Significance: While several features of brain activity can be used to predict the variability of painful percepts within a given individual, it is much more difficult to predict pain variability across individuals. Here, we used electrophysiology to sample brain activity of humans and rodents, and demonstrated that laser-induced gamma oscillations sampled by central electrodes predict pain sensitivity across individuals both reliably and selectively: reliably, because they consistently predict between-subject pain intensity in both humans and rodents; selectively, because they do not track the between-subject reported intensity of nonpainful but equally salient auditory, visual, and nonnociceptive somatosensory stimuli. This discovery indicates that variability in an individual’s pain sensitivity is, at least partly, explained by variability in the amplitude of gamma oscillations of that individual.

Pain inhibition by additional somatosensory input is the rationale for the widespread use of Transcutaneous Electrical Nerve Stimulation (TENS) to relieve pain. Two main types of TENS produce analgesia in animal models: high-frequency (∼50-100 Hz) and low-intensity 'conventional' TENS, and low-frequency (∼2-4 Hz) and high-intensity 'acupuncture-like' TENS. However, TENS efficacy in human participants is debated, raising the question of whether the analgesic mechanisms identified in animal models are valid in humans. Here, we used a sham-controlled experimental design to clarify the efficacy and the neurobiological effects of 'conventional' and 'acupuncture-like' TENS in 80 human volunteers. To test the analgesic effect of TENS we recorded the perceptual and brain responses elicited by radiant heat laser pulses that activate selectively Aδ and C cutaneous nociceptors. To test whether TENS has a long-lasting effect on brain state we recorded spontaneous electrocortical oscillations. The analgesic effect of 'conventional' TENS was maximal when nociceptive stimuli were delivered homotopically, to the same hand that received the TENS. In contrast, 'acupuncture-like' TENS produced a spatially-diffuse analgesic effect, coupled with long-lasting changes both in the state of the primary sensorimotor cortex (S1/M1) and in the functional connectivity between S1/M1 and the medial prefrontal cortex, a core region in the descending pain inhibitory system. These results demonstrate that 'conventional' and 'acupuncture-like' TENS have different analgesic effects, which are mediated by different neurobiological mechanisms.

Ongoing fluctuations of intrinsic cortical networks determine the dynamic state of the brain, and influence the perception of forthcoming sensory inputs. The functional state of these networks is defined by the amplitude and phase of ongoing oscillations of neuronal populations at different frequencies. The contribution of functionally different cortical networks has yet to be elucidated, and only a clear dependence of sensory perception on prestimulus alpha oscillations has been clearly identified. Here, we combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in a large sample of healthy participants to investigate how ongoing fluctuations in the activity of different cortical networks affect the perception of subsequent nociceptive stimuli. We observed that prestimulus EEG oscillations in the alpha (at bilateral central regions) and gamma (at parietal regions) bands negatively modulated the perception of subsequent stimuli. Combining information about alpha and gamma oscillations predicted subsequent perception significantly more accurately than either measure alone. In a parallel experiment, we found that prestimulus fMRI activity also modulated the perception of subsequent stimuli: perceptual ratings were higher when the BOLD signal was higher in nodes of the sensorimotor network and lower in nodes of the default mode network. Similar to what observed in the EEG data, prediction accuracy was improved when the amplitude of prestimulus BOLD signals in both networks was combined. These findings provide a comprehensive physiological basis to the idea that dynamic changes in brain state determine forthcoming behavioral outcomes. Hum Brain Mapp 37:501–514, 2016. © 2015 Wiley Periodicals, Inc.

Intense radiant heat pulses concomitantly activate Aδ- and C-fiber skin nociceptors, and elicit a typical double sensation: an initial Aδ-related pricking pain is followed by a C-related prolonged burning sensation. It has been repeatedly reported that C-fiber laser-evoked potentials (C-LEPs) become detectable only when the concomitant activation of Aδ-fibers is avoided or reduced. Given that the saliency of the eliciting stimulus is a major determinant of LEPs, one explanation for these observations is that the saliency of the C-input is smaller than that of the preceding Aδ-input. However, even if the saliency of the C-input is reduced because of the preceding Aδ-input, a C-LEP should still be visible even when preceded by an Aδ-LEP response. Here we tested this hypothesis by applying advanced signal processing techniques (peak alignment and time-frequency decomposition) to electroencephalographic data collected in two experiments conducted in 34 and 96 healthy participants. We show that, when using optimal stimulus parameters (delivering >80 stimuli within a small skin territory), C-LEPs can be reliably detected in most participants. Importantly, C-LEPs are observed even when preceded by Aδ-LEPs, both in average waveforms and single trials. By providing quantitative information about several response properties of C-LEPs (latency jitter, stimulus-response and perception–response functions, dependency on stimulus repetitions and stimulated area), these results define optimal parameters to record C-LEPs simply and reliably. These findings have important clinical implications for assessing small-fiber function in neuropathies and neuropathic pain.