Abstracts

Rationale: For the past two decades, high frequency oscillations (defined here as HFOs >250Hz) have been considered one of the most promising epilepsy biomarkers that is often used in the presurgical evaluation of patients with drug-resistant temporal lobe epilepsy (TLE). HFOs positively correlate with seizure burden, often occur in between seizures, and are often present at seizure onset. All this data raise the hypothesis that disrupting HFOs may help reduce seizures. However, HFOs have not been targeted selectively to test whether seizures would be reduced. Selective targeting of these HFOs is critical because oscillations in lower frequencies such as those in 80-200Hz occur in the normal hippocampus and if reduced, memory can be affected, and seizure outcome may not be favorable. In contrast, HFOs >250Hz are not present in the normal human and mouse hippocampi. Here we tested whether selective disruption of such HFOs (i) improves memory performance and (ii) reduces seizures in two mouse models of TLE.


Methods: Experiments used the intrahippocampal kainic acid (IHKA) and pilocarpine (PILO) models of TLE as well as saline-injected controls. To selectively disrupt HFOs, we developed a novel closed-loop protocol to detect HFOs in real time and immediately abort them using either optogenetic silencing or electrical stimulation. Controls used no stimulation or stimulation in mice expressing a fluorophore control (optogenetics). All experiments targeted hippocampal area CA2 where we found that HFOs are robust. Importantly, CA2 is remarkably resistant to cell loss in TLE models and humans and thus amenable to stimulation. To test whether CA2 HFOs contribute to memory deficits, we used a social memory task that is dependent on CA2 where IHKA- and PILO-treated mice are impaired. In this task, HFOs were disrupted using optogenetic silencing of CA2 pyramidal neurons for 1hr between learning and testing trials (memory consolidation phase). Effects of HFO disruption on spontaneous seizures were tested by disrupting HFOs for at least 3 days using brief (10ms) electrical pulses. The success of HFO disruption was assessed by comparing the number of cycles, duration, and power of HFOs between periods of stimulation vs controls.


Results: We found that selective disruption of HFOs during the memory consolidation phase of a social memory task was sufficient to restore memory in both TLE models. Importantly, control stimulations in fluorophore-expressing epileptic mice failed to affect HFOs (number of cycles, duration, power) or memory performance. Notably, continuous disruption of HFOs was associated with shorter and less severe seizures.


Conclusions: The results provide the first pre-clinical evidence that selective disruption of HFOs can restore memory and improve seizure outcomes. These findings are notable because previously the role of HFOs had only been tested non-selectively i.e., through surgical removal of brain tissue with robust HFOs. Hence, selective HFO disruption could represent a new strategy to improve epilepsy outcomes and comorbidities in patients who do not respond to treatment or suffer debilitating side effects.


Funding: NYU FACES (Finding a Cure for Epilepsy and Seizures); NINDS R01NS106983