Original Article Abnormal frontal white matter tracts in bipolar disorder: a diffusion tensor imaging study Several lines of evidence, including morphometric and functional imaging studies, suggest the pres- ence of prefrontal cortical dysfunction in patients with bipolar disorder (1). Changes in prefrontal cortical activation and the associated cognitive deficits observed in bipolar disorder have been hypothesized to represent elements of a dysfunc- tional network linking prefrontal regions with other subcortical and cortical structures. This hypothesis has been buttressed by a study from Ketter and colleagues showing linkage between decreased glucose metabolism in the prefrontal cortex of depressed patients with bipolar disorder and increased subcortical metabolism (2). One element of this putative network dysfunction has been suggested to be a dysconnectivity syndrome involving white matter pathways connecting struc- tures functionally and anatomically linked to the prefrontal cortex, similar to that suggested to be involved in schizophrenia (3– 5). Evidence of neuropathology in white matter tracts serving the prefrontal cortex however, has been mixed. Increased numbers of white matter hyperintensities (WMH) have been widely observed in patients with bipolar disorder, a phenomenon suggested to be linked to white Adler CM, Holland SK, Schmithorst V, Wilke M, Weiss KL, Pan H, Strakowski SM. Abnormal frontal white matter tracts in bipolar disorder: a diffusion tensor imaging study. Bipolar Disord 2004: 6: 197–203. ª Blackwell Munksgaard, 2004 Objectives: Prefrontal white matter has been hypothesized to be integral to the pathophysiology of bipolar disorder. Recent morphometric studies however, have not observed changes in white matter in bipolar patients. We hypothesized that changes in prefrontal function in bipolar disorder, widely reported in the literature, may be related to a loss of white matter tract integrity with a resultant dysconnectivity syndrome. In this study we utilized diffusion tensor imaging (DTI) to examine prefrontal white matter in patients with bipolar disorder. Methods: Ninepatientswithbipolardisorderandninehealthycontrols were recruited. DTI and localizing anatomic data were acquired, and regions of interest (ROIs) identified in the prefrontal white matter at 15, 20, 25, and 30 mm superior to the anterior commissure (AC). Fractional anisotropy (FA) and trace apparent diffusion coefficient (TADC) were compared by ROI between study groups. Results: TheFAofROIs25and30mmabovetheACwassignificantly reduced in patients with bipolar disorder; FA of all ROIs showed high- medium to large effect sizes. No significant group differences were identified in TADC. Conclusions: Our findings suggest that a loss of bundle coherence is presentinprefrontalwhitematter.Thislossofcoherencemaycontribute to prefrontal cortical pathology in patients with bipolar disorder. Caleb M Adler a,c , Scott K Holland b , Vince Schmithorst b , Marko Wilke b , Kenneth L Weiss a,c,d,e , Hai Pan c and Stephen M Strakowski a,c a Bipolar and Psychotic Disorders Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, b Imaging Research Center, Children’s Hospital Medical Center, University of Cincinnati, c Center for Imaging Research, University of Cincinnati College of Medicine, d Department of Radiology, University of Cincinnati College of Medicine, e Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA Key words: bipolar disorder – diffusion tensor imaging – functional imaging – prefrontal cortex – white matter Received 3 July 2003, revised and accepted for publication 6 February 2004 Corresponding author: Caleb M. Adler MD, Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0559, USA. Fax: 513 558 3399; e-mail: cal.adler@psychiatry.uc.edu Each author declares that they have no commercial interests that might pose a conflict of interest in connection with this manuscript. Bipolar Disorders 2004: 6: 197–203 Copyright ª Blackwell Munksgaard 2004 BIPOLAR DISORDERS 197