Electrophysiological Dose-Response to Anterior Thalamic Deep Brain Stimulation in Drug-Resistant Focal Epilepsy

Study Design This is a prospective, single-center, single-arm mechanistic pilot study involving 10 adults with drug-resistant focal epilepsy. Bilateral anterior thalamic deep brain stimulation (ANT-DBS) implantation using a sensing-enabled neurostimulator (Medtronic Percept PC) is determined as part of standard clinical care, independently of study participation.

The study consists of two periods. During the standardized stimulation period (activation to 3 months), stimulation frequency (145 Hz), pulse width (90 μs), and cycling follow the SANTE protocol, with scheduled chronic stimulation amplitudes of 2.0 mA at activation and 3.5 mA at 1 month. Adjustments are permitted whenever clinically necessary. From 3 to 12 months, stimulation parameters are managed according to routine clinical care, with all changes documented.

Study Visits Research assessments are performed during scheduled clinical visits. Before implantation, participants undergo baseline clinical, seizure-frequency, neuropsychological, and mood assessments. Within 1 week after implantation, two 120-second stimulation-OFF recordings are obtained to select sensing contacts and determine the chronic sensing frequency band.

Acute stimulation challenges are performed at activation (2.0 mA), 1 month after activation (2.0 and 3.5 mA), and 3 months after activation (2.0, 3.5, and up to 5.0 mA). The final clinical and electrophysiological assessments are performed at 12 months after activation.

Acute Stimulation Challenge Each stimulation condition is assessed against a stable, 2-minute stimulation-OFF baseline, followed by continuous stimulation at the target amplitude and 60 seconds of stable local field potential (LFP) recording after the target amplitude is reached. Stimulation is then switched OFF for a minimum 5-minute washout interval, with the final 2 minutes serving as the local baseline for the subsequent block when stability criteria are met.

Each amplitude is tested at least twice using a prespecified counterbalanced sequence. At the 3-month visit, the high-amplitude condition targets 5.0 mA, approached in 0.5-mA increments from 3.5 mA. If 5.0 mA is not tolerated bilaterally, the maximum amplitude tolerated on both sides is used and analyzed separately from the complete-dose primary analysis.

Challenges are conducted under direct medical supervision with predefined safety criteria. Transient mild adverse symptoms require immediate interruption of the affected block, while persistent or clinically significant symptoms, mood or behavioral changes, or seizures require termination of the session and appropriate clinical management.

Electrophysiological and Imaging Analyses The primary electrophysiological measure is the stimulation-induced change in 20-50 Hz slow-gamma power, calculated as the natural logarithm of the ratio of stimulation-ON to local stimulation-OFF integrated band power.

Within-session reproducibility and longitudinal electrophysiological adaptation are evaluated using repeated acute recordings and device-derived chronic sensing data. Correspondence between broadband acute slow-gamma measures and device-matched narrow-band measures is assessed before examining their longitudinal relationships.

Electrode locations are reconstructed using postoperative CT co-registered to preoperative MRI. Electric-field or volume-of-tissue-activated modeling is performed using Lead-DBS or an equivalent validated pipeline to explore relationships between anatomical network engagement and electrophysiological responses.

Statistical Analysis The primary dose-response analysis uses repeated stimulation challenges obtained at the 3-month visit. A linear mixed-effects model includes stimulation amplitude as a categorical fixed effect and participant as a random intercept, using restricted maximum likelihood estimation with Kenward-Roger or Satterthwaite degrees-of-freedom adjustment.

Given the pilot sample size (N=10), interpretation emphasizes estimated effects, 95% confidence intervals, within-participant reproducibility, and individual response trajectories rather than statistical significance alone.

The primary frequency band, response metric, and analysis framework are prespecified and will not be modified based on observed clinical outcomes. Associations between electrophysiological measures and seizure-frequency reduction during months 7-12 are considered exploratory.