Authors :
Presenting Author: Florian Donneger, PhD – Stanford University
Ryan Jamiolkowski, MD, PhD – Stanford University
Charlotte Porter, BS – Stanford University
Peter Klein, PhD – Stanford University
Keith Murphy, PhD – Stanford University
Jordan Farrell, PhD – Stanford University
Ivan Soltesz, PhD – Stanford University
Rationale:
Lennox–Gastaut syndrome (LGS) is a severe childhood-onset epilepsy characterized by frequent, treatment-resistant seizures, intellectual disability, and generalized slow spike–wave activity on EEG. Current treatments, including antiseizure medications, vagus nerve stimulation, ketogenic diet, and corpus callosotomy, provide only partial relief and do not halt disease progression. Deep brain stimulation (DBS) of the centromedian thalamus (CMT) can reduce seizures in LGS patients (Velasco et al. 1987, 2006, 2007; Dalic et al. 2022) but is limited by surgical risks and cost (Fenoy et al. 2014). Low-intensity focused ultrasound (FUS) is a non-invasive, spatially precise alternative for modulating deep brain structures. We recently developed a Photometry Coupled to Ultrasound-based Neuromodulation (PhoCUS) approach, which combines FUS with fiber photometry to monitor real-time calcium activity in specific neuronal populations (Murphy et al. 2022). Using PhoCUS, we identified parameter sets that differentially modulate specific neuronal populations tuned specifically for targeted brain regions, including stimulation parameters for CMT modulation that alter arousal-related circuits in vivo (Murphy et al. 2024). While FUS has shown promise in suppressing epileptiform activity in temporal lobe epilepsy, its potential in LGS was previously unexplored. We therefore tested whether CMT-targeted FUS could reduce pathological network activity in a genetically validated LGS mouse model.
Methods:
We performed continuous (24/7) EEG recordings in mice carrying Kcnb1 mutations linked to LGS: Kcnb1R306C/+, Kcnb1G379R/+, or Kcnb1G379R/G379R (Hawkins et al 2021; Kang et al 2024). We quantified interictal discharge (IID) rates, seizure occurrence/severity, and mortality. We then applied open-loop CMT-targeted FUS in Kcnb1G379R/G379R mice, using parameters from our prior optimization study.
Results:
Kcnb1G379R/G379R mice exhibited markedly higher IID rates than Kcnb1R306C/+ and Kcnb1G379R/+ mice and were the only genotype where we observed spontaneous behavioral seizures. Seizures were predominantly severe (modified Racine stage 7: running/jumping) and 2/4 mice experienced sudden death during a seizure, consistent with SUDEP. Open-loop CMT-targeted FUS significantly reduced IID frequency in all tested Kcnb1G379R/G379R mice.
Conclusions:
Our preliminary results demonstrate that low-intensity FUS targeting the CMT, using parameters optimized for neuromodulation in awake mice, can suppress epileptiform activity in an LGS mouse model with high seizure burden and SUDEP risk. Future work will focus on whether closed-loop intervention in this LGS mouse model can reliably terminate behavioral seizures. If successful, this study will lay the foundation for translating FUS-based therapies to clinical use in LGS, helping children achieve better seizure control without the risks of invasive brain surgery. It will also inform future investigations into whether FUS can mitigate LGS-associated cognitive impairments and normalize disrupted neural dynamics.
Funding:
Lennox-Gastaut Foundation Cure LGS 365 research grant