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Objective: Diffusion-weighted magnetic resonance imaging (MRI) has shown increased sensitivity in detecting brain white matter disease compared to traditional T2-weighted MRI. Diffusion-weighted imaging (DWI) can quantitatively assess the microstructural integrity of white matter using the average apparent diffusion coefficient (ADCav), a measure of the extent to which water molecules move freely within tissue. On the basis of numerous studies suggesting white matter disease in bipolar patients, particularly patients with more severe illness, this study aimed to test the utility of DWI in assessing the white matter integrity of bipolar patients with severe illness. Methods: The existing MRI scans of eight bipolar patients and eight age-matched controls with neurological illness were examined retrospectively. ADCav values for pixels within white matter regions of interest (ROIs) were calculated and used to plot ADCav frequency histograms for each ROI. Mean ADCav values for the two groups were then compared by ANCOVA. Results: The bipolar mean ADCav (0.855 ± 0.051 × 10−3 mm2/s) for combined white matter ROIs significantly exceeded that of controls (0.799 ± 0.046 × 10−3 mm2/s), while covarying for age ( F = 4.47, df = 3, p = 0.025). Conclusions: This is the first report of an elevated ADCav in the white matter of a group of patients with bipolar disorder. In this group of patients with severe illness, increased white matter ADCav suggests microstructural changes consistent with decreased white matter integrity. DWI may be an additional, useful tool to assess white matter abnormalities in bipolar disorder. [ABSTRACT FROM AUTHOR]