Threshold and rate sensitivity of low‐threshold thermal nociception

Previous studies have shown that sensations of burning, stinging or pricking can be evoked by warming or cooling the skin to innocuous temperatures [low‐threshold thermal nociception (LTN)] below the thresholds of cold‐ and heat‐sensitive nociceptors. LTN implies that some primary afferent fibers classically defined as warm and cold fibers relay stimulation to the nociceptive system. We addressed this question in humans by determining if different adaptation temperatures (ATs) and rates of temperature change would affect thermal sensation and LTN similarly. In Experiment 1 subjects rated the intensity of warmth, cold and nociceptive sensations produced by increasing steps in temperature (±0.5°C increments) from ATs of 35, 33 and 31°C for cooling, and 30, 32 and 34°C for heating. Depending upon the AT, thresholds for nociceptive and thermal sensations estimated from the rating data differed by as little as ?1.0°C for cooling and +1.5°C for heating. Thresholds of thermal and nociceptive sensations shifted by similar amounts across the three ATs during cooling, whereas during heating the nociceptive threshold was significantly affected only between ATs of 32 and 34°C. In Experiment 2, increasing the rate of temperature change from 0.5 to 4.0°C/s increased the intensity of thermal and nociceptive sensations significantly but the effect was greatest for nociceptive sensations during heating. The results of both experiments are consistent with the mediation of LTN by low‐threshold thermoreceptors, although LTN caused by heating may depend on a subset of fibers that express less sensitive TRP channels than those that serve sensations of warmth at the mildest temperatures.     

Vibrotactile atonal interval correlated with activity in peripheral mechanoreceptive units innervating the human hand

The quality of sensations and the vibrotactile atonal interval-the gap between detection and vibration thresholds-were studied with vibratory stimuli of varying frequency (20, 80 and 160 Hz) and duration (100, 400 and 800 ms) applied to the hairy and glabrous skin of the hand. Detection and vibration thresholds were also determined while simultaneously recording single unit activity from the radial nerve innervating the hairy skin of the hand. Both thresholds were lower on the glabrous than the hairy skin, and the thresholds decreased on both skin areas with increasing vibration frequency. A sensation of short duration was elicited at detection threshold only with a 20-Hz stimulus of 100-ms duration; with other frequency-duration combinations sensations of longer duration were reported. Considerably larger vibration amplitudes were needed on both skin areas for the sensations to be unequivocal with respect to duration and pitch (vibration threshold). There was no significant effect of stimulus duration on vibrotactile thresholds. The width of the average atonal intervals was above 10 dB on both skin areas, and with increasing vibration frequency, decreasing values of atonal intervals were obtained on the hairy skin, whereas considerably increasing values were obtained on the glabrous skin. Recording of single unit activity indicates that on the hairy skin detection of the stimulus at 20 Hz is correlated with activation of slowly adapting (SA) type II and the most sensitive rapidly adapting (RA) units, while distinct vibratory sensations involve entrainment of RA units. Also at 80 Hz, non-pacinian units could contribute to the mechanism of vibrotactile thresholds, whereas at 160 Hz only pacinian (PC) units are involved.     

Peripheral neural basis of tactile sensations in man: II. Characteristics of human mechanoreceptors in the hairy skin and correlations of their activity with tactile sensations

Properties of the human mechanoreceptors in the hairy skin of the back of the hand were studied by microelectrode measurements from the radial nerve. Correlations of unit activity with sensations elicited by tactile pulses (single cycle sinusoids of 20, 60 and 150 Hz) were examined with simultaneous measurements of unit activity and sensation thresholds and magnitude.A total of 264 mechanoreceptive units were identified. Of all units 66% were classified as slowly adapting (SA) and 34% as rapidly adapting (RA) units. Mechanical thresholds of the units as well as simultaneously measured sensation thresholds decreased with increasing frequency of the pulse. The thresholds of several SA units were identical with the subjective thresholds.The responses of the units to supraliminal pulses consisted maximally of 7 impulses. Most SAI and RA units were able to code to some extent the stimulus amplitude on the basis of number of impulses, but only RA units had stimulus-response functions indicating velocity coding. Comparisons of the estimates of sensation magnitude with the number of impulses in the response indicated that the estimate may be based mainly on activity in a population of RA units. The comparison of the present results with earlier reports on properties of receptors in the glabrous skin of the human hand indicates that there are some differences between the characteristics of receptors in the hairy and glabrous skin. However, human receptors in the hairy skin do not seem to differ from the corresponding receptors in the animals.     

Small nerve fiber selectivity of laser and intraepidermal electrical stimulation: A comparative study between glabrous and hairy skin

ObjectivesIn clinical neurophysiology practice, various methods of stimulation can be used to activate small-diameter nociceptive cutaneous afferents located in the epidermis. These methods include different types of laser and intraepidermal electrical stimulation techniques. The diffusion of the stimulation in the skin, inside or under the epidermis, depends on laser wavelength and electrode design, in particular. The aim of this study was to compare several of these techniques in their ability to selectively stimulate small nerve fibers.MethodsIn 8 healthy subjects, laser stimulation (using a CO₂ or Nd:YAP laser) and intraepidermal electrical stimulation (using a micropatterned, concentric planar, or concentric needle electrode), were applied at increasing energy or intensity on the dorsal or volar aspect of the right hand or foot. The subjects were asked to define the perceived sensation (warm, pinprick, or electric shock sensation, corresponding to the activation of C fibers, Aδ fibers, or Aβ fibers, respectively) after each stimulation. Depending on the difference in the sensations perceived between dorsal (hairy skin with thin stratum corneum) and volar (glabrous skin with thick stratum corneum) stimulations, the diffusion of the stimulation inside or under the epidermis and the nature of the activated afferents were determined.ResultsRegarding laser stimulation, the perceived sensations turned from warm to pinprick with increasing energies of stimulation, in particular with the Nd:YAP laser, of which pulse could penetrate deep in the skin according to its short wavelength. In contrast, CO₂ laser stimulation produced only warm sensations and no pricking sensation when applied to the glabrous skin, perhaps due to a thicker stratum corneum and the shallow penetration of the CO₂ laser pulse. Regarding intraepidermal electrical stimulation using concentric electrodes, the perceived sensations turned from pinprick to a combination of pinprick and electrical shocks with increasing intensities. Using the concentric planar electrode, the sensations perceived at high stimulation intensity even consisted of electric shocks without concomitant pinprick. In contrast, using the micropatterned electrode, only pinprick sensations were produced by the stimulation of the hairy skin, while the stimulation of the glabrous skin produced no sensation at all within the limits of stimulation intensities used in this study.ConclusionsUsing the CO₂ laser or the micropatterned electrode, pinprick sensations were selectively produced by the stimulation of hairy skin, while only warm sensation or no sensation at all were produced by the stimulation of glabrous skin. These two techniques appear to be more selective with a limited diffusion of the stimulation into the skin, restricting the activation of sensory afferents to the most superficial and smallest intraepidermal nerve fibers.     

Influence of the rate of temperature change on thermal thresholds in man

Thermal thresholds (cool, warm, heat, heat pain) were determined in four skin regions (cheek, glabrous skin of the hand, hairy forearm, leg) of eight healthy human subjects. The thermostimulator was composed of Peltier elements and three rates of continuous stimulation were used: 1.4, 2.4, and 3.9 degrees C/s. Warm, heat, and heat pain thresholds increased with increasing rate of temperature change, and the increase was of equal magnitude with these three thresholds. However, the effect of increasing stimulus rate on cool thresholds was nonsignificant. Similar results were obtained in all skin regions studied. It is suggested that liminal warm, heat, and heat pain sensations are mediated by afferent fibers with conduction velocities of the same range (C-fibers) whereas liminal cool sensations are signaled by faster conducting afferent fibers.     

High resolution topographical mapping of warm and cold sensitivities

OBJECTIVE: This study aims to explore the thermal sensitivity distribution (topographical mapping) over the glabrous skin of the hand in males and females. METHODS: Warm (WT) and cold (CT) thresholds were measured in 25 healthy volunteers (12 females), applying a multi-site test of 23 locations on the volar part of the hand. RESULTS: The palm area was more sensitive than the fingers to both warm (P<0.001) and cold (P<0.001) stimuli. On the palm itself, the proximal part was the most sensitive (P<0.05). Heterogeneity was also found to both warm and cold sensibilities within dermatomes (P<0.05) as well as to cold sensitivity across dermatomes (P<0.001). Females were more sensitive than males to both warm (P<0.001) and cold sensations (P<0.001). In addition, painful components were frequently reported as accompanying warm/cold sensations during mild warming/cooling. CONCLUSIONS: The thermal sensitivity distribution over the glabrous skin of the hand is highly heterogeneous. SIGNIFICANCE: It is appropriate to precisely define testing locations when conducting thermal examinations on the hand.     

The conduction velocities of peripheral nerve fibres conveying sensations of warming and cooling.

With the current practice of measuring thresholds for warming and cooling separately, the question of the exact nature of afferents subserving these sensations assumes new importance. Experiments to measure reaction times to warming and cooling stimuli at two sites on the lower limb are described. The conduction velocity for each sensation was estimated from the conduction distance and conduction time in the limb. The estimated mean conduction velocity for warming was 0.5, SD 0.2 m/s and cooling 2.1, SD 0.8 m/s. These figures confirm that the sensation of warming is conveyed in unmyelinated and cooling in small myelinated peripheral nerve fibres.     

Responses recorded from human scalp evoked by cutaneous thermal stimulation

When the glabrous palmar skin of the human hand was rapidly cooled, a change in the recorded electrical potential was localized at the contralateral scalp site that approximated the primary projection of the hand on the postcentral gyrus. Typical features of the evoked potential were an initial positive peak of large amplitude (25–36 μV), long peak latency (325 msec), long duration (200–325 msec) and it was graded to the intensity of the cooling. Little, if any, potential change was simultaneously recorded from the corresponding ipsilateral scalp site. While the evoked response is specific to skin cooling neither its receptor origin nor its relationship to thermal sensation has been established. We were not able to record an evoked potential of any form to rapid warming of the hand.     

Is heat hypoalgesia a useful parameter in quantitative thermal testing of alcoholic polyneuropathy?

Detection of thermal hypoaesthesia, hyperalgesia, and paradoxical sensation significantly contribute to the diagnosis of polyneuropathy (PNP). There is controversy about the clinical usefulness of detected heat hypoalgesia. In 50 chronic alcoholic patients we compared the prevalence and diagnostic value of heat hypoalgesia (HPT) to that of cold (CT) and warm (WT) hypoaesthesia using a “Marstock” thermotest. Clinical examination revealed PNP in 56%, cold hypoaesthesia was present in 62%, warm hypoaesthesia in 24%, paradoxical thermal sensation in 10%, cold and heat hyperalgesia in 12%, and heat hpypoalgesia in 22%. Only 1 patient (2%) presented with heat hypoalgesia but normal warm and cold thresholds; he reported paradoxical thermal sensation and had PNP. One patient suffered first degree burn injury from heat pain examination. Heat hypoalgesia contributed least to the diagnosis of polyneuropathy (HPT versus CT: P < 0.001). In patients with sensory loss, testing heat hypoalgesia bears some risk of burn injury. In contrast to thermal hypoaesthesia and hyperalgesia, it does not significantly enrich the diagnostic workup of alcoholic polyneuropathies. © 1994 John Wiley & Sons, Inc.     

Investigation into the correlation between sensation and leg movement in restless legs syndrome.

We evaluated rest effects on restless legs syndrome (RLS) sensory and motor symptoms. During two 60-minute Suggested Immobilization Tests (SIT) subject's signals of RLS leg sensations and periodic leg movements while awake (PLMW) were recorded. Sensations, PLMW, sensations preceding or after PLMW, sensations occurring without following PLMW, and PLMW occurring without preceding sensation were determined. The RLS patients were divided into equal-sized high and low PLMW groups for further analysis. Data from 46 subjects (28 RLS and 18 controls) revealed sensations increased linearly with rest in RLS patients and controls. Movement rate increased linearly with rest for controls but increased rapidly for the first 45 minutes for all RLS patients. PLMW/hour increased with further rest for low but not high PLMW patients. Sensations followed by PLMW and PLMW without preceding sensations followed similar patterns. Sensations without subsequent PLMW increased dramatically in the last 15 minutes of the SITs. Whereas both sensory and motor signs of RLS increase with rest, there is minimal increase for controls. Patients with higher but not lower PLMW rates reached a ceiling for PLMW after 35 to 40 minutes. The temporal dissociation between sensory and motor events supports viewing these motor and sensory events as separate but loosely linked manifestations of RLS.     

Brain mapping of digestive sensations elicited by cortical electrical stimulations

Abstract  The aim of the study was to obtain a comprehensive map of cortical areas from where digestive sensations during intracerebral electrical stimulations (ES) in epileptic patients are elicited. Direct cortical ESs were performed in 339 medically intractable epileptic patients selected to presurgical evaluation using chronically stereotaxically implanted intracerebral electrodes and audio–video-EEG monitoring system. Digestive sensations were electrically induced on 723 different anatomical sites in 172 subjects (51%). According to the exclusion criteria, the final analysis includes 174 relevant stimulations evoked in 87 patients. The reported sensations referred predominantly to the upper part of the digestive tract including the epigastria and area over the periumbilical ( n  = 83; 48%), retrosternal ( n  = 17; 10%), pharyngeal ( n  = 31; 18%) and oral ( n  = 18; 10%) regions. The temporal pole (BA 38), hippocampus, amygdala and anterior cingulate cortex (ACC; BA 24/BA 32) were the typical anatomical locations connected with epigastric sensations. Retrosternal sensations were preferentially related to the ACC, while oro-pharyngeal sensations were most related to the suprasylvian opercular cortex and the insula. Cortical ESs are followed by a great variability of induced digestive and associated symptoms corresponding to a widely distributed cortical network of visceral sensation processing, in which the limbic and paralimbic structures play a critical role.     

Evidence that tactile stimulation inhibits nociceptive sensations produced by innocuous contact cooling

It was recently shown that stinging, pricking or burning is reliably perceived by some individuals when the skin is cooled to temperatures as mild as 25-30 degrees C. These seemingly paradoxical sensations, which have been termed innocuous-cold nociception (ICN), were significant only when cooling was produced by a thermode resting statically on the skin (static contact); touching an already cooled thermode to the skin (dynamic contact) produced reports of only coolness and cold. The present study investigated the hypothesis that ICN is inhibited by tactile stimulation produced when a thermode contacts the skin. Experiment 1 pitted the tactile hypothesis against an alternative explanation that inhibition results from higher rates of skin cooling during dynamic contact. ICN was measured at three different cooling rates (-1.0, -2.5, -5.0 degrees C/s) when the thermode was resting on the skin or was touched to the skin at the moment cooling began. The results supported the tactile hypothesis: faster cooling rates during static contact led to stronger rather than weaker nociceptive sensations, and ICN was suppressed even when dynamic contact was coincident with the onset of cooling, and thus could not affect cooling rate. Experiment 2 confirmed the latter result and showed that suppression was greatest at 28 degrees C, less at 24 degrees C, and not significant at 18 degrees C. We conclude that dynamic tactile stimulation produced by contact with a surface inhibits the nociceptive component of innocuous but not noxious cooling. The implications of this conclusion for the role of cold perception in behavioral thermoregulation versus haptic perception, and for theories of cold perception in general, are discussed.     

Optimizing temperature threshold testing in small‐fiber neuropathy

Introduction: We examined optimization of a temperature threshold testing (TTT) protocol for patients with suspected small‐fiber neuropathy (SFN) to lessen the burden for both patients and technicians, without sacrificing accuracy. Methods: Data from 81 patients with SFN (skin biopsy and TTT abnormal) and 81 without SFN (skin biopsy and TTT normal) were used. Warm, cold, and heat pain sensation thresholds were determined bilaterally on the thenar eminence and foot dorsum by methods of limits and levels. Diagnostic accuracy was determined for various sensory modality combinations through comparative corresponding area under the receiver‐operator characteristic curves. Results: Assessment of warm and cold thresholds in all extremities by the method of levels showed the best discriminatory ability (area under the curve 0.95, sensitivity 84.2%, specificity 93.8%). Conclusions: These assessments are suggested for TTT examination in possible SFN patients. By applying this combination, the time needed for TTT can be reduced, maintaining diagnostic accuracy. Muscle Nerve 51 : 870–876, 2015     

Latency to detection of first pain

The latency to detection of heat stimuli applied to the distal forearm and thenar eminence was measured in 3 subjects in order to determine whether short latency responses correlated with perception of first pain. Only one temperature was used in a given run and stimuli ranged from 39 to 51 °C. In addition, subjects were interviewed at the end of each run regarding the quality of sensations experienced. In one series of experiments the quality of the first sensation evoked by each stimulus rather than latency was recorded. The median response latency decreased exponentially from 1100 ms to 400 ms for the distal arm and 1100 ms to 700 ms for the hand. The higher temperatures elicited a double pain sensation on the arm, but not on the glabrous hand. Warmth was always the first sensation felt on the hand. It is concluded that short latencies (less than 450 ms) reliably denote the presence of first pain, and that at least some portion of the primary afferents that signal first pain must have conduction velocities greater than 6m/s.     

More than cool: promiscuous relationships of menthol and other sensory compounds

Several temperature-activated transient receptor potential (thermoTRP) ion channels are the molecular receptors of natural compounds that evoke thermal and pain sensations. Menthol, popularly known for its cooling effect, activates TRPM8--a cold-activated thermoTRP ion channel. However, human physiological studies demonstrate a paradoxical role of menthol in modulation of warm sensation, and here, we show that menthol also activates heat-activated TRPV3. We further show that menthol inhibits TRPA1, potentially explaining the use of menthol as an analgesic. Similar to menthol, both camphor and cinnamaldehyde (initially reported to be specific activators of TRPV3 and TRPA1, respectively) also modulate other thermoTRPs. Therefore, we find that many "sensory compounds" presumed to be specific have a promiscuous relationship with thermoTRPs.     

The extent of small fibre sensory neuropathy in diabetics with plantar foot ulceration.

Thresholds for cutaneous warming and cooling stimuli were measured in 20 diabetics with neuropathic foot ulcers. All patients had a profound disturbance of sensory perception in the ulcerated foot with complete loss of perception of warming; thresholds for vibration and cooling were highly abnormal in all but two patients. Measurements of thermal threshold were made on both feet in 10 patients: warming was lost bilaterally in all, and cooling was bilaterally absent in six. There was no clear pattern of sensory loss in those diabetics with unilateral foot ulceration to suggest that sensory impairment was the determining factor for the development of a plantar ulcer. Measurements of thermal thresholds were made at additional sites in 13 patients and although the most marked abnormalities of sensation were always found in the feet, in some severe neuropaths, abnormal thresholds on the hand and even the face were demonstrated. Thresholds for warming were invariably more abnormal than thresholds for cooling. The diabetics with neuropathic ulceration in this study all had severe generalised peripheral nerve disease involving large myelinated as well as both small myelinated and unmyelinated sensory fibres. The quantitative evidence on the distribution of sensory loss for thermal sensations supports the hypothesis that the neuropathic process affecting the small myelinated and unmyelinated fibres is length dependent.     

Differential labeling of the vestibular complex following unilateral injections of horseradish peroxidase into the cat and rat locus coeruleus

In anaesthetized cats, lumbar dorsal horn neurons were excited by brief noxious radiant heating of glabrous hindpaw skin. These nociceptive responses were inhibited by concomitant repetitive electrical stimulation of the ipsilateral deep radial nerve. Noxious heat responses were linearly correlated with skin temperature during heating. The slope of this stimulus-response function was decreased, and the response threshold increased, by deep radial nerve stimulation. Microinjection of lidocaine into the medullary raphe attenuated the inhibition induced by deep radial nerve stimulation. The results indicate that in the cat, ‘diffuse noxious inhibitory controls’ (DNIC) involve medial medullary regions.     

Diffuse noxious inhibitory controls of lumbar spinal neurons involve a supraspinal loop in the cat

In anaesthetized cats, lumbar dorsal horn neurons were excited by brief noxious radiant heating of glabrous hindpaw skin. These nociceptive responses were inhibited by concomitant repetitive electrical stimulation of the ipsilateral deep radial nerve. Noxious heat responses were linearly correlated with skin temperature during heating. The slope of this stimulus-response function was decreased, and the response threshold increased, by deep radial nerve stimulation. Microinjection of lidocaine into the medullary raphe attenuated the inhibition induced by deep radial nerve stimulation. The results indicate that in the cat, ‘diffuse noxious inhibitory controls’ (DNIC) involve medial medullary regions.     

Difference in somatosensory evoked fields elicited by mechanical and electrical stimulations: Elucidation of the human homunculus by a noninvasive method

We recently recorded somatosensory evoked fields (SEFs) elicited by compressing the glabrous skin of the finger and decompressing it by using a photosensor trigger. In that study, the equivalent current dipoles (ECDs) for these evoked fields appeared to be physiologically similar to the ECDs of P30m in median nerve stimulation. We sought to determine the relations of evoked fields elicited by mechanically stimulating the glabrous skin of the great toe and those of electrically produced P40m. We studied SEFs elicited by mechanical and electrical stimulations from the median and tibial nerves. The orientations of dipoles from the mechanical stimulations were from anterior-to-posterior, similar to the orientations of dipoles for P30m. The direction of the dipole around the peak of N20m from median nerve electrical stimulation was opposite to these directions. The orientations of dipoles around the peak of P40m by tibial nerve stimulation were transverse, whereas those by the compression and decompression stimulation of the toe were directed from anterior-to-posterior. The concordance of the orientations in ECDs for evoked fields elicited by mechanical and electrical stimulations suggests that the ECDs of P40m are physiologically similar to those of P30m but not to those of N20m. The discrepancy in orientations in ECDs for evoked field elicited by these stimulations in the lower extremity suggests that electrical and compression stimulations elicit evoked fields responding to fast surface rubbing stimuli and/or stimuli to the muscle and joint.     

Unmyelinated nociceptive units in two skin areas of the rat

Responses of unmyelinated afferent fibres were investigated in two skin nerves of Sprague-Dawley rats. The units were tested as to whether they responded to mechanical probing of the skin, to controlled radiant heat stimulation, and/or to cooling of the skin(to 5°C). Ninety-six units in a n. saphenus and 129 units in a n. coccygealis werre studied, which were identified as afferents by means of the above-mentioned stimuli. In both nerves mechano- and heat-sensitive units (CMHs) were most frequent (56% in n. saphenus and 74% in n. coccygealis). There were, however, significantly more purely mechanoceptive units (CMs) in n. saphenus than in n. coccygealis (30% vs 5%). In contrast cold-sensitive units (CCs) were more frequent in n. coccygealis. They constituted 25% of the afferent C-fibres in this nerve. When testing heat sensitivity of CMHs with ramp stimuli raising the temperature to 55°C at a rate of 0.8°C/s, heat thresholds had a wide range of between 30 and 55°C. Since CMHs with low heat thresholds had the highest discharge rates and the greatest dynamic sensitivity in the range of noxious temperatures, they most probably also had nociceptive functions. It was shown that the low heat thresholds of some CMHs were not due to sensitization by preceding heat stimuli. It is argued that low-frequency discharges ( 2Hz) observed in some nociceptive CMHs of the rat at nonnoxious temperatures are insignificant for nociception. When comparing discharges during a first ramp heat stimulus to 50°C (rise time 1°C/s) with those during a second stimulus of identical time course delivered 5–10 min later, 44% of the CMHs were sensitized, 24% were desensitized and the remainder were not clearly influeced. We did not find a significant correlation between initial heat thresholds and tendency to sensitization or desensitization.