Scientists discover deep brain stimulation physically reshapes the brain’s information superhighway

Scientists at Mount Sinai discovered that deep brain stimulation for depression physically reshapes white matter in the brain, altering communication across neural networks. The study in Nature Neuroscience shows that long-term benefits stem from structural remodeling, not just immediate electrical changes, explaining the delayed but sustained improvement in patients.

Deep brain stimulation is an emerging treatment for severe depression, but exactly how it alters the brain to relieve symptoms has remained somewhat of a mystery. A recent study published in Nature Neuroscience provides evidence that this therapy reshapes the physical structure of the brain’s wiring and alters communication across major neural networks. These findings suggest that the long-term benefits of the treatment might stem from physical remodeling of the brain rather than just immediate changes in electrical activity. Deep brain stimulation is a surgical procedure that involves implanting small wires, called electrodes, into specific areas of the brain. These electrodes connect to a device placed in the chest, which sends mild electrical impulses to the brain. Doctors frequently use this therapy to manage movement conditions like Parkinson’s disease. In recent years, the medical field has adapted the procedure to treat psychiatric conditions, particularly depression that does not respond to medication or therapy. When treating movement conditions, the electrodes target gray matter, which is the brain tissue made mostly of cell bodies. For depression, doctors instead target white matter. White matter consists of the bundles of nerve fibers, or axons, that connect different parts of the brain and allow them to communicate. You can think of white matter as the brain’s information superhighway, carrying signals rapidly from one region to another. The authors designed this study to see if electrical stimulation could physically change the microscopic structure of white matter. They also wanted to understand how these potential physical changes might influence how different regions of the brain communicate with one another. “The idea for the project came when Dr. Helen Mayberg joined Mount Sinai about eight years ago,” explained Peter H. Rudebeck https://labs.neuroscience.mssm.edu/project/rudebeck-lab/ , a professor of neuroscience and psychiatry at the Icahn School of Medicine at Mount Sinai, and Satoka H. Fujimoto, a researcher at the institution. “Dr. Mayberg works with patients with depression who have not been helped by any of the other treatments that are available such as anti-depressants and cognitive behavioral therapy.” “Twenty years ago she pioneered a new approach to help treat these patients where deep brain stimulation DBS was directed to a part of the anterior cingulate cortex ACC called the subcallosal ACC,” the researchers noted. “DBS works by focally delivering electrical impulses to a piece of the brain, causing activity in that area to be altered.” “In recent clinical trials, DBS to the subcallosal ACC is effective at improving 70 to 80 percent of patients’ depression and in some cases people were completely free from depression,” Rudebeck and Fujimoto said. “Dr. Mayberg noticed that in her patients that had been successfully treated with DBS, that their recovery from depression was not immediate. Instead, after an initial rapid improvement there was a prolonged period of improvement that spanned many weeks or months.” “The rapid improvement made sense in light of what was known about how electrical impulses change brain activity, but the longer term improvement was not,” the researchers explained. “Thus, the study was motivated by a desire to figure out what mechanisms in the brain underlie these fast and slow responses to DBS and how these help people to recover from depression.” Add PsyPost to your preferred sources https://www.google.com/preferences/source?q=psypost.org To carry out the experiment, the scientists worked with macaque monkeys. The main experimental group included three adult male monkeys between seven and nine years old. Two of the animals received the active deep brain stimulation treatment, while the third monkey underwent the surgery but did not receive any electrical stimulation, acting as a control subject. The team also used functional brain imaging data from three additional monkeys that did not undergo any surgery. This second control group helped the authors verify that any changes in brain communication over time were genuinely linked to the electrical stimulation. Including these unoperated animals provided a baseline for normal brain network fluctuations. For the two monkeys in the active treatment group, the researchers implanted a miniaturized electrode into a specific intersection of three white matter pathways. One of these pathways is the cingulum bundle, which serves as a major communication route for the brain’s emotional centers. Identifying the precise convergence of these three tracts requires advanced mapping techniques, as individual brain anatomy can vary. After a four-week recovery period, the treatment group monkeys received continuous electrical stimulation for six weeks. This timeline mirrors the approach taken in human clinics. It also matches the period when human patients typically begin to show significant symptom improvement. The researchers used magnetic resonance imaging, commonly known as MRI, to scan the monkeys’ brains before the electrode implantation and immediately after the six weeks of stimulation. They specifically looked at a measure called fractional anisotropy. This metric helps scientists evaluate the physical integrity and organization of white matter tracts in a living brain. Fractional anisotropy is a mathematical value derived from how water molecules diffuse through tissue. In healthy, well-organized white matter, water tends to move smoothly along the direction of the nerve fibers. An increase in this metric suggests that the nerve fibers have become more structurally sound, densely packed, or better insulated. The MRI data revealed that six weeks of stimulation led to a distinct increase in white matter integrity in the cingulum bundle. This pathway connects different areas of the brain involved in emotion and mood regulation. Interestingly, this physical change occurred in a section of the pathway that was somewhat distant from the actual stimulation site. Following the MRI scans, the team examined the brain tissue at a microscopic level. They used specialized microscopes to look at the cellular structure of the white matter fibers. The scientists specifically counted the number of oligodendrocytes, which are specialized cells that produce myelin. Myelin is a fatty substance that wraps around nerve fibers, acting like insulation on an electrical wire to help signals travel faster. The researchers found a higher number of myelin-producing oligodendrocytes in the exact same region where the MRI showed increased white matter integrity. They also used an advanced technique called electron microscopy to measure the exact thickness of this myelin sheath in the targeted brain regions. The myelin sheaths surrounding the nerve fibers in this area were thicker compared to the unstimulated side of the brain. This allowed them to see structural changes that are invisible to a standard MRI. “We were surprised to find evidence of white matter remodeling after a relatively short period of stimulation, only six weeks,” Rudebeck and Fujimoto said. “In particular, we found that myelin, the insulating sheath around neural fibers that supports efficient information transfer, had become thicker as a result of DBS.” “What made this especially interesting was where this change occurred,” they noted. “The structural change was localized to the mid-cingulate bundle, a white matter pathway located away from the stimulation site. Importantly, this pathway helps link the stimulation site with key regions of the default mode network, a brain network strongly implicated in depression.” “This was unexpected because it suggests that DBS may influence not only local brain activity near the electrode, but also the structure of distant, connected brain pathways,” the researchers explained. “One way to think about this is that DBS may not only adjust the activity of important ‘cities’ in the brain, but may also help reshape the ‘roads’ that connect those cities, allowing the broader network to function more effectively.” The researchers also monitored the animals’ basic behaviors to ensure the stimulation was having a biological effect. They found that the stimulated monkeys spent more time moving and foraging in their home cages after the treatment started. They did not observe any negative neurological deficits or signs of motor impairment. The control monkey that received the implant without any stimulation did not show these behavioral or structural improvements. In fact, the surgical insertion of the electrode without electrical stimulation tended to cause a slight decrease in white matter integrity. This detail indicates that the physical remodeling of the brain was a direct result of the electrical impulses. Beyond the physical changes, the authors examined functional connectivity, which refers to how well different parts of the brain synchronize their activity. They found that the localized white matter changes were accompanied by widespread shifts in communication across the entire brain. The deep brain stimulation tended to decrease overall communication between outer cortical areas while increasing communication between deeper subcortical regions. Most notably, the stimulation altered how the targeted area communicated with the default mode network. The default mode network is a group of interconnected brain regions that becomes highly active when a person is resting, daydreaming, or ruminating. In humans, depression is often associated with hyperactivity and altered connectivity in this specific network. The deep brain stimulation tended to decrease the communication between the stimulation site and the default mode network. This suggests a potential rebalancing of brain activity in pathways that manage mood and attention. At the same time, the treatment increased communication between the stimulation site and sensory and motor networks. Brain networks are known to dynamically rebalance themselves to optimize inputs and outputs between different areas. The localized structural changes in the white matter appear to support much larger functional shifts across the whole brain. This fits with previous evidence that a small number of structural connections can maintain wide-reaching communication networks. “The main takeaway is that DBS may do more than adjust brain activity, it actually rewires the brain,” Rudebeck and Fujimoto summarized. “Specifically, our study provides evidence that stimulation of brain circuits relevant to depression can induce structural changes in white matter, the fiber pathways that connect different brain regions and transmit neural information.” “These changes were accompanied by functional changes in brain networks, particularly in the default mode network, which has been strongly implicated in depression,” they said. “This means that our findings indicate that the recovery from depression requires rewiring the brain to promote recovery.” While the study provides strong evidence for brain remodeling, it does have some limitations. The research relied on a small sample size of monkeys, which is common in non-human primate studies but requires caution when applying the findings to larger human populations. Additionally, the subjects were healthy animals without depression. “Our study was not conducted in the human brain but used healthy animals so that we could uncover the cellular mechanisms that are engaged by DBS in the absence of pathology related to depression,” Rudebeck and Fujimoto explained. “Such a level of analysis could not have been obtained in patients who received DBS.” A brain affected by a psychiatric condition might respond to stimulation differently, or on a different timeline, than a healthy brain. The researchers also conducted the MRI scans while the animals were under mild anesthesia to prevent movement. Although they used a low dose designed to preserve normal brain network activity, anesthesia can still subtly alter functional connectivity patterns. Another limitation involves the removal of the electrode before the final MRI scans. The researchers had to extract the device to prevent it from distorting the brain images and causing tissue damage in the scanner. Removing the device meant the stimulation was turned off during the scan, which could have allowed some brain networks to experience a rapid rebound effect. Future research will need to explore whether these exact structural changes occur in human patients undergoing the therapy for depression. Scientists also plan to study how different stimulation frequencies or intensities might impact white matter remodeling. Understanding these biological mechanisms could help doctors optimize treatment settings and perhaps develop new, non-surgical methods to encourage the brain to repair its own white matter. “Now, Dr. Mayberg and her team at the Center for Advanced Circuit Therapeutics are now working to see if fMRI measures of white matter structure are changed in people who receive DBS,” the researchers added. “This has been made possible by new approaches that allow people with implanted DBS devices to be scanned using MRI.” “One of the things that still puzzles us about the results is that the location in the brain that shows the biggest change in response to DBS is not close to the location where stimulation is delivered,” Rudebeck and Fujimoto said. “We don’t know why this is, but it is probably important.” “We are now working to figure that out with a number of different approaches in animals,” they noted. “If we can figure that out it may be possible to make DBS even better than it is as well as potentially unlock new ways to try to treat depression.” The study, “ Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks https://doi.org/10.1038/s41593-026-02301-4 ,” was authored by 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, and Peter H. Rudebeck.