Spatial summation of perceived pressure,sharpness and mechanically evoked cutaneous pain

Psychophysically, spatial summation can be demonstrated as a decrease in threshold accompanying an increased field of stimulation. The present study examined to what extent different mechanically evoked percepts (pressure, sharpness, and pain) show spatial summation. Various probes were used to apply prescribed forces to the dorsal surface of the digits of 19 healthy subjects. The threshold for three perceptual qualities showed differing degrees of spatial summation: sharpness showed no statistically significant spatial summation; pain demonstrated some significant summation (46% on average); pressure showed the greatest degree of spatial summation (76% on average). The lack of significant spatial summation for sharpness threshold is consistent with the theory that perceived sharpness can be evoked by near threshold activity of a single nociceptor. The modest amount of spatial summation for pain implies that distinctly suprathreshold activation of nociceptors is required for mechanically evoked pain perception, and such input summates centrally, but not completely. The greater spatial summation observed for pressure vs. pain thresholds implies a greater degree of central summation for slowly adapting mechanoreceptors vs. nociceptors.     

Body Site Variation of Heat Pain Sensitivity

Thirty-two healthy human subjects provided thresholds for the perception of slight and moderate heat pain. Four body sites were tested bilaterally: thenar eminence of the hand, plantar surface of the foot, dorsolateral forearm, and lateral calf. Thresholds for the glabrous skin of the hand and foot were significantly greater than thresholds for the hairy skin of the arm and leg, the average difference being 1.3°c. Laterality was not a statistically significant factor. Thresholds increased progressively over 2–4 weeks of repeated testing, resulting in values averaging 0.6°c higher in the later sessions. The difference between moderate and slight pain thresholds averaged 1.1°c, and was consistent across body sites and with repeated testing.

The threshold values were normally distributed across subjects. Considerable intersubject variability was observed for both slight and moderate pain thresholds, more so on glabrous than on hairy skin sites. In comparison, the distribution of right-left difference values was narrower, demonstrating less intrasubject versus intersubject variability.

The highly significant difference in thresholds between glabrous and hairy skin sites demonstrates the importance of skin type for heat pain sensitivity. In contrast, there was no significant difference in heat pain sensitivity between comparable sites on the upper versus lower extremities, or between left and right sides.     

Influence of surface anesthesia on the pressure pain threshold measured with different-sized probes

Transcutaneous pressure with pressure probes of arbitrary diameters have been commonly used for measuring the threshold and magnitude of muscle pain, yet this procedure lacks scientific validation. To examine the valid probe dimensions, we conducted physiological experiments using 34 human subjects. Pin-prick pain, pressure pain threshold (PPT) to pressure probes of various diameters, heat pain threshold, and electrical pain threshold of deep tissues were measured before and after application of surface lidocaine anesthesia to the skin surface over the brachioradial muscle in a double-blinded manner. The anesthesia neither affected PPT with larger probes (diameters: 1.6 and 15?mm) nor increased electric pain threshold of deep structures, whereas it diminished pain count in pin-prick test and PPT with a 1.0?mm diameter probe, suggesting that mechanical pain thresholds measured with 1.6 and 15?mm probes reflect the pain threshold of deep tissues, possibly muscle. Pain thresholds to heat did not change after application of the anesthesia. These results suggest that larger pressure probes can give a better estimation of muscular pain threshold.     

Influence of surface anesthesia on the pressure pain threshold measured with different-sized probes

Transcutaneous pressure with pressure probes of arbitrary diameters have been commonly used for measuring the threshold and magnitude of muscle pain, yet this procedure lacks scientific validation. To examine the valid probe dimensions, we conducted physiological experiments using 34 human subjects. Pin-prick pain, pressure pain threshold (PPT) to pressure probes of various diameters, heat pain threshold, and electrical pain threshold of deep tissues were measured before and after application of surface lidocaine anesthesia to the skin surface over the brachioradial muscle in a double-blinded manner. The anesthesia neither affected PPT with larger probes (diameters: 1.6 and 15 mm) nor increased electric pain threshold of deep structures, whereas it diminished pain count in pin-prick test and PPT with a 1.0 mm diameter probe, suggesting that mechanical pain thresholds measured with 1.6 and 15 mm probes reflect the pain threshold of deep tissues, possibly muscle. Pain thresholds to heat did not change after application of the anesthesia. These results suggest that larger pressure probes can give a better estimation of muscular pain threshold.     

Topically applied capsaicin inhibits sensitivity to touch but not to warmth or heat-pain in the region of secondary mechanical hyperalgesia

The aim of this study was to investigate tactile sensitivity near the site of primary hyperalgesia evoked by capsaicin applied topically to the dorsolateral aspect of the hand. In the first experiment (N = 15), touch thresholds increased in the fifth finger ipsilateral to the topically applied capsaicin, but remained unchanged at greater distances from the site of capsaicin treatment. In a second experiment (N = 12), the effect of the capsaicin treatment on sensations evoked not only by light touch but also by warmth, heat-pain, and pressure-pain to a 2-mm diameter steel probe was investigated in the fifth finger. Again, tactile sensitivity was inhibited at the fifth finger, even though stimulation with a cotton bud evoked no discomfort; moreover, sensitivity to warmth and heat-pain were unimpaired. However, sensitivity to pressure-pain increased in the fifth finger after the capsaicin treatment, possibly due to activation of nociceptors sandwiched between the probe tip and bone that normally responded to sharp stimuli. These findings suggest that the central mechanisms that mediate secondary mechanical hyperalgesia suppress sensitivity to innocuous tactile sensations. This effect may contribute to tactile hypoesthesia in chronic pain conditions.     

Nociceptor activation and pain

This paper reviews advances in our knowledge on the physiological properties of human nociceptors and their capacity to signal pain. Conventional microneurography was used in combination with intraneural microstimulation in subjects who estimated the magnitude of pain from nociceptor stimulation. The experimental evidence favours the notion that C polymodal nociceptors can provide a peripheral neuronal basis for determination of heat pain threshold and also an essential peripheral code for suprathreshold magnitude judgments of heat pain. Furthermore, sensitized C polymodal nociceptors can contribute to hyperalgesia after a mild heat injury to hairy skin. Temporal summation is documented for dull, delayed C fibre pain, which is different in quality and less accurately projected than the fast, sharp pain from high-threshold A delta nociceptors. A segmental organization is shown for projected and referred pain from deep structures. Examples are given of central inhibition of pain by a prostaglandin synthetase inhibitor, and by physical manoeuvres such as vibration and cooling. Recent reports on microneurographic findings after nerve injury indicate that the technique may be useful for future studies on pathophysiological pain mechanisms.     

Reductions in finger blood flow in men and women induced by 125-Hz vibration: association with vibration perception thresholds

Vibration of one hand reduces blood flow in the exposed hand and in the contralateral hand not exposed to vibration, but the mechanisms involved are not understood. This study investigated whether vibration-induced reductions in finger blood flow are associated with vibrotactile perception thresholds mediated by the Pacinian channel and considered sex differences in both vibration thresholds and vibration-induced changes in digital circulation. With force and vibration applied to the thenar eminence of the right hand, finger blood flow and finger skin temperature were measured in the middle fingers of both hands at 30-s intervals during seven successive 4-min periods: 1) pre-exposure with no force or vibration, 2) pre-exposure with force, 3) vibration 1, 4) rest with force, 5) vibration 2, 6) postexposure with force, and 7) recovery with no force or vibration. A 2-N force was applied during periods 2-6 and 125-Hz vibration at 0.5 and 1.5 ms(-2) root mean square (r.m.s.; unweighted) was applied during periods 3 and 5, respectively. Vibrotactile thresholds were measured at the thenar eminence of right hand using the same force, contact conditions, and vibration frequency. When the vibration magnitude was greater than individual vibration thresholds, changes in finger blood flow were correlated with thresholds (with both 0.5 and 1.5 ms(-2) r.m.s. vibration): subjects with lower thresholds showed greater reductions in finger blood flow. Women had lower vibrotactile thresholds and showed greater vibration-induced reductions in finger blood flow. It is concluded that mechanoreceptors responsible for mediating vibration perception are involved in the vascular response to vibration.     

Site-dependent and subject-related variations in perioral thermal sensitivity

The Marstock method of limits was used to obtain thresholds for detection of cooling, warming, cold pain and heat pain for 34 young adults, upon eight spatially matched sites on the left and right sides of the face, the right ventral forearm and the scalp. Male and female subjects were tested by both a male and a female experimenter. Neither the experimenter nor the gender of the subject individually influenced the thresholds. The thermal thresholds varied greatly across facial sites: sixfold and tenfold for cool and warmth, respectively, from the most sensitive sites on the vermilion to the least sensitive facial site, the preauricular skin. Warm thresholds were 68% higher than cool thresholds, on average, and 12% higher on the left compared to the right side of the face. The mean cold pain threshold increased from 21.0°C on the hairy upper lip to 17.8°C on the preauricular skin. Sites on the upper lip were also most sensitive to noxious heat with pain thresholds of 42–43°C. The scalp was notably insensitive to innocuous and noxious changes in temperature. For the sensations of nonpainful cool and warmth, the more sensitive a site, the less the estimates of the thresholds differed between subjects. In contrast, for heat pain, the more sensitive a site, the more the estimates differed between subjects. Subjects who were relatively more sensitive to cool tended to be relatively more sensitive to warmth. Subjects’ sensitivities to nonpainful cool and warmth were less predictive of their sensitivities to painful cold and heat, respectively. Short-term within-subject variability increased with the magnitude of the thresholds. The lower the threshold, the more similar were repeated measurements of it, within a 5–25?s period.     

Site-dependent and subject-related variations in perioral thermal sensitivity

The Marstock method of limits was used to obtain thresholds for detection of cooling, warming, cold pain and heat pain for 34 young adults, upon eight spatially matched sites on the left and right sides of the face, the right ventral forearm and the scalp. Male and female subjects were tested by both a male and a female experimenter. Neither the experimenter nor the gender of the subject individually influenced the thresholds. The thermal thresholds varied greatly across facial sites: sixfold and tenfold for cool and warmth, respectively, from the most sensitive sites on the vermilion to the least sensitive facial site, the preauricular skin. Warm thresholds were 68% higher than cool thresholds, on average, and 12% higher on the left compared to the right side of the face. The mean cold pain threshold increased from 21.0 degrees C on the hairy upper lip to 17.8 degrees C on the preauricular skin. Sites on the upper lip were also most sensitive to noxious heat with pain thresholds of 42-43 degrees C. The scalp was notably insensitive to innocuous and noxious changes in temperature. For the sensations of nonpainful cool and warmth, the more sensitive a site, the less the estimates of the thresholds differed between subjects. In contrast, for heat pain, the more sensitive a site, the more the estimates differed between subjects. Subjects who were relatively more sensitive to cool tended to be relatively more sensitive to warmth. Subjects' sensitivities to nonpainful cool and warmth were less predictive of their sensitivities to painful cold and heat, respectively. Short-term within-subject variability increased with the magnitude of the thresholds. The lower the threshold, the more similar were repeated measurements of it, within a 5-25 s period.     

The Sensory Effects of l-Menthol on Human Skin

Psychophysical measurements were made of the sensory effects of l-menthol applied topically to the forearm under controlled thermal conditions. In the first experiment, subjects judged the intensity and quality of sensations produced by warming or cooling the skin in the presence of menthol or the vehicle. During cooling, menthol intensified cutaneous sensations and increased reports of burning. During warming, menthol intensified sensations transiently at low temperatures and weakened them lastingly at higher temperatures; the frequency of reports of burning varied with intensity. A second experiment tested the hypothesis that menthol would lower the threshold for warmth and raise the threshold for heat pain. No change in either threshold was observed. The primary sensory effects of l-menthol on hairy skin are therefore to heighten the perception of cooling and to attenuate the perception of moderate warming. In contrast with other common chemical irritants, menthol's pungent qualities appear to be enhanced by cooling and suppressed by warming; this suggests that its sensory irritancy may be attributable to the stimulation of a population of high-threshold cold fibers or cold-sensitive nociceptors.     

Exposure to oscillating magnetic fields influences sensitivity to electrical stimuli. II. experiments on humans

To assess the effect of a magnetic treatment on pain perception, we compared the sensory threshold in 18 healthy volunteers. We determined the threshold by noninvasive electrical stimulation of the tooth pulp and skin before and after exposure to an altered magnetic field of low intensity and to a sham treatment. Five different parameters were recorded: the sensory and pain thresholds for the tooth and the sensory, pain, and tolerance thresholds for the skin. Two hours of exposure to a weak, oscillating magnetic field induced a significant decrease in three parameters (dental sensory and cutaneous pain and tolerance thresholds), whereas the other two parameters showed a similar tendency. When the same subjects were exposed to a sham treatment, only marginal, nonsignificant variations in all parameters were observed. These results represent the first piece of evidence that weak alterations of the magnetic field may induce hyperalgesia in humans. © 1995 Wiley-Liss, Inc.     

Systemic Inflammation Decreases Pain Threshold in Humans In Vivo

Background

Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods.

Methods and Results

Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20±4 % and 13±3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7±3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques.

Conclusions and Significance

In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.     

The Fine Tuning of Pain Thresholds: A Sophisticated Double Alarm System

Two distinctive features characterize the way in which sensations including pain, are evoked by heat: (1) a thermal stimulus is always progressive; (2) a painful stimulus activates two different types of nociceptors, connected to peripheral afferent fibers with medium and slow conduction velocities, namely Aδ- and C-fibers. In the light of a recent study in the rat, our objective was to develop an experimental paradigm in humans, based on the joint analysis of the stimulus and the response of the subject, to measure the thermal thresholds and latencies of pain elicited by Aδ- and C-fibers. For comparison, the same approach was applied to the sensation of warmth elicited by thermoreceptors. A CO₂ laser beam raised the temperature of the skin filmed by an infrared camera. The subject stopped the beam when he/she perceived pain. The thermal images were analyzed to provide four variables: true thresholds and latencies of pain triggered by heat via Aδ- and C-fibers. The psychophysical threshold of pain triggered by Aδ-fibers was always higher (2.5–3°C) than that triggered by C-fibers. The initial skin temperature did not influence these thresholds. The mean conduction velocities of the corresponding fibers were 13 and 0.8 m/s, respectively. The triggering of pain either by C- or by Aδ-fibers was piloted by several factors including the low/high rate of stimulation, the low/high base temperature of the skin, the short/long peripheral nerve path and some pharmacological manipulations (e.g. Capsaicin). Warming a large skin area increased the pain thresholds. Considering the warmth detection gave a different picture: the threshold was strongly influenced by the initial skin temperature and the subjects detected an average variation of 2.7°C, whatever the initial temperature. This is the first time that thresholds and latencies for pain elicited by both Aδ- and C-fibers from a given body region have been measured in the same experimental run. Such an approach illustrates the role of nociception as a “double level” and “double release” alarm system based on level detectors. By contrast, warmth detection was found to be based on difference detectors. It is hypothesized that pain results from a CNS build-up process resulting from population coding and strongly influenced by the background temperatures surrounding at large the stimulation site. We propose an alternative solution to the conventional methods that only measure a single “threshold of pain”, without knowing which of the two systems is involved.     

Measuring Changes in Tactile Sensitivity in the Hind Paw of Mice Using an Electronic von Frey Apparatus

Measuring inflammation-induced changes in thresholds of hind paw withdrawal from mechanical pressure is a useful technique to assess changes in pain perception in rodents. Withdrawal thresholds can be measured first at baseline and then following drug, venom, injury, allergen, or otherwise evoked inflammation by applying an accurate force on very specific areas of the skin. An electronic von Frey apparatus allows precise assessment of mouse hind paw withdrawal thresholds that are not limited by the available filament sizes in contrast to classical von Frey measurements. The ease and rapidity of measurements allow for incorporation of assessment of tactile sensitivity outcomes in diverse models of rapid-onset inflammatory and neuropathic pain as multiple measurements can be taken within a short time period. Experimental measurements for individual rodent subjects can be internally controlled against individual baseline responses and exclusion criteria easily established to standardize baseline responses within and across experimental groups. Thus, measurements using an electronic von Frey apparatus represent a useful modification of the well-established classical von Frey filament-based assays for rodent mechanical allodynia that may also be applied to other nonhuman mammalian models.     

Evaluating tactile sensitivity adaptation by measuring the differential threshold of archers

This study investigated the relationship between the force applied to a finger and the differential threshold of the force. Further, it presented an improvement function for tactile perception in archers by adapting to circumstances in which enhanced tactile perception and finger dexterity are required to practice archery on a daily basis. For this purpose, a tactile display using an air jet was developed. The air was aimed at the center of the fingertip of the index finger. The inner diameter of the nozzle was set to 3 mm. In this study, a psychophysical experiment was conducted to obtain the differential threshold from two subject groups-an archery athlete group and a control group. A total of six levels of standard stimuli ranging from 2.0 gf to 7.0 gf was obtained. As a result, the differential threshold of the archery group was significantly higher than that of the control group. The Weber ratio of the archery group remained around 0.13 and that of control group was 0.10. The experiment also revealed that the differential threshold for archers exhibited less fluctuation between the trials and between the days, which implied that the tactile perception of archery athletes may be more stable than that of non-experienced subjects. This may be a plasticity property of tactile perception.     

Subjects with Knee Osteoarthritis Exhibit Widespread Hyperalgesia to Pressure and Cold

Hyperalgesia to mechanical and thermal stimuli are characteristics of a range of disorders such as tennis elbow, whiplash and fibromyalgia. This study evaluated the presence of local and widespread mechanical and thermal hyperalgesia in individuals with knee osteoarthritis, compared to healthy control subjects. Twenty-three subjects with knee osteoarthritis and 23 healthy controls, matched for age, gender and body mass index, were recruited for the study. Volunteers with any additional chronic pain conditions were excluded. Pain thresholds to pressure, cold and heat were tested at the knee, ipsilateral heel and ipsilateral elbow, in randomized order, using standardised methodology. Significant between-groups differences for pressure pain and cold pain thresholds were found with osteoarthritic subjects demonstrating significantly increased sensitivity to both pressure (p = .018) and cold (p = .003) stimuli, compared with controls. A similar pattern of results extended to the pain-free ipsilateral ankle and elbow indicating widespread pressure and cold hyperalgesia. No significant differences were found between groups for heat pain threshold, although correlations showed that subjects with greater sensitivity to pressure pain were also likely to be more sensitive to both cold pain and heat pain. This study found widespread elevated pain thresholds in subjects with painful knee osteoarthritis, suggesting that altered nociceptive system processing may play a role in ongoing arthritic pain for some patients.     

Control of internal temperature threshold for active cutaneous vasodilation by dynamic exercise.

Exercise induces shifts in the internal temperature threshold at which cutaneous vasodilation begins. To find whether this shift is accomplished through the vasoconstrictor system or the cutaneous active vasodilator system, two forearm sites (0.64 cm2) in each of 11 subjects were iontophoretically treated with bretylium tosylate to locally block adrenergic vasoconstrictor control. Skin blood flow was monitored by laser-Doppler flowmetry (LDF) at those sites and at two adjacent untreated sites. Mean arterial pressure (MAP) was measured noninvasively. Cutaneous vascular conductance was calculated as LDF/MAP. Forearm sweat rate was also measured in seven of the subjects by dew point hygrometry. Whole body skin temperature was raised to 38 degrees C, and supine bicycle ergometer exercise was then performed for 7-10 min. The internal temperature at which cutaneous vasodilation began was recorded for all sites, as was the temperature at which sweating began. The same subjects also participated in studies of heat stress without exercise to obtain vasodilator and sudomotor thresholds from rest. The internal temperature thresholds for cutaneous vasodilation were higher during exercise at both bretylium-treated (36.95 +/- 0.07 degrees C rest, 37.20 +/- 0.04 degrees C exercise, P less than 0.05) and untreated sites (36.95 +/- 0.06 degrees C rest, 37.23 +/- 0.05 degrees C exercise, P less than 0.05). The thresholds for cutaneous vasodilation during rest or during exercise were not statistically different between untreated and bretylium-treated sites (P greater than 0.05). The threshold for the onset of sweating was not affected by exercise (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Body Site Variation of Cool Perception Thresholds,with Observations on Paradoxical Heat

Thresholds for the perception of coolness and heat pain were determined in sessions that randomly intermixed temperature increases and decreases. Four body sites were tested bilaterally: thenar eminence of the hand, plantar surface of the foot, dorsolateral forearm, and lateral calf. Coolness thresholds were lowest for the hand, intermediate for the forearm, and highest for the leg and foot. Laterality differences were not statistically significant.

In 34% of the sessions, subjects did not consistently report cool or cold sensations with detectable temperatue decreases. When they did not report cool or cold, they most often reported heat or pain, thus exhibiting the phenomenon of “paradoxical heat”. There were significantly more paradoxical heat responses when cooling stimuli were intermixed with painfully hot stimuli than when they were intermixed with only warm stimuli.

There was no significant correlation observed between thresholds for coolness and heat pain, either across body sites or across subjects at any single body site. This result implies that the various factors relevant to thermal sensitivity (i.e., thermal properties of the epidermis, innervation density) are differentially important for cool versus heat pain perception.     

Association between ABO blood types and pain perception

Aim of the study: Pain perception is associated with different phenotypic characteristics such as sex, eye, and hair color. Hence, it is assumed that ABO blood type can also affect pain perception.

Materials and methods: In order to investigate this hypothesis, an experimental study with healthy volunteers (18–40?years) was designed. The experimental procedure included a blood type test and two rounds of pressure pain threshold assessments separated by a cold pressor test. Pressure pain threshold was assessed bilaterally at the temporalis, masseter, and deltoid muscles, where the muscle sites were randomized. Cold pressor test was conducted by immersion of participants’ non-dominant hand into iced water of 1–4?°C for 2?min.

Results: Thirty-seven healthy volunteers, distributed in the four blood type groups, completed the study. Participants with blood type B scored the highest pressure pain thresholds at the examined craniofacial muscles, while participants with blood type AB tended to score the lowest. Furthermore, participants with blood type AB displayed the highest elevation in pressure pain thresholds after cold pressor test.

Conclusions: Participants with blood type B displayed the lowest mechanical pain sensitivity and the blood type AB group exhibited the strongest conditioned pain modulation effect. These findings emphasize the necessity of considering ABO blood types in future pain research.     

The relationship of facial two-point discrimination to applied force under clinical test conditions

When an interside comparison is hampered, for example, in cases of bilateral trauma, normal threshold values of two-point discrimination from healthy subjects might be used to delineate abnormal from normal sensory function in patients. To determine threshold pin distances, two devices, the Disk-Criminator and the Aesthesiometer, have often been applied in a clinical setting. Because these devices are hand-operated, the force of applying a device might vary considerably. The general applicability of normal threshold values from the literature may therefore be questioned. Five subjects participated in experiments with two observers, in which a hand-operated device with a constant pin distance (5 or 10 mm) was pushed on a facial site, until the point at which blanching of the skin started, and the applied force was recorded. To that end, the devices were modified by providing them with force transducers. These recordings revealed a considerable variation in force variables (level, duration, and rate). Significant differences in mean force level, duration, and rate occurred, particularly between devices, pin distances, and/or sites (cheek, upper and lower lips, and mental region) and also in mean duration between observers (p < 0.01 to 0.001, analysis of variance). However, the observed force levels were always at an extremely supra-threshold stimulus intensity. The threshold pin distances in subsequent experiments (four subjects, the two devices and two sites: cheek and mental region) were therefore almost invariant to the difference in the extreme low and high force levels that were applied, using acoustic feedback on the force signal. Furthermore, these thresholds were also similar when one or two observers performed repeated measures on groups of 15 to 18 subjects under the influence of a usual variation of force level, using an interval of at least 1 week and both nonmodified devices. Because of invariance, normal values of threshold pin distance are generally applicable to any well-trained observer and are related to the density of afferent nerve fibers. In contrast, recently reported force thresholds determined at a constant pin distance might not be related to fiber density only. The findings regarding dependency on site and pin distance of the force level suggest that force thresholds will also be related to tissue stiffness and to the extent to which a pair of pins co-operate mechanically.