Published in the October 1 issue of the American Journal of Psychiatry, the study examined the largest group of patients to date from multiple independent cohorts who underwent subcallosal cingulate cortex deep brain stimulation (SCC DBS) for treatment-resistant depression.

The researchers found that sustained improvement was consistently associated with electrical stimulation reaching three specific white matter pathways:

• the cingulate fasciculus;
• the forceps minor; and
• the medial uncinate fasciculus/ventral amygdala pathway.

These findings support using detailed maps of the brain’s connections to determine where DBS electrodes should be implanted, rather than relying primarily on anatomical landmarks. This approach, known as connectome-based targeting, is already helping shape the ongoing Abbott TRANSCEND clinical trial, a randomized controlled study that uses personalized brain connectivity maps to guide SCC DBS treatment.

“This study highlights the importance of individualized surgical targeting to achieve optimal outcomes with deep brain stimulation for depression,” said Helen Mayberg, MD, Mount Sinai Professor of Neurotherapeutics and founder of the Nash Family Center for Advanced Circuit Therapy at the Icahn School of Medicine at Mount Sinai.

“In randomized controlled trials of neuromodulatory treatments, precise lead placement and confirmation that the intended brain target is engaged are critical first steps. While there is still much to learn about which patients are likely to benefit most from stimulation of this particular target, developing image-based signatures that can match patients to optimal treatment remains a central goal of our research.”

How deep brain stimulation targets treatment-resistant depression

For people with treatment-resistant depression, standard treatments may not provide sufficient relief. Researchers are investigating deep brain stimulation as a possible treatment for individuals living with severe and persistent symptoms.

DBS involves surgically placing electrodes in the brain to deliver controlled electrical signals to circuits involved in depression. However, accurately positioning the electrodes remains one of the procedure’s biggest challenges.

Electrical stimulation affects more than the brain tissue closest to the implanted electrodes. It may also influence larger neural networks through white matter pathways that connect different brain regions. As a result, two patients with electrodes implanted in approximately the same location may experience different outcomes depending on which connections are stimulated.

Previous 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, researchers developed a method to identify white matter pathways associated with successful SCC DBS treatment and to plan electrode placement using brain connectivity maps.

In the latest study, the researchers examined whether these associations also appeared in patients treated at other study centers. They also investigated whether differences in the pathways reached by stimulation could help explain why some patients do not respond to treatment.

Three brain connections associated with lasting improvement

Researchers analyzed information from several clinical studies, including the BROADEN trial and a patient cohort at the University of Toronto, where SCC DBS was first developed.

They used a computer model of the electrical field generated by each patient’s implanted electrodes together with a brain connectivity map. This allowed them to estimate which pathways were stimulated and compare those patterns across patient groups.

The results showed a consistent relationship between sustained improvement and stimulation of the cingulate fasciculus, forceps minor, and medial uncinate fasciculus/ventral amygdala pathway.

One finding was particularly notable: Across study sites, patients who did not respond to treatment after two years showed a lack of stimulation involvement in the left cingulate bundle.

The researchers did not investigate whether moving the electrodes to reach this pathway would improve patients’ symptoms. However, the pattern offers a possible explanation for why similar electrode placements can produce different results. Even when electrodes are placed in the correct general area, they may not activate every connection associated with sustained improvement.

“This study addresses an important question in DBS: not just which regions of the brain to stimulate, but which connections within those regions need to be engaged,” said Brian Kopel, MD, director of the Mount Sinai Neuromodulation Center.

“For network diseases such as depression, we can determine millimeter by millimeter whether a stimulus will reach the pathway we are trying to modulate. Identifying and reproducibly engaging these pathways provides more precise surgical targeting and provides a framework for understanding why similar electrode placements may have different clinical outcomes.”

Toward more personalized depression treatment

Although reaching the three pathways appears to be important, the researchers emphasize that electrode placement alone is unlikely to determine whether a patient improves.

The study focused on identifying the brain connections that should receive stimulation. Additional research is needed to determine which patients are most likely to benefit from SCC DBS and how electrical stimulation should be adjusted as treatment continues.

The brain imaging data also had limitations. Individual diffusion MRI scans, which can provide information about a person’s white matter connectivity, were not available for all participants. Consequently, many analyses used generalized brain connectivity maps rather than maps created specifically for each patient.

For the Emory patient group, researchers compared results from generalized connectivity maps with results based on individual diffusion imaging. Both approaches produced consistent findings, further supporting the importance of the identified pathways. However, more research is needed to establish the value of patient-specific imaging.

Future studies will examine whether additional brain imaging measurements, including white matter integrity and functional connectivity, can help identify appropriate patients, improve electrode placement, and guide treatment settings.

“Our findings demonstrate that precisely engaging these white matter pathways is a critical first step toward sustained responses,” said Ki Sueng Choi, PhD, imaging core leader and associate professor in the Center for Advanced Circuit Therapies at Mount Sinai and corresponding author of the study.

“The next step is to characterize the abnormal brain functional and structural states along these pathways in order to build more detailed models to set patient-specific stimulation parameters such as 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 more targeted treatments for severe depression, but further clinical research is needed to determine how much these approaches can improve outcomes.

Research funding and disclosures

This research was supported by the National Institutes of Health BRAIN Initiative through grant UH3NS103550, the Depression Research Foundation, and the DANA Foundation.

Abbott’s neuromodulation business provided data from the BROADEN clinical trial but did not participate in the design or analysis of the current study.

Conflict of interest disclosures: Dr. Brian Kopel serves as a paid consultant for Abbott Laboratories.

Dr. Helen Mayberg is credited as a co-inventor of the use of deep brain stimulation in the subcallosal cingulate region to treat treatment-resistant depression. This method was licensed to Abbott Laboratories. Dr. Mayberg has received royalty payments from Functional Neuroscience in connection with this technology and is eligible for additional payments in the future. She also serves as a paid consultant to Abbott Laboratories in connection with clinical trials on DBS for depression.

Dr. Ki Sueng Choi and Dr. Martijn Figee are also paid consultants for Abbott Laboratories.

Dr. Mayberg, Dr. Kopel, and Dr. Choi have been named co-inventors on a patent application for technology designed to identify optimal electrode placement in deep brain stimulation for depression. The application was filed through Mount Sinai, and the technology remains unlicensed. However, this approach is being used in the TRANSCEND clinical trial.