Implementation of Intra and Extracellular Nonperiodic Scale-Free Stimulation in silico for the NEURON Simulator

Electrical stimulation of the brain is a largely used alternative for the treatment of myriad neurological disorders. Although recognizably efficacious and safe, many details of the underlying mechanisms remain obscure. Our group devised and successfully tested, in animal models of epilepsy, a novel nonstandard form of electrical stimulation in which the intervals between pulses are randomized. Termed Nonperiodic Stimulation (NPS), it has been specifically tailored to suppress hypersynchronism supporting seizure generation. For a better understanding of the underpinnings of NPS, we sought to carry out in silico investigation, but we found no easy way to implement its temporal pattern in the very successful NEURON simulator, given the unconventional nature of our stimulus. In this work, we report two approaches devised and tested to implement NPS applied both intra and extracellularly using the NEURON simulator. Neuronal responses reproduced the distinct temporal patterns of stimulation in a high-fidelity fashion, while being influenced by both stimulus polarity and distance from electrode tip. These results suggest our solutions successfully implemented intra and extracellular NPS (as well as other temporal patterns of interest) and represent an early but essential step in enabling in silico investigation of the mechanisms of such neuromodulation method.