Responses of Cortical Neurons to Intracortical Microstimulation in Awake Primates

Abstract

Intracortical microstimulation (ICMS) is commonly used in many experimental and clinical paradigms; however, its effects on the activation of neurons are still not completely understood. To document the responses of cortical neurons in awake non-human primates to stimulation, we recorded single-unit activity while delivering single-pulse stimulation via Utah arrays implanted in primary motor cortex of three macaque monkeys. Stimuli between 5-50 μA delivered to single channels reliably evoked spikes in neurons recorded throughout the array with delays of up to 12 milliseconds. ICMS pulses also induced a period of inhibition lasting up to 150 ms that typically followed the initial excitatory response. Higher current amplitudes led to a greater probability of evoking a spike and extended the duration of inhibition. The likelihood of evoking a spike in a neuron was dependent on the spontaneous firing rate as well as the delay between its most recent spike time and stimulus onset. Tonic repetitive stimulation between 2 and 20 Hz often modulated both the probability of evoking spikes and the duration of inhibition; high-frequency stimulation was more likely to change both responses. On a trial-by-trial basis, whether a stimulus evoked a spike did not affect the subsequent inhibitory response; however, their changes over time were often positively or negatively correlated. Our results document the complex dynamics of cortical neural responses to electrical stimulation that need to be considered when utilizing ICMS for scientific and clinical applications.Significance statementIntracortical microstimulation (ICMS) is commonly used to probe the cortex, and previous studies have characterized the responses of single neurons to ICMS. However, these studies typically explored the averaged effects of ICMS throughout each experimental session, rather than by a trial-by-trial basis for each stimulation pulse. By shifting the approach, we explored the dependence of neural responses to ICMS on the spontaneous neural activity as well as the dynamics of responses over time produced by repetitive stimulation in awake non-human primates. Our results reveal how the responses of neurons to ICMS are related to interactions between local excitatory and inhibitory cortical circuits. These results will help inform the design of ICMS for both basic research and clinically relevant stimulation protocols.

Microstimulation reveals anesthetic state-dependent effective connectivity of neurons in cerebral cortex

“…Consistent with prior studies we found that intracortical microstimulation generally produced a biphasic neuronal response consisting of an early increase in firing within 10 ms followed by a transient suppression of 100 ms or so (Butovas and Schwarz, 2003;Sombeck et al, 2022;Yun et al, 2023). This biphasic pattern was conserved at all levels of anesthesia although the spike rate increases were lower during anesthesia than in the awake state.…”

“…Stimulation pulses were charge-balanced, biphasic waveforms (Merrill et al, 2005) that were initially varied with respect to cathodic-anodic temporal order and asymmetry of duration and amplitude. Preliminary tests with 5, 10, 20, and 40 μA stimulation currents showed that maximum response was afforded by 40 μA in agreement with other studies (Voigt and Kral, 2019;Sombeck et al, 2022;Yun et al, 2023). Therefore, in subsequent experiments a maximum stimulus current of 40 μA was used.…”

“…This biphasic pattern was conserved at all levels of anesthesia although the spike rate increases were lower during anesthesia than in the awake state. The exact duration of these phases was reported to vary with stimulus intensity (Yun et al, 2023), although this aspect was not investigated further here. Also, as found before (McIntyre and Grill, 2000;Voigt and Kral, 2019), cathodic-leading chargebalanced stimulus waveforms were more effective in stimulating neuron firing than the reverse waveforms, although this difference in our preparation was quite small.…”

“…This biphasic pattern was conserved at all levels of anesthesia although the spike rate increases were lower during anesthesia than in the awake state. The exact duration of these phases was reported to vary with stimulus intensity (Yun et al, 2023), although this aspect was not investigated further here.…”

Neural mechanisms of the temporal response of cortical neurons to intracortical microstimulation

“…Butovas and colleagues quantified the temporal response to ICMS of neurons in the somatosensory cortex (S1) of rats [1,13]. At stimulation threshold, single pulse ICMS evoked a short latency excitatory response followed by long-lasting inhibition [1], and a number of other groups subsequently replicated these findings [2,11,12,[14][15][16][17][18][19][20][21][22]. The strength of short-latency excitation increased, and the duration of the inhibition became longer, with increased stimulation intensity [11,12].…”