Small fiber neuropathy (SFN) is a common and debilitating disease in which the terminals of small diameter sensory axons degenerate, producing sensory loss, and in many patients neuropathic pain. While a substantial number of cases are attributable to diabetes, almost 50% are idiopathic. An underappreciated aspect of the disease is its late onset in most patients. Animal models of human genetic mutations that produce SFN also display age-dependent phenotypes suggesting that aging is an important contributor to the risk of development of the disease. In this review we define how particular sensory neurons are affected in SFN and discuss how aging may drive the disease. We also evaluate how animal models of SFN can define disease mechanisms that will provide insight into early risk detection and suggest novel therapeutic interventions.

Tactile perception encompasses several submodalities that are realized with distinct sensory subsystems. The processing of those submodalities and their interactions remains understudied. We developed a paradigm consisting of three types of touch tuned in terms of their force and velocity for different submodalities: discriminative touch (haptics), affective touch (C-tactile touch), and knismesis (alerting tickle). Touch was delivered with a high-precision robotic rotary touch stimulation device. A total of 39 healthy individuals participated in the study. EEG cluster analysis revealed a decrease in alpha and beta range (mu-rhythm) as well as theta and delta increase most pronounced to the most salient and fastest type of stimulation. The participants confirmed that slower stimuli targeted to affective touch low-threshold receptors were the most pleasant ones, and less intense stimuli aimed at knismesis were indeed the most ticklish ones, but those sensations did not form an EEG cluster, probably implying their processing involves deeper brain structures that are less accessible with EEG.

Conflicting evidence points to the contribution of several key nodes of the \'social brain\' to the processing of both discriminatory and affective qualities of interpersonal touch. Whether the primary somatosensory cortex (S1) and the medial prefrontal cortex (mPFC), two brain areas vital for tactile mirroring and affective mentalizing, play a functional role in shared representations of C-tactile (CT) targeted affective touch is still a matter of debate. Here, we used offline continuous theta-burst transcranial magnetic stimulation (cTBS) to mPFC, S1 and vertex (control) prior to participants providing ratings of vicarious touch pleasantness for self and others delivered across several body sites at CT-targeted velocities. We found that S1-cTBS led to a significant increase in touch ratings to the self, with this effect being positively associated to levels of interoceptive awareness. Conversely, mPFC-cTBS reduced pleasantness ratings for touch to another person. These effects were not specific for CT-optimal (slow) stroking velocities, but rather they applied to all types of social touch. Overall, our findings challenge the causal role of the S1 and mPFC in vicarious affective touch and suggest that self- vs other-directed vicarious touch responses might crucially depend on the specific involvement of key social networks in gentle tactile interactions.

Preterm infants are challenged to adapt to an extrauterine milieu, while their interoceptive system and autonomic regulation capacity is still immature. Caressing parental touch is known to foster parasympathetic regulation in infants by stimulating C-tactile (CT) afferents and in preterm infants, slow stroking stimulation also leads to a heart rate decrease. The particular impact of maternal stroking has not yet been investigated and factors influencing the maturation of the CT system in preterm infants remain unclear. We therefore analysed 53 standardized events in which preterm infants (24 to 36 weeks gestational age at birth) were stroked by their mothers. Video analysis revealed that mothers use CT optimal velocities to stroke their preterm child. Analysis of pulse oximetric data showed no effect of stroking on infantile blood oxygenation, but a significant decrease of the heart rate. Compared to term-born children, this decrease was delayed by about two minutes. Furthermore, our data suggested that more immature preterm infants benefited less from stroking than more mature ones. We conclude that maternal stroking touch targets CT afferents in preterm infants and that the preterm CT system is not yet mature.

Slow stroking touch activates C-tactile (CT) fibres in the human skin and is typically described as pleasant. Over a longer duration of stroking, affective habituation sets in, indicated by a reduction in rated pleasantness. However, it is not clear whether the group level effect is represented on an individual level. We analyse the stability of individual ratings of slow stroking touch and their relationship to behavioural and physiological measures. Forty-eight participants (23 women) were repeatedly stroked with a velocity maximally activating CT fibres. The perceived pleasantness was rated on a visual analogue scale. In order to examine the stability of pleasantness ratings, the experiment was repeated after a couple of days. During the experiment, electrocardiogram (ECG) and facial-electromyography (EMG) data were recorded. On the group-level, previous results of affective habituation to touch were replicated and stable across sessions. On the individual level, however, less than half of the participants showed a significant reduction of pleasantness in the course of the experiment. Moreover, the remaining participants showed either no change, random rating behaviour or even an increase in pleasantness ratings during the course of the experiment. The individual response patterns were variable across sessions but stable above the chance level. Furthermore, the response patterns could not be explicitly associated with any of the behavioural or physiological measures. Our findings indicate a lack of group-to-individual generalizability for affective habituation to touch. The variability of rating patterns over time indicates that they are not conclusively determined by stable individual characteristics. Future research investigating touch should favour a more individual approach to the more commonly applied group analysis.

Affective touch plays an important role in human social bonding, affiliative behavior, and in general emotional well-being. A system of unmyelinated low-threshold mechanosensitive C-type afferents innervating hairy skin (C-tactile or CT system) is postulated to provide the neurophysiological background of affective touch perception. C-tactile afferents respond optimally to soft and slow strokes, and this response correlates positively with pleasure ratings of tactile stimuli. As gentle touch is consistently associated with oxytocin release further promoting prosocial behavior, it has been suggested that this effect is mediated by the response of C-tactile afferents. This study assesses a possible link between CT-optimal touch, its subjective pleasantness, EEG indices of cortical arousal, and peripheral oxytocin response. EEG was recorded in 28 healthy volunteers during resting state and tactile stimulation[gentle slow brush strokes on forearm (CT-targeted touch) and palm (non-CT-targeted touch)]. Saliva samples were collected before and after the touch stimulation. Oxytocin concentration increase was significantly associated with greater subjective ratings of CT-targeted touch but not of non-CT-targeted touch, and with lower peak alpha frequency values indicating decreased cortical arousal. The findings suggest that CT-targeted stimulation triggers oxytocin release but only when the touch is perceived at an individual level as having clearly positive affective salience. This corresponds to previous studies reporting that oxytocin response to touch can be related to different personality factors, and bears important implications for planning touch-based interventions in social and medical care.

Social touch is important for interpersonal interaction. Gentle touch and slow brushing are typically perceived as pleasant, the degree of pleasantness is linked to the activity of the C-tactile (CT) fibers, a class of unmyelinated nerves in the skin. The inability to experience pleasure in general is called anhedonia, a common phenomenon in the chronic pain condition fibromyalgia. Here, we studied the perception and cortical processing of gentle touch in a well-characterized cohort of fibromyalgia. Patients and controls participated in functional brain imaging while receiving tactile stimuli (brushing) on the forearm. They were asked to provide ratings of pleasantness of the tactile stimulus and ongoing pain. We found high distress, pain catastrophizing, and insomnia, and a low perceived state of health in fibromyalgia. Further, patients rated both slow (CT-optimal) and fast (CT-suboptimal) brushing as less pleasant than healthy participants. While there was no difference in brain activity during touch, patients showed deactivation in the right posterior insula (contralateral to the stimulated arm) during pleasantness rating and activation during pain rating. The opposite pattern was observed in healthy participants. Voxel-based morphometry analysis revealed reduced grey matter density in patients, in the bilateral hippocampus and anterior insula. Our results suggest anhedonia to gentle touch in fibromyalgia with intact early-stage sensory processing but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in fibromyalgia.

The unmyelinated C-tactile afferents system holds a hedonic function in touch experiences, shaping social functioning in the so-called affective touch hypothesis. Despite the fact that females are recognized as more sensitive to discriminative aspects of touch and respond more positively to touch than men, sex differences in the perception of affective touch have not been extensively investigated. We aimed to fill this gap by meta-analyzing existing studies on this topic. Thirteen studies were eligible and pooled effect sizes (Hedges\' g) were compared. Random effect models were used. Results, which are not influenced by publication bias, show that there is a sex asymmetry in the pleasantness perceived during an affective tactile stimulation, with females showing higher pleasantness ratings than males. The size of the association does not vary as a function of sex distribution, age and methodological quality. Hormonal as well as evolutionary differences related to the caregiving and nurturing function of females may explain sex differences in affective touch. Results are limited by the small number of studies included in the meta-analysis.

The building of physiological self-regulation during bonding is a crucial developmental process based on early cardio-respiratory maturation. The mother\'s role as a facilitator of this physiological maturation has been evidenced and recognized in many respects. Research in fathers, however, remains sparse which may be due to the belief that bonding is a physiological behavior reserved for a mother\'s maternal instinct. In the current study we compared the impact of paternal and maternal nurturing stroking touch on infants\' physiological self-regulation in terms of respiratory sinus arrhythmia (RSA). We compared the impact of a 3-min stroking period (STROKING) with a pre-baseline (PRE-STROKING) and post-baseline (POST-STROKING) of 25 mothers and 25 fathers (unrelated to one another) on their infants, aged 4-16 weeks. We registered infant electrocardiogram (ECG) and respiration to calculate infant RR-interval (RRI), respiration rate (fR) and (respiratory corrected) RSA (RSAcorr). Based on video-recordings, we analyzed the stroking speed. Infants\' RSAcorr significantly increased during and after stroking, no matter whether touch was delivered by fathers or mothers. This effect was mediated by both heart rate (HR) and respiration. However, respiratory mediation occurred later when delivered by fathers than by mothers. Both mothers\' and fathers\' stroking speed occurred within the optimal stimulation range of c-tactile (CT) afferents, a particular class of cutaneous unmyelinated, low-threshold mechano-sensitive nerves hypothesized to be involved in inter-personal bonding. The discussion builds on the idea to mitigate fathers\' doubts about their paternal capabilities and proposes a research agenda regarding the further examination of the role of nurturing touch and its underlying mechanisms within the development of infants\' physiological self-regulation. Finally, the importance of respiratory measurements in infant physiological research is emphasized.

The beneficial effects of touch in development were already observed in different types of skin-to-skin care. In the current study, we aimed at studying potential underlying mechanisms of these effects in terms of parasympatho-inhibitory regulation. We examined the specific impact of affective maternal stroking versus non-stroking touch on the cardio-respiration of both mothers and infants in terms of respiratory sinus arrhythmia (RSA). We compared a 3-min TOUCH PERIOD (stroking or non-stroking touch) with a baseline before (PRE-TOUCH) and after (POST-TOUCH) in 45 dyads (24 stroking/21 non-stroking touch) with infants aged 4-16 weeks. We registered mother-infant ECG, respiration and made video-recordings. We calculated RR-interval (RRI), respiration rate (fR) and (respiratory corrected) RSA and analyzed stroking mean velocity rate (MVR) of the mothers. ANOVA-tests showed a significant different impact on infants\' respiratory corrected RSA of stroking touch (increase) versus non-stroking touch (decrease). Further, during and after stroking touch, RRI significantly increased whereas fR significantly decreased. Non-stroking touch had no significant impact on infants\' RRI and fR. In the mothers, RRI significantly decreased and fR significantly increased during the TOUCH PERIOD. The mothers\' MVR occurred within the range of 1-10 cm/s matching with the optimal afferent stimulation range of a particular class of cutaneous unmyelinated, low-threshold mechano-sensitive nerves, named c-tactile (CT) afferents. We suggest CT afferents to be the a potential missing link between the processing of affective touch and the development of physiological and emotional self-regulation. The results are discussed with regard to the potential role of CT afferents within the building of early self-regulation as part of a multisensory intuitive parenting system and the importance to respect this ecological context of an infant in research and clinical applications.