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Abstract: Recent evidence suggests that cranial sutures could serve as conduits for nociceptive transmission from extracranial to intracranial fibres, potentially influencing headache pathophysiology. Animal studies indicate extracranial stimulation affects dural nerve activity, and suture-targeted therapies like botulinum toxin show efficacy in chronic migraine. However, the role of the "suture pathway" in human headache generation remains unclear. This study investigates whether extracranial stimulation over cranial sutures induces more intracranial activation, ie, headache generation, than stimulation at nonsutural sites. Sixty healthy participants from 3 cohorts (n = 20 each) received noninvasive capsaicin or electrical stimulation at sutural and nonsutural sites in a pseudorandomised parallel-group crossover design. Headache occurrence, intensity, and duration were compared. The 3 study cohorts were comparable in terms of the sex and age distribution (50% being female, with an average age between 25 and 30 years). After stimulation, the incidence of headaches at the suture site point was 35%, 60%, and 25% in cohorts 1, 2, and 3, respectively. No significant difference was found between sutural and nonsutural sites (P > 0.05 in all 3 cohorts). The functional relevance of the sutural pathway remains inconclusive in humans. Although extracranial stimulation indeed may result in headache, this effect appears to be independent of the stimulation sites. Adjacent structures, including epicranial muscles, may modulate the headache induction rate. The functional role of the connection may be different in patients with headache than in healthy controls. Future research should explore these mechanisms using an optimised stimulation protocol, with a focus on patients with headache.

Abstract: Primary nociceptors are essentially characterized as afferent neurons carrying noxious sensory information from the periphery to the central nervous system. However, the information flow on primary nociceptors is bidirectional. Nociceptor peripheral terminals release a variety of mediators to the target organ near the injured area. These mediators promote sensitization of adjacent sensory neurons, vasodilation, and edema, affecting innate and adaptive immunity, leading to hyperalgesia and inflammation that often expands beyond the injured areas. While many studies associate these phenomena with the antidromic action-potential propagation along nociceptor terminals, direct evidence demonstrating that activation of a single nociceptor terminal can, through efferent signaling, recruit neighboring unstimulated terminals has been missing. In this study, using in vivo calcium imaging from the individual nociceptive terminals innervating the cornea of male mice, together with a computational approach, we demonstrated that brief activation of a single terminal in vivo by capsaicin was sufficient to evoke a response in a remote, unstimulated terminal, branching from the same nociceptor fiber. The activation of the remote unstimulated terminal was dependent on the activation of voltage-gated sodium and calcium channels. Moreover, we showed that in the model of acute hyperalgesia, following exposure to proinflammatory cytokines, the efferent signaling along nociceptive terminals increases, culminating in enhanced calcium signaling in the remote unstimulated terminals. This increase in intraterminal calcium could trigger an enhanced release of inflammatory mediators, affecting wider areas and terminals from adjacent unstimulated receptive fields, leading to the expansion of hyperalgesia and inflammation.

Abstract: Impairments in lumbar sensory perception, including reduced tactile acuity, occur in patients with nonspecific low back pain (LBP). Tactile acuity is linked to primary somatosensory cortex (S1) activity and structure, but neural markers of lumbar-specific tactile acuity tests remain unvalidated. This cross-sectional study investigated associations between lumbar two-point discrimination (TPD) and estimation (TPE) with functional and structural properties of S1, as well as S1-thalamic connectivity. Resting-state functional MRI and diffusion-weighted MRI assessed S1-thalamic functional connectivity (FC) and structural connectivity, as well as regional homogeneity (ReHo) and mean diffusivity (MD) of S1 grey matter in 78 LBP patients and 39 pain-free controls. Participants with LBP were subdivided into 2 groups: 1 with pain (LBP+, n = 39) and 1 without pain (LBP-, n = 39) on the day of assessment. Higher TPD (ie, worse tactile acuity) was associated with higher contralateral S1-thalamic FC (β = 19.97 mm, 95% CI = 8.47-31.46 mm) and lower contralateral S1-MD (β = -76.98 mm, 95% CI = -142.83 to -11.13 mm). Higher TPE was associated with higher S1-ReHo (β = 19.67 mm, 95% CI = 0.35-39 mm). Two-point discrimination and two-point estimation were positively correlated (r = 0.25, P < 0.001). No between-group differences were found for the MRI variables or TPE, but the LBP+ group showed higher TPD thresholds than pain-free controls (MDiff. = 6.05 mm, Padj . = 0.023). Our findings question the validity of TPE as a measure of tactile acuity. Both neural markers of TPD may not explain tactile acuity impairments in LBP but instead reflect a baseline indicator of tactile performance capability, suggesting poor validity as an LBP-specific marker of neuroplasticity.