Evaluating the Efficacy of Targeted Deep Brain Stimulation (DBS) in Attenuating Refractory Infantile Epilepsy Spasm Syndrome (IESS) in a Rodent Model

Infantile Epileptic Spasms Syndrome (IESS) is a devastating early-onset epilepsy syndrome characterized by spasms and interictal hypsarrhythmia on EEG occurring during infancy. Current treatments, including ACTH and vigabatrin, frequently fail and carry serious side effects such as immune suppression and vision loss. There is a pressing need for safer, more effective therapies, particularly for drug-resistant cases. This proposal explores deep brain stimulation (DBS) targeting specific hypothalamic nuclei as a novel strategy to suppress seizures and normalize EEG in IESS. Our central hypothesis is that frequency-specific DBS of the paraventricular hypothalamic nucleus (PVH) and arcuate nucleus (Arc) will modulate pathological network excitability, suppress spasms and hypsarrhythmia, and prevent subsequent spontaneous seizures. Preliminary microinfusion data strongly support a central role for the PVH-Arc network in regulation of spasms. DBS targeting of this circuitry offers a mechanistically guided, neuromodulatory strategy that may overcome limitations of current therapies. Using a validated rat model that recapitulates both the clinical and electrographic features of IESS (via prenatal betamethasone exposure followed by postnatal NMDA-induced spasms) we will test the following aims: Aim 1: Evaluate proof-of-principle therapeutic efficacy of DBS in PVH or Arc using high- frequency (HF) stimulation in Arc and low-frequency (LF) stimulation in PVH, mimicking inhibitory and excitatory neuromodulation, respectively. Aim 2: Optimize DBS stimulation paradigms by (a) assessing how LF vs HF stimulation of each target modulates seizures and EEG features, and (b) evaluating the effects of concurrent stimulation in both PVH and Arc. Key outcome measures include spasm frequency and latency, EEG quantification of hypsarrhythmia and electro-decrement, and assessment of spontaneous seizures later in development. Data will be benchmarked against pharmacologic interventions including ACTH and ANAVEX®2-73 [blarcamesine]. By leveraging techniques in developmental EEG monitoring and DBS in a rigorously validated animal model, this study has the potential to transform therapeutic approaches for IESS and open new avenues for treating drug-resistant pediatric epilepsies. Project Number: 1R03NS148675-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: LIBOR VELISEK | Institution: NEW YORK MEDICAL COLLEGE, VALHALLA, NY | Award Amount: $162,400 | Activity Code: R03 | Study Section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT] View on NIH RePORTER: https://reporter.nih.gov/project-details/11354757