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Chronic pain is a major health care problem. A better mechanistic understanding and new treatment approaches are urgently needed. In the brain, pain has been associated with neural oscillations at alpha and gamma frequencies, which can be targeted using transcranial alternating current stimulation (tACS). Thus, we investigated the potential of tACS to modulate pain and pain-related autonomic activity in an experimental model of chronic pain in 29 healthy participants. In 6 recording sessions, participants completed a tonic heat pain paradigm and simultaneously received tACS over prefrontal or somatosensory cortices at alpha or gamma frequencies or sham tACS. Concurrently, pain ratings and autonomic responses were collected. Using the present setup, tACS did not modulate pain or autonomic responses. Bayesian statistics confirmed a lack of tACS effects in most conditions. The only exception was alpha tACS over somatosensory cortex where evidence was inconclusive. Taken together, we did not find significant tACS effects on tonic experimental pain in healthy humans. Based on our present and previous findings, further studies might apply refined stimulation protocols targeting somatosensory alpha oscillations. TRIAL REGISTRATION: The study protocol was pre-registered at ClinicalTrials.gov (NCT03805854). PERSPECTIVE: Modulating brain oscillations is a promising approach for the treatment of pain. We therefore applied transcranial alternating current stimulation (tACS) to modulate experimental pain in healthy participants. However, tACS did not modulate pain, autonomic responses, or EEG oscillations. These findings help to shape future tACS studies for the treatment of pain., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Autonomic responses are an essential component of pain. They serve its adaptive function by regulating homeostasis and providing resources for protective and recuperative responses to noxious stimuli. To be adaptive and flexible, autonomic responses are not only determined by noxious stimulus characteristics, but likely also shaped by perceptual and motor responses to noxious stimuli. However, it is not fully known how noxious stimulus characteristics, perceptual responses, and motor responses interact in shaping autonomic responses. To address this question, we collected perceptual, motor, and autonomic responses to brief noxious laser stimuli of different intensities in 47 healthy human participants. Multilevel 2-path mediation analyses revealed that perceptual, but not motor responses mediated the translation of noxious stimuli into autonomic responses. Multilevel 3-path mediation analyses further specified that motor responses indirectly related to autonomic responses through their close association with perceptual responses. These findings confirm that autonomic responses are not only a reflexive reaction to noxious stimuli, but directly and indirectly shaped by perceptual and motor responses, respectively. These effects of motor and perceptual processes on autonomic responses likely allow for the integration of contextual processes into protective and regulatory autonomic responses, aiding adaptive and flexible coping with threat.

Pain is a complex phenomenon involving perceptual, motor, and autonomic responses, but how the brain translates noxious stimuli into these different dimensions of pain is unclear. Here, we assessed perceptual, motor, and autonomic responses to brief noxious heat stimuli and recorded brain activity using electroencephalography (EEG) in humans. Multilevel mediation analysis reveals that each pain dimension is subserved by a distinct pattern of EEG responses and, conversely, that each EEG response differentially contributes to the different dimensions of pain. In particular, the translation of noxious stimuli into autonomic and motor responses involved the earliest N1 wave, whereas pain perception was mediated by later N2 and P2 waves. Gamma oscillations mediated motor responses rather than pain perception. These findings represent progress towards a mechanistic understanding of the brain processes translating noxious stimuli into pain and suggest that perceptual, motor, and autonomic dimensions of pain are partially independent rather than serial processes.

Pain serves the protection of the body by translating noxious stimulus information into a subjective percept and protective responses. Such protective responses rely on autonomic responses that allocate energy resources to protective functions. However, the precise relationship between objective stimulus intensity, subjective pain intensity, autonomic responses, and brain activity is not fully clear yet. Here, we addressed this question by continuously recording pain ratings, skin conductance, heart rate, and electroencephalography during tonic noxious heat stimulation of the hand in 39 healthy human subjects. The results confirmed that pain intensity dissociates from stimulus intensity during 10 minutes of noxious stimulation. Furthermore, skin conductance measures were significantly related to stimulus intensity but not to pain intensity. Correspondingly, skin conductance measures were significantly related to alpha and beta oscillations in contralateral sensorimotor cortex, which have been shown to encode stimulus intensity rather than pain intensity. No significant relationships were found between heart rate and stimulus intensity or pain intensity. The findings were consistent for stimulation of the left and the right hands. These results suggest that sympathetic autonomic responses to noxious stimuli in part directly result from nociceptive rather than from perceptual processes. Beyond, these observations support concepts of pain and emotions in which sensory, motor, and autonomic components are partially independent processes that together shape emotional and painful experiences.