Distinct neocortical mechanisms underlie human SI responses to median nerve and laser-evoked peripheral activation.

Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically relevant tools that have long been used to measure electromagnetic fields in the somatosensory cortex evoked by innocuous and noxious somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in the primary somatosensory cortex (SI) linked to innocuous and noxious sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful and/or painful somatosensation. Through a literature review, we detailed features of MN and LE responses source-localized to SI that are robust and reproducible across studies. We showed that the first peak in the MN response at 20 ms post-stimulus (i.e., MN N1) corresponds to upward-directed deep-to-superficial electrical current flow through the cortical laminae, which is followed by downward-directed current at ~30 ms (i.e., MN P1). In contrast, the initial LE response occurs later at ~170 ms (i.e., LE N1) and is directed downward and opposite the direction of the MN N1. We then examined the neocortical circuit mechanisms contributing to the robust features of each response using the Human Neocortical Neurosolver (HNN) neural modeling software tool (Neymotin et al., 2020). Using HNN as a hypothesis development and testing tool, model results predicted the MN response can be simulated with a sequence of layer-specific thalamocortical and cortico-cortical synaptic drive similar to that previously reported for tactile evoked responses (S. R. Jones et al., 2007; Neymotin et al., 2020), with the novel discovery that an early excitatory input to supragranular layers at ~30 ms is an essential mechanism contributing to the downward current flow of the MN P1. Model results further predicted that the initial ~170 ms downward current flow of the LE N1 was generated by a burst of repetitive gamma-frequency (40 Hz) excitatory synaptic drive to supragranular layers, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as somatic sensitivity and acute neuropathic pain.