Joint Anatomical, Histological, and Imaging Investigation of the Midbrain Target Region for Superolateral Medial Forebrain Bundle Deep Brain Stimulation

Introduction: Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) is currently being researched in clinical trials and open case series as a therapeutic option for treatment-resistant major depressive disorder and treatment-resistant obsessive- compulsive disorder (TR-OCD). There are numerous publications describing stimulation in such proximity to the ventral tegmental area (VTA) and open questions remain concerning the stimulation target and its functional environment. As of right now, we are not aware of any publications that compare the typical electrode placements with the histologically supported tractographic depiction of the target structure. Methods: We used three cadaver midbrain samples with presumed unaltered anatomy. After fi xation, staining and slicing, the histological samples were warped to the Montreal Neurological Institute (MNI) big brain environment. Utilizing a tractographic atlas, a qualitative analysis of the typical slMFB stimulation site in the lateral VTA utilizing a subset of clinically implanted DBS electrodes in n = 12 patients, successfully implanted for TR-OCD was performed. Results: A joint qualitative overlay analysis of predominantly tyrosine hydroxylase stained histology at different resolutions in an anatomical common space was achieved. Localization of the DBS lead bodies was found in the typical positions in front of the red nuclei in the lateral VTA. DBS lead tip region positions explained the oculomotor side effects of stimulation related to paranigral or parabrachial pigmented sub-nuclei of the VTA, respectively. The location of active electrode contacts suggests downstream and antidromic effects on the greater VTA related medial forebrain bundle system. Conclusion: This is the fi rst dedicated joint histopathological overlay analysis of DBS electrodes targeting the slMFB and lateral VTA in a common anatomical space. This analysis might serve to better understand the DBS target region for this procedure.