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White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging Bipolar disorder (BD) is strongly associated with white matter abnormalities. Postmortem studies have revealed a reduction in glial cells in the subgenual prefrontal cortex (1) and there is evidence from T 2 -weighted magnetic resonance imaging (MRI) that patients with BD have an increase in white matter hyperintensities compared to healthy controls (2, 3). T 1 -weighted MRI has also revealed white matter reductions using both region of interest (ROI) (4, 5) and voxel-based morphometry (VBM) approaches (6).Conventional T 1 -weighted MRI is, however, limited in its ability to identify abnormalities of white matter, since the signal is largely dependent upon water content and is potentially confounded by non-neuronal tissue components. Diffusion tensor imaging (DTI) is a more recent technique that measures the diffusivity of water molecules within tissues in vivo. Yet there have been few DTI studies in BD and all of these have had relatively small sample sizes. Their findings have included Objectives: Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders.Methods: DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis.Results: Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication.Conclusions: Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T 1 -weighted MRI) and integrity (DTI) was ascertained. Subjects with the riskassociated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

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