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

Abstract

BackgroundIntracortical microstimulation (ICMS) is used to map neuronal circuitry in the brain and restore lost sensory function, including vision, hearing, and somatosensation. The temporal response of cortical neurons to single pulse ICMS is remarkably stereotyped and comprises short latency excitation followed by prolonged inhibition and, in some cases, rebound excitation. However, the neural origin of the different response components to ICMS are poorly understood, and the interactions between the three response components during trains of ICMS pulses remains unclear. ObjectiveWe used computational modeling to determine the mechanisms contributing to the temporal response to ICMS in model cortical pyramidal neurons. MethodsWe built a biophysically based computational model of a cortical column comprising neurons with realistic morphology and synapses and quantified the temporal response of cortical neurons to different ICMS protocols. We characterized the temporal responses to single pulse ICMS across stimulation intensities and inhibitory (GABA-B/GABA-A) synaptic strengths. To probe interactions between response components, we quantified the response to paired pulse ICMS at different inter-pulse intervals and the response to short trains at different stimulation frequencies. Finally, we evaluated the performance of biomimetic ICMS trains in evoking a sustained neural response. ResultsSingle pulse ICMS evoked short latency excitation followed by a period of inhibition, but model neurons did not exhibit post-inhibitory rebound excitation. The strength of short latency excitation increased and the duration of inhibition increased with increased stimulation amplitude. Prolonged inhibition resulted from both after-hyperpolarization currents and GABA-B synaptic transmission. During the paired pulse protocol, the strength of short latency excitation evoked by a test pulse decreased marginally compared to those evoked by a single pulse for interpulse intervals (IPI) <100 ms. Further, the duration of inhibition evoked by the test pulse was prolonged compared to single pulse for IPIs < 40ms and was not predicted by linear superposition of individual inhibitory responses. For IPIs>40 ms, the duration of inhibition evoked by the test pulse was comparable to those evoked by a single pulse. Short ICMS trains evoked repetitive excitatory responses against a background of inhibition. However, the strength of the repetitive excitatory response declined during ICMS at higher frequencies. Further, the duration of inhibition at the cessation of ICMS at higher frequencies was prolonged compared to the duration following a single pulse. Biomimetic pulse trains evoked comparable neural response between the onset and offset phases despite the presence of stimulation induced inhibition. ConclusionsThe cortical column model replicated the short latency excitation and long-lasting inhibitory components of the stereotyped neural response documented in experimental ICMS studies. Both cellular and synaptic mechanisms influenced the response components generated by ICMS. The non-linear interactions between response components resulted in dynamic ICMS-evoked neural activity and may play an important role in mediating the ICMS-induced precepts. HIGHLIGHTSO_LIImplemented a biophysically based computational model of the cortical column to study the temporal response of neurons to intracortical microstimulation (ICMS) C_LIO_LITemporal response of model neurons comprised short latency excitation followed by a long-lasting inhibition but did not include rebound excitation. C_LIO_LIExcitation was mediated by both direct (antidromic) and indirect synaptic mechanisms and inhibition by both cellular (after-hyperpolarizing currents) and synaptic (GABAergic) mechanisms. C_LIO_LIThe temporal dynamics of the response to ICMS should be considered when designing paradigms for sensory prosthetic applications. C_LI