A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine.

Unmyelinated tactile (C-tactile or CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here, we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves. The most distal receptive fields were located on the proximal phalanx of the third finger for the superficial branch of the radial nerve and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n = 27), radial (n = 8), and peroneal (n = 4) nerves. Moreover, we found that although CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared with C-nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.NEW & NOTEWORHY Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and are thought to signal features of social affective touch. We show that CTs are also present but are relatively sparse in the lower leg compared with C-nociceptors. CTs display similar physiological properties across the arm and leg nerves. Furthermore, CT afferents do not respond to the cooling agent menthol or the pruritogen histamine, and their mechanical response properties are not altered by these chemicals.

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 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.

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 Aß 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.

The ability to sense pain is critical to our survival. Normally, pain is provoked by intense heat or cold temperatures, strong force or a chemical stimulus, for example, capsaicin, the pain-provoking substance in chili peppers. However, if nerve fibers in the arms or legs are damaged, pain can occur in response to touch or pressure stimuli that are normally painless. This hypersensitivity is called mechanical allodynia. A protein called calcitonin gene-related peptide, or CGRP, has been implicated in mechanical allodynia and other chronic pain conditions, such as migraine. CGRP is found in, and released from, the neurons that receive and transmit pain messages from tissues, such as skin and muscles, to the spinal cord. However, only a few distinct groups of CGRP-expressing neurons have been identified and it is unclear if these nerve cells also contribute to mechanical allodynia. To investigate this, Löken et al. genetically engineered mice so that all nerve cells containing CGRP produced red fluorescent light when illuminated with a laser. This included a previously unexplored group of CGRP-expressing neurons found in a part of the spinal cord that is known to receive information about non-painful stimuli. Using neuroanatomical methods, Löken et al. monitored the activity of these neurons in response to various stimuli, before and after a partial nerve injury. This partial injury was induced via a surgery that cut off a few, but not all, branches of a key leg nerve. The experiments showed that in their normal state, the CGRP-expressing neurons hardly responded to mechanical stimulation. In fact, it was difficult to establish what they normally respond to. However, after a nerve injury, brushing the mice's skin evoked significant activity in these cells. Moreover, when these CGRP cells were artificially stimulated, the stimulation induced hypersensitivity to mechanical stimuli, even when the mice had no nerve damage. These results suggest that this group of neurons, which are normally suppressed, can become hyperexcitable and contribute to the development of mechanical allodynia. In summary, Löken et al. have identified a group of nerve cells in the spinal cord that process mechanical information and contribute to touch-evoked pain. Future studies will identify the nerve circuits that are targeted by CGRP released from these nerve cells. These circuits represent a new therapeutic target for managing chronic pain conditions related to nerve damage, specifically mechanical allodynia, which is the most common complaint of patients with chronic pain.

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

C-tactile (CT) afferents were long-believed to be lacking in humans, but these 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 characteristics comparable with 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 seven 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 Aß 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 of their existence on the hand, albeit at a relatively low density. Glabrous skin CTs may provide modulatory reinforcement of gentle tactile interactions during touch using the hands.

Low-threshold mechanoreceptors play a frequency-dependent dual role in subjective ratings of mechanical allodynia.

In the setting of injury, myelinated primary afferent fibers that normally signal light touch are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aß afferents increase. However, it is not known if varying the firing rates of Aß afferents have any consequence to the perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aß afferents increase. Using a stimulus-response protocol established in normal skin, where an increase in brush velocity results in an increase of Aß afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated low-threshold mechanoreceptor firing activity influenced perception and brain activity (functional MRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aß firing rates and unpleasantness such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently to this, we found increased cortical activity in response to low Aß firing rates in regions previously implicated in pain processing during brushing of sensitized skin, but not normal skin. We suggest that Aß signals do not merely switch modality to signal pain during injury. Instead, they exert a high- and low-frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences. NEW & NOTEWORTHY We suggest that Aß signals do not simply switch modality to signal pain during injury but play a frequency-dependent and dual role in the injured state with both pleasant and unpleasant consequences. These results provide a framework to resolve the apparent paradox of how touch can inhibit pain, as proposed by the Gate Control Theory and the existence of dynamic mechanical allodynia.

Disturbances in affective touch in hereditary sensory & autonomic neuropathy type III.

Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley-Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30 cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1-10 cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity.

Physiological and behavioral responses reveal 9-month-old infants' sensitivity to pleasant touch.

Caregiving touch has been shown to be essential for the growth and development of human infants. However, the physiological and behavioral mechanisms that underpin infants' sensitivity to pleasant touch are still poorly understood. In human adults, a subclass of unmyelinated peripheral nerve fibers has been shown to respond preferentially to medium-velocity soft brushing. It has been theorized that this privileged pathway for pleasant touch is used for close affiliative interactions with conspecific individuals, especially between caregivers and infants. To test whether human infants are sensitive to pleasant touch, we examined arousal (heart rate) and attentional engagement (gaze shifts and duration of looks) to varying velocities of brushing (slow, medium, and fast) in 9-month-old infants. Our results provide physiological and behavioral evidence that sensitivity to pleasant touch emerges early in development and therefore plays an important role in regulating human social interactions.

Pleasantness of touch in human glabrous and hairy skin: order effects on affective ratings.

The tactile sense comprises pathways for both discriminative and affective touch. Low threshold unmyelinated mechanoafferents (C tactile, CT) in the human hairy skin have recently been linked to pleasant touch sensation. Here, we investigated how perception of the hedonic aspect of tactile stimulation differs between the hairy skin of the arm, and the glabrous skin of the palm, which is not innervated by CT afferents. Three groups of naïve, healthy subjects (total n=28) rated pleasantness on a visual analogue scale (VAS) when we stroked with a soft brush with speeds from 0.1 to 30cm/s on the palm or forearm. We used two different experimental approaches: in experiments 1 and 2, stimuli were delivered successively on the palm and arm (or arm and palm) in temporally separate sequential blocks. In experiment 3, stimuli were delivered alternately on arm and palm. We found that the order of stimulus presentation, palm/arm or arm/palm, has an effect on pleasantness ratings of gentle brush stroking with varying velocity. Notably, the perception of pleasantness for palm stimulation was affected by previous stimulation of the arm, but not vice versa. Thus, assessment of valence of touch may be influenced by affective reactions elicited by activation of the CT afferent pathway.

Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch.

We examined patients with a heritable disorder associated with a mutation affecting the nerve growth factor beta gene. Their condition has been classified as hereditary sensory and autonomic neuropathy type V. Carriers of the mutation show a reduction in density of thin and unmyelinated nerve fibres, including C afferents. A distinct type of unmyelinated, low-threshold mechanoreceptive C fibre, the C-tactile afferent, is present in hairy but not glabrous skin of humans and other mammals. They have been implicated in the coding of pleasant, hedonic touch of the kind that occurs in affiliative social interactions. We addressed the relationship between C fibre function and pleasant touch perception in 10 individuals from a unique population of mutation carriers in Sweden. We also investigated the effect of reduced C-fibre density on patients' evaluation of observed interpersonal touch (empathy). Results showed that patients perceived gentle, slow arm stroking, optimal for eliciting C-tactile afferent responses (1-10 cm/s), as less pleasant than did matched controls and also differed in their rating patterns across stimulation velocities. Further, patients' blood-oxygen-level-dependent responses in posterior insular cortex--a target for C afferents--were not modulated by stimulation optimal for activating C-tactile afferents. Hence, perception of the hedonic aspect of dynamic touch likely depends on C-tactile afferent density. Closely similar patterns between individuals' ratings of felt and seen touch suggest that appraisal of others' touch is anchored in one's own perceptual experience, whether typical or atypical.

The skin as a social organ.

In general, social neuroscience research tends to focus on visual and auditory channels as routes for social information. However, because the skin is the site of events and processes crucial to the way we think about, feel about, and interact with one another, touch can mediate social perceptions in various ways. This review situates cutaneous perception within a social neuroscience framework by discussing evidence for considering touch (and to some extent pain) as a channel for social information. Social information conveys features of individuals or their interactions that have potential bearing on future interactions, and attendant mental and emotional states. Here, we discuss evidence for an affective dimension of touch and explore its wider implications for the exchange of social information. We consider three important roles for this affective dimension of the cutaneous senses in the transmission and processing of social information: first, through affiliative behavior and communication; second, via affective processing in skin-brain pathways; and third, as a basis for intersubjective representation.

Somatotopic organization of gentle touch processing in the posterior insular cortex.

A network of thin (C and A delta) afferents relays various signals related to the physiological condition of the body, including sensations of gentle touch, pain, and temperature changes. Such afferents project to the insular cortex, where a somatotopic organization of responses to noxious and cooling stimuli was recently observed. To explore the possibility of a corresponding body-map topography in relation to gentle touch mediated through C tactile (CT) fibers, we applied soft brush stimuli to the right forearm and thigh of a patient (GL) lacking A beta afferents, and six healthy subjects during functional magnetic resonance imaging (fMRI). For improved fMRI analysis, we used a highly sensitive multivariate voxel clustering approach. A somatotopic organization of the left (contralateral) posterior insular cortex was consistently demonstrated in all subjects, including GL, with forearm projecting anterior to thigh stimulation. Also, despite denying any sense of touch in daily life, GL correctly localized 97% of the stimuli to the forearm or thigh in a forced-choice paradigm. The consistency in activation patterns across GL and the healthy subjects suggests that the identified organization reflects the central projection of CT fibers. Moreover, substantial similarities of the presently observed insular activation with that described for noxious and cooling stimuli solidify the hypothesized sensory-affective role of the CT system in the maintenance of physical well-being as part of a thin-afferent homeostatic network.

Coding of pleasant touch by unmyelinated afferents in humans.

Pleasant touch sensations may begin with neural coding in the periphery by specific afferents. We found that during soft brush stroking, low-threshold unmyelinated mechanoreceptors (C-tactile), but not myelinated afferents, responded most vigorously at intermediate brushing velocities (1-10 cm s(-1)), which were perceived by subjects as being the most pleasant. Our results indicate that C-tactile afferents constitute a privileged peripheral pathway for pleasant tactile stimulation that is likely to signal affiliative social body contact.

Cortical processing of lateral skin stretch stimulation in humans.

Direction discrimination of a moving tactile stimulus requires intact dorsal columns and provides a sensitive clinical test of somatosensory dysfunction. Cortical mechanisms are poorly understood. We have applied tangential skin pulls to the right lower leg during functional magnetic resonance imaging. Healthy subjects judged the direction of the skin pulls (task experiment, n = 7) or received skin pulls passively (no task experiment, n = 8). Second somatosensory cortex (S2) was activated in the task as well as no task experiment, and there was no significant difference in cortical activation between the two experiments. Within S2 nearly all subjects had prominent activations in the caudal and superficial part, i.e., in the opercular parietal (OP) area 1. S1 was activated in only one of the subjects. Thus, S2 and especially OP 1 seems to be important for processing of lateral skin stretch stimulation. The finding suggests that a lesion of this area might cause a disturbance in tactile direction discrimination which should be relevant for clinical testing.

Discriminative touch and emotional touch.

Somatic sensation comprises four main modalities, each relaying tactile, thermal, painful, or pruritic (itch) information to the central nervous system. These input channels can be further classified as subserving a sensory function of spatial and temporal localization, discrimination, and provision of essential information for controlling and guiding exploratory tactile behaviours, and an affective function that is widely recognized as providing the afferent neural input driving the subjective experience of pain, but not so widely recognized as also providing the subjective experience of affiliative or emotional somatic pleasure of touch. The discriminative properties of tactile sensation are mediated by a class of fast-conducting myelinated peripheral nerve fibres--A-beta fibres--whereas the rewarding, emotional properties of touch are hypothesized to be mediated by a class of unmyelinated peripheral nerve fibres--CT afferents (C tactile)--that have biophysical, electrophysiological, neurobiological, and anatomical properties that drive the temporally delayed emotional somatic system. CT afferents have not been found in the glabrous skin of the hand in spite of numerous electrophysiological explorations of this area. Hence, it seems reasonable to conclude that they are lacking in the glabrous skin. A full understanding of the behavioural and affective consequences of the differential innervation of CT afferents awaits a fuller understanding of their function.