Abstracts

Rationale: The goal of this work is to establish the feasibility of ameliorating spontaneously recurring limbic seizures with closed-loop direct neurostimulation therapy in tandem with on-demand pulsatile intracerebral delivery of the novel antiepileptic drug (AED) carisbamate (Johnson & Johnson Pharmaceutical Research and Development). Methods: Twenty Fischer344 male rats (5 animals/group) were used. Stereotactic coordinates were chosen to guide a customized 16-contact dual fluidic-recording microelectrode shaft (NeuroNexus Technologies) into the right dorsal dentate gyrus (DG), and a 16-contact non-fluidic microelectrode shaft into the left dorsal DG. A stainless steel Teflon-coated twisted bipolar electrode was stereotactically placed in the medial division of the right perforant path (PP) 8mm posterior to bregma. Evoked potentials were used to confirm placement of all electrodes. Following a 6 day post-implant recovery period, a 1hr baseline electrocorticogram was acquired. Each animal then underwent a 90min electrical SSLSE protocol, inducing spontaneous limbic seizures. A line length signal processing algorithm (DataWave Technologies) was used to detect electrographic ictal onsets recorded from the distal eight serially arranged contacts in the right DG. Successful detection of this pattern automatically triggered delivery of stimulation therapy parameters (50uA less than the afterdischarge current, 1ms pulse duration, 100ms train duration at 50Hz). Subjects were designated to receive focal stimulation therapy delivered through the right PP either in the presence or absence of a 20nl [14C]-carisbamate bolus (rate=500nl/min) The AED was delivered in the right DG. In addition, a group received direct delivery of carisbamate alone. A final group received stimulation therapy concurrent with vehicle only. Each animal was sacrificed and brain tissue immediately frozen after an 8hr therapy session. [14C]-sensitive film was exposed to 10um tissue sections and developed 28 days later to determine AED distribution. Frequency and duration of ictal runs were assessed by a blinded evaluator reviewing the entirety of the electrocorticography with video. Results: Preliminarily, direct neurostimulation therapy delivered in the PP can abort an ictus detected at a distance in either ipsi- or contralateral DG. In addition, a trend is seen of a decreased frequency of ictal runs in those subjects receiving closed-loop direct neurostimulation therapy in tandem with on-demand intra-parenchymal carisbamate delivery, compared to closed-loop stimulation therapy alone. Conclusions: 1) Closed-loop detection of the ictal onset at a distance from axonally-connected delivery of direct stimulation therapy can stabilize an active epileptic circuit. 2) On-demand delivery of nanobolused intraparenchymal carisbamate is a promising strategy for augmenting closed-loop direct stimulation therapy in a rat model of spontaneously recurring limbic seizures. Supported by a grant from Ortho-McNeil Janssen, LLC