Abstracts

Rationale: Spatial and temporal targeting of neurotransmitter action to specific brain regions immediately prior to and during seizure onset, would represent a significant advancement in the ability to stop seizures without side effects. The 2000 Curing Epilepsy Specific Benchmark III.E. states to “Successfully use a device (e.g., a very small detector and/or drug pump that can be placed in the brain) that, in at least one type of epilepsy, will detect an oncoming seizure and apply treatment to stop the seizure before it begins.” Recently we proposed a novel cell-based closed-loop neural prosthetic to provide seizure-induced release of the inhibitory neurotransmitter, GABA. In this approach a wireless electrical device is integrated with “living electrodes” for chronic and controllable GABA delivery from exogenous cells for seizure prevention. Here we present an in vitro prototype of this novel hybrid cellular-silicon neural implant device. Methods: The wireless device uses custom application-specific integrated circuits (ASICs) with sensing, stimulating, telemetry and powering modules to record and transmit in vivo neural signals and simultaneously stimulate biological tissue via traditional electrodes and/or exogenous cells via living electrodes. To demonstrate controlled GABA release, the stimulation module was coupled to two different neural cell types: 1) immortalized neuronal precursors engineered to express the GABA producing enzyme, glutamate decarboxylase (GAD) and 2) retinoic acid differentiated neurons from the pluripotent P19 cell line. Stimulated GABA and glutamate from the device were measured by GC/MS.Results: The sensing module uses chopper-stabilization to greatly reduce noise effects allowing higher fidelity in monitoring activity. Additional savings in power consumption allow us to greatly increase the number of channels that can be monitored simultaneously. The stimulating circuit has a high output impedance to ensure current flow into cells in the living electrode, and is charge balanced. The stimulator can deliver constant current at any waveform within the limits of the digital circuitry resolution. The telemetry module increases the carrier frequency to 5.8 GHz, doubling the data-rate, and reducing antenna area by a factor of four. Because of the higher carrier frequency, lower power consumption, and on-board digitization, the new circuit has the capability of sensing and transmitting from 1024 channels simultaneously. Release from P19 cells was linearly related to stimulation current. As expected both glutamate and GABA release was observed from the heterogeneous P19 neuron population. GABA release from the engineered cells was not linear and required higher current amplitudes as would be predicted for non-vesicular release mechanisms. As expected, no stimulated glutamate release was measured for these cells. The stimulation frequency changes the slope and dynamic range of the GABA release calibration. Conclusions: This work demonstrates for the first time controlled neurotransmitter release from a hybrid cell-silicon neural prosthetic.