Summary: A new Mount Sinai study provides the first direct evidence that deep brain stimulation (DBS) can physically remodel white matter pathways and rewire large-scale neural networks. The findings show that DBS does more than transiently change electrical activity: delivering high-frequency impulses to subcortical targets drives structural plasticity, increasing myelination and repairing disrupted mood-regulation circuits in severe, treatment-resistant depression.
Key Facts
- The diagnostic blind spot solved: Although DBS is FDA-approved for conditions such as Parkinson’s disease, essential tremor, epilepsy, and OCD—and has delivered sustained benefit for some patients with treatment-resistant depression—its long-term biological mechanisms were unclear. This study demonstrates a durable, structural mechanism beyond short-term electrical modulation.
- Direct biological isolation: Co-senior authors Dr. Peter Rudebeck and Dr. Helen Mayberg targeted white matter adjacent to the subcallosal anterior cingulate cortex (SCC) in a non-human primate model. Using healthy animals removed confounds from underlying disease, allowing isolation of the stimulation’s direct effects.
- White matter remodeling: SCC-targeted DBS selectively increased fractional anisotropy (FA), an MRI marker of white matter microstructure, within the cingulum bundle—an important tract for mood regulation.
- Cellular myelination changes: Microscopic analysis showed growth in both the number of myelinated oligodendrocytes and the extent of myelination along the stimulated pathway, a change that would improve the speed and reliability of signal transmission through mood-related circuits.
- Network-level reconfiguration: The intervention produced widespread alterations in functional connectivity across brain networks, most prominently affecting the default mode network, which is strongly implicated in depression, anxiety, and maladaptive rumination.
- Translational horizon: Supported in part by the NIH BRAIN Initiative, the Nash Family Center for Advanced Circuit Therapeutics is moving this work toward human clinical studies. Demonstrating DBS-driven white matter plasticity opens the door to optimizing electrode strategies and exploring non-surgical approaches that target the same structural remodeling.
Source: Mount Sinai Hospital
Researchers at the Icahn School of Medicine at Mount Sinai report the first direct evidence that deep brain stimulation can remodel white matter and alter communication across brain-wide networks, identifying a structural mechanism that may underlie DBS-related recovery in severe depression.
Published in Nature Neuroscience (June 1), the study targeted white matter near the subcallosal anterior cingulate cortex (SCC), a validated human target for depression therapy. Deep brain stimulation involves surgically implanted electrodes that deliver high-frequency electrical impulses to specific brain regions; while clinical benefits for several neurological and psychiatric disorders are well established, how DBS produces sustained therapeutic change has been uncertain.
Using macaque models, the Mount Sinai team isolated the direct effects of SCC-DBS without interference from disease processes. The researchers observed a selective rise in fractional anisotropy in the cingulum bundle, a tract strongly linked to mood regulation. At the cellular level, stimulated tissue contained more myelinated oligodendrocytes and showed increased myelin content, indicating active structural rebuilding of axonal insulation. These cellular changes support faster, more reliable long-range signaling across affected circuits.
In parallel with local structural remodeling, SCC-DBS reshaped functional connectivity across multiple networks. Changes in interactions between the SCC and other brain regions included pronounced effects on the default mode network, a circuit consistently associated with depressive symptoms and persistent negative thinking. Together, the microstructural and network-level results suggest a mechanism by which DBS can produce durable clinical improvements—by changing the brain’s physical architecture as well as its dynamic communication patterns.
“These findings change how we think about DBS,” said Peter Rudebeck, PhD. “For the first time, we show DBS can remodel white matter structure, effectively rewiring circuits implicated in depression.” Co-senior author Helen Mayberg, MD, added that the work fills a major gap in understanding how stimulation contributes to long-term recovery—an outcome seen in clinical DBS trials for depression.
The investigators and their collaborators are now exploring whether similar white matter remodeling occurs in human patients receiving SCC-DBS for depression, and they plan further studies to map how stimulation alters activity patterns at the single-neuron and network levels. These efforts aim to refine stimulation methods and to inform the design of noninvasive treatments that reproduce beneficial structural effects without surgery.
Key Questions Answered
Q: Why is it significant that DBS physically changes white matter rather than only modulating electrical activity?
A: Modulating electrical activity can be temporary, tied to active stimulation. Structural changes in white matter represent durable architectural upgrades—improved myelination and increased oligodendrocyte numbers—that can sustain better communication across mood-regulating circuits and support long-term therapeutic effects.
Q: What are oligodendrocytes and how do they help in depression?
A: Oligodendrocytes are glial cells that wrap axons with myelin, enhancing the speed and fidelity of neural signaling. In severe depression, disruptions in these communication pathways can occur. The study found DBS increases myelinated oligodendrocytes and myelin density, strengthening the structural highways that connect mood-regulatory regions.
Q: How can a surgical discovery guide non-surgical therapies?
A: By identifying the cellular and circuit-level targets responsible for durable recovery, researchers can design noninvasive interventions—such as refined magnetic or electrical stimulation techniques—that aim to induce similar white matter remodeling without implanting electrodes.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff to clarify translational implications.
About this neurotech and depression research news
Author: Elizabeth Dowling
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
Image credit: Neuroscience News
Original Research (open access): Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks. Authors: Satoka H. Fujimoto, Atsushi Fujimoto, Catherine Elorette, Adela Seltzer, Emma Andraka, Keondre Herbert, Gaurav Verma, William G. M. Janssen, Lazar Fleysher, Davide Folloni, Ki Sueng Choi, Brian E. Russ, Helen S. Mayberg & Peter H. Rudebeck. DOI: 10.1038/s41593-026-02301-4
Abstract
Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks
Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant neurological and psychiatric disorders. Despite clinical success in some conditions, the anatomical and functional mechanisms underlying DBS have been poorly understood.
This study delivered DBS to white matter adjacent to the subcallosal anterior cingulate cortex (SCC-DBS) in macaques, modeling a human depression treatment approach. SCC-DBS produced a selective increase in fractional anisotropy in the cingulum bundle, associated with white matter microstructure.
At the cellular level, these imaging changes corresponded with increases in myelinated oligodendrocytes and the degree of myelination in the mid-cingulum bundle. SCC-DBS also altered brain-wide functional connectivity, particularly between the SCC and networks such as the default mode network, which has been implicated in depression.
Together, these results indicate that white matter remodeling and selective network changes may contribute to the therapeutic efficacy of DBS.