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Hedonic Tone Is Associated with Left Supero-Lateral Medial Forebrain Bundle Microstructure

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Hedonic Tone Is Associated with Left Supero-Lateral Medial Forebrain Bundle Microstructure Psychological Medicine (2015), 45, 865–874. © Cambridge University Press 2014 ORIGINAL ARTICLE doi:10.1017/S0033291714001949 Hedonic tone is associated with left supero-lateral medial forebrain bundle microstructure T. Bracht1,2*, A. N. Doidge1,2, P. A. Keedwell2 and D. K. Jones1,2 1 Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK 2 Neuroscience, Mental Health Research Institute, Cardiff University, Cardiff, UK Background. The medial forebrain bundle (MFB) is an important pathway of the reward system. Two branches have been described using diffusion magnetic resonance imaging (MRI)-based tractography: the infero-medial MFB (imMFB) and the supero-lateral MFB (slMFB). Previous studies point to white-matter microstructural alterations of the slMFB in major depressive disorder (MDD) during acute episodes. To extend this finding, this study investigates whether white-matter microstructure is also altered in MDD patients that are in remission. Further, we explore associa- tions between diffusion MRI-based metrics of white-matter microstructure of imMFB, slMFB and hedonic tone, the abil- ity to derive pleasure. Method. Eighteen remitted depressed (RD) and 22 never depressed (ND) participants underwent high angular resol- ution diffusion-weighted imaging (HARDI) scans. To reconstruct the two pathways of the MFB (imMFB and slMFB) we used the damped Richardson–Lucy (dRL) algorithm. Mean fractional anisotropy (FA) was sampled along the tracts. Results. Mean FA of imMFB, slMFB and a comparison tract (the middle cerebellar peduncle) did not differ between ND and RD participants. Hedonic capacity correlated negatively with mean FA of the left slMFB, explaining 21% of the variance. Conclusions. Diffusion MRI-based metrics of white-matter microstructure of the MFB in RD do not differ from ND. Hedonic capacity is associated with altered white-matter microstructure of the slMFB. Received 2 March 2013; Revised 17 July 2014; Accepted 17 July 2014; First published online 15 August 2014 Key words: Anhedonia, depression, diffusion tensor imaging, fibre tracking, remission, white matter. Introduction feature of major depressive disorder (MDD). Given its prominent role in the reward system (Schultz et al. The medial forebrain bundle (MFB) is the central 1997; Nestler & Carlezon, 2006), the MFB has become pathway of the reward system, which mediates feelings a major focus in the search for the neurobiological and expectations of pleasure (Schultz et al. 1997; Coenen underpinnings of MDD (Blood et al. 2010; Bracht et al. 2011). Traditionally the MFB was described as et al. 2014). In particular, the slMFB may be involved an assembly of loosely arranged, thin fibres extending in the neurobiology of depression (Schlaepfer et al. from the septal area. Fibres traverse the lateral 2014) and becomes an increasingly important region preoptico-hypothalamic area and proceed to the teg- for deep brain stimulation (DBS) in treatment-resistant mentum of the midbrain (Nieuwenhuys et al. 2008). MDD (Schlaepfer et al. 2013). Coenen et al. (2009) were the first to reconstruct the Diffusion MRI allows white-matter microstructure to MFB using diffusion magnetic resonance imaging be probed by indirectly measuring the hindrance of (MRI)-based fibre tracking. In addition to this infero- diffusion of water molecules (Basser et al. 1994). The medial MFB (imMFB) branch, the researchers described most commonly used diffusion MRI-based measure a supero-lateral branch (slMFB) proceeding from the in clinical studies is fractional anisotropy (FA) (Basser ventral tegmental area (VTA) to the forebrain and the & Pierpaoli, 1996). Reductions in FA indicates differ- frontal lobe (Coenen et al. 2009, 2012). ences in barriers to diffusion of water molecules. Anhedonia, the reduced capacity to derive pleasure This may reflect altered white-matter microstructure, from previously rewarding experiences, is a core which in turn could have functional significance in the mediation of hedonic responses to positive events (Keedwell et al. 2012). * Address for correspondence: T. Bracht, Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff, Two studies have used diffusion MRI in order to fi UK. speci cally assess white-matter microstructure of the (Email: [email protected]) MFB. One study demonstrated a trend towards This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://www.cambridge.org/core. IP address: 170.106.40.139, on 24 Sep 2021 at 22:22:10, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0033291714001949 866 T. Bracht et al. reduced FA in the imMFB in currently depressed Carlezon, 2006), we included dorsal segments of the patients (Blood et al. 2010). A recent diffusion MRI- VTA projecting to the nucleus accumbens (NAc) and based fibre-tracking approach identified reduced FA the prefrontal cortex (Nieuwenhuys et al. 2008; Bracht in severely depressed melancholic MDD patients in et al. 2014) in our tract reconstructions. segments of the slMFB connecting the VTA with To establish the specificity of potential findings we the medial orbitofrontal cortex (OFC) and the dorso- reconstructed the middle cerebellar peduncle (MCP) lateral prefrontal cortex (dlPFC) (Bracht et al. 2014). as a comparison tract. We also performed a whole Lower FA was associated with more pronounced brain group comparison of FA to complement the anhedonia and depression severity (Bracht et al. tract reconstruction approach. 2014). Moreover, voxel-based diffusion MRI (Zou et al. 2008; Liao et al. 2013), region of interest (Bae et al. 2006; Blood et al. 2010) and tract-based spatial Method statistics (TBSS) (Korgaonkar et al. 2011; Zhu et al. Sample and measures 2011) studies have demonstrated reductions of FA in acute depression in the anterior limb of the inter- Eighteen RD, unmedicated women with a history nal capsule and in prefrontal brain regions that likely of MDD and 22 healthy controls without a history of incorporate segments of the slMFB (Coenen et al. MDD (ND, never depressed) were recruited from the 2009, 2012). staff and student body of the School of Psychology, However, it has not been determined if white-matter Cardiff. We recruited individuals of one gender only changes in these reward tracts are state-dependent or to reduce the potential effect of gender-based varia- trait markers of vulnerability to depression. To date, bility of brain structure (Kanaan et al. 2014), thereby no studies have examined if changes in FA in the increasing the power to detect group differences. MFB persist into remission. Females were specifically chosen because they have a Decreases of FA in the ventromedial prefrontal higher incidence of depression than men, attributable cortex, a region adjacent to the slMFB, were found in to a greater incidence of first onset as opposed to treatment-resistant depressed MDD but not in remitted chronicity or recurrence (Kessler et al. 1993). Controls depressed (RD) (de Diego-Adelino et al. 2014), suggest- were matched for age, gender and pre-morbid intelli- ing that remodelling of white-matter microstructure gence. Inclusion criteria for all participants were occurs during remission. However, we note previous right handedness and fluency in English. Exclusion studies where voxel-based analyses failed to show a criteria were contraindications for magnetic resonance group effect, but tract-specific approaches showed a imaging (MRI) scans, a diagnosis of Axis I disorder, a significant effect (Cullen et al. 2010; Keedwell et al. current episode of depression, substance dependence 2012; Bracht et al. 2014). and psychotropic medication. The Mini International Based on previous work, the present study was Neuropsychiatric Inventory (MINI; Sheehan et al. designed to test the following hypotheses: First, that 1998) was used to exclude a current episode of de- FA would be reduced in the MFB in RD compared pression in all participants. Further, the MINI was with never depressed (ND) individuals, consistent used to confirm a history of a depressive episode with the proposition that this represents a trait marker in RD and the absence of a history of depression in of MDD. Second, that, consistent with findings in acute ND (see Appendix). Results of the MINI were corrobo- MDD, FA in the slMFB tract would correlate positively rated by a medical history. The MINI was also used with a measure of hedonic tone (or higher FA=lower to screen participants for a history of psychiatric disor- anhedonia). ders and drug or alcohol dependence. We employed In accordance with previous approaches dividing additional questions (regarding hospitalization, treat- tracts into subdivisions (Jones et al. 2013a) we recon- ments, suicidal behaviour and psychosis) in order to structed the two branches of the MFB (imMFB, rate RD participants on the Bipolar Affective Disorder slMFB) and analysed them separately. As a methodo- Dimension Scale (BADDS) – a dimensional scale for logical refinement of previous studies, we employed rating lifetime psychopathology in bipolar and uni- the damped Richardson–Lucy (dRL) algorithm polar disorders, taking in to account the number and (Dell’acqua et al. 2010), which in contrast to diffusion severity
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