HbA1c and the risk of developing peripheral neuropathy in childhood-onset type 1 diabetes: A follow-up study over 3 decades.

AIMS: We have evaluated long-term weighted mean HbA1c (wHbA1c), HbA1c variability, diabetes duration, and lipid profiles in relation to the development of diabetic peripheral neuropathy (DPN), nephropathy, and retinopathy in childhood-onset type 1 diabetes. MATERIALS AND METHODS: In a longitudinal cohort study, 49 patients (21 women) with childhood-onset type 1 diabetes were investigated with neurophysiological measurements, blood tests, and clinical examinations after a diabetes duration of 7.7 (±3.3) years (baseline) and followed with repeated examinations for 30.6 (±5.2) years. We calculated wHbA1c by integrating the area under all HbA1c values since the diabetes diagnosis. Lipid profiles were analysed in relation to the presence of DPN. Long-term fluctuations of HbA1c variability were computed as the standard deviation of all HbA1c measurements. Data regarding the presence of other diabetes complications were retrieved from medical records. RESULTS: In this follow-up study, 51% (25/49) of the patients fulfilled electrophysiological criteria for DPN. In nerve conduction studies, there was a deterioration in the amplitudes and conduction velocities for the median, peroneal, and sural nerves over time. Patients with DPN had a longer duration of diabetes, higher wHbA1c, and increased HbA1c variability. The lowest wHbA1c value associated with the development of DPN was 62 mmol/mol (7.8%). The presence of albuminuria and retinopathy was positively correlated with the presence of neuropathy. CONCLUSIONS: More than half of the patients had developed DPN after 30 years. None of the patients who developed DPN had a wHbA1c of less than 62 mmol/mol (7.8%).

Slow touch and ultrafast pain fibres: Revisiting peripheral nerve classification.

One hundred years ago, Erlanger and Gasser demonstrated that conduction velocity is correlated with the diameter of a peripheral nerve axon. Later, they also demonstrated that the functional role of the axon is related to its diameter: touch is signalled by large-diameter axons, whereas pain and temperature are signalled by small-diameter axons. Certain discoveries in recent decades prompt a modification of this canonical classification. Here, we review the evidence for unmyelinated (C) fibres signalling touch at a slow conduction velocity and likely contributing to affective aspects of tactile information. We also review the evidence for large-diameter Aß afferents signalling pain at ultrafast conduction velocity and likely contributing to the rapid nociceptive withdrawal reflex. These discoveries imply that conduction velocity is not as clear-cut an indication of the functional role of the axon as previously thought. We finally suggest that a future taxonomy of the peripheral afferent nervous system might be based on the combination of the axons molecular expression and electrophysiological response properties.

Human Foot Outperforms the Hand in Mechanical Pain Discrimination.

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterized. Here, we measured the capacity for mechanical pain discrimination using a two-alternative forced choice paradigm, with force-calibrated indentation stimuli (Semmes-Weinstein monofilaments) applied to the hand and foot dorsa of healthy human volunteers. In order to characterize the relationship between peripheral nociceptor activity and pain perception, we recorded single-unit activity from myelinated (A) and unmyelinated (C) mechanosensitive nociceptors in the skin using microneurography. At the perceptual level, we found that the foot was better at discriminating noxious forces than the hand, which stands in contrast to that for innocuous force discrimination, where the hand performed better than the foot. This observation of superior mechanical pain discrimination on the foot compared to the hand could not be explained by the responsiveness of individual nociceptors. We found no significant difference in the discrimination performance of either the myelinated or unmyelinated class of nociceptors between skin regions. This suggests the possibility that other factors such as skin biophysics, receptor density or central mechanisms may underlie these regional differences.

Thin Films on the Skin, but not Frictional Agents, Attenuate the Percept of Pleasantness to Brushed Stimuli.

Brushed stimuli are perceived as pleasant when stroked lightly on the skin surface of a touch receiver at certain velocities. While the relationship between brush velocity and pleasantness has been widely replicated, we do not understand how resultant skin movements - e.g., lateral stretch, stick-slip, normal indentation - drive us to form such judgments. In a series of psychophysical experiments, this work modulates skin movements by varying stimulus stiffness and employing various treatments. The stimuli include brushes of three levels of stiffness and an ungloved human finger. The skin's friction is modulated via non-hazardous chemicals and washing protocols, and the skin's thickness and lateral movement are modulated by thin sheets of adhesive film. The stimuli are hand-brushed at controlled forces and velocities. Human participants report perceived pleasantness per trial using ratio scaling. The results indicate that a brush's stiffness influenced pleasantness more than any skin treatment. Surprisingly, varying the skin's friction did not affect pleasantness. However, the application of a thin elastic film modulated pleasantness. Such barriers, though elastic and only 40 microns thick, inhibit the skin's tangential movement and disperse normal force. The finding that thin films modulate affective interactions has implications for wearable sensors and actuation devices.

Single-Soma Deep RNA sequencing of Human DRG Neurons Reveals Novel Molecular and Cellular Mechanisms Underlying Somatosensation.

The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human DRG (hDRG) neurons-critical in-formation to decipher their functions-are lacking due to technical difficulties. Here, we developed a novel approach to isolate individual hDRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9,000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed remarkable divergence among pain-sensing neurons and the existence of human-specific nociceptor types. Our deep RNA-seq dataset was especially powerful for providing insight into the molecular mechanisms underlying human somatosensation and identifying high potential novel drug targets. Our dataset also guided the selection of molecular markers to visualize different types of human afferents and the discovery of novel functional properties using single-cell in vivo electrophysiological recordings. In summary, by employing a novel soma sequencing method, we generated an unprecedented hDRG neuron atlas, providing new insights into human somatosensation, establishing a critical foundation for translational work, and clarifying human species-species properties.

Social Touch Reduces Pain Perception-An fMRI Study of Cortical Mechanisms.

Unmyelinated low-threshold mechanoreceptors (C-tactile, CT) in the human skin are important for signaling information about hedonic aspects of touch. We have previously reported that CT-targeted brush stroking by means of a robot reduces experimental mechanical pain. To improve the ecological validity of the stimulation, we developed standardized human-human touch gestures for signaling attention and calming. The attention gesture is characterized by tapping of the skin and is perceived as neither pleasant nor unpleasant, i.e., neutral. The calming gesture is characterized by slow stroking of the skin and is perceived as moderately to very pleasant. Furthermore, the attention (tapping) gesture is ineffective, whereas the calming (stroking) gesture is effective in activating CT-afferents. We conducted an fMRI study (n = 32) and capitalized on the previous development of touch gestures. We also developed an MR compatible stimulator for high-precision mechanical pain stimulation of the thenar region of the hand. Skin-to-skin touching (stroking or tapping) was applied and was followed by low and high pain. When the stroking gesture preceded pain, the pain was rated as less intense. When the tapping gesture preceded the pain, the pain was rated as more intense. Individual pain perception related to insula activation, but the activation was not higher for stroking than for tapping in any brain area during the stimulation period. However, during the evaluation period, stronger activation in the periaqueductal gray matter was observed after calming touch compared to after tapping touch. This finding invites speculation that human-human gentle skin stroking, effective in activating CT-afferents, reduced pain through neural processes involving CT-afferents and the descending pain pathway.

Get a New Perspective on EEG: Convolutional Neural Network Encoders for Parametric t-SNE.

t-distributed stochastic neighbor embedding (t-SNE) is a method for reducing high-dimensional data to a low-dimensional representation, and is mostly used for visualizing data. In parametric t-SNE, a neural network learns to reproduce this mapping. When used for EEG analysis, the data are usually first transformed into a set of features, but it is not known which features are optimal. The principle of t-SNE was used to train convolutional neural network (CNN) encoders to learn to produce both a high- and a low-dimensional representation, eliminating the need for feature engineering. To evaluate the method, the Temple University EEG Corpus was used to create three datasets with distinct EEG characters: (1) wakefulness and sleep; (2) interictal epileptiform discharges; and (3) seizure activity. The CNN encoders produced low-dimensional representations of the datasets with a structure that conformed well to the EEG characters and generalized to new data. Compared to parametric t-SNE for either a short-time Fourier transform or wavelet representation of the datasets, the developed CNN encoders performed equally well in separating categories, as assessed by support vector machines. The CNN encoders generally produced a higher degree of clustering, both visually and in the number of clusters detected by k-means clustering. The developed principle is promising and could be further developed to create general tools for exploring relations in EEG data.

Hand Function After an Electrical Accident-A Case-Control Study.

OBJECTIVE: Electrical accidents cause both acute and long-term injuries. The care of acute injuries is somewhat standardized, but currently recommendations or assessment tools are not available for assessing the long-term effects of an accident on hand function. METHODS: A case-control study of 24 healthy controls and 24 cases, 1 to 5 years after an electrical accident and with self-reported neurosensory symptoms, was performed using three hand-function tests: the Disabilities of the Arm, Shoulder, and Hand questionnaire, the Purdue Pegboard test, and the Shape and Texture Identification test. RESULTS: Compared with the control group, patients received statistically significantly lower scores for the Disabilities of the Arm, Shoulder, and Hand outcome measure and the Purdue Pegboard and for one finger on the Shape and Texture Identification test. CONCLUSION: Hand function is affected after an electrical accident in individuals with self-reported neurosensory symptoms.

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aß deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aß input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

Neural processing of self-touch and other-touch in anorexia nervosa and autism spectrum condition.

INTRODUCTION: The tactile sense plays a crucial role in the development and maintenance of a functional bodily self. The ability to differentiate between self- and nonself-generated touch contributes to the perception of the bodies' boundaries and more generally to self-other-distinction, both of which are thought be altered in anorexia nervosa (AN) and autism spectrum condition (AS). While it has been suggested that AN and AS are characterized by overlapping symptomatology, they might differ regarding body perception and self-other-distinction. METHODS: Participants with a diagnosis of AN (n = 25), AS (n = 29), and a comparison group without diagnoses (n = 57) performed a self-other-touch task during functional brain imaging. In the experimental conditions, they stroked their own arm or were stroked on the arm by an experimenter. RESULTS: As shown previously, the CG group showed lower activation or deactivation in response to self-touch compared to social touch from someone else. A main group effect was found in areas including somatosensory cortex, frontal and temporal gyri, insula, and subcortical regions. This was driven by increased activations in participants with AN, while participants in the AS group showed mostly comparable activations to the comparison group. CONCLUSIONS: AN diagnosis was associated with an increased neural activity in response to both self-touch and social touch. Failure to attenuate self-touch might relate to altered predictions regarding the own body and reduced perception of bodily boundaries. Participants with an AS diagnosis were mostly comparable to the comparison group, potentially indicating unaltered tactile self-other-distinction.

Clinical Evaluation of Nerve Function in Electrical Accident Survivors with Persisting Neurosensory Symptoms.

OBJECTIVE: Work related electrical accidents are prevalent and can cause persisting symptoms. We used clinical neurophysiological techniques to assess neurosensory function following electrical accidents and correlated test results with the patients' symptoms. METHODS: We studied 24 patients who reported persisting neurosensory symptoms following a workplace electrical accident. We assessed nerve function using quantitative sensory testing (QST), thermal roller testing, laser evoked potential (LEP), and electroneurography. The patients' results were compared with previously established normative data. RESULTS: Altogether, 67% of the patients showed at least one neurosensory impairment with a large heterogeneity in test results across patients. At a group level, we observed significant deviations in in QST, LEP, and sensory and motor neurography. Overall, we found a weak correlation between test results and self-reported symptoms. CONCLUSIONS: In a majority of patients with neurosensory symptoms after a workplace electrical accident, neurosensory testing confirmed the existence of an underlying impairment of the nervous system.

The Language of Social Touch Is Intuitive and Quantifiable.

Touch is a powerful communication tool, but we have a limited understanding of the role played by particular physical features of interpersonal touch communication. In this study, adults living in Sweden performed a task in which messages (attention, love, happiness, calming, sadness, and gratitude) were conveyed by a sender touching the forearm of a receiver, who interpreted the messages. Two experiments (N = 32, N = 20) showed that within close relationships, receivers could identify the intuitive touch expressions of the senders, and we characterized the physical features of the touches associated with successful communication. Facial expressions measured with electromyography varied by message but were uncorrelated with communication performance. We developed standardized touch expressions and quantified the physical features with 3D hand tracking. In two further experiments (N = 20, N = 16), these standardized expressions were conveyed by trained senders and were readily understood by strangers unacquainted with the senders. Thus, the possibility emerges of a standardized, intuitively understood language of social touch.

Naturalistic stimuli in touch research.

Neural mechanisms of touch are typically studied in laboratory settings using robotic or other types of well-controlled devices. Such stimuli are very different from highly complex naturalistic human-to-human touch interactions. The lack of scientifically useful naturalistic stimuli hampers progress, particularly in social touch research. Vision science, on the other hand, has benefitted from inventions such as virtual reality systems that have provided researchers with precision control of naturalistic stimuli. In the field of touch research, producing and manipulating stimuli is particularly challenging due to the complexity of skin mechanics. Here, we review the history of touch neuroscience focusing on the contrast between strictly controlled and naturalistic stimuli, and compare the field to vision science. We discuss new methods that may overcome obstacles with precision-controlled tactile stimuli, and recent successes in naturalistic texture production. In social touch research, precise tracking and measurement of naturalistic human-to-human touch interactions offer exciting new possibilities.

A psychophysical and neuroimaging analysis of genital hedonic sensation in men.

Current understanding of human genital-brain interactions relates primarily to neuroendocrine and autonomic control, whereas interactions during sexual stimulation remain largely unexplored. Here we present a systematic approach towards identifying how the human brain encodes sensory genital information. Using a validated affective touch paradigm and functional magnetic resonance imaging, we found that hedonic responses to discriminatory versus affective tactile stimulation were distinctly different for both penile shaft and forearm. This suggests that, as with other body sites, genital skin contains small diameter mechanoreceptive nerve fibres that signal pleasant touch. In the brain, secondary somatosensory cortex (S2) distinguished between affective and discriminative touch for the penile shaft, but not for the forearm. Frenulum stimulation induced the greatest reports of subjective pleasure and led to the greatest deactivation of the default-mode network. This study represents a first pass at investigating, in humans, the relationship between innervation of genital surfaces, hedonic feelings, and brain mechanisms, in a systematic way.

3D Visual Tracking to Quantify Physical Contact Interactions in Human-to-Human Touch.

Across a plethora of social situations, we touch others in natural and intuitive ways to share thoughts and emotions, such as tapping to get one's attention or caressing to soothe one's anxiety. A deeper understanding of these human-to-human interactions will require, in part, the precise measurement of skin-to-skin physical contact. Among prior efforts, each measurement approach exhibits certain constraints, e.g., motion trackers do not capture the precise shape of skin surfaces, while pressure sensors impede skin-to-skin contact. In contrast, this work develops an interference-free 3D visual tracking system using a depth camera to measure the contact attributes between the bare hand of a toucher and the forearm of a receiver. The toucher's hand is tracked as a posed and positioned mesh by fitting a hand model to detected 3D hand joints, whereas a receiver's forearm is extracted as a 3D surface updated upon repeated skin contact. Based on a contact model involving point clouds, the spatiotemporal changes of hand-to-forearm contact are decomposed as six, high-resolution, time-series contact attributes, i.e., contact area, indentation depth, absolute velocity, and three orthogonal velocity components, together with contact duration. To examine the system's capabilities and limitations, two types of experiments were performed. First, to evaluate its ability to discern human touches, one person delivered cued social messages, e.g., happiness, anger, sympathy, to another person using their preferred gestures. The results indicated that messages and gestures, as well as the identities of the touchers, were readily discerned from their contact attributes. Second, the system's spatiotemporal accuracy was validated against measurements from independent devices, including an electromagnetic motion tracker, sensorized pressure mat, and laser displacement sensor. While validated here in the context of social communication, this system is extendable to human touch interactions such as maternal care of infants and massage therapy.

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.

Subtle Contact Nuances in the Delivery of Human-to-Human Touch Distinguish Emotional Sentiment.

We routinely communicate distinct social and emotional sentiments through nuanced touch. For example, we might gently hold another's arm to offer a sense of calm, yet intensively hold another's arm to express excitement or anxiety. As this example indicates, distinct sentiments may be shaped by the subtlety in one's touch delivery. This work investigates how slight distinctions in skin-to-skin contact influence both the recognition of cued emotional messages (e.g., anger, sympathy) and the rating of emotional content (i.e., arousal, valence). By self-selecting preferred gestures (e.g., holding, stroking), touchers convey distinct messages by touching the receiver's forearm. Skin-to-skin contact attributes (e.g., velocity, depth, area) are optically tracked in high resolution. Contact is then examined within gesture, between messages. The results indicate touchers subtly, but significantly, vary contact attributes of a gesture to communicate distinct messages, which are recognizable by receivers. This tuning also correlates with receivers' arousal and valence. For instance, arousal increases with velocity for stroking, and depth for holding. Moreover, as shown here with human-to-human touch, valence is tied with velocity, which is the same trend as reported with brushes. The findings indicate that subtle nuance in skin-to-skin contact is important in conveying social messages and inducing emotions.

Investigations into an overlooked early component of painful nociceptive withdrawal reflex responses in humans.

Introduction: The role of pain as a warning system necessitates a rapid transmission of information from the periphery for the execution of appropriate motor responses. The nociceptive withdrawal reflex (NWR) is a physiological response to protect the limb from a painful stimulus and is often considered an objective measure of spinal nociceptive excitability. The NWR is commonly defined by its latency in the presumed Aδ-fiber range consistent with the canonical view that "fast pain" is signaled by Aδ nociceptors. We recently demonstrated that human skin is equipped with ultrafast (Aß range) nociceptors. Here, we investigated the short-latency component of the reflex and explored the relationship between reflex latency and pain perception. Methods: We revisited our earlier work on NWR measurements in which, following convention, only reflex responses in the presumed Aδ range were considered. In our current analysis, we expanded the time window to search for shorter latency responses and compared those with pain ratings. Results: In both cohorts, we found an abundance of recordings with short-latency reflex responses. In nearly 90% of successful recordings, only single reflex responses (not dual) were seen which allowed us to compare pain ratings based on reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range. Conclusion: We found a preponderance of short-latency painful reflex responses. Based on this finding, we suggest that short-latency responses must be considered in future studies. Whether these are signaled by the ultrafast nociceptors remains to be determined.

Altered relationship between subjective perception and central representation of touch hedonics in adolescents with autism-spectrum disorder.

An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affective touch is an important means of social interaction, and C-Tactile (CT) afferents are thought to play a key role in the peripheral detection and encoding of these stimuli. Exploring the neural and behavioral mechanisms for processing CT-optimal touch (~3 cm/s) may therefore provide useful insights into the pathophysiology of ASD. We examined the relationship between touch hedonics (i.e. the subjective pleasantness with which affective touch stimuli are perceived) and neural processing in the posterior superior temporal sulcus (pSTS). This region is less activated to affective touch in individuals with ASD, and, in typically developing individuals (TD), is correlated positively with touch pleasantness. TD and ASD participants received brushing stimuli at CT-optimal, and CT-non-optimal speeds during fMRI. Touch pleasantness and intensity ratings were collected, and affective touch awareness, a measure of general touch hedonics was calculated. As expected, slow touch was perceived as more pleasant and less intense than fast touch in both groups, whereas affective touch awareness was moderately higher in TD compared to ASD. There was a strong, positive correlation between right pSTS activation and affective touch awareness in TD, but not in ASD. Our findings suggest that altered neural coupling between right pSTS and touch hedonics in ASD may be associated with social touch avoidance in ASD.