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…

The National Institute of Neurological Disorders and Stroke awarded New York Medical College $162,400 on May 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to evaluate deep brain stimulation targeting the paraventricular hypothalamic nucleus and arcuate nucleus as a novel therapeutic strategy for refractory infantile epileptic spasms syndrome in a validated rat model.

The research will test proof-of-principle efficacy of DBS using frequency-specific stimulation patterns (high-frequency in the arcuate nucleus, low-frequency in the paraventricular hypothalamic nucleus) to suppress seizures, reduce hypsarrhythmia on EEG, and prevent spontaneous seizures in a rodent model that recapitulates both clinical and electrographic features of infantile epileptic spasms syndrome. A second aim will optimize stimulation paradigms by comparing low-frequency versus high-frequency stimulation effects on each target individually and evaluating concurrent stimulation in both structures, with outcome measures including spasm frequency, latency, and quantified hypsarrhythmia features. The work addresses the clinical need for safer, more effective treatments for drug-resistant infantile epileptic spasms syndrome, as current standard therapies including ACTH and vigabatrin frequently fail and carry serious adverse effects such as immune suppression and vision loss.

The period of performance runs from May 1, 2026, through April 30, 2028, with work performed in Valhalla, New York. New York Medical College is a subsidiary of Touro University.

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.