EEG frequency tagging using ultra-slow periodic heat stimulation of the skin reveals cortical activity specifically related to C fiber thermonociceptors

The recording of event-related brain potentials triggered by a transient heat stimulus is used extensively to study nociception and diagnose lesions or dysfunctions of the nociceptive system in humans. However, these responses are related exclusively to the activation of a specific subclass of nociceptive afferents: quickly-adapting thermonociceptors. In fact, except if the activation of A delta fibers is avoided or if A fibers are blocked, these responses specifically reflect activity triggered by the activation of Type 2 quickly-adapting A fiber mechano-heat nociceptors (AMH-2). Here, we propose a novel method to isolate, in the human electroencephalogram (EEG), cortical activity related to the sustained periodic activation of heat-sensitive thermonociceptors, using very slow (0.2 Hz) and long-lasting (75 s) sinusoidal heat stimulation of the skin between baseline and 50 degrees C. In a first experiment, we show that when such long-lasting thermal stimuli are applied to the hand dorsum of healthy volunteers, the slow rises and decreases of skin temperature elicit a consistent periodic EEG response at 0.2 Hz and its harmonics, as well as a periodic modulation of the magnitude of theta, alpha and beta band EEG oscillations. In a second experiment, we demonstrate using an A fiber block that these EEG responses are predominantly conveyed by unmyelinated C fiber nociceptors. The proposed approach constitutes a novel mean to study C fiber function in humans, and to explore the cortical processing of tonic heat pain in physiological and pathological conditions.