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This study investigates WM microstructural integrity in nongeriatric MDD patients recruited as part of the International Study to Predict Optimized Treatment in Depression clinical trial and establishes the validity of diffusion tensor imaging measures for the investigation of depression. Baseline diffusion tensor imaging data from 29 nongeriatric MDD participants (11 with melancholia) and 39 healthy control participants were used in this analysis. We performed tract\u2010based spatial statistics analyses to evaluate WM microstructural integrity (1) between all healthy controls and all MDD participants, (2) between melancholic and nonmelancholic MDD participants, and (3) between each subgroup (melancholic and nonmelancholic) and controls. Significant WM integrity deficits were seen only for the melancholic MDD participants compared with controls. Compared with controls, melancholic participants showed an average reduction of 7.8% in fractional anisotropy over WM regions associated with the limbic system, dorsolateral prefrontal cortex, thalamic projection fibers, corpus callosum, and other association fibers. These fractional anisotropy deficits were also associated with decreased axial and increased radial diffusivity in these WM regions, suggesting a pattern of decreased myelination or other degeneration change. Our findings of WM structural abnormalities associated with the limbic system, the frontal cortex, and the thalamus support the prevailing theory of limbic\u2010dorsolateral prefrontal cortex\u2010thalamic dysfunction in depression. Our results also suggest that these deficits are most prominent in the melancholic subtype of MDD. Hum Brain Mapp, 2011. \u00a9 2010 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/hbm.21178","type":"journal-article","created":{"date-parts":[[2010,12,17]],"date-time":"2010-12-17T16:18:08Z","timestamp":1292602688000},"page":"2161-2171","source":"Crossref","is-referenced-by-count":185,"title":["Loss of white matter integrity in major depressive disorder: Evidence using tract\u2010based spatial statistical analysis of diffusion tensor imaging"],"prefix":"10.1002","volume":"32","author":[{"given":"Mayuresh S.","family":"Korgaonkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart M.","family":"Grieve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen H.","family":"Koslow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.E.","family":"Gabrieli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evian","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leanne M.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,12,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.159.11.1929"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2007.07050744"},{"key":"e_1_2_7_4_1","unstructured":"AnderssonJLR JenkinsonM SmithSM(2007a): Non\u2010linear optimisation. 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