Experimental nerve block study on painful withdrawal reflex responses in humans.

The nociceptive withdrawal reflex (NWR) is a protective limb withdrawal response triggered by painful stimuli, used to assess spinal nociceptive excitability. Conventionally, the NWR is understood as having two reflex responses: a short-latency Aß-mediated response, considered tactile, and a longer-latency Aδ-mediated response, considered nociceptive. However, nociceptors with conduction velocities similar to Aß tactile afferents have been identified in human skin. In this study, we investigated the effect of a preferential conduction block of Aß fibers on pain perception and NWR signaling evoked by intradermal electrical stimulation in healthy participants. We recorded a total of 198 NWR responses in the intact condition, and no dual reflex responses occurred within our latency bandwidth (50-150 ms). The current required to elicit the NWR was higher than the perceptual pain threshold, indicating that NWR did not occur before pain was felt. In the block condition, when the Aß-mediated tuning fork sensation was lost while Aδ-mediated nonpainful cooling was still detectable (albeit reduced), we observed that the reflex was abolished. Further, short-latency electrical pain intensity at pre-block thresholds was greatly reduced, with any residual pain sensation having a longer latency. Although electrical pain was unaffected at suprathreshold current, the reflex could not be evoked despite a two-fold increase in the pre-block current and a five-fold increase in the pre-block pulse duration. These observations lend support to the possible involvement of Aß-fiber inputs in pain and reflex signaling.

Altered somatosensory processing in adult attention deficit hyperactivity disorder.

BACKGROUND: Tactile sensitivity and sensory overload in ADHD are well-documented in clinical-, self-, and parent- reports, but empirical evidence is scarce and ambiguous and focuses primarily on children. Here, we compare both empirical and self-report tactile sensitivity and ADHD symptomatology in adults with ADHD and neurotypical controls. We evaluate whether tactile sensitivity and integration is more prevalent in ADHD and whether it is related to ADHD symptom severity. METHODS: Somatosensory evoked potential (SEP) amplitudes were measured in 27 adults with ADHD and 24 controls during four conditions (rest, stroking of the own arm, stroking of the arm by a researcher, and stroking of an object). Participants also filled out questionnaires on tactile sensitivity and ADHD symptoms and performed a Qb-test as an objective measure of ADHD symptom severity. RESULTS: Participants with ADHD self-reported greater tactile sensitivity and ADHD symptom severity than controls and received higher scores on the Qb-test. These values correlated with one another. ADHD participants showed lower tolerable threshold for electrical radial nerve stimulus, and greater reduction in cortical SEP amplitudes during additional tactile stimuli which was correlated with ADHD symptoms. CONCLUSIONS: We find that ADHD symptomatology and touch sensitivity are directly linked, using both self-reports and experimental measures. We also find evidence of tactile sensory overload in ADHD, and an indication that this is linked to inattention specifically. Tactile sensitivity and sensory overload impact the functioning and life quality of many people with ADHD, and clinicians should consider this when treating their patients.

Primary somatosensory cortical processing in tactile communication.

Touch is an essential form of non-verbal communication. While language and its neural basis are widely studied, tactile communication is less well understood. We used fMRI and multivariate pattern analyses in pairs of emotionally close adults to examine the neural basis of human-to-human tactile communication. In each pair, a participant was designated either as sender or as receiver. The sender was instructed to communicate specific messages by touching only the arm of the receiver, who was inside the scanner. The receiver then identified the message based on the touch expression alone. We designed two multivariate decoder algorithms-one based on the sender's intent (sender-decoder), and another based on the receiver's response (receiver-decoder). We identified several brain areas that significantly predicted behavioural accuracy of the receiver. Regarding our a priori region of interest, the receiver's primary somatosensory cortex (S1), both decoders were able to accurately differentiate the messages based on neural activity patterns here. The receiver-decoder, which relied on the receivers' interpretations of the touch expressions, outperformed the sender-decoder, which relied on the sender's intent. Our results identified a network of brain areas involved in human-to-human tactile communication and supported the notion of non-sensory factors being represented in S1. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'.

Ketamine reduces the neural distinction between self- and other-produced affective touch: a randomized double-blind placebo-controlled study.

A coherent sense of self is crucial for social functioning and mental health. The N-methyl-D-aspartate antagonist ketamine induces short-term dissociative experiences and has therefore been used to model an altered state of self-perception. This randomized double-blind placebo-controlled cross-over study investigated the mechanisms for ketamine's effects on the bodily sense of self in the context of affective touch. Thirty healthy participants (15 females/15 males, age 19-39) received intravenous ketamine or placebo while performing self-touch and receiving touch by someone else during functional MRI - a previously established neural measure of tactile self-other-differentiation. Afterwards, tactile detection thresholds during self- and other-touch were assessed, as well as dissociative states, interoceptive awareness, and social touch attitudes. Compared to placebo, ketamine administration elicited dissociation and reduced neural activity associated with self-other-differentiation in the right temporoparietal cortex, which was most pronounced during other-touch. This reduction correlated with ketamine-induced reductions in interoceptive awareness. The temporoparietal cortex showed higher connectivity to somatosensory cortex and insula during other- compared to self-touch. This difference was augmented by ketamine, and correlated with dissociation strength for somatosensory cortex. These results demonstrate that disrupting the self-experience through ketamine administration affects neural activity associated with self-other-differentiation in a region involved in touch perception and social cognition, especially with regard to social touch by someone else. This process may be driven by ketamine-induced effects on top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. These findings provide further evidence for the intricate relationship of the bodily self with the tactile sense.

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.

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.

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.

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.

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 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.