Highlights Stimulation closer to tracts was associated with better outcome in DBS for depression. Lead placement was consistent across (non)responders w.r.t. anatomical landmarks. Tractography-guided surgery needed to ensure tracts lie within activated tissue.

Objective: Deep brain stimulation (DBS) is an innovative treatment for treatment-resistant depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%). Methods: We associated distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response. We performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response. Results: Stimulation closer to both tracts was significantly correlated to a larger symptom decrease (r=0.61, p=0.02), suggesting that stimulation more proximal to the tracts was beneficial. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy. Conclusions: Our results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.