Three White Matter Pathways Linked to Sustained Response to Depression DBS

The central challenge in deep brain stimulation for severe depression may be less about finding the right brain region than ensuring stimulation reaches the right connections within it. A multi-cohort study from Mount Sinai links sustained improvement after subcallosal cingulate stimulation to engagement of three white matter pathways, adding evidence for surgical planning based on individual brain connectivity.

Published October 1 in the American Journal of Psychiatry, the study analyzed the largest group assembled across independent cohorts of patients treated with subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression. The team found that better long-term outcomes were consistently associated with stimulation of the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

Why the connections matter

DBS delivers controlled electrical signals through electrodes implanted in the brain. In depression, researchers are studying the approach for people whose symptoms have not improved enough with standard treatments. One persistent challenge is placing the electrodes so stimulation engages the intended neural circuitry.

The electrical field around an electrode can influence connected regions through white matter, the fibers that link parts of the brain. That means two people with electrodes in nearly the same anatomical position may receive stimulation across different networks—and may have different clinical outcomes. The study’s findings suggest that electrode coordinates alone may not capture whether the treatment is reaching the pathways associated with lasting improvement.

The researchers combined computer models of the electrical fields around implanted electrodes with brain connectivity maps. They used those models to estimate which pathways were stimulated, then compared the results across patient groups, including participants in the BROADEN trial and a cohort from the University of Toronto, where SCC DBS was originally developed.

The three pathways showed a consistent relationship with sustained improvement across the groups. A notable pattern emerged among patients who had not responded after two years: their stimulation did not appear to engage the left cingulum bundle. The study did not test whether repositioning electrodes to reach that pathway would improve symptoms, so the finding points to a possible explanation for nonresponse rather than a proven remedy.

From anatomical placement to connectivity-guided targeting

Mount Sinai and Emory University researchers have spent years examining the role of brain networks in SCC DBS. Earlier work published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry, and Nature identified pathways associated with successful treatment and developed a planning method based on brain connectivity maps.

The new analysis extends that work by asking whether the same connections matter in patients treated at other research centers, and whether variation in the pathways reached by stimulation could help explain why some patients do not benefit. Its results strengthen the rationale for connectome-based targeting: planning electrode placement around the connections likely to be engaged, rather than relying mainly on nearby anatomical landmarks.

That approach is already shaping the Abbott TRANSCEND clinical trial, a randomized, controlled study that uses individualized connectivity maps to guide SCC DBS treatment. Helen Mayberg, MD, Mount Sinai Professor in Neurotherapeutics and founding Director of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai, said precise placement and confirmation that the intended target is engaged are essential early steps in a randomized trial of neuromodulation.

“We still have much to learn about which patients are most likely to benefit from stimulation of this particular target,” Mayberg said. She described matching patients to treatment through imaging-based signatures as a central research goal.

Brian Kopell, MD, Director of Mount Sinai’s Center for Neuromodulation, framed the findings as a shift in the targeting question: researchers need to know which connections within a brain area must be stimulated, not only which area to select. In a network disorder such as depression, he said, small differences in lead placement can determine whether the intended pathways are reached. Reproducibly engaging them could help explain why similar-looking placements produce different outcomes.

Personalized maps remain a work in progress

The analysis has an important imaging limitation: individual diffusion MRI scans, which can reveal a person’s white matter connections, were not available for every participant. Much of the work therefore relied on generalized connectivity maps rather than maps built from each patient’s own scan.

For the Emory cohort, the researchers could compare estimates based on generalized maps with those based on individual diffusion imaging. The two approaches produced consistent findings, supporting the pathway results. Still, that comparison does not settle how much patient-specific imaging can improve targeting or outcomes; further work is needed to establish its value.

Nor do the three pathways appear to determine response on their own. The study focused on identifying which connections should receive stimulation. Researchers still need to learn which patients are likely to benefit from SCC DBS and how settings should change over the course of treatment.

Future studies will examine whether additional imaging measures—including white matter integrity and functional connectivity—can help select patients, refine electrode placement, and guide stimulation settings. Ki Sueng Choi, PhD, Associate Professor and Imaging Core Leader at Mount Sinai’s Center for Advanced Circuit Therapeutics, said the next step is to characterize structural and functional brain states along the pathways. That could support more detailed models for tailoring amplitude, frequency, and pulse width.

The study received support from the National Institutes of Health BRAIN Initiative through grant UH3NS103550, the Hope for Depression Research Foundation, and the DANA Foundation. Abbott’s Neuromodulation business provided data from the BROADEN trial and did not take part in designing or analyzing this study.

The authors disclosed financial and intellectual property relationships relevant to the work. Kopell, Mayberg, Choi, and Martijn Figee serve as paid Abbott Laboratories consultants. Mayberg is a named co-inventor of a subcallosal cingulate DBS method licensed to Abbott and has received royalty payments from Functional Neuroscience, with eligibility for future payments. Mayberg, Kopell, and Choi are also named co-inventors on a Mount Sinai patent application for a technique to identify optimal electrode placement; the technology remains unlicensed, though the approach is used in TRANSCEND.

The practical takeaway is that successful DBS may depend on whether stimulation reaches a particular network, not simply where a lead sits on an anatomical map. The three pathways offer researchers a more specific target to test as they develop patient-level imaging and stimulation strategies.

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