Abstracts

Rationale: Over a third of epilepsy patients have seizures that are refractory to medication (French, 2006). Thus identifying and testing novel antiepileptic drugs remains an important research goal, as is developing useful platforms for novel surgical or device interventions. While a considerable amount of research has emphasized rodent models and patient populations, this study is focused on the development of a non-human primate model of seizure and epilepsy. We used optogenetic techniques to modulate CA3 of hippocampus while recording whole head MEG. Specifically CA3 was targeted because it has an important role in mesial temporal lobe epilepsy and as a deep structure there is uncertainty regarding the efficacy of MEG in detecting its activity. Our goal was to test whether differential modulation of CA3 with optogenetics would result in epileptiform discharges localizable with MEG; and whether specific activation regimens would generate responses resembling ictal patterns observed in epilepsy patients. Our goal is a NHP model of seizure for use in MEG to study the mechanisms of local circuit interactions with seizure in nonhuman primates, with important benefits of preclinical evaluation of AEDs, devices and surgical interventions.Methods: Stereotaxic MRI was used to target area CA3 of hippocampus in vervet monkeys. 4µl of AAV10-CaMKIIα-ChR2-eYFP was delivered stereotaxically to the target along with a recording electrode and optical fiber. Immediately after recovery pre-expression control stimulation experiments were conducted in order to evaluate the possibility of stimulation artifact prior to ChR2 expression. After a period of 6-10 weeks, stimulation protocols were again performed while conducting simultaneous MEG and LFP depth recordings. Optical stimulation protocols included single light pulses and train stimulations at a variety of frequencies and intensities. In rodent models train stimulation paradigms are known to cause global synchrony, while single pulse stimulations elicit population discharges with a time course and waveform similar to the interictal spike.Results: Spectral analysis and waveform characteristics of LFP recordings from hippocampus demonstrated optogenetically evoked population discharges analogous to interictal spikes. MEG data were then preprocessed and analyzed using both Synthetic Aperture Magnetometry (SAM) from MISL and a vector-based minimum norm beamformer using CURRY. Both techniques were able to accurately localize the source of activation as well as identify distant responses to the stimulation. Additionally, different stimulation paradigms resulted in different patterns activity which engaged distant brain regions while respecting known anatomical and functional relationships High-frequency stimulation engaged the whole brain in synchronous oscillatory activity.Conclusions: This series of experiments represents the first combination of optogenetics with MEG and represents a potentially new platform for drug discovery, honing pre-surgical evaluation, and improving basic understanding of seizure dynamics.