Beyer et al. Reference Beyer, Taylor, MacFall, Kuchibhatla, Payne, Provenzale, Cassidy and Krishnan2005; Wang et al. Reference Wang, Kalmar, Edmiston, Chepenik, Bhagwagar, Spencer, Pittman, Jackowski, Papademetris, Constable and Blumberg2008a, Reference Wang, Jackowski, Kalmar, Chepenik, Tie, Qiu, Gong, Pittman, Jones, Shah, Spencer, Papademetris, Constable and Blumbergb; Barnea-Goraly et al. Reference Barnea-Goraly, Chang, Karchemskiy, Howe and Reiss2009).
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. Reference Bearden, Thompson, Dutton, Frey, Peluso, Nicoletti, Dierschke, Hayashi, Klunder, Glahn, Brambilla, Sassi, Mallinger and Soares2008; Zhang et al. Reference Zhang, Xu, Jiang, Xiao, Yan, He, Wang, Bi, Li, Kong and Li2008; Brambilla et al. Reference Brambilla, Bellani, Yeh and Soares2009b; Tondo & Baldessarini, Reference Tondo and Baldessarini2009). However, a recent DTI study did not find any lithium effect on DTI measures in patients suffering from BD (Benedetti et al. Reference Benedetti, Yeh, Bellani, Radaelli, Nicoletti, Poletti, Falini, Dallaspezia, Colombo, Scotti, Smeraldi, Soares and Brambilla2011).
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. Reference Wang, Kalmar, Edmiston, Chepenik, Bhagwagar, Spencer, Pittman, Jackowski, Papademetris, Constable and Blumberg2008a; Barnea-Goraly et al. Reference Barnea-Goraly, Chang, Karchemskiy, Howe and Reiss2009; Chaddock et al. Reference Chaddock, Barker, Marshall, Schulze, Hall, Fern, Walshe, Bramon, Chitnis, Murray and McDonald2009). 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.
