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%).

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.

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.

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.

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.

Distinction of self-produced touch and social touch at cortical and spinal cord levels.

Differentiation between self-produced tactile stimuli and touch by others is necessary for social interactions and for a coherent concept of "self." The mechanisms underlying this distinction are unknown. Here, we investigated the distinction between self- and other-produced light touch in healthy volunteers using three different approaches: fMRI, behavioral testing, and somatosensory-evoked potentials (SEPs) at spinal and cortical levels. Using fMRI, we found self-other differentiation in somatosensory and sociocognitive areas. Other-touch was related to activation in several areas, including somatosensory cortex, insula, superior temporal gyrus, supramarginal gyrus, striatum, amygdala, cerebellum, and prefrontal cortex. During self-touch, we instead found deactivation in insula, anterior cingulate cortex, superior temporal gyrus, amygdala, parahippocampal gyrus, and prefrontal areas. Deactivation extended into brain areas encoding low-level sensory representations, including thalamus and brainstem. These findings were replicated in a second cohort. During self-touch, the sensorimotor cortex was functionally connected to the insula, and the threshold for detection of an additional tactile stimulus was elevated. Differential encoding of self- vs. other-touch during fMRI correlated with the individual self-concept strength. In SEP, cortical amplitudes were reduced during self-touch, while latencies at cortical and spinal levels were faster for other-touch. We thus demonstrated a robust self-other distinction in brain areas related to somatosensory, social cognitive, and interoceptive processing. Signs of this distinction were evident at the spinal cord. Our results provide a framework for future studies in autism, schizophrenia, and emotionally unstable personality disorder, conditions where symptoms include social touch avoidance and poor self-vs.-other discrimination.

Defining pleasant touch stimuli: a systematic review and meta-analysis.

Pleasantness is generally overlooked when investigating tactile functions. Addition of a pleasant stimulus could allow for a more complete characterisation of somatosensory function. The aims of this review were to systematically assess the methodologies used to elicit a pleasant sensation, measured via psychophysical techniques, and to perform a meta-analysis to measure the effect of brush stroking velocity on touch pleasantness. Eighteen studies were included in the systematic review, with five studies included in the meta-analysis. The review found that factors such as texture, velocity, force, and the duration of continuous stroking influence tactile evoked pleasantness. Specifically, using a soft material and stroking at a velocity of 3 cm/s with light force is generally considered as particularly pleasant. The meta-analysis showed that a brush stroking velocity of 30 cm/s was rated as less pleasant than 3 cm/s, on the forearm. The present study collates the factors that are most likely to provide a stimulus to elicit a pleasant sensation. The results should be important for studies requiring a well-defined pleasant stimulus including neurosensory assessment protocols, allowing for a more complete multimodality assessment of somatosensory function.

Reliability of orofacial quantitative sensory testing for pleasantness and unpleasantness.

BACKGROUND: Quantitative sensory testing protocols for perceptions of pleasantness and unpleasantness based on the German Research Network on Neuropathic Pain protocol were recently introduced. However, there are no reliability studies yet published. AIM: To evaluate the intra-examiner (test-retest) and inter-examiner reliability for orofacial pleasantness and unpleasantness quantitative sensory testing protocols. METHODS: Sixteen healthy participants from Aarhus University (11 women and five men, mean age 24, range 21-26 years) contributed. Two examiners were trained in performing the entire quantitative sensory testing protocols for pleasantness and unpleasantness, which included the additional dynamic tactile stimulation test using a goat-hair brush. Each participant underwent examination of both protocols by each examiner (inter-examiner reliability) on day 1. They returned at least 8 days following the testing to be re-examined by one examiner (intra-examiner reliability). All testing was performed on the skin of the right mandibular mental region. The intraclass correlation (ICC) was used to determine reliability. RESULTS: For the protocol investigating pleasantness, the majority of parameters had good to excellent intra-examiner (11/14: Intraclass correlation 0.67-0.87) and inter-examiner (13/14: Intraclass correlation 0.62-0.96) reliabilities. Similarly, the protocol investigating unpleasantness had good to excellent intra-examiner (intraclass correlation 0.63-0.99) and inter-examiner (intraclass correlation 0.65-0.98) reliabilities for most (13/15) of the parameters. CONCLUSION: Intra and inter-examiner reliabilities in the majority of quantitative sensory testing parameters (apart from the summation ratio) investigating pleasantness and unpleasantness are acceptable when assessing somatosensory function of the orofacial region.Trial registration: NA.

Cutaneous warmth, but not touch, increases muscle sympathetic nerve activity during a muscle fatigue hand-grip task.

In homeostasis, somatosensory C fibre afferents are hypothesised to mediate input to the brain about interactions with external stimuli and sympathetic efference provides the output that regulates bodily functions. We aimed to test this hypothesis and whether different types of innocuous somatosensory input have differential effects. Healthy volunteers performed a muscle fatigue (hand-grip) task to exhaustion, which produces increased muscle sympathetic nerve activity (MSNA), as measured through microneurography. Participants completed the muscle fatigue task without concurrent cutaneous sensory stimulation (control) or we applied skin warming (heat pack) as a C fibre stimulation, slow brush stroking as C and Aß fibre stimulation, or vibration as Aß fibre stimulation, to the participant's forearm. We also measured heart rate, the duration of the hand-grip task, and ratings of pain at the end of the task. Concurrent skin warming showed increased MSNA compared to the other conditions. Tactile stimuli (brushing, vibration) were not significantly different to the control (no intervention) condition. Warming increased the pain from the muscle contraction, whereas the tactile stimuli did not. We interpret the effect of warming on MSNA as providing relevant afferent information during muscle contraction, which needed to be counteracted via vasoconstriction to maintain homeostasis. Brushing and vibration were less homeostatically relevant stimuli for the muscle contraction and hence had no significant effect. The findings add sensory specificity to our current understanding of homeostatic regulation through somatosensory afferent and sympathetic efferent pathways.

Modulation of experimental facial pain via somatosensory stimuli targeting sensations of different valence.

BACKGROUND: Knowledge of pain modulation from oro-facial somatosensory stimuli with different valence (pleasant-unpleasant) is limited. OBJECTIVES: To investigate (a) the modulatory effects of painful, pleasant and unpleasant somatosensory stimuli on two models of experimental facial pain, (b) whether modulation could be changed by blocking peripheral nerves via application of a local anaesthetic, EMLA, or blocking endogenous opioid receptors via naltrexone and (c) whether pain ratings were significantly correlated with participant psychological profiles. METHODS: Thirty-eight healthy women received experimental facial skin burning pain or jaw myalgia for four randomised sessions on different days. The painful region was stimulated with mechanical or thermal painful, pleasant, unpleasant and control stimuli, with ratings recorded before and during stimulation. Sessions differed in pre-treatment: EMLA/naltrexone/placebo tablet/cream. RESULTS: Significant effects of thermal or mechanical stimuli (P < .017), but not session (P > .102), were found on pain ratings for both models. In myalgia, painful cold resulted in a greater reduction in pain ratings than unpleasant cold, pleasant cold, control and pleasant warmth (P < .004). Decreases in pain ratings from painful, unpleasant and pleasant mechanical stimuli were greater than control (P < .002). In burning pain, painful cold resulted in a greater reduction in pain ratings than all but one of the other thermal stimuli (P < .033). The pleasant mechanical stimulus reduced pain ratings more than all other mechanical stimuli (P ≤ .003). There were no significant correlations between pain and psychometrics. CONCLUSION: Valence-targeted thermal and mechanical stimuli modulated experimental myalgia and skin burning pain (P < .017). Partially blocking peripheral afferents or opioid receptors did not affect modulation.

Affective and non-affective touch evoke differential brain responses in 2-month-old infants.

Caressing touch is an effective way to communicate emotions and to create social bonds. It is also one of the key mediators of early parental bonding. The caresses are generally thought to represent a social form of touching and indeed, slow, gentle brushing is encoded in specialized peripheral nerve fibers, the C-tactile (CT) afferents. In adults, areas such as the posterior insula and superior temporal sulcus are activated by affective, slow stroking touch but not by fast stroking stimulation. However, whether these areas are activated in infants, after social tactile stimulation, is unknown. In this study, we compared the total hemoglobin responses measured with diffuse optical tomography (DOT) in the left hemisphere following slow and fast stroking touch stimulation in 16 2-month-old infants. We compared slow stroking (optimal CT afferent stimulation) to fast stroking (non-optimal CT stimulation). Activated regions were delineated using two methods: one based on contrast between the two conditions, and the other based on voxel-based statistical significance of the difference between the two conditions. The first method showed a single activation cluster in the temporal cortex with center of gravity in the middle temporal gyrus where the total hemoglobin increased after the slow stroking relative to the fast stroking (p = 0.04 uncorrected). The second method revealed a cluster in the insula with an increase in total hemoglobin in the insular cortex in response to slow stroking relative to fast stroking (p = 0.0005 uncorrected; p = 0.04 corrected for multiple comparisons). These activation clusters encompass areas that are involved in processing of affective, slow stroking touch in the adult brain. We conclude that the infant brain shows a pronounced and adult-like response to slow stroking touch compared to fast stroking touch in the insular cortex but the expected response in the primary somatosensory cortex was not found at this age. The results imply that emotionally valent touch is encoded in the brain in adult-like manner already soon after birth and this suggests a potential for involvement of touch in bonding with the caretaker.

Grey matter correlates of autistic traits in women with anorexia nervosa.

BACKGROUND: Patients with anorexia nervosa exhibit higher levels of behaviours typically associated with autism-spectrum disorder (ASD), but the neural basis is unclear. We sought to determine whether elevated autistic traits in women with anorexia nervosa may be reflected in cortical morphology. METHODS: We used voxel-based morphometry (VBM) to examine regional grey matter volumes in high-resolution MRI structural brain scans in women with anorexia nervosa and matched healthy controls. The Autism-spectrum Quotient (AQ) scale was used to assess autistic traits. RESULTS: Women with anorexia nervosa (n = 25) had higher AQ scores and lower bilateral superior temporal sulcus (STS) grey matter volumes than the control group (n = 25). The AQ scores correlated negatively with average left STS grey matter volume in women with anorexia nervosa. LIMITATIONS: We did not control for cognitive ability and examined only women with ongoing anorexia nervosa. CONCLUSION: Elevated autistic traits in women with anorexia nervosa are associated with morphometric alterations of brain areas linked to social cognition. This finding provides neurobiological support for the behavioural link between anorexia nervosa and ASD and emphasizes the importance of recognizing autistic traits in preventing and treating anorexia nervosa.

Encoding of Touch Intensity But Not Pleasantness in Human Primary Somatosensory Cortex.

UNLABELLED: Growing interest in affective touch has delineated a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, have cast doubt on the segregation of touch discrimination and affect, suggesting that S1 also encodes affective qualities. We used functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) to examine the role of S1 in processing touch intensity and pleasantness. Twenty-six healthy human adults rated brushing on the hand during fMRI. Intensity ratings significantly predicted activation in S1, whereas pleasantness ratings predicted activation only in the anterior cingulate cortex. Nineteen subjects also received inhibitory rTMS over right hemisphere S1 and the vertex (control). After S1 rTMS, but not after vertex rTMS, sensory discrimination was reduced and subjects with reduced sensory discrimination rated touch as more intense. In contrast, rTMS did not alter ratings of touch pleasantness. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. SIGNIFICANCE STATEMENT: Growing interest in affective touch has identified a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, cast doubt on the separation of touch discrimination and affect. We used functional magnetic resonance imaging and repetitive transcranial magnetic stimulation to demonstrate the representation of touch discrimination and intensity in S1, but the representation of pleasantness in the anterior cingulate cortex, not S1. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. Our study contributes to growing delineation of the affective touch system, a crucial step in understanding its dysregulation in numerous clinical conditions such as autism, eating disorders, depression, and chronic pain.

Optimal delineation of single C-tactile and C-nociceptive afferents in humans by latency slowing.

C-mechanoreceptors in humans comprise a population of unmyelinated afferents exhibiting a wide range of mechanical sensitivities. C-mechanoreceptors are putatively divided into those signaling gentle touch (C-tactile afferents, CTs) and nociception (C-mechanosensitive nociceptors, CMs), giving rise to positive and negative affect, respectively. We sought to distinguish, compare, and contrast the properties of a population of human C-mechanoreceptors to see how fundamental the divisions between these putative subpopulations are. We used microneurography to record from individual afferents in humans and applied electrical and mechanical stimulation to their receptive fields. We show that C-mechanoreceptors can be distinguished unequivocally into two putative populations, comprising CTs and CMs, by electrically evoked spike latency changes (slowing). After both natural mechanical stimulation and repetitive electrical stimulation there was markedly less latency slowing in CTs compared with CMs. Electrical receptive field stimulation, which bypasses the receptor end organ, was most effective in classifying C-mechanoreceptors, as responses to mechanical receptive field stimulation overlapped somewhat, which may lead to misclassification. Furthermore, we report a subclass of low-threshold CM responding to gentle mechanical stimulation and a potential subclass of CT afferent displaying burst firing. We show that substantial differences exist in the mechanisms governing axonal conduction between CTs and CMs. We provide clear electrophysiological "signatures" (extent of latency slowing) that can be used in unequivocally identifying populations of C-mechanoreceptors in single-unit and multiunit microneurography studies and in translational animal research into affective touch. Additionally, these differential mechanisms may be pharmacologically targetable for separate modulation of positive and negative affective touch information.NEW & NOTEWORTHY Human skin encodes a plethora of touch interactions, and affective tactile information is primarily signaled by slowly conducting C-mechanoreceptive afferents. We show that electrical stimulation of low-threshold C-tactile afferents produces markedly different patterns of activity compared with high-threshold C-mechanoreceptive nociceptors, although the populations overlap in their responses to mechanical stimulation. This fundamental distinction demonstrates a divergence in affective touch signaling from the first stage of sensory processing, having implications for the processing of interpersonal touch.

C-Tactile Mediated Erotic Touch Perception Relates to Sexual Desire and Performance in a Gender-Specific Way.

BACKGROUND: Unmyelinated low-threshold mechanoreceptors-the so-called C-tactile (CT) afferents-play a crucial role in the perception and conduction of caressing and pleasant touch sensations and significantly contribute to the concept of erotic touch perception. AIM: To investigate the relations between sexual desire and sexual performance and the perception of touch mediated by CT afferents. METHODS: Seventy healthy participants (28 men, 42 women; mean age ± SD = 24.84 ± 4.08 years, range = 18-36 years) underwent standardized and highly controlled stroking stimulation that varied in the amount of CT fiber stimulation by changing stroking velocity (CT optimal = 1, 3 and 10 cm/s; CT suboptimal = 0.1, 0.3, and 30 cm/s). Participants rated the perceived pleasantness, eroticism, and intensity of the applied tactile stimulation on a visual analog scale, completed the Sexual Desire Inventory, and answered questions about sexual performance. OUTCOMES: Ratings of perceived eroticism of touch were related to self-report levels of sexual desire and sexual performance. RESULTS: Pleasantness and eroticism ratings showed similar dependence on stroking velocity that aligned with the activity of CT afferents. Erotic touch perception was related to sexual desire and sexual performance in a gender-specific way. In women, differences in eroticism ratings between CT optimal and suboptimal velocities correlated positively with desire for sexual interaction. In contrast, in men, this difference correlated to a decreased frequency and longer duration of partnered sexual activities. CLINICAL IMPLICATIONS: The present results lay the foundation for future research assessing these relations in patients with specific impairments of sexual functioning (eg, hypoactive sexual desire disorder). STRENGTHS AND LIMITATIONS: The strength of the study is the combination of standardized neurophysiologic methods and behavioral data. A clear limitation of the study design is the exclusion of exact data on the female menstrual cycle and the recruitment of an inhomogeneous sample concerning sexual orientation. CONCLUSION: The present results provide further evidence that unmyelinated CT afferents play a role in the complex mechanism of erotic touch perception. The ability to differentiate between CT optimal and suboptimal stimuli relates to sexual desire and performance in a gender-specific way. Bendas J, Georgiadis JR, Ritschel G. C-Tactile Mediated Erotic Touch Perception Relates to Sexual Desire and Performance in a Gender-Specific Way. J Sex Med 2017;14:645-653.

Grey matter correlates of autistic traits in women with anorexia nervosa

Background: Patients with anorexia nervosa exhibit higher levels of behaviours typically associated with autism-spectrum disorder (ASD), but the neural basis is unclear. We sought to determine whether elevated autistic traits in women with anorexia nervosa may be reflected in cortical morphology. Methods: We used voxel-based morphometry (VBM) to examine regional grey matter volumes in high-resolution MRI structural brain scans in women with anorexia nervosa and matched healthy controls. The Autism-spectrum Quotient (AQ) scale was used to assess autistic traits. Results: Women with anorexia nervosa (n = 25) had higher AQ scores and lower bilateral superior temporal sulcus (STS) grey matter volumes than the control group (n = 25). The AQ scores correlated negatively with average left STS grey matter volume in women with anorexia nervosa. Limitations: We did not control for cognitive ability and examined only women with ongoing anorexia nervosa. Conclusion: Elevated autistic traits in women with anorexia nervosa are associated with morphometric alterations of brain areas linked to social cognition. This finding provides neurobiological support for the behavioural link between anorexia nervosa and ASD and emphasizes the importance of recognizing autistic traits in preventing and treating ­anorexia nervosa.

Low threshold unmyelinated mechanoafferents can modulate pain.

BACKGROUND: Human, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C-fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients. METHODS: Experiment I: 20 SFN-patients (12 women, median age 52.0 years) and 20 healthy controls (14 women, median age 43.0 years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch. RESULTS: Experiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (p = 0.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (p = 0.038). CONCLUSIONS: CT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired - as in SFN -, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN-patients.

Olfactory modulation of affective touch processing - A neurophysiological investigation.

Touch can be highly emotional, and depending on the environment, it can be perceived as pleasant and comforting or disgusting and dangerous. Here, we studied the impact of context on the processing of tactile stimuli using a functional magnetic resonance imaging (fMRI) paradigm. This was achieved by embedding tactile stimulation in a variable olfactory environment. Twenty people were scanned with BOLD fMRI while receiving the following stimulus blocks: Slow stroking Touch, Civette odor (feces like), Rose odor, Touch+Civette, and Touch+Rose. Ratings of pleasantness and intensity of tactile stimuli and ratings of disgust and intensity of olfactory stimuli were collected. The impact of the olfactory context on the processing of touch was studied using covariance analyses. Coupling between olfactory processing and somatosensory processing areas was assessed with psychophysiological interaction analysis (PPI). A subjectively disgusting olfactory environment significantly reduced the perceived pleasantness of touch. The touch fMRI activation in the secondary somatosensory cortex, operculum 1 (OP1), was positively correlated with the disgust towards the odors. Decreased pleasantness of touch was related to decreased posterior insula activity. PPI analysis revealed a significant interaction between the OP1, posterior insula, and regions processing the disgust of odors (orbitofrontal cortex and amygdala). We conclude that the disgust evaluation of the olfactory environment moderates neural reactivity in somatosensory regions by upregulation of the OP1 and downregulation of the posterior insula. This adaptive regulation of affective touch processing may facilitate adaptive reaction to a potentially harmful stimulus.

Temporal dynamics of brain activation during 40 minutes of pleasant touch.

INTRODUCTION: Touch is important for individuals' subjective well-being, is typically rewarding, and is one of few sensory stimuli which are experienced as pleasant for a rather long time. This study tracked brain activation during slow stroking stimulation of the arm that was applied continuously for 40min - a much longer time than what previous studies have investigated. METHODS: 25 subjects were stroked for 40min with a soft brush while they were scanned with functional Magnetic Resonance Imaging, and rated the perceived pleasantness of the brush stroking. Two resting baselines were included. Whole brain-based analyses investigated the neural response to long-lasting stroking. RESULTS: Stroking was perceived as pleasant throughout scanning and activated areas that were previously found to be involved in the processing of pleasant touch. Activation in primary somatosensory cortex (S1) and S2, subdivision OP1, decreased over time, whereas activation in orbito-frontal gyrus (OFC) and putamen strongly increased until reaching a plateau after approximately 20min. Similarly, functional connectivity of posterior insula with middle cingulate and striatal regions increased over time. DISCUSSION: Long-lasting stroking was processed in similar areas as shorter-lasting stroking. The decreased activation in somatosensory cortices over time may represent stimulus habituation, whereas increased activation in OFC and putamen may relate to the stimulation's subjective reward value. This involvement of reward-related brain circuits can facilitate maintenance of long-lasting social touch interactions.

Placebo improves pleasure and pain through opposite modulation of sensory processing.

Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the story. We compared placebo improvement of painful touch (analgesia) with placebo improvement of pleasant touch (hyperhedonia) using functional MRI and a crossover design. Somatosensory processing was decreased during placebo analgesia and increased during placebo hyperhedonia. Both placebo responses were associated with similar patterns of activation increase in circuitry involved in emotion appraisal, including the pregenual anterior cingulate, medial orbitofrontal cortex, amygdala, accumbens, and midbrain structures. Importantly, placebo-induced coupling between the ventromedial prefrontal cortex and periaqueductal gray correlated with somatosensory decreases to painful touch and somatosensory increases to pleasant touch. These findings suggest that placebo analgesia and hyperhedonia are mediated by activation of shared emotion appraisal neurocircuitry, which down- or up-regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.