The temporal pattern of intracortical microstimulation pulses elicits distinct temporal and spatial recruitment of cortical neuropil and neurons

Abstract

Objective. The temporal spacing or distribution of stimulation pulses in therapeutic neurostimulation waveforms—referred to here as the Temporal Pattern (TP)—has emerged as an important parameter for tuning the response to deep-brain stimulation and intracortical microstimulation (ICMS). While it has long been assumed that modulating the TP of ICMS may be effective by altering the rate coding of the neural response, it is unclear how it alters the neural response at the network level. The present study is designed to elucidate the neural response to TP at the network level. Approach. We use in vivo two-photon imaging of mice expressing the calcium sensor Thy1-GCaMP or the glutamate sensor hSyn-iGluSnFr to examine the layer II/III neural response to ICMS with different TPs. We study the neuronal calcium and glutamate response to TPs with the same average frequency (10 Hz) and same total charge injection, but varying degrees of bursting. We also investigate one control pattern with an average frequency of 100 Hz and 10X the charge injection. Main Results. Stimulation trains with the same average frequency and same total charge injection but distinct TPs recruit distinct sets of neurons. More than half (60% of 309 cells) of neurons prefer one TP over the other. Despite their distinct spatial recruitment patterns, cells exhibit similar ability to follow 30 s trains of both TPs without failing, and they exhibit similar levels of glutamate release during stimulation. Both neuronal calcium and glutamate release entrain to the bursting TP pattern, with a ∼21-fold increase in relative power at the frequency of bursting. Bursting also results in a statistically significant elevation in the correlation between somatic calcium activity and neuropil activity, which we explore as a metric for inhibitory-excitatory tone. Interestingly, soma-neuropil correlation during the bursting pattern is a statistically significant predictor of cell preference for TP, which exposes a key link between TP and inhibitory-excitatory tone. Finally, using mesoscale imaging, we show that both TPs result in distal inhibition during stimulation, which reveals complex spatial and temporal interactions between TP and inhibitory-excitatory tone in ICMS. Significance. Our results may ultimately suggest that TP is a valuable parameter space to modulate inhibitory-excitatory tone and to recruit distinct network activity in ICMS. This presents a broader mechanism of action than rate coding, as previously thought. By implicating these additional mechanisms, TP may have broader utility in the clinic and should be pursued to expand the efficacy of ICMS therapies.

Brain circuits for pain and its treatment

“…In vivo voltage dye imaging in cat cortex found a progressive rise in excitation at the targeted region throughout a 10-Hz electrical stimulus train (300), supporting previous slice electrophysiology studies that had similarly concluded that high-frequency stimulation in cortical tissue preferentially activates excitatory neurons (301). Furthermore, a recent calcium imaging study in mice showed that excitatory neurons in L2/3 activate in response to specific stimulation frequencies, similar to visual cortical neurons tuned to a specific direction of drifting grating stimuli (296). Although our understanding of the biophysics underlying brain stimulation is evolving, many important questions remain to be explored.…”

“…In contrast, tDCS is less temporally and spatially specific than ES and TMS and acts by hyperpolarizing the resting membrane potential, making the anode region more excitable and the cathode less (292). Studies in human subjects and animal models both show that high-frequency stimulus trains excite the target more efficiently than low-frequency trains (293)(294)(295)(296)(297). Theta burst stimulation, a TMS protocol commonly used for cortical stimulation, uses three pulse bursts delivered at high frequency (for example, 50 Hz), repeated every 200 ms (5 Hz) (293).…”

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

“…Additionally, we demonstrated that during 100 Hz-stimulation the activity of some neurons subsides during the pulse train after a short (1-2s) period of activation, whereas activation remains stable for others(28-30). This “onset” effect is thought to be mediated by inhibitory network recruitment in part because inhibitory neurons may entrain to 100 Hz-stimulation longer than excitatory neurons(28, 29). Therefore, investigating the temporal activation of cortical neurons during 100 Hz-stimulation with different waveforms could elucidate how the asymmetry of stimulation waveform modulates recruitment patterns(13, 23, 24, 29).…”

“…This “onset” effect is thought to be mediated by inhibitory network recruitment in part because inhibitory neurons may entrain to 100 Hz-stimulation longer than excitatory neurons(28, 29). Therefore, investigating the temporal activation of cortical neurons during 100 Hz-stimulation with different waveforms could elucidate how the asymmetry of stimulation waveform modulates recruitment patterns(13, 23, 24, 29).…”

A Biomimetic, SoC-Based Neural Stimulator for Novel Arbitrary-Waveform Stimulation Protocols

“…Neural stimulator employed by Wagner et al (2018) produces stimulation trains with multiple discrete frequencies ( Figure 1D ) to enable locomotion in patients with a spinal cord injury. Brocker et al (2013) , Eles et al (2020) , and Soto-Breceda et al (2018) demonstrate delivery of a series of pulses with irregular inter-pulse-intervals to reduce synaptic fatigue in retina tissue or improve therapeutic effects in Parkinson’s treatments. Stimulators designed for these protocols require a dynamic control of timing of each individual pulse in the series ( Figure 1E ).…”