Biomarker Driven, Parcel-Guided TMS for Suicidal Thoughts and Behaviors in Depression

Background: Left dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) is FDA-approved for treatment resistant depression (TRD). Some open-label rTMS studies have found rapid reductions in suicidal thoughts and behaviors (STBs). Patients with STBs often report suicide-related imagery during crisis. Mounting evidence suggests that function and connectivity of the frontal and visual cortex is disrupted in patients with STBs. We have recently developed a new biomarker to measure fronto-visual dysfunction in STBs and established its utility in predicting STBs response to brain stimulation therapies. We have already examined the feasibility of parcel-guided TMS (pgTMS) in the clinical setting using a recently published surface-based, multimodal parcellation; but in that study, we targeted the fronto-limbic pathway (area 46) in TMS-resistant TRD patients, while in this study we aim to target the fronto-visual biomarker (area p9 46v) in TRD patients with active STBs.

Objectives: To test (1) the neurobiological mechanisms and (2) clinical outcomes underlying pgTMS targeting the fronto-visual biomarker (area p9-46v).

Methods: In 20 TRD patients with active STBs, an intensive protocol of accelerated intermittent theta burst stimulation (iTBS) will be applied over the left DLPC parcel p9-46v, in a double-blind sham-controlled pilot study. Study participants will be randomized 1:1 to either pgTMS (n=10) or sham rTMS (n=10). Patients will receive 20 iTBS sessions over 4 days. Resting state functional connectivity (rsfc) fMRI will be assessed between parcel p9-46v and predefined nodes within the visual network pre/post rTMS. Secondary analyses will compare pgTMS results with collected data on rsfc pre/post sdTMS and ECT.

Results: There will be no significant difference in baseline STBs scores between the groups. Alterations in rsfc between frontal and visual networks will differ significantly over time between the groups. We will observe a significant decrease in STBs over time, unrelated to depression-response. Significantly more patients treated with pgTMS will achieve a major clinical response compared to the reference groups. Improvements in STBs will correlate with alterations in frontal-visual rsfc within each treatment group.

Conclusion: The outcome of our study will provide preliminary support for the efficacy of pgTMS targeted at the left DLPFC parcel p9-46v for STBs compared to that of sham and existing brain stimulation therapies (based on previously and separately acquired data). Future prospective, biomarker-driven clinical trials appear warranted.