Research report White matter microstructure alterations of the medial forebrain bundle in melancholic depression Tobias Bracht a,n , Helge Horn a , Werner Strik a , Andrea Federspiel b , Susanne Schnell c , Oliver Höfle a , Katharina Stegmayer a , Roland Wiest d , Thomas Dierks b , Thomas J. Müller a , Sebastian Walther a a University Hospital of Psychiatry, University of Bern, Bolligenstrasse 111, 3000 Bern 60, Switzerland b University Hospital of Psychiatry, Department of Psychiatric Neurophysiology, University of Bern, Bolligenstrasse 111, 3000 Bern 60, Switzerland c Departments of Radiology and Biomedical Engineering, Northwestern University, Feinberg School of Medicine, 737 N. Michigan Ave Suite 1600, Chicago, IL 60611, USA d Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Freiburgstrasse 3010, Bern, Switzerland article info Article history: Received 7 August 2013 Received in revised form 1 October 2013 Accepted 29 October 2013 Available online 5 November 2013 Keywords: Anhedonia Mood disorder Structural imaging Diffusion tensor imaging abstract Background: The medial forebrain bundle (MFB) is a key structure of the reward system and connects the ventral tegmental area (VTA) with the nucleus accumbens (NAcc), the medial and lateral orbitofrontal cortex (mOFC, lOFC) and the dorsolateral prefrontal cortex (dlPFC). Previous diffusion tensor imaging (DTI) studies in major depressive disorder point to white matter alterations of regions which may be incorporated in the MFB. Therefore, it was the aim of our study to probe white matter integrity of the MFB using a DTI-based probabilistic fibre tracking approach. Methods: 22 patients with major depressive disorder (MDD) (12 melancholic-MDD patients, 10 non- melancholic-MDD patients) and 21 healthy controls underwent DTI scans. We used a bilateral probabilistic fibre tracking approach to extract pathways between the VTA and NACC, mOFC, lOFC, dlPFC respectively. Mean fractional anisotropy (FA) values were used to compare structural connectivity between groups. Results: Mean-FA did not differ between healthy controls and all MDD patients. Compared to healthy controls melancholic MDD-patients had reduced mean-FA in right VTA-lOFC and VTA-dlPFC connections. Furthermore, melancholic-MDD patients had lower mean-FA than non-melancholic MDD-patients in the right VTA-lOFC connection. Mean-FA of these pathways correlated negatively with depression scale rating scores. Limitations: Due to the small sample size and heterogeneous age group comparisons between melan- cholic and non-melancholic MDD-patients should be regarded as preliminary. Conclusions: Our results suggest that the melancholic subtype of MDD is characterized by white matter microstructure alterations of the MFB. White matter microstructure is associated with both depression severity and anhedonia. & 2013 Elsevier B.V. All rights reserved. 1. Introduction Anhedonia, the loss of previously rewarding experiences is a core feature of major depressive disorder (MDD) and may underlie a dysfunction of the reward system, which mediates feelings of pleasure and is essential for motivated behaviour (Haber and Knutson, 2010; Keedwell et al., 2005; Wacker et al., 2009). Core regions of the reward system include the ventral tegmental area (VTA), the nucleus accumbens (NAcc), the orbitofrontal cortex (OFC) and the dorsolateral prefrontal cortex (dlPFC) (Haber and Knutson, 2010). Previous functional magnetic resonance imaging (fMRI) studies have repeatedly demonstrated alterations of the medial forebrain bundle in major depressive disorder (MDD) when processing rewarding stimuli. For instance, in patients with MDD the blood oxygenation level dependent (BOLD) response of the NAcc and the caudate nucleus is less responsive to monetary reward (Pizzagalli et al., 2009) which has been shown to normalize after successful antidepressive therapy (Stoy et al., 2012). The medial forebrain bundle (MFB) connects above mentioned brain regions and may contribute to reduced motivation and anhedonia in MDD (Schultz et al., 1997; Tye et al., 2013). Using Diffusion Tensor Imaging (DTI) based tractography the MFB was Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/jad Journal of Affective Disorders 0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.10.048 n Corresponding author. Tel.: þ41 31 930 9111; fax: þ41 31 930 9404. E-mail address: bracht@puk.unibe.ch (T. Bracht). Journal of Affective Disorders 155 (2014) 186–193