Millimeters matter: Scientists pinpoint three brain pathways behind lasting depression relief from DBS

For patients with depression so severe that medications, psychotherapy, and electroconvulsive therapy have all failed, a surgically implanted electrode delivering electrical pulses deep in the brain remains one of the last options. Whether that electrode actually works, a new study finds, may come down to millimeters — and which brain connections it manages to reach.

Researchers at Mount Sinai have identified three specific white matter pathways whose stimulation is consistently linked to sustained symptom relief in patients receiving subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression. Published October 1 in the American Journal of Psychiatry, the study drew on the largest multi-site patient group ever assembled for this type of research, pulling data from participants in the BROADEN trial and a cohort at the University of Toronto, the institution where SCC DBS was first developed.

The three pathways are the cingulum bundle, the forceps minor, and the medial uncinate fasciculus/ventral amygdalofugal pathway. Using computer models of the electrical fields generated by implanted electrodes alongside detailed maps of brain connectivity, the researchers estimated which pathways each patient's stimulation actually reached — then compared those patterns against clinical outcomes across the different sites.

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.— Brian Kopell, MD, Director of the Center for Neuromodulation at Mount Sinai

The finding cuts to a long-standing puzzle in DBS research: two patients with electrodes implanted in nearly identical locations can have dramatically different outcomes. The study offers a concrete explanation. Even when an electrode is placed in broadly the right area of the brain, it may not reach all the connections tied to durable improvement — a consequence of the fact that electrical stimulation extends beyond the tissue immediately around the electrode, traveling through white matter pathways to influence wider brain networks.

One pattern stood out with particular clarity. Across every study site, patients who had not responded to treatment after two years shared a consistent feature: insufficient stimulation of the left cingulum bundle. The researchers did not test whether repositioning those patients' electrodes to better reach that pathway would have improved their symptoms, but the pattern offers a potential explanation for otherwise unexplained treatment failures.

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.— Brian Kopell, MD, Director of the Center for Neuromodulation at Mount Sinai

The results build on earlier work by Mount Sinai and Emory University, published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry, and Nature, which first identified white matter pathways associated with successful SCC DBS and developed a method for planning electrode placement using brain connectivity maps. Connectome-based targeting, as that method is called, has already influenced the design of the ongoing Abbott TRANSCEND clinical trial, a randomized, controlled study in which individualized brain connectivity maps are used to direct SCC DBS treatment.

This study underscores the importance of individualized surgical targeting for achieving optimal outcomes with deep brain stimulation for depression. 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.— 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

A separate but related line of research from the same institution adds a deeper biological dimension to these findings. A study published June 1 in Nature Neuroscience — also from the Icahn School of Medicine at Mount Sinai — provided the first direct evidence that DBS does not merely shift electrical activity while the device is running. Working with a non-human primate model, researchers found that SCC DBS brings about physical changes in white matter: fractional anisotropy within the cingulum bundle — a marker tied to white matter integrity — rose selectively, as did both the count of myelinated oligodendrocytes and the extent of myelination along the pathway. In plain terms, the stimulation appeared to structurally rebuild and better insulate the brain circuits involved in mood regulation.

For the first time, we show that DBS does not simply alter electrical activity in the brain in the short term — it can actually remodel white matter structure, essentially rewiring brain circuits associated with depression.— Peter Rudebeck, PhD, Professor of Neuroscience and Psychiatry at the Icahn School of Medicine at Mount Sinai

Functional connectivity shifted broadly across the brain in the Nature Neuroscience study as well, with the default mode network — a cluster of regions closely tied to depression and rumination — showing particular involvement. Whether the same white matter remodeling takes place in human patients undergoing DBS for depression is a question the Mount Sinai team is now working to answer.

Now that we know DBS can drive structural plasticity in white matter, we can begin thinking about how to optimize stimulation approaches and potentially develop novel therapies that target these mechanisms through nonsurgical means.— Helen Mayberg, MD, Professor of Neurology, Neurosurgery, Psychiatry, and Neuroscience at the Icahn School of Medicine at Mount Sinai

Together, the two studies reframe what DBS is actually doing in the brain — and what needs to go right for it to work. The October findings tell clinicians which connections must be engaged; the June findings suggest that when they are engaged correctly and for long enough, the brain may not just be temporarily adjusted but structurally repaired. The researchers note, however, that electrode placement by itself is unlikely to account for whether a given patient improves, and that pinpointing which patients stand to benefit most from SCC DBS remains an open and pressing question.

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.— 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

Why it matters — For the estimated patients with depression that resists all standard treatments, these findings move DBS closer to a precision medicine — one where brain connectivity maps, not surgical approximation, guide where electrodes go and why some placements succeed where others fail.

Reported by sciencedaily.com, mountsinai.org, neurosciencenews.com