Non-Invasively Targeting, Probing, and Modulating a Deep Brain Circuit for Depression Alleviation

Effective repetitive transcranial magnetic stimulation (rTMS) treatment for depression has often focused on modulating the subgenual anterior cingulate cortex (sgACC), yet no studies have related TMS-evoked responses in the sgACC to clinical effects following rTMS. We used interleaved single-pulse TMS/fMRI to demonstrate circuit engagement via TMS-evoked responses in the sgACC to stimulation of functionally-connected cortical targets in a cohort study of unmedicated depressed patients (n=36; ClinicalTrials.gov ID NCT04014959). Targets were identified using rs-fMRI scans seeding the sgACC to identify individualized connectivity clusters. TMS/fMRI was assessed before and after a 3-day open label intervention using intermittent theta burst (iTBS) rTMS targeting the sgACC pathway. TMS-evoked fMRI BOLD responses in the sgACC and depression symptom scores were assessed pre- and post-intervention. Pre-intervention TMS-evoked response magnitude in the sgACC predicted depression improvement: more negative evoked responses were associated with greater clinical improvement. Larger post-intervention changes in evoked responses were also associated with depression improvement. The prognostic sgACC associations were specific to the intervention pathway and significantly associated with depression but not anxiety improvement. Here we demonstrate causal evidence of sgACC engagement with TMS/fMRI and show the clinical relevance of engagement and modulation of the targeted prefrontal-sgACC circuit.