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

Abstract

Objective: 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). We hypothesized that stimulation waveform asymmetry would differentially modulate preferential activation of certain neural populations, and the differential population activity would be frequency-dependent. Approach: 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 duration of the leading phase to the duration of the return phase of charge-balanced cathodal- and anodal-first waveforms (i.e. longer leading phase relative to return has larger asymmetry). Main Results: Neurons within 40-60µm 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 tended to increase over time during 10 hz stimulation for some waveforms, whereas activity remained at the same level throughout stimulation for other waveforms. During 100 Hz stimulation, neural activity decreased over time for all waveforms, but decreased more for the waveforms that resulted in increasing neural activity during 10 Hz stimulation. Significance: 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.

Biomimetic microstimulation of sensory cortices

“…ICMS can drive sparse and distributed activation of excitatory neurons by recruiting passing axons [33],[60],[61] but the recruitment of inhibitory neurons near the electrode may contribute to more focal activation of functional units for feature encoding after onset [62]–[65]. Here, higher amplitudes and frequencies drove more rapid adaptation of neurons, agreeing with previous results [31],[32],[36],[66]. Higher frequencies and amplitudes then may result in increased recruitment of inhibitory neurons [35] at onset, driving strong rapid adaptation.…”

“…Here, higher amplitudes and frequencies drove more rapid adaptation of neurons, agreeing with previous results [31], [32], [36], [66]. Higher frequencies and amplitudes then may result in increased recruitment of inhibitory neurons [35] at onset, driving strong rapid adaptation.…”

“…Measuring the neural response to ICMS in humans is difficult due to safety and ethical concerns over human transgenic manipulation and limitations of hardware and high-resolution imaging. Transgenic mouse models with high-resolution imaging have been useful for studying how ICMS parameters affect the spatiotemporal response of the brain and how ICMS parameters can change neural responses [30]–[36].…”

Activation and depression of neural and hemodynamic responses induced by the intracortical microstimulation and visual stimulation in the mouse visual cortex

“…In order to make progress towards these applications, a deeper understanding of the underlying mechanisms that govern the spatiotemporal properties of neuronal activation by different ICMS parameters is crucial. Despite significant advancements [26][27][28][29][30][31][32], there are still numerous gaps in our understanding of the stimulation paradigm, as the parameter space associated with ICMS is vast. Many aspects of the interactions between ICMS and local networks also remain largely unexplored.…”

Transformation of neural coding for vibrotactile stimuli along the ascending somatosensory pathway

“…4a and fig. S6 ) ( 29 ). First, the vibration frequency tuning of S1 neurons was determined using two photon calcium imaging in anesthetized CaMKII-tTA × TRE -GCaMP6s mice (see Methods ).…”