Three White Matter Pathways Predict Lasting DBS Response in Depression

Sustained improvement after subcallosal cingulate deep brain stimulation for treatment-resistant depression tracks with electrical engagement of exactly three white matter pathways, according to the largest multi-cohort analysis of the therapy to date, published October 1 in the American Journal of Psychiatry (183(10):764).

The finding matters at millimeter scale. Patients who failed to improve after two years of SCC DBS shared one striking pattern across all study sites: stimulation that never reached the left cingulum bundle. Electrodes sat in the correct general region. The connection stayed silent.

For clinicians who program or refer for DBS in severe depression, the study reframes the surgical question — not which area to stimulate, but which fibers within it must carry the current.

Which pathways did the analysis implicate?

Researchers led by corresponding author Ki Sueng Choi, PhD, of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai, pooled data from several clinical studies, including Abbott's BROADEN trial and a University of Toronto cohort — the center where SCC DBS was originally developed. It is the largest patient group assembled across independent cohorts to date.

Using computer models of the electrical fields generated by implanted electrodes, combined with brain connectivity maps, the team estimated which pathways received stimulation in each patient. Lasting improvement correlated consistently with current reaching:

• the cingulum bundle,
• the forceps minor,
• the medial uncunate fasciculus/ventral amygdalofugal pathways.

The non-responder signal was equally consistent. Across sites, patients without benefit at two years showed absent engagement of the left cingulum bundle. The investigators did not test whether relocating electrodes to capture that pathway would rescue symptoms — an open question, not a demonstrated one.

Why do similar electrode positions produce different outcomes?

DBS does not act only on the tissue adjacent to the contact. Current propagates through white matter into larger networks, so two patients with leads placed in nearly indistinguishable anatomical positions can diverge clinically if the engaged fiber sets differ. This study offers a mechanistic account for a phenomenon every DBS program has observed.

"For a network disorder such as depression, millimeters can determine whether stimulation reaches the pathways we intend to modulate," said Brian Kopell, MD, Director of the Center for Neuromodulation at Mount Sinai. "Identifying and reproducibly engaging those pathways gives us a more precise surgical target and a framework for understanding why otherwise similar electrode placements may produce different clinical outcomes."

What changes for surgical targeting?

The results strengthen the case for connectome-based targeting — planning electrode placement from individual connectivity maps rather than anatomical landmarks alone. That strategy already informs the ongoing Abbott TRANSCEND trial, a randomized, controlled study using personalized connectivity maps to guide SCC DBS.

"This study underscores the importance of individualized surgical targeting for achieving optimal outcomes with deep brain stimulation for depression," said Helen Mayberg, MD, Mount Sinai Professor in Neurotherapeutics and founding Director of the Nash Family Center. "In any randomized controlled trial of a neuromodulation treatment, precise lead placement and confirmation that the intended brain target has been engaged are essential first steps."

The work builds on a documented lineage: Mount Sinai and Emory teams identified the relevant pathways and developed connectivity-based planning in papers published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry, and Nature. The new study's contribution is external validation across independent cohorts — plus a candidate explanation for non-response.

Note the regulatory status. SCC DBS for depression remains investigational; no device discussed here is FDA-cleared for this indication. All data are human clinical data.

What are the limits?

Electrode placement alone is unlikely to determine outcome. Individual diffusion MRI scans were unavailable for many participants, so much of the analysis relied on generalized rather than patient-specific connectivity maps. For the Emory group, both approaches produced consistent results, but the value of per-patient imaging needs dedicated study.

"Our findings show precisely engaging these white matter pathways is a critical first step toward sustained response," Choi said. "The next step is to characterize abnormal functional and structural brain states along these pathways to build more detailed models for setting patient-specific stimulation parameters, including amplitude, frequency, and pulse width."

Future work will test whether white matter integrity and functional connectivity measurements can refine patient selection, electrode placement, and stimulation settings. The National Institutes of Health BRAIN Initiative (grant UH3NS103550), the Hope for Depression Research Foundation, and the DANA Foundation funded the research; Abbott supplied BROADEN data without participating in design or analysis. If connectomic signatures hold up prospectively, the field moves closer to matching each patient to the lead position and parameter set their anatomy demands.