White matter integrity in major depressive disorder: Implications of childhood trauma, 5-HTTLPR and BDNF polymorphisms Erica L. Tatham a , Rajamannar Ramasubbu b , Ismael Gaxiola-Valdez c , Filomeno Cortese c , Darren Clark b , Bradley Goodyear c , Jane Foster d , Geoffrey B. Hall a,e,n a McMaster Integrative Neuroscience Discovery and Study Program, McMaster University, Hamilton, Ontario, Canada b Department of Psychiatry, and Clinical Neurosciences, Hotchkiss Brain Institute, Mathison Center for Mental Health Research and Education, University of Calgary, Alberta, Canada c Hotchkiss Brain Institute, University of Calgary, Canada d Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada e Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ontario, Canada article info Article history: Received 13 August 2015 Received in revised form 22 April 2016 Accepted 25 April 2016 Available online 27 April 2016 Keywords: Depression DTI Trauma 5-HTTLPR BDNF abstract This study examined the impact of childhood neglect, serotonin transporter (5-HTTLPR) and brain de- rived neurotrophic factor (BDNF) polymorphisms on white matter (WM) integrity in major depressive disorder (MDD) using diffusion tensor imaging (DTI). Fifty-five medication-free MDD patients and 18 controls underwent diffusion tensor imaging scanning, genotyping and completed the Childhood Trauma Questionnaire. Tract based spatial statistics (TBSS) findings revealed reduced fractional anisotropy (FA) in the MDD group in the anterior internal capsule. 5-HTTLPR–S′L′ heterozygotes in the MDD group exhibited reduced FA in the internal capsule relative to S′S′ and reduced FA in corona radiata compared to L′L′. Probabilistic tractography revealed higher FA in the uncinate fasciculus (UF) for BDNF val/val genotype relative to met-carriers, particularly in individuals with high depression severity. High depression se- verity and experiences of childhood physical or emotional neglect predicted higher FA in the UF and superior longitudinal fasciculus. Reductions in FA were identified for subgroups of MDD patients who were 5-HTTLPR heterozygotes and BDNF-met carriers. An association between emotional/physical ne- glect and FA was observed in subjects with high depressive symptoms. Our findings suggest that WM connectivity within frontal and limbic regions are affected by depression and influenced by experiences of neglect and genetic risk factors. & 2016 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Growing evidence suggests that major depressive disorder (MDD) is a complex brain disorder that results from structural and functional abnormalities of multiple limbic and cortical brain re- gions involved in mood regulation. In order to understand the structural connectivity of brain regions implicated in MDD, much research has focused on the abnormalities of white matter in- tegrity and fiber tracts between brain regions. Diffusion tensor imaging (DTI) provides a non-invasive MR-method of assessing myelin integrity (and thus neuronal connectivity between asso- ciated brain regions). Fractional anisotropy (FA) is a DTI parameter that reflects the ratio of directional to non-directional water movement in a single imaging voxel and provides information on relative axonal size, myelination, axon connections and orientation (Sexton et al., 2009; Smith et al., 2006). In regions with reduced white matter structure integrity and axon connectivity, FA values are low. The potential use of diffusion tensor imaging as a tool to guide treatment has promoted investigations to determine whe- ther FA can predict depression severity, illness course/duration and treatment outcomes. A number of DTI studies on MDD have reported white matter abnormalities in tracts and regions including the superior long- itudinal fasciculus (SLF) (Dalby et al., 2010; Wu et al., 2011; Zuo et al., 2012; see Murphy and Frodl (2011) for meta-analysis), the fornix (Zou et al., 2008), internal capsule (Zuo et al., 2012), ex- ternal capsule (Guo et al., 2012), corpus callosum (Guo et al., 2012; Kieseppä et al., 2010; Korgaonkar et al., 2011), sagittal striatum (Kieseppä et al., 2010), hippocampus (Zhou et al., 2011; Zhu et al., 2011), cingulum (Keedwell et al., 2012), uncinate fasciculus (Cullen et al., 2010; Dalby et al., 2010) and projection fibers associated with the thalamus (Korgaonkar et al., 2012). However, these findings have been variable in terms of location and FA changes. Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/psychresns Psychiatry Research: Neuroimaging http://dx.doi.org/10.1016/j.pscychresns.2016.04.014 0925-4927/& 2016 Elsevier Ireland Ltd. All rights reserved. n Corresponding author at: Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ontario, Canada. E-mail address: hallg@mcmaster.ca (G.B. Hall). Psychiatry Research: Neuroimaging 253 (2016) 15–25