Ketamine and deep brain stimulation may influence overlapping brain activity in treatment-resistant depression, but those signals do not necessarily carry the same meaning. New intracranial recordings suggest that interpreting them may require attention to timing, laterality, and the patient’s emotional context.
Major depressive disorder remains difficult to treat for many patients, even after medication, psychotherapy, transcranial magnetic stimulation, or electroconvulsive therapy. Ketamine can produce rapid symptom relief, while subcallosal cingulate deep brain stimulation may support longer-term improvement in carefully selected patients. However, little is known about how ketamine affects this deep brain region while stimulation is active.
A Rare View Inside A Depression Circuit
Researchers examined chronic recordings from one woman with long-standing treatment-resistant depression. She had bilateral electrodes implanted in the subcallosal cingulate, or SCC, and continued receiving 300 mg of intranasal ketamine twice weekly.
The SCC connects limbic, cognitive, and autonomic networks involved in mood regulation. Its central position makes it a promising stimulation target, but also means that a single electrical feature may reflect multiple physiological states.
Using a sensing-enabled DBS system, the researchers analyzed 5,907 hours of bilateral SCC activity, 485 participant-triggered recordings collected across 193 days, and 47 ketamine dosing episodes. They also captured continuous recordings during one supervised in-clinic ketamine session.
This combination provided both controlled observations and a view of brain activity during daily life.
Ketamine And Deep Brain Stimulation Share A Fast-Band Signal
Following ketamine administration, SCC activity shifted away from lower frequencies of approximately 5 to 20 Hz and toward faster activity between 21 and 40 Hz. This redistribution appeared in both hemispheres across the home recordings and the in-clinic session.
Activity at 23.44 Hz, a frequency selected for long-term monitoring by the implanted device, increased bilaterally after ketamine. The increase remained significant after the researchers adjusted for clock time, stimulation settings, pulse width, and study date.
During the supervised session, the change emerged soon after dosing and continued through the final recording. The increase was present on both sides but was larger in the right SCC.
The participant also reported early increases in mood and optimism, an initial reduction in anxiety, and a temporary increase in energy. These observations were descriptive and cannot establish that the recorded signal caused the clinical changes.
Emotional States Produced Different Temporal Patterns
The same 23.44 Hz frequency range also changed around self-reported emotional events, but its trajectory differed from the ketamine response.
Anxious and sad events were associated with larger bilateral increases that began before the participant logged the emotion and peaked approximately 15 minutes afterward. Neutral and happy events were followed by smaller decreases. Medication onset produced more modest and lateralized changes.
At the exact moment an event was recorded, the spectra did not clearly separate the emotional categories. Their differences became visible only when researchers examined how activity evolved over tens of minutes.
This distinction matters because a static threshold could classify ketamine exposure and negative emotional states as equivalent simply because both engage fast-band activity.
Why Context May Matter For Adaptive DBS
Ketamine is thought to affect depression through several interacting mechanisms. NMDA receptor blockade may reduce inhibitory control within neural circuits, while AMPA receptor activity, BDNF signaling, and synaptic plasticity may contribute over longer periods. Human electrophysiology studies have similarly reported increased beta or gamma activity alongside reductions in slower frequencies after ketamine.
The current findings extend those observations into the SCC during active DBS. They suggest that the clinical meaning of a signal may depend on its magnitude, which hemisphere is involved, and how it changes over time.
That framework could influence future adaptive DBS systems. Instead of increasing or decreasing stimulation whenever one frequency crosses a threshold, a system might evaluate an evolving pattern and distinguish a medication response from worsening negative affect.
A Detailed Case With Important Boundaries
The depth of recording is unusual, but the study involved only one participant and remains a preprint that has not completed peer review. Home dosing times were based on participant-entered markers, emotional events occurred at different times of day, and the in-clinic response came from a single ketamine session.
The findings therefore identify a patient-specific physiological pattern rather than a validated biomarker. Replication across patients, repeated dosing sessions, and consistent stimulation conditions will be necessary.
Even with those limitations, the study shows why future psychiatric neurotechnology may need to decode changing circuit states instead of treating brain activity as a simple high-or-low signal.
Citations
Sumarac S, et al. “Chronic Sensing During Subcallosal Cingulate Deep Brain Stimulation Captures Ketamine-Associated Changes in Major Depressive Disorder.” medRxiv, 2026. https://doi.org/10.64898/2026.09.08.26362080
Tian F, et al. “Characterizing Brain Dynamics During Ketamine-Induced Dissociation and Subsequent Interactions With Propofol Using Human Intracranial Neurophysiology.” Nature Communications, 2023. https://doi.org/10.1038/s41467-023-37463-3
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