Scientists at Mount Sinai have identified three important brain connections associated with long-term improvement in patients receiving deep brain stimulation (DBS) for severe depression that has not responded to conventional treatments. The discovery could help researchers make this experimental therapy more precise and effective.
Published October 1 in the American Journal of Psychiatry, the research examined the largest group of patients assembled across multiple independent cohorts to date who had received subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression.
The researchers found that lasting improvements were consistently associated with electrical stimulation reaching three specific white matter pathways: the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.
These findings strengthen the case for using detailed maps of the brain’s connections to determine exactly where electrodes should be implanted, rather than choosing their positions based primarily on anatomical landmarks. Known as connectome-based targeting, this strategy has already helped shape the ongoing Abbott TRANSCEND clinical trial, a randomized, controlled study that uses individualized brain connectivity maps to guide SCC DBS treatment.
“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 for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai. “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. We still have much to learn about which patients are most likely to benefit from stimulation of this particular target, but developing imaging-based signatures that can match patients to their optimal treatment remains a central goal of our research.”
How Deep Brain Stimulation Targets Severe Depression
For people with treatment-resistant depression, standard therapies have failed to provide adequate relief. Researchers are investigating deep brain stimulation as a possible treatment for individuals living with severe, persistent symptoms.
The procedure involves surgically placing electrodes inside the brain to deliver controlled electrical signals to circuits involved in depression. However, positioning the electrodes correctly remains one of the greatest challenges.
Electrical stimulation does not simply affect the brain tissue closest to an implanted electrode. It can also influence larger networks through the white matter pathways that connect different brain regions. As a result, two patients with electrodes implanted in nearly identical locations may experience very different outcomes depending on which connections are actually stimulated.
Earlier research from Mount Sinai and Emory University helped establish the importance of these networks. In studies published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry, and Nature, the teams identified white matter pathways associated with successful SCC DBS treatment and developed a method for planning electrode placement using brain connectivity maps.
The latest investigation sought to determine whether those connections were also important in patients treated at other research centers. Scientists also wanted to understand whether differences in the pathways reached by stimulation could help account for patients who did not benefit.
Three Brain Connections Linked to Lasting Improvement
To investigate, the researchers examined information from several clinical studies, including the BROADEN trial and a patient cohort at the University of Toronto, where SCC DBS was originally developed.
They used computer models of the electrical fields generated by implanted electrodes alongside maps of brain connectivity. This allowed them to estimate which pathways received stimulation and compare those patterns across different patient groups.
The results showed a consistent relationship between sustained improvement and stimulation of the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.
One finding was especially notable. Across the study sites, patients who had not responded to treatment after two years showed a lack of stimulation engagement with the left cingulum bundle.
The researchers did not investigate whether moving electrodes to reach this pathway would improve those patients’ symptoms. Nevertheless, the pattern offers a possible explanation for why apparently similar electrode placements can produce different results. An electrode might be positioned in the correct general region but still fail to activate all the connections associated with lasting improvement.
“This study addresses an important question in DBS: not simply which area of the brain to stimulate, but which connections within that area need to be engaged,” said Brian Kopell, MD, Director of the Center for Neuromodulation at Mount Sinai. “For a network disorder such as depression, millimeters can determine whether stimulation reaches the pathways we intend to modulate. 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.”
Toward More Personalized Depression Treatments
Although reaching these three pathways appears important, the researchers emphasize that electrode placement alone is unlikely to determine whether a patient improves.
The investigation concentrated on identifying the brain connections that should receive stimulation. Additional studies are needed to determine which individuals are most likely to benefit from SCC DBS and how electrical stimulation should be adjusted as treatment continues.
There were also limitations to the brain imaging data. Individual diffusion MRI scans, which can provide information about a person’s white matter connections, were not available for every participant. Consequently, much of the analysis used generalized maps of brain connectivity rather than maps created specifically for each patient.
For the Emory patient group, the researchers were able to compare results obtained from generalized connectivity maps with those based on individual diffusion imaging. Both approaches produced consistent findings, providing further support for the importance of the identified pathways. However, more research is needed to establish the value of patient-specific imaging.
Future investigations will explore whether additional brain imaging measurements, including white matter integrity and functional connectivity, can help identify suitable patients, improve electrode placement, and guide treatment settings.
“Our findings show precisely engaging these white matter pathways is a critical first step toward sustained response,” said Ki Sueng Choi, PhD, Associate Professor, Imaging Core Leader at the Center for Advanced Circuit Therapeutics at Mount Sinai, and corresponding author of the study. “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, for precision medicine.”
By combining increasingly detailed brain maps with personalized stimulation settings, scientists hope to better understand why some people experience lasting relief while others do not. The findings represent another step toward developing more targeted treatments for severe depression, although further clinical research is necessary to establish how much these approaches can improve outcomes.
Research Funding and Disclosures
The research 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 supplied data from the BROADEN clinical trial but did not participate in designing or analyzing the current study.
Conflict of Interest Disclosures: Dr. Brian Kopell serves as a paid consultant to Abbott Laboratories.
Dr. Helen Mayberg is a named co-inventor of a method that uses deep brain stimulation (DBS) in a particular brain region (the subcallosal cingulate area) to treat treatment-resistant depression. The method was licensed to Abbott Laboratories. Dr. Mayberg has received royalty payments from Functional Neuroscience related to this technology and is eligible to receive additional payments in the future. She also serves as a paid consultant to Abbott Laboratories in connection with its clinical trials involving DBS for depression.
Dr. Ki Sueng Choi and Dr. Martijn Figee are also paid consultants to Abbott Laboratories.
Dr. Mayberg, Dr. Kopell, and Dr. Choi are named co-inventors on a patent application covering a technique for identifying optimal electrode placement in deep brain stimulation for depression. The patent application was filed through Mount Sinai, and the technology remains unlicensed. However, the approach has been used in the TRANSCEND clinical trial.
