Dissecting the neural underpinnings of the short-latency response to transcranial magnetic stimulation of motor cortex: A computational modeling study

Abstract

Abstract Objective: 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. The D-wave is thought to be caused by direct activation of corticospinal axons, while I-waves are believed to be generated by trans-synaptic activation of corticospinal axons. The cortical circuits and mechanisms involved in the generation of I-waves by TMS of M1 remain unclear. Methods: We implemented a computational model of a cortical column with biophysically-based cortical neurons, following an existing model (Traub 2005). The TMS induced E-field was modeled as intracellular current injections of monophasic TMS pulses into the axon terminals of pyramidal neurons (PN). We constructed dose–response curves of spiking activity averaged across layer 5 (L5) PN as a function of the proportion of activated PN. Results: Model-based responses were compared to I-waves recorded from L5 PN in rodent M1 during TMS (Li 2017), and the network model reproduced I-waves only during the activation of axon terminals of L5 PN in contrast to activation of axon terminals of L2/3 or L6 PN. Inhibitory interneurons in deep layers fired in synchrony during the late phases of I-waves offering a potential explanation for the reduction in magnitude of late I-waves seen in experimental studies after administration of GABA-A agonists. Virtual lesioning of model neurons revealed that recurrent synaptic connections between L5 PN mediated by AMPA receptors play a prominent role in the generation of I-waves. Conclusions: Activation of presynaptic terminal of L5 PN is necessary to generate an I-wave response to TMS. Further, recurrent excitatory synaptic connections between L5 PN play a prominent role in the generation of I-wave response. Significance: Gaining a better understanding of circuit mechanisms of TMS of the M1 could enable optimization of stimulation paradigms. Keywords: Transcranial magnetic stimulation, I-waves, Cortical column model, Motor cortex