TMS Targets for Multiple Sclerosis Related Depression Derived Using a Precomputed Functional Connectome
William Drew1, Isaiah Kletenik1, Rohit Bakshi1, Michele Cavallari1, Tanuja Chitnis1, Bonnie Glanz1, Charles Guttmann1, Miklos Palotai1, Michael Fox1, Shan Siddiqi1
1Brigham and Women's Hospital
Objective:

Deriving TMS targets for multiple sclerosis related depression using a precomputed functional connectome.

Background:
Depression in multiple sclerosis (MS) is poorly responsive to conventional pharmacotherapy, highlighting the need for clinical TMS trials. However, it is unclear if MS depression is suitable for circuit-targeted therapeutics. We developed a technique for identifying treatment targets based on distributed brain circuits derived from symptom-causing brain lesions. We tested this technique using published maps that define circuits connected to lesions associated with greater depression and that have been shown to predict TMS outcomes.
Design/Methods:

We analyzed a recently-published “MS depression circuit map” based on the normative connectivity of brain lesions that increase risk of depression in MS (Siddiqi et al., Nature Mental Health 2023). We constructed a precomputed functional connectome using mean whole-brain functional connectivity of 292,019 brain voxels across 1,000 participants. We compared each voxel’s connectivity map to the MS depression circuit map using spatial correlations. Voxels whose connectivity maps most correlate with the MS depression circuit map are identified as potential TMS targets. As a comparator, we conducted the same analysis using a published depression circuit map derived from stroke lesions and penetrating head trauma (N=461), which has been shown to reveal better TMS targets (Siddiqi et al., Nature Human Behaviour 2021).

Results:

The peak lesion-derived TMS target for MS depression was at MNI coordinates (-38,44,34). This target was within 1cm of the TMS target derived from other lesion types located at (-44,38,30) and a previous TMS target derived from subgenual cingulate anti-correlations at (-42,44,30).

Conclusions:

The precomputed functional connectome is a high-resolution atlas of voxel-wise functional connectivity that reveals potential therapeutic neuromodulation targets by comparing their connectivity to a template brain map. Our proposed TMS target for MS depression is near the current clinical TMS targets for depression, suggesting that MS depression may respond to TMS.

10.1212/WNL.0000000000204117