Deep brain stimulation (DBS) has shown effectiveness in treating treatment-resistant depression, but its exact mechanism remains unknown. Scientists worldwide are actively seeking objective biomarkers to optimize, approve, and disseminate this experimental approach to those in need. A recent study published in Translational Psychiatry on November 3 presents compelling evidence that brief intraoperative exposure to therapeutic stimulation during implantation surgery induces rapid and consistent changes in the brain’s electrophysiological state. These changes are reflected by a decrease in beta power at the stimulation site and are associated with a significant and sustained reduction in depressive symptoms outside the operating room, without additional stimulation. This reduction in beta power serves as a novel biomarker for optimizing DBS treatment.

The research, conducted collaboratively by Emory University and the Icahn School of Medicine at Mount Sinai, is part of an ongoing National Institutes of Health (NIH) BRAIN Initiative-funded project led by Dr. Helen S. Mayberg, Mount Sinai Professor in Neurotherapeutics and Founding Director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai.

DBS is an FDA-approved neurosurgical procedure for essential tremor, Parkinson’s disease, epilepsy, and obsessive-compulsive disorder. Although still in the experimental phase, DBS targeting the subcallosal cingulate (SCC, Area 25) – a brain region implicated in depression – has shown promise as an intervention for treatment-resistant depression. Stimulation of this specific depression circuit, guided by individualized neuroimaging, reliably elicits acute behavioral changes and long-term antidepressant responses. However, the timeline of recovery varies among patients, emphasizing the need to understand the mechanisms behind the initial rapid and reproducible behavioral effects and their role in predicting long-term responses.

The study found that within minutes of stimulation in the operating room, there was a noticeable change in the brain’s beta rhythm. Patients who experienced larger changes in beta rhythm during stimulation showed greater relief from depression in the week following surgery. The beta rhythm is traditionally associated with the brain’s decision-making process regarding whether to continue or cease a particular course of action. Neurologists target beta rhythm with DBS for movement disorders, and now researchers speculate that it may function by releasing the “brake” on fatigue and slowness or interrupting negative self-focused thoughts.

The study employed machine learning and explainable artificial intelligence approaches to uncover hidden changes in brain state that explain the observed behavioral changes. Eight patients with treatment-resistant depression underwent electrophysiological recording in the operating room during DBS lead implantation surgeries. Using pre-surgery patient-specific tractography models, researchers identified the optimal target within the SCC for lead placement. Stimulation was delivered over an hour while recording local field potentials (LFPs) – electrical signals between neurons deep in the brain. A machine learning classification method was then used to distinguish between LFPs recorded at baseline and those after the first exposure to stimulation. Spectral inputs (theta, alpha, and beta frequency bands) were evaluated for their importance in successful classification and as predictors of the antidepressant response. A 45.6% decline in depression scores was observed after one week, and this early response correlated with a decrease in beta power in the SCC LFP, which was the most influential factor for successful classification.

Typically, it takes weeks to months for depression treatment to exhibit stable and meaningful changes. However, this study demonstrates consistent and reproducible changes in a brain readout within the first minutes of optimized stimulation in individual patients. These findings enhance our understanding of the “depression switch” that transitions a patient from a state of sustained mental pain and immobility to relief and restored engagement.


Source: Science Daily