Link between structural connectivity of the medial forebrain bundle, functional connectivity of the ventral tegmental area, and anhedonia in unipolar depression

The ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) are essential for experiencing pleasure and initiating motivated behaviour. The VTA, NAcc, and PFC are connected through the medial forebrain bundle (MFB). In humans, two branches have been described: an infero-medial branch (imMFB) and a supero-lateral branch (slMFB). This study aimed to explore the associations between structural connectivity of the MFB, functional connectivity (FC) of the VTA, anhedonia, and depression severity in patients with depression. Fifty-six patients with unipolar depression and 22 healthy controls matched for age, sex, and handedness were recruited at the University Hospital of Psychiatry and Psychotherapy in Bern, Switzerland. Diffusion-weighted imaging and resting-state functional magnetic resonance imaging scans were acquired. Using manual tractography, the imMFB and slMFB were reconstructed bilaterally for each participant. Seed-based resting-state FC was computed from the VTA to the PFC. Hedonic tone was assessed using the Fawcett-Clark Pleasure Scale. We identified reduced tract volume and reduced number of tracts in the left slMFB. There was an increase in FC between the VTA and right medial PFC in patients with depression. Depression severity was associated with reduced tract volume and fewer tracts in the left slMFB. Reduced hedonic tone was associated with reduced tract volume. Conversely, reduced hedonic tone was associated with increased FC between the VTA and the PFC. In conclusion, our results suggest reduced structural connectivity of the slMFB in patients with depression. Increases in FC between the VTA and PFC may be associated with anhedonia or compensatory hyperactivity.