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Supplemental material, sj-docx-1-pss-10.1177_09567976211059801 for The Language of Social Touch Is Intuitive and Quantifiable by Sarah McIntyre, Steven C. Hauser, Anikó Kusztor, Rebecca Boehme, Athanasia Moungou, Peder Mortvedt Isager, Lina Homman, Giovanni Novembre, Saad S. Nagi, Ali Israr, Ellen A. Lumpkin, Freddy Abnousi, Gregory J. Gerling and Håkan Olausson in Psychological Science

In Sweden, a large family with a point mutation in the nerve growth factor-beta gene has previously been identified. The carriers of this mutation have reduced small-fibre density and selective deficits in deep pain and temperature modalities. The clinical findings in this population are described as hereditary sensory and autonomic neuropathy type V. The purpose of the current study was to investigate the prevalence of carpal tunnel syndrome in hereditary sensory and autonomic neuropathy type V based on clinical examinations and electrophysiological measurements. Furthermore, the cross-sectional area of the median nerve at the carpal tunnel inlet was measured with ultrasonography. Out of 52 known individuals heterozygous for the nerve growth factor-beta mutation in Sweden, 23 participated in the current study (12 males, 11 females; mean age 55 years; range 25–86 years). All participants answered a health questionnaire and underwent clinical examination followed by median nerve conduction study in a case–control design, and measurement of the nerve cross-sectional area with ultrasonography. The diagnosis of carpal tunnel syndrome was made based on consensus criteria using patient history and nerve conduction study. The prevalence of carpal tunnel syndrome in the hereditary sensory and autonomic neuropathy group was 35% or 52% depending on whether those individuals who had classic symptoms of carpal tunnel syndrome but negative nerve conduction studies were included or not. Those who had a high likelihood of carpal tunnel syndrome based on classic/probable patient history with positive nerve conduction study had a significantly larger median nerve cross-sectional area than those who had an unlikely patient history with negative nerve conduction study. The prevalence of carpal tunnel syndrome was 10–25 times higher in individuals heterozygous for the nerve growth factor-beta mutation than the general Swedish population. Further studies are needed to better understand the underlying pathophysiological mechanisms., In a unique group of heterozygous carriers of a rare mutation in the nerve growth factor-beta gene, we investigated the prevalence of carpal tunnel syndrome and found it to be manifold higher in the carriers than the general Swedish population., Graphical Abstract Graphical Abstract

The nociceptive withdrawal reflex (NWR) is used to probe spinal cord excitability in chronic pain states. Here, we used an automated and unbiased procedure for determining the NWR threshold and compared the reflex thresholds and corresponding pain ratings in a well-characterized cohort of fibromyalgia (n = 29) and matched healthy controls (n = 21). Surface electrical stimuli were delivered to the foot in a stepwise incremental and decremental manner. The surface electromyographic activity was recorded from the ipsilateral tibialis anterior muscle. Fibromyalgia patients reported significantly higher scores for psychological distress and pain-related disability and a significantly lower score for perceived state of health compared to the matched controls. The subjective pain ratings were significantly higher in patients. The NWR thresholds were similar to the controls. In the patients, but not in controls, the NWR thresholds and subjective pain ratings were significantly correlated. Our results showed an increased subjective pain sensitivity in fibromyalgia, but we found no evidence for spinal sensitization based on the reflex measures. Funding agencies: Swedish Research CouncilSwedish Research Council [2018-02470]; County Council of Ostergotland [ALF: LIO-700931, LIO-900631]

Background and aims: The canonical view is that pain in humans is signaled exclusively by slowly conducting, thinly myelinated (u2018fastu2019 pain) or unmyelinated (u2018slowu2019 pain) afferents. While other mammals have rapidly conducting nociceptors, these have not been demonstrated in humans. Methods: We performed single-unit axonal recordings (microneurography) from mechanoreceptive cutaneous afferents in the peroneal and radial nerves of healthy participants, and psychophysical observations in patient groups with selective deafferentation or channelopathy. Results: We identified myelinated high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and had conduction velocities similar to thickly myelinated low-threshold mechanoreceptors. Intra-neural electrical stimulation of single A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed that pain judgments to graded mechanical stimuli were impaired only in the condition of absent thickly myelinated fibers. This function was preserved in patients with loss-of-function mutation in mechanotransduction channel PIEZO2. Conclusions: Mechanical pain in humans does not require the PIEZO2 channel, and can be signaled by thickly myelinated, rapidly conducting afferents. Their existence in humans questions the validity of dichotomous fast touch-slow pain systems in classical teaching. This calls for a reappraisal of neurological views that mechanical pain examination specifically assesses small-fiber function, and that painful neuropathies imply small-fiber involvement, opening up novel therapeutic targets in pain disorders.

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 Aβ deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aβ 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., Competing Interests: Conflict of interest. None

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.

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.