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 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. Repetitive stimulation often modulated both the probability of evoking spikes and the duration of inhibition, although high frequency stimulation in particular was more likely to change both responses. Comparisons between stimuli that evoked a spike and stimuli that did not revealed that the excitatory and inhibitory responses were independent of one another on a trial-by-trial basis; however, their changes over time were frequently 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.

Paired stimulation for spike-timing dependent plasticity quantified with single neuron responses in primate motor cortex

“…Although delivering electrical stimulation to a cortical site activates excitatory fibers projecting to a neighboring site, it also activates fibers projecting to interneurons in the local circuitry that subsequently inhibit the recorded principal cells (Butovas et al, 2006; Logothetis et al, 2010; Yun et al, 2022). Thus, improper timing of stimulation delivered to the Post site may enhance the inhibitory activity rather than the firing of the spike (Figure 14).…”

“…Test stimuli were delivered at 5 Hz, Poisson distributed and paired stimulation during Conditioning were delivered at 10 Hz, Poisson distributed. These frequencies have been shown not to heavily affect the stimulus responses over time (Yun et al, 2022). The interstimulus interval (ISI) between the paired stimuli was randomly determined each day.…”

“…The interstimulus interval (ISI) between the paired stimuli was randomly determined each day. All stimuli used an amplitude of 15 µA as previous studies showed it to be sufficient to reliably activate the stimulated site and generate responses in sites up to 4 mm away (Butovas & Schwarz, 2003; Hao et al, 2016; Yun et al, 2022). The stimulus intensity was kept the same across all sessions rather than adjusted to the stimulus response to limit current spread.…”

“…Detailed methods of detecting stimulus evoked spikes and calculating the inhibitory response duration can be found in Yun et al 2022. In brief, stimulus evoked spikes were found by calculating the peristimulus time histogram (PSTH) of each spike.…”

“…We hypothesized that two factors may be limiting our understanding of applying paired stimulation in vivo . First, electrical stimulation in the context of paradigms for inducing plasticity is typically considered to be excitatory, but several studies have shown that stimulus response consists of a short-term excitatory response immediately followed by a long-term inhibitory response that is often strong enough to completely silence the cell for up to hundreds of milliseconds (Butovas & Schwarz, 2003; Logothetis et al, 2010; Yun et al, 2022). Electrical stimulation activates a bundle of fibers that project to the recorded site that excites the recorded neuron but also activates the surrounding inhibitory circuitry resulting in GABAergic inhibition (Butovas et al, 2006).…”