Do current neuroimaging-based biomarkers developed to ‘objectively’ assess pain perception truly relate to pain? Mouraux and Iannetti critically review the evidence, and examine the utility of brain biomarkers for achieving mechanism-based patient stratification, predicting treatment responses and offering personalized treatments.

Individuals exhibit considerable and unpredictable variability in painful percepts in response to the same nociceptive stimulus. Previous work has found neural responses that, while not necessarily responsible for the painful percepts themselves, can still correlate well with intensity of pain perception within a given individual. However, there is no reliable neural response reflecting the variability in pain perception across individuals. Here, we use an electrophysiological approach in humans and rodents to demonstrate that brain oscillations in the gamma band [gamma-band event-related synchronization (γ-ERS)] sampled by central electrodes reliably predict pain sensitivity across individuals. We observed a clear dissociation between the large number of neural measures that reflected subjective pain ratings at within-subject level but not across individuals, and γ-ERS, which reliably distinguished subjective ratings within the same individual but also coded pain sensitivity across different individuals. Importantly, the ability of γ-ERS to track pain sensitivity across individuals was selective because it did not track the between-subject reported intensity of nonpainful but equally salient auditory, visual, and nonnociceptive somatosensory stimuli. These results also demonstrate that graded neural activity related to within-subject variability should be minimized to accurately investigate the relationship between nociceptive-evoked neural activities and pain sensitivity across individuals.

In order to evaluate whether cortical motor reorganization occurs in the earliest phase of multiple sclerosis, we studied patients after a first clinical attack of hemiparesis. From a consecutive series of 70 patients enrolled in a study of patients with clinically isolated syndrome and serial MRI findings indicative of multiple sclerosis, we retrospectively selected 10 patients with hemiparesis as the onset symptom and no further clinical episode [mean age 32 +/- 9 years, disease duration 24 +/- 14 months, median Expanded Disability Status Score (EDSS) 1.25]. Ten age-matched, healthy subjects served as controls. Each subject was submitted to two functional MRI trials (one per hand) using a 1.5 T magnet during a sequential finger-to-thumb opposition task. Image analysis was performed using SPM99 software. Movements of both the 'affected' and the 'unaffected' hand activated significantly larger areas in patients than in controls in both the contralateral and ipsilateral cortical motor areas. Patients activated a greater number of foci than controls during both the right-hand and the left-hand movement. Most of these foci were located in cortical areas which were less or not at all activated in controls, such as the lateral premotor cortex [Brodmann area (BA) 6], the insula and the inferior parietal lobule (BA 40). Between-group analysis of patients versus controls showed significant (P < 0.001) foci in these areas, principally located in the ipsilateral hemisphere during right-hand movement and in both the cerebral hemispheres during left-hand movement. Time since clinical onset showed a significant positive correlation with the extent of activation in the ipsilateral motor areas (P = 0.006) during the right-hand movement and with the extent of activation in both the ipsilateral (P = 0.02) and contralateral (P = 0.006) motor areas during the left-hand movement. The T(1) lesion load along the motor pathway showed a significant positive correlation (P = 0.007) with the extent of activation in the contralateral motor areas during right-hand movement. Our study shows functional adaptive changes that involve both the symptomatic and asymptomatic hemisphere during a simple motor task in patients who had suffered a single clinical attack of hemiparesis. The extent of these changes increased with the time elapsed since disease onset and the severity of brain damage.

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.

No abstract

Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID syndrome, is emerging as a major health issue in patients with previous SARS-CoV-2 infection. Symptoms commonly experienced by patients include fatigue, palpitations, chest pain, dyspnea, reduced exercise tolerance, and “brain fog”. Additionally, symptoms of orthostatic intolerance and syncope suggest the involvement of the autonomic nervous system. Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.

Survival in a suddenly-changing environment requires animals not only to detect salient stimuli, but also to promptly respond to them by initiating or revising ongoing motor processes. We recently discovered that the large vertex brain potentials elicited by sudden supramodal stimuli are strongly coupled with a multiphasic modulation of isometric force, a phenomenon that we named cortico-muscular resonance (CMR). Here, we extend our investigation of the CMR to the time-frequency domain. We show that (i) both somatosensory and auditory stimuli evoke a number of phase-locked and non-phase-locked modulations of EEG spectral power. Remarkably, (ii) some of these phase-locked and non-phase-locked modulations are also present in the Force spectral power. Finally, (iii) EEG and Force time-frequency responses are correlated in two distinct regions of the power spectrum. An early, low-frequency region (∼4 Hz) reflects the previously-described coupling between the phase-locked EEG vertex potential and force modulations. A late, higher-frequency region (beta-band, ∼20 Hz) reflects a second coupling between the non-phase-locked increase of power observed in both EEG and Force. In both time-frequency regions, coupling was maximal over the sensorimotor cortex contralateral to the hand exerting the force, suggesting an effect of the stimuli on the tonic corticospinal drive. Thus, stimulus-induced CMR occurs across at least two different types of cortical activities, whose functional significance in relation to the motor system should be investigated further. We propose that these different types of corticomuscular coupling are important to alter motor behaviour in response to salient environmental events.

A central mechanism of analgesia in mice and humans lacking the sodium channel Na V 1.7 Highlights d Loss of sodium channel Na V 1.7 abolishes pain without silencing peripheral nociceptors d Synaptic input to dorsal horn is compromised by an opioiddependent mechanism d Impaired neurotransmission from olfactory sensory neurons is opioid independent d Blocking opioid receptors reverses analgesia in mice and humans lacking Na V 1.7