Exploring the tolerability of spatiotemporally complex electrical stimulation paradigms.

A modified cortical stimulation model was used to investigate the effects of varying the synchronicity and periodicity of electrical stimuli delivered to multiple pairs of electrodes on seizure initiation. In this model, electrical stimulation of the motor cortex of rats, along four pairs of a microwire electrode array, results in an observable seizure with quantifiable electrographic duration and behavioural severity. Periodic stimuli had a constant inter-stimulus intervals across the two-second stimulus duration, whilst synchronous stimuli consisted of singular biphasic, bipolar pulses delivered to the four pairs of electrodes at precisely the same time for the entire two second stimulation period. In this way four combinations of stimulation were possible; periodic/synchronous (P/S), periodic/asynchronous (P/As), aperiodic/synchronous (Ap/S) and aperiodic/asynchronous (Ap/As). All stimulation types were designed with equal pulse width, current intensity and mean frequency of stimulation (60 Hz), standardizing net charge transfer. It was expected that the periodicity of the stimulus would be the primary determinant of seizure initiation and therefore severity and electrographic duration. However, the results showed that significant differences in both severity and duration only occurred when the synchronicity was altered. For periodic stimuli, synchronous delivery increased median seizure duration from 5 s to 13 s and increased median Racine severity from 1 to 3. In the aperiodic case, synchronous stimulus delivery increased median duration from 5.5 s to 11s and resulted in seizures of median severity 3 vs. 0 in the asynchronous case. These findings may have implications for the design of future neurostimulation waveform designs as higher numbers of electrodes and stimulator output channels become available in next generation implants.