Middleton, Perini et al. show that the role of Na(v)1.7 extends beyond pain perception. Using a multidisciplinary, cross-species approach, they show that Na(v)1.7 is also essential for C-low threshold mechanoreceptor function in mice and humans, regulating pleasant touch, punctate discrimination and sensitivity to cooling. Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

Emotionally-laden tactile stimulationsuch as a caress on the skin or the feel of velvetmay represent a functionally distinct domain of touch, underpinned by specific cortical pathways. In order to determine whether, and to what extent, cortical functional neuroanatomy supports a distinction between affective and discriminative touch, an activation likelihood estimate (ALE) meta-analysis was performed. This meta-analysis statistically mapped reported functional magnetic resonance imaging (fMRI) activations from 17 published affective touch studies in which tactile stimulation was associated with positive subjective evaluation (n=291, 34 experimental contrasts). A separate ALE meta-analysis mapped regions most likely to be activated by tactile stimulation during detection and discrimination tasks (n=1,075, 91 experimental contrasts). These meta-analyses revealed dissociable regions for affective and discriminative touch, with posterior insula (PI) more likely to be activated for affective touch, and primary somatosensory cortices (SI) more likely to be activated for discriminative touch. Secondary somatosensory cortex had a high likelihood of engagement by both affective and discriminative touch. Further, meta-analytic connectivity (MCAM) analyses investigated network-level co-activation likelihoods independent of task or stimulus, across a range of domains and paradigms. Affective-related PI and discriminative-related SI regions co-activated with different networks, implicated in dissociable functions, but sharing somatosensory co-activations. Taken together, these meta-analytic findings suggest that affective and discriminative touch are dissociable both on the regional and network levels. However, their degree of shared activation likelihood in somatosensory cortices indicates that this dissociation reflects functional biases within tactile processing networks, rather than functionally and anatomically distinct pathways.

Affective touch is a dynamic process. In this fMRI study we investigated affective touch by exploring its effects on overt behavior. Arm and palm skin were stroked with a soft brush at five different velocities (0.3, 1, 10, 3, and 30 cm s(-1)), using a novel feedback-based paradigm. Following stimulation in each trial, participants actively chose whether the caress they would receive in the next trial would be the same speed ("repeat") or different ("change"). Since preferred stroking speeds should be sought with greater frequency than non-preferred speeds, this paradigm provided a measure of such preferences in the form of active choices. The stimulation velocities were implemented with respect to the differential subjective pleasantness ratings they elicit in healthy subjects, with intermediate velocities (1, 10, and 3 cm s(-1)) considered more pleasant than very slow or very fast ones. Such pleasantness ratings linearly correlate with changes in mean firing rates of unmyelinated low-threshold C-tactile (CT) afferent nerves in the skin. Here, gentle, dynamic stimulation optimal for activating CT-afferents not only affected behavioral choices, but engaged brain regions involved in reward-related behavior and decision-making. This was the case for both hairy skin of the arm, where CTs are abundant, and glabrous skin of the palm, where CTs are absent. These findings provide insights on central and behavioral mechanisms underlying the perception of affective touch, and indicate that seeking affective touch involves value-based neural processing that is ultimately reflected in behavioral preferences.