Optogenetic stimulation of the superior colliculus suppresses genetic absence seizures.

While anti-seizure medications are effective for many patients, nearly one-third of individuals have seizures that are refractory to pharmacotherapy. Prior studies using evoked pre-clinical seizure models have shown that pharmacological activation or excitatory optogenetic stimulation of the Deep and Intermediate Layers of the Superior Colliculus (DLSC) display multi-potent anti-seizure effects. Here we monitored and modulated DLSC activity to suppress spontaneous seizures in the WAG/Rij genetic model of absence epilepsy. Female and male WAG/Rij adult rats were employed as study subjects. For electrophysiology studies, we recorded single unit activity from microwire arrays placed within the DLSC. For optogenetic experiments animals were injected with virus coding for channelrhodopsin-2 or a control vector, and we compared the efficacy of continuous neuromodulation to that of closed-loop neuromodulation paradigms. For each, we compared three stimulation frequencies on a within-subject basis (5, 20, 100 Hz). For closed-loop stimulation, we detected seizures in real time based on the EEG power within the characteristic frequency band of SWDs. We quantified the number and duration of each SWD during each two-hour-long observation period. Following completion of the experiment, virus expression and fiber optic placement were confirmed. We found that single unit activity within the DLSC decreases seconds prior to SWD onset, and increases during and after seizures. Nearly 40% of neurons displaying suppression of firing in response to the start of SWDs. Continuous optogenetic stimulation of the DLSC (at each of the three frequencies) resulted in a significant reduction of SWDs in males, and was without effect in females. By contrast, closed-loop neuromodulation was effective in both females and males at all three frequencies. These data demonstrate that activity within the DLSC is suppressed prior to SWD onset, increases at SWD onset, and that excitatory optogenetic stimulation of the DLSC exerts anti-seizure effects against absence seizures. The striking difference between open and closed-loop neuromodulation approaches underscores the importance of the stimulation paradigm in determining therapeutic effects.