Computational investigation of circuit mechanisms underlying short-latency responses to cortical stimulation

Abstract

Transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) elicits a series of high frequency volleys termed D- and I-waves measured epidurally in the corticospinal tract of awake humans. Further, intracortical microstimulation (ICMS) in M1 of non-human primates evokes D- and I-wave responses similar to those observed in TMS. The cortical circuits and mechanisms involved in the generation of D- and I-waves by stimulation of M1 remain unclear. Here, we implemented computational models of cortical columns with laminarly-organized biophysically-based neurons, following existing models published in the literature: (1) M1 - single compartment (SC), (2) M1 - multi-compartment (MC), (3) primary auditory cortex (A1) - MC, and (4) primary somatosensory cortex (S1) - MC. The network connectivity of each model represented wiring found in the respective cortical regions. The direct effects of stimulation-induced electric fields were modeled as activation of different proportions of pyramidal neurons (PNs) across layers, and dose–response curves were constructed for layer 5 (L5) PNs. Both the M1 and A1 models reproduced D- and I-waves, with the magnitude of I-waves increasing with higher recruitment of layer 2/3 and layer 5 PNs. The S1-MC model evoked rhythmic firing activity but with timings mismatched to experimental I-waves. The models replicated the experimentally observed effects of pharmacological agents on I-waves, and virtual lesions of specific neural populations across models revealed plausible microcircuit explanations for the first and later I-waves. This comprehensive comparison of models across multiple cortical regions identified consistent mechanisms underlying the cortical response to TMS and contributes to the refinement of computational strategies for optimizing stimulation paradigms. Significance Statement Cortical stimulation modalities such as transcranial magnetic stimulation and intracortical microstimulation applied to the primary motor cortex generate highly stereotyped, short-latency responses termed D- and I-waves, measured epidurally in the corticospinal tract of humans and non-human primates. Direct recording of the TMS- and ICMS-evoked neural response in the cortex is extremely challenging due to stimulation-induced artifacts. Furthermore, the short-latency responses evoked by stimulation of non-motor cortical regions remain unknown. Using sophisticated computational models representing different cortical areas, we simulated the immediate responses to cortical stimulation modalities including TMS and ICMS to characterize the circuit mechanisms underlying D- and I-waves. Gaining a better understanding of the cortical circuit mechanisms enables the interpretation and optimization of stimulation paradigms.