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.

Human perceptual learning is delayed by the N-methyl-D-aspartate receptor partial agonist D-cycloserine.

BACKGROUND: The optimisation of learning has long been a focus of scientific research, particularly in relation to improving psychological treatment and recovery of brain function. Previously, partial N-methyl-D-aspartate agonists have been shown to augment reward learning, procedural learning and psychological therapy, but many studies also report no impact of these compounds on the same processes. AIMS: Here we investigate whether administration of an N-methyl-D-aspartate partial agonist (D-cycloserine) modulates a previously unexplored process - tactile perceptual learning. Further, we use a longitudinal design to investigate whether N-methyl-D-aspartate-related learning effects vary with time, thereby providing a potentially simple explanation for apparent mixed effects in previous research. METHODS: Thirty-four volunteers were randomised to receive one dose of 250 mg D-cycloserine or placebo 2 h before tactile sensitivity training. Tactile perception was measured using psychophysical methods before and after training, and 24/48 h later. RESULTS: The placebo group showed immediate within-day tactile perception gains, but no further improvements between-days. In contrast, tactile perception remained at baseline on day one in the D-cycloserine group (no within-day learning), but showed significant overnight gains on day two. Both groups were equivalent in tactile perception by the final testing - indicating N-methyl-D-aspartate effects changed the timing, but not the overall amount of tactile learning. CONCLUSIONS: In sum, we provide first evidence for modulation of perceptual learning by administration of a partial N-methyl-D-aspartate agonist. Resolving how the effects of such compounds become apparent over time will assist the optimisation of testing schedules, and may help resolve discrepancies across the learning and cognition domains.

Selective impairment of slowly adapting type 1 mechanoreceptors in mice following vincristine treatment.

Loss of the sense of touch in fingertips and toes is one of the earliest sensory dysfunctions in patients receiving chemotherapy with anti-cancer drugs such as vincristine. However, mechanisms underlying this chemotherapy-induced sensory dysfunction is incompletely understood. Whisker hair follicles are tactile organs in non-primate mammals which are functionally equivalent to human fingertips. Here we used mouse whisker hair follicles as a model system and applied the pressure-clamped single-fiber recording technique to explore how vincristine treatment affect mechanoreceptors in whisker hair follicles. We showed that in vivo treatment of mice with vincristine impaired whisker tactile behavioral responses. The pressure-clamped single-fiber recordings made from whisker hair follicle afferent nerves showed that mechanical stimulations evoked three types of mechanical responses, rapidly adapting response (RA), slowly adapting type 1 response (SA1) and slowly adapting type 2 response (SA2). Vincristine treatment significantly reduced SA1 responses but did not significantly affect RA and SA2 responses. Our findings suggest that SA1 mechanoreceptors were selectively impaired by vincristine leading to the impairment of in vivo whisker tactile behavioral responses.

The Territory of my Body: Testosterone Prevents Limb Cooling in the Rubber Hand Illusion.

The Rubber Hand Illusion (RHI) is an experimental paradigm for assessing changes in body ownership. Recent findings in the field suggest that social emotions can influence such changes and that empathic motivation in particular appears to positively predict the malleability of body representations. Since the steroid hormone, testosterone, is well known to interrupt certain forms of empathic processing, in the current study we investigated whether 0.5 mg of testosterone affected ownership indices of the RHI. Forty-nine females participated in a double-blind, placebo-controlled experiment in which the RHI was induced. Compared to placebo, testosterone had no effects on the alteration of subjective ownership over the rubber limb or on subjective sense of proprioceptive drift. However, unlike the placebo group, testosterone-treated participants did not display an objective decline in the temperature of their own (hidden) hand following induction of the illusion. These findings suggest that testosterone strengthens implicit but not explicit bodily self-representations. We propose that effective maintenance of implicit body boundaries can be regarded, conceptually, as a primary defensive state facilitating integrity of the self.

Alcohol and nicotine co-Administration during pregnancy and lactation periods alters sensory discrimination of adult NMRI mice offspring.

The present study investigated the impacts of alcohol, nicotine, and their co-administration during pregnancy and lactation on sensory information processing including visual, tactile, and auditory discrimination in adult NMRI mice offspring. Pregnant mice were injected with saline or 20% alcohol (3 g/kg), or nicotine (1 mg/kg) or their co-administration alcohol+nicotine, intraperitoneally until the end of lactation. The offspring were separated from their mothers after lactation period on postnatal day (PND) 28. The locomotor activity, novel object recognition-dependent on visual system (NOR-VS), novel texture discrimination- dependent on somatosensory system (NTR-SS), and acoustic startle reflex were evaluated in PND90. The results revealed no statistical significance for locomotor activity of alcohol, nicotine, and co-administration alcohol+nicotine groups compared to the saline group in the open field task. The results, however, showed a significant decline in the ability of novel object discrimination in the nicotine and co-administration alcohol + nicotine groups compared to the saline group (P < 0.05) in the NOR-VS task. In the NTR-SS and acoustic startle reflex tasks, texture discrimination and the prepulse inhibition abilities in the offspring administered with nicotine and alcohol alone were reduced when compared to the saline group. Also, co-administration of alcohol+nicotine groups showed a decline in the aforementioned tests compared to the saline group (P <0.05). Administration of alcohol and nicotine during fetal and postpartum development disrupts sensory processing of inputs of visual, tactile, and auditory systems in adult mice.

Comparison of pre-pulse inhibition, tactile discrimination learning and barrel cortical neural response in adult male rats following chronic exposure to morphine, methadone and buprenorphine.

Chronic exposure to opioids is the most common treatment plan to reduce the pain. In this study, the stereotyped behaviors and cognitive functions related to different types of tactile and auditory inputs were investigated in the rats following chronic exposure to the morphine, methadone, and buprenorphine. Here, three addicted groups received morphine, methadone, and buprenorphine while the control rats received saline for 21 days. Our results demonstrated that the opioid-treated groups showed stereotyped behaviors including grooming and rearing. In the behavioral level, prepulse inhibition and preference indices were not changed significantly in the opioids-treated groups compared to those of the saline group as two criteria for acoustic startle reflex and tactile discrimination, respectively. In the neuronal level, chronic morphine and methadone treatment changed the response properties of the barrel cortical neurons to the whisker deflections in the experimental groups compared to the saline group. Thus, it was concluded that the excitatory receptive fields of neurons in the barrel cortex can be changed as a result of chronic exposure to morphine and methadone.

Inhibition in the somatosensory system: An integrative neuropharmacological and neuroimaging approach.

The presented study investigates the functional role of GABA in somatosensory processing, using a combined neuropharmacological-neuroimaging approach. Three different GABA agonists (GABAA: alprazolam, ethanol; GABAB: baclofen) were investigated in a double blind cross-over design in 16 male participants, accomplishing a tactile perception task. Somatosensory evoked magnetic fields modulated by GABAR-agonists and placebo were recorded using whole-head magnetoencephalography. Peak latencies and amplitudes of primary (SI) and secondary (SII) somatosensory cortex source activities confirmed the previously reported role of GABA as a modulator of somatosensory processing. Significant inhibitory effects on the latency of SII and on the amplitude of SI and SII were found exclusively for alprazolam, a positive allosteric modulator at GABAA receptors. The GABAB agonist baclofen did not have any modulatory effect. Moreover, we investigated whether the observed effects of alprazolam on the level of SII were explainable by the mere propagation of activity from SI to SII modulated by GABAA receptors, independently from any further GABAA-mediated inhibition in SII. By estimating the transfer function between SI and SII activation under placebo conditions, we were able to predict SII activity for the administration of GABA receptors agonists under the assumption that GABA exclusively acts at the level of SI. By comparing measured and predicted data, we propose a model in which the initial activation of SI is modulated through GABAA receptors and subsequently propagated to SII, without any significant further inhibition. In addition, initial GABAA effects in SI appear to be strongly potentiated with time, selectively in SI but not in SII.

Effects of MDMA on attention to positive social cues and pleasantness of affective touch.

The psychostimulant drug ±3,4-methylenedioxymethamphetamine (MDMA) reportedly produces distinctive feelings of empathy and closeness with others. MDMA increases social behavior in animal models and has shown promise in psychiatric disorders, such as autism spectrum disorder (ASD) and post-traumatic stress disorder (PTSD). How it produces these prosocial effects is not known. This behavioral and psychophysiological study examined the effects of MDMA, compared with the prototypical stimulant methamphetamine (MA), on two measures of social behavior in healthy young adults: (i) responses to socially relevant, "affective" touch, and (ii) visual attention to emotional faces. Men and women (N = 36) attended four sessions in which they received MDMA (0.75 or 1.5 mg/kg), MA (20 mg), or a placebo in randomized order under double-blind conditions. Responses to experienced and observed affective touch (i.e., being touched or watching others being touched) were assessed using facial electromyography (EMG), a proxy of affective state. Responses to emotional faces were assessed using electrooculography (EOG) in a measure of attentional bias. Subjective ratings were also included. We hypothesized that MDMA, but not MA, would enhance the ratings of pleasantness and psychophysiological responses to affective touch and increase attentional bias toward positive facial expressions. Consistent with this, we found that MDMA, but not MA, selectively enhanced ratings of pleasantness of experienced affective touch. Neither drug altered the ratings of pleasantness of observed touch. On the EOG measure of attentional bias, MDMA, but not MA, increased attention toward happy faces. These results provide new evidence that MDMA can enhance the experience of positive social interactions; in this case, pleasantness of physical touch and attentional bias toward positive facial expressions. The findings are consistent with evidence that the prosocial effects are unique to MDMA relative to another stimulant. Understanding the behavioral and neurobiological processes underlying the distinctive social effects of MDMA is a key step to developing the drug for psychiatric disorders.

Effects of opioid receptor stimulation and blockade on touch pleasantness: a double-blind randomised trial.

The µ-opioid receptor (MOR) system has long been thought to underpin the rewarding properties of pleasant touch. Numerous non-human animal studies implicate MORs in social behaviours involving touch, but little is currently known about MOR involvement in human touch reward. Here, we employed a bi-directional pharmacological double-blind crossover design to assess the role of the human MOR system for touch pleasantness and motivation. Forty-nine male volunteers received 10 mg per-oral morphine, 50 mg per-oral naltrexone and placebo before being brushed on their forearm at three different velocities (0.3, 3 and 30 cm/s). In a touch liking task, pleasantness ratings were recorded after each 15 s brushing trial. In a touch wanting task, participants actively manipulated trial duration through key presses. As expected, 3 cm/s was the preferred velocity, producing significantly higher pleasantness ratings and wanting scores than the other stimuli. Contrary to our hypothesis, MOR drug manipulations did not significantly affect either touch pleasantness or wanting. The null effects were supported by post hoc Bayesian analyses indicating that the models with no drug effect were more than 25 times more likely than the alternative models given the data. We conclude that µ-opioid signalling is unlikely to underpin non-affiliative touch reward in humans.

Blocking tactile input to one finger using anaesthetic enhances touch perception and learning in other fingers.

Brain plasticity is a key mechanism for learning and recovery. A striking example of plasticity in the adult brain occurs following input loss, for example, following amputation, whereby the deprived zone is "invaded" by new representations. Although it has long been assumed that such reorganization leads to functional benefits for the invading representation, the behavioral evidence is controversial. Here, we investigate whether a temporary period of somatosensory input loss to one finger, induced by anesthetic block, is sufficient to cause improvements in touch perception ("direct" effects of deafferentation). Further, we determine whether this deprivation can improve touch perception by enhancing sensory learning processes, for example, by training ("interactive" effects). Importantly, we explore whether direct and interactive effects of deprivation are dissociable by directly comparing their effects on touch perception. Using psychophysical thresholds, we found brief deprivation alone caused improvements in tactile perception of a finger adjacent to the blocked finger but not to non-neighboring fingers. Two additional groups underwent minimal tactile training to one finger either during anesthetic block of the neighboring finger or a sham block with saline. Deprivation significantly enhanced the effects of tactile perceptual training, causing greater learning transfer compared with sham block. That is, following deafferentation and training, learning gains were seen in fingers normally outside the boundaries of topographic transfer of tactile perceptual learning. Our results demonstrate that sensory deprivation can improve perceptual abilities, both directly and interactively, when combined with sensory learning. This dissociation provides novel opportunities for future clinical interventions to improve sensation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Pyrroloquinoline quinone improves abnormal functional development of whisker-mediated tactile perception and social behaviors caused by neonatal whisker trimming.

Abnormalities in tactile perception and response, such as sensory defensiveness, are core features of autism spectrum disorder (ASD) and may be associated with impaired communication skills. However, the influences of tactile perception deficits on the development of social behaviors and neuronal circuits related to emotional regulation of social interactions remain unclear. Whiskers are the most important tactile apparatus in rodents. We previously reported that adult mice receiving bilateral whisker trimming for 10 days after birth (BWT10) exhibited deficits in whisker-mediated tactile discrimination, abnormal social behaviors, and hyperactivity of brain emotional systems under psychological stress. Pyrroloquinoline quinone (PQQ) is an essential nutrient with important roles in central nervous system development and function through modulation of glutamatergic N-methyl-d-aspartate receptor (NMDAR) activity. Here we examined the effect of neonatal PQQ administration on the behavioral abnormalities of BWT10 mice. PQQ treatment significantly reversed abnormal social behavior in adult BWT10 mice as detected by three-chamber social interaction and social dominance tube tests, and improved whisker perception as revealed by the gap-crossing test. In addition, PQQ reversed hyperactivity in emotional systems as evidenced by c-Fos expression pattern following elevated-platform stress. These data suggest that PQQ may be a promising candidate therapeutic drug for neurodevelopmental disorders such as ASD.

Instrumental and sensory methodologies to characterize the residual film of topical products applied to skin.

BACKGROUND: The work is aimed at the development of a methodology to characterize the tactile properties of topical products during application. Specific attention was paid to the study of the residual properties left at the surface of the skin. This approach was interestingly used to better understand the formulation factors governing the skinfeel of topical preparations. MATERIALS AND METHODS: Cosmetic and pharmaceutical topical products were selected based on their various texture, galenic form (gel or emulsion), and composition (polymer used as texturing agent). Key texture attributes namely Firmness, Stickiness, Spreadability, and Amount of residue were objectively evaluated using sensory analysis. Additionally, texture analysis (compression test), rheology (flow test), and tribology (in vivo friction test) were carried out. RESULTS: Sensory evaluations highlighted a great diversity of tactile properties among products when applied to skin. For example, assessors perceived an important amount of residue left by emulsions whereas gels were not leaving any residue after application to the skin. These results were confirmed by in vivo tactile friction measurements with two distinct evolutions in time of the residual film properties. CONCLUSION: The present investigation shows how the tactile properties of topical gels and emulsions are studied using complementary tests in order to understand and improve the skinfeel of topical preparations.

Foot massage evokes oxytocin release and activation of orbitofrontal cortex and superior temporal sulcus.

Massage may be an important method for increasing endogenous oxytocin concentrations and of potential therapeutic benefit in disorders with social dysfunction such as autism where basal oxytocin levels are typically reduced. Here we investigated oxytocin release and associated neural responses using functional near infrared spectroscopy (fNIRS) during hand- or machine-administered massage. 40 adult male subjects received 10 min of light foot massage either by hand or machine in a counterbalanced order and then rated pleasure, intensity, arousal and how much they would pay for the massage. Blood samples were taken before and after each massage condition to determine plasma oxytocin concentrations. Neural responses from medial and lateral orbitofrontal cortex, superior temporal sulcus and somatosensory cortex were measured (fNIRS oxy-Hb) together with skin conductance responses (SCR), ratings of the massage experience, autistic traits and sensitivity to social touch. Results showed subjects gave higher ratings of pleasure, but not intensity or arousal, after hand- compared with machine-administered massage and there were no differential effects on SCR. Subjects were also willing to pay more for the hand massage. Plasma oxytocin increased after both massage by hand or machine, but more potently after massage by hand. Both basal oxytocin concentrations and increases evoked by hand-, but not machine-administered massage, were negatively associated with trait autism and attitudes towards social touch, but massage by hand-evoked changes were significant in higher as well as lower trait individuals. Increased neural responses to hand vs. machine-administered massage were found in posterior superior temporal sulcus and medial/lateral orbitofrontal cortex but not somatosensory cortex. Orbitofrontal cortex and superior temporal cortex activation during hand massage was associated with the amount of money subjects were willing to pay and between orbitofrontal cortex activation and autism scores. Thus, hand-administered massage can potently increase oxytocin release and activity in brain regions involved in social cognition and reward but not sensory aspects of affective touch. Massage by hand induced changes in both oxytocin concentrations and neural circuits involved in processing social affective trust may have therapeutic potential in the context of autism.

Embodied Precision: Intranasal Oxytocin Modulates Multisensory Integration.

Multisensory integration processes are fundamental to our sense of self as embodied beings. Bodily illusions, such as the rubber hand illusion (RHI) and the size-weight illusion (SWI), allow us to investigate how the brain resolves conflicting multisensory evidence during perceptual inference in relation to different facets of body representation. In the RHI, synchronous tactile stimulation of a participant's hidden hand and a visible rubber hand creates illusory body ownership; in the SWI, the perceived size of the body can modulate the estimated weight of external objects. According to Bayesian models, such illusions arise as an attempt to explain the causes of multisensory perception and may reflect the attenuation of somatosensory precision, which is required to resolve perceptual hypotheses about conflicting multisensory input. Recent hypotheses propose that the precision of sensorimotor representations is determined by modulators of synaptic gain, like dopamine, acetylcholine, and oxytocin. However, these neuromodulatory hypotheses have not been tested in the context of embodied multisensory integration. The present, double-blind, placebo-controlled, crossover study ( n = 41 healthy volunteers) aimed to investigate the effect of intranasal oxytocin (IN-OT) on multisensory integration processes, tested by means of the RHI and the SWI. Results showed that IN-OT enhanced the subjective feeling of ownership in the RHI, only when synchronous tactile stimulation was involved. Furthermore, IN-OT increased an embodied version of the SWI (quantified as estimation error during a weight estimation task). These findings suggest that oxytocin might modulate processes of visuotactile multisensory integration by increasing the precision of top-down signals against bottom-up sensory input.

Effects of intranasal oxytocin on tactile perception.

In addition to its role in childbirth labor and lactation, oxytocin is a well-known neurohormone, having several prosocial effects. Moreover, oxytocin seems to play a significant modulatory role in painful experiences, due to its participation in central and peripheral processing of nociceptive somatosensory information. Despite studies on oxytocin in pain modulation, there is a scarce literature investigating the role of oxytocin in tactile perception. Here we investigate the effects of 24 and 40 IU intranasal administration of oxytocin in the non-harmful mechanical tactile detection threshold in men. The data showed a significant increase in tactile perception in an experimental 40 IU oxytocin group. We suggest that this effect could be the basis for the oxytocin-bonding effect via touch.

The time course of brief and prolonged topical 8% capsaicin-induced desensitization in healthy volunteers evaluated by quantitative sensory testing and vasomotor imaging.

Topically applied high-concentration capsaicin induces reversible dermo-epidermal denervation and depletion of capsaicin-sensitive nociceptors. This causes desensitization of distinct sensory modalities and is used to treat peripheral neuropathic pain and itch. For high-concentration capsaicin, the selectivity of loss of function and functional recovery rates of various afferent fibers subpopulations are unknown. This study used comprehensive quantitative sensory testing and vasomotor imaging to assess effectiveness, duration and sensory selectivity of high-concentration 8% capsaicin-ablation. Skin areas in 14 healthy volunteers were randomized to treatment with 8% capsaicin/vehicle patches for 1 and 24 h and underwent comprehensive sensory and vasomotor testing at 1, 7 and 21 days postpatch removal. Tests consisted of thermal detection and pain thresholds, tactile and vibration detection thresholds, mechanical pain threshold and mechanical pain sensitivity as well as micro-vascular and itch reactivity to histamine provocations. The 24 h capsaicin drastically inhibited warmth detection (P < 0.001), heat pain (P < 0.001) as well as histamine-induced itch (P < 0.05) and neurogenic flare (P < 0.001), but had no impact on tactile sensitivity, cold detection and cold pain. A marginal decrease in mechanical pain sensitivity was observed (P < 0.05). Capsaicin for 1 h had limited and transient sensory effects only affecting warmth and heat sensations. Time-dependent functional recovery was almost complete 21 days after the 24 h capsaicin exposure, while recovery of neurogenic inflammatory responsiveness remained partial. The psychophysically assessed sensory deficiencies induced by the used 8% capsaicin-ablation correspond well with a predominant effect on TRPV1+-cutaneous fibers. The method is easy to apply, well tolerated, and utilizable for studies on, e.g., interactions between skin barrier, inflammation and capsaicin-sensitive afferents.

Relief from intractable phantom pain by combining psilocybin and mirror visual-feedback (MVF).

AL's leg was amputated resulting in phantom-limb pain (PLP). (1) When a volunteer placed her foot on or near the phantom - touching it evoked organized sensations in corresponding locations on AL's phantom. (2) Mirror-visual-feedback (MVF) relieved PLP, as did, "phantom massage". (3) Psilocybin-MVF pairing produced synergistic effects, complete elimination of PLP, and reduction in paroxysmal episodes. (4) Touching the volunteer's leg where AL previously had external fixators, evoked sensation of nails boring through the leg. Using a "telescoping" nail, we created the illusion of a nail being removed with corresponding pain relief. (5) Artificial flames produced warmth in the phantom.

Altered somatosensory processing in Parkinson's disease and modulation by dopaminergic medications.

BACKGROUND: Somatosensory abnormalities contribute to the pathophysiology of Parkinson's disease (PD). The goal of this study was to identify abnormalities in the tactile-evoked activation of the somatosensory and motor cortices in PD, and in a sensorimotor circuit that traverses both of these cortical loci. The second goal was to investigate the impact of dopaminergic medication on these measures. METHODS: Individuals with PD (n = 10, age 61 ±â€¯8 years) and aged-matched controls (n = 11, age 52.3 ±â€¯10.4 years) were studied. PD subjects were studied on and off dopaminergic medications. Using high-resolution functional magnetic resonance, imaging data was acquired over the primary somatosensory and motor cortices during passively delivered, computer-automated tactile stimulation of digits 2 and 5 of the more affected hand in PD and the analogous hand in controls. Short and long-latency afferent inhibition (SAI, LAI) were assessed via median nerve stimulation followed by transcranial magnetic stimulation over the motor cortical representation of the first dorsal interosseous muscle. RESULTS: Compared to controls, PD subjects demonstrated diminished activation within the somatosensory cortex, reduced LAI and normal SAI, of which all were insensitive to dopaminergic medications. In addition to improving motor symptoms, dopaminergic medications reduced the hyperactivity observed within primary motor cortex in PD. CONCLUSIONS: Somatosensory processing is deficient in PD. Reduction in tactile-evoked activation within primary motor cortex may contribute to improvement in motor symptoms with dopaminergic medications.

Referred cramping phantom hand pain elicited in the face and eliminated by peripheral nerve block.

Phantom limb pain is a restricting condition for a substantial number of amputees with quite different characteristics of pain. Here, we report on a forearm amputee with constant phantom pain in the hand, in whom we could regularly elicit the rare phenomenon of referred cramping phantom pain by touching the face. To clarify the underlying mechanisms, we followed the cramp during the course of an axillary blockade of the brachial plexus. During the blockade, both phantom pain and the referred cramp were abolished, while a referred sensation of "being touched at the phantom" persisted. Furthermore, to identify the cortical substrate, we elicited the cramp during functional magnetic imaging. Imaging revealed that referred cramping phantom limb pain was associated with brain activation of the hand representation in the primary sensorimotor cortex. The results support the hypothesis that referred cramping phantom limb pain in this case is associated with a substantial brain activation in the hand area of the deafferented sensorimotor cortex. However, this alone is not sufficient to elicit referred cramping phantom limb pain. Peripheral inputs, both, from the arm nerves affected by the amputation and from the skin in the face at which the referred cramp is evoked, are a precondition for referred cramping phantom limb pain to occur, at least in this case.