Intracortical microstimulation pulse waveform and frequency recruits distinct spatiotemporal patterns of cortical neuron and neuropil activation

Abstract

Background: Neural prosthetics often use intracortical microstimulation (ICMS) for sensory restoration. To restore natural and functional feedback, we must first understand how stimulation parameters influence the recruitment of neural populations. ICMS waveform asymmetry modulates the spatial activation of neurons around an electrode at 10 Hz; however, it is unclear how asymmetry may differentially modulate population activity at frequencies typically employed in the clinic (e.g. 100 Hz). Objective: We hypothesized that stimulation waveform asymmetry would differentially modulate preferential activation of certain neural populations, and the differential population activity would be frequency-dependent. Methods: We quantified how asymmetric stimulation waveforms delivered at 10 Hz or 100 Hz for 30s modulated spatiotemporal activity of cortical layer II/III pyramidal neurons using in vivo two-photon and mesoscale calcium imaging in anesthetized mice. Asymmetry is defined in terms of the ratio of the leading phase to the return phase of charge-balanced cathodal- and anodal-first waveforms. Results: Neurons within 40-60 micron of the electrode display stable stimulation-induced activity indicative of direct activation, which was independent of waveform asymmetry. The stability of 72% of activated neurons and the preferential activation of 20-90 % of neurons depended on waveform asymmetry. Additionally, this asymmetry-dependent activation of different neural populations was associated with differential progression of population activity. Specifically, neural activity increased over time for some waveforms at 10 Hz, but decreased more at 100 Hz than other waveforms. Conclusion: These data demonstrate that at frequencies commonly used for sensory restoration, stimulation waveform alters the pattern of activation of different but overlapping populations of excitatory neurons. The impact of these waveform specific responses on the activation of different subtypes of neurons as well as sensory perception merits further investigation.

Spatiotemporal recruitment of inhibition and excitation in the mammalian cortex during electrical stimulation

“…The use of 2-photon imaging has been critical for expanding our understanding of how electrical currents can shape neural responses patterns. We know, for example, that neurons activated by electrical stimulation are sensitive to the temporal pattern of stimulation, and spatiotemporal activation of neural populations is achieved by changing the frequency and precise timing of delivered stimulation pulses [5, 12, 7, 22]. But maybe the first study using 2-photon imaging to examine stimulation-evoked neural activity was the most dramatic in how it shifted our perception of how electrical stimulation works.…”