A pathway for pleasant touch: linking peripheral receptors to central processing and hedonic experience

This thesis investigates the mechanisms underpinning pleasant touch, describes a pathway from peripheral nerve endings in the skin to the insular cortex, and relates these findings to the subjective hedonic experience of touch. In Paper I, the relationship between primary afferent encoding and perception of pleasantness was investigated by combining microneurography recordings from human mechanoreceptors with psychophysical measurements during soft brush stroking at 6 different velocities between 0.1–30 cm/s. Results showed that low-threshold unmyelinated fibers (C tactile, CT), but not myelinated afferents, responded most vigorously to intermediate brushing velocities (1–10 cm/s), which were perceived by subjects as being the most pleasant. In Paper II, a group of patients with reduced C fiber density due to a rare inheritable disorder (hereditary sensory and autonomic neuropathy type V, HSAN-V), provided the opportunity to address how pleasantness is perceived when the number of CT afferents is reduced. In comparison with healthy control subjects the C fiber denervated patients displayed atypical pleasantness ratings for soft brush stroking across different brushing velocities. These results suggest that conventional pleasant touch is dependent on CT fiber density. CT afferents are lacking in glabrous skin which suggests that pleasant touch is perceived differently in the palm compared to the forearm. In Paper III, three different experiments were performed on three different groups of experimentally naive, healthy subjects. In experiment 1, a series of brush strokes was first applied to the palm followed by a series of brush strokes on the arm; in experiment 2, this order was reversed. In experiment 3, brush strokes were applied to the palm and arm in an alternating fashion. In experiment 1 subjects rated gentle stroking as less pleasant on the palm compared to the arm. In experiments 2 and 3, similar ratings were seen for the palm and arm. These results suggest that the perception of pleasantness on the palm is affected by previous stimulation of the arm, but not vice versa. It was speculated that assessment of pleasant touch may be influenced by affective reactions elicited through activation of the CT afferent pathway. Paper IV investigated whether CT afferents project to the cortex in a somatotopic fashion. In order to distinguish between cortical activations evoked by myelinated (Aβ) fibers and those specifically related to CT afferents six healthy subjects were compared to a unique patient (GL), who lacks Aβ afferents. Soft brush stimulation was applied to the participants’ arm and thigh during functional magnetic resonance imaging (fMRI). CT afferents were shown to project somatotopically to the posterior insular cortex in a similar fashion to those previously identified for signalling temperature and pain. In conclusion, this thesis provides an improvement to the understanding of the neural substrates governing pleasant touch. Further knowledge on the mechanisms behind affective touch may be useful for understanding certain psychiatric disorders, such as autism, where gentle touch is perceived as unpleasant

Evidence for sparse C-tactile afferent innervation of glabrous human hand skin

International audienceC-tactile (CT) afferents were long-believed to be lacking in humans, but were subsequently shown to densely innervate the face and arm skin, and to a lesser extent the leg. Their firing frequency to stroking touch at different velocities has been correlated with ratings of tactile pleasantness. CT afferents were thought to be absent in human glabrous skin; however, tactile pleasantness can be perceived across the whole body, including glabrous hand skin. We used microneurography to investigate mechanoreceptive afferents in the glabrous skin of the human hand, during median and radial nerve recordings. We describe CTs found in the glabrous skin, with comparable characteristics to those in hairy arm skin, and detail recordings from three such afferents. CTs were infrequently encountered in the glabrous skin and we estimate that the ratio of recorded CTs relative to myelinated mechanoreceptors (1:80) corresponds to an absolute innervation density of around 7 times lower than in hairy skin. This sparse innervation sheds light on discrepancies between psychophysical findings of touch perception on glabrous skin and hairy skin, although the role of these CT afferents in the glabrous skin remains subject to future work. New & Noteworthy: Human touch is encoded by low-threshold mechanoreceptors, including myelinated Aβ afferents and unmyelinated C-tactile (CT) afferents. CTs are abundant in hairy skin and are thought to code gentle, stroking touch that signals positive affective interactions. CTs have never been described in human glabrous skin, yet we show evidence for their existence on the hand, albeit at relatively low density. Glabrous skin CTs may provide modulatory reinforcement of gentle tactile interactions during touch using the hands

Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity.

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury

Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury

Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.

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 EMG (n = 3 CIP participants and n = 8 healthy controls) we have found that these patients also have abnormalities in the encoding of affective touch which is mediated by the specialised 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