Scientists Identify 3 Brain Connections Linked to Lasting Relief From Severe Depression

Scientists at Mount Sinai have identified three white matter pathways in the brain associated with sustained improvement among patients receiving deep brain stimulation (DBS) for treatment-resistant depression. The findings could help researchers refine this experimental treatment by improving the precision of electrode placement and understanding why some patients respond better than others.

Published on October 1 in the American Journal of Psychiatry, the study analysed the largest group of patients assembled across multiple independent cohorts to date who had undergone subcallosal cingulate deep brain stimulation (SCC DBS) for severe depression that had not improved sufficiently with conventional treatments.

The researchers found that lasting clinical improvement was consistently associated with electrical stimulation reaching three specific pathways: the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

The results support an approach known as connectome-based targeting, which uses maps of brain connectivity to guide surgeons towards the neural pathways most relevant to treatment. Rather than relying primarily on anatomical landmarks, this method aims to identify the connections that need to be stimulated for better outcomes.

The approach has already helped inform the ongoing Abbott TRANSCEND clinical trial, a randomised, controlled study that uses individualised 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,” 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 told Science Daily. “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 Works For Treatment-Resistant Depression

Treatment-resistant depression describes a condition in which standard treatments have failed to provide adequate relief. For people living with persistent, severe symptoms, researchers are investigating DBS as a potential alternative.

The procedure involves surgically implanting electrodes in specific brain regions to deliver controlled electrical impulses to neural circuits involved in depression. One of the central challenges is determining the precise placement needed to achieve a sustained therapeutic response.

The effects of stimulation can extend beyond the brain tissue immediately surrounding an electrode. Electrical impulses can also influence white matter pathways, which connect different brain regions and allow signals to travel between them. Consequently, patients with electrodes implanted in nearly identical positions may experience different outcomes if the stimulation activates different neural connections.

Earlier research conducted by teams at Mount Sinai and Emory University helped establish the importance of these pathways. Studies published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry and Nature identified white matter connections associated with successful SCC DBS treatment. The researchers also developed a method for planning electrode placement using brain connectivity maps.

The latest investigation extended this work by examining whether the previously identified connections were also relevant to patients treated at other research centres. The researchers also sought to understand whether differences in the pathways receiving stimulation could help explain why some patients did not benefit.

Three Brain Pathways Associated With Sustained Improvement

The research team analysed data from several clinical studies, including the BROADEN trial and a patient cohort at the University of Toronto, where SCC DBS was originally developed.

Using computer models of the electrical fields produced by implanted electrodes, alongside maps of brain connectivity, the researchers estimated which white matter pathways were reached during stimulation. They then compared these patterns across the different patient cohorts.

The analysis identified three pathways consistently associated with lasting improvement:

• Cingulum bundle: A white matter pathway involved in communication between brain regions associated with emotion, cognition and related functions.
• Forceps minor: A group of fibres connecting the frontal regions of the brain across the corpus callosum.
• Medial uncinate fasciculus/ventral amygdalofugal pathways: Connections involved in communication between regions associated with emotional processing and other brain functions.

A particularly notable finding concerned the left cingulum bundle. Across the participating research sites, patients who had not responded to treatment after two years showed a lack of stimulation engagement with this pathway.

However, the study did not test whether repositioning electrodes to stimulate the left cingulum bundle would improve symptoms in these patients. The association therefore does not establish that stimulating this connection alone would guarantee a response.

Instead, the results offer a possible explanation for the differences in outcomes among patients whose electrodes appear to be placed in similar anatomical locations. An electrode may be positioned within the intended general region without adequately engaging all the pathways associated with sustained 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.”

Why Individualised Brain Mapping Could Improve Treatment

The findings highlight the potential of using detailed brain connectivity maps to guide surgical planning. By identifying the pathways that need to be reached, connectome-based targeting could help clinicians move beyond electrode placement based primarily on anatomical landmarks.

Nevertheless, the researchers emphasise that reaching the three identified pathways is unlikely to be the only factor determining whether a patient experiences meaningful improvement. Further research is needed to establish which individuals are most likely to benefit from SCC DBS and how stimulation settings should be adjusted throughout treatment.

The study also had limitations related to brain imaging. Individual diffusion magnetic resonance imaging (MRI) scans, which provide information about the organisation of white matter connections, were not available for every participant. Much of the analysis therefore relied on generalised brain connectivity maps rather than maps generated specifically for each patient.

For the Emory cohort, researchers compared findings from generalised connectivity maps with those obtained using individual diffusion imaging. Both approaches produced consistent results, offering additional support for the identified pathways. However, further investigation is required to determine how much patient-specific imaging improves treatment planning and clinical outcomes.

Future studies will examine whether additional imaging measures, including white matter integrity and functional connectivity, can help identify suitable candidates for DBS, improve electrode placement and guide decisions about stimulation settings.

These settings include amplitude, which determines the strength of electrical stimulation; frequency, which determines how frequently pulses are delivered; and pulse width, which refers to the duration of each electrical pulse.

“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 Therapies 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.”

What The Findings Mean For The Future Of Depression Treatment

The study adds to ongoing efforts to make deep brain stimulation more targeted and individualised for people with severe depression who have not responded adequately to conventional therapies.

By combining detailed maps of brain connections with personalised stimulation settings, researchers hope to better explain differences in treatment response and develop more effective approaches for selecting patients and planning procedures.

The identification of three pathways associated with sustained improvement provides a more specific framework for investigating how SCC DBS affects the brain’s interconnected networks. However, the findings do not establish that the procedure will work for every patient or that improved targeting will necessarily lead to better outcomes.

Further clinical research is needed to determine how these connections can be used to guide treatment reliably, identify those most likely to benefit and optimise stimulation over time. For now, the research represents another step towards more precise, personalised approaches to treating severe and persistent depression.