Adaptation to warming but not cooling at slow rates of stimulus change in thermal threshold measurements

The relationship between thermal detection threshold and rate of temperature change of the thermal stimulus when slow (<1°C?s^?1) rates of change are employed was investigated. Using both the reaction time (RT) inclusive Method of Limits and RT exclusive Method of Levels healthy volunteers had warming (WDT) and cooling detection thresholds (CDT) measured at four different rates of temperature change (0.3, 0.5, 0.7 and 1.0°C?s^?1) from the thenar and/or mental regions using a contact thermode. With the Method of Limits, CDT increased linearly with rate of temperature change suggesting increments were due to RT artefacts. This was further supported by threshold assessment with the Method of Levels which showed CDT were unaffected by the rate of change in the RT exclusive method (P?>?0.1). In contrast, WDT did not increase linearly with rate of stimulus temperature change when the Method of Limits was used and threshold assessment with the Method of Levels showed WDT assessed using a 0.3°C?s^?1 ramp rate were significantly higher than those measured with a 1°C?s^?1 rate of change (P?<?0.05). This study indicates that adaptation to a warming stimulus can occur at faster rates of stimulus change than previously anticipated and identifies differences in warming and cooling pathways in sensitivity to adaptation.     

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.     

Adaptation to warming but not cooling at slow rates of stimulus change in thermal threshold measurements

The relationship between thermal detection threshold and rate of temperature change of the thermal stimulus when slow (<1 degrees C s(-1)) rates of change are employed was investigated. Using both the reaction time (RT) inclusive Method of Limits and RT exclusive Method of Levels healthy volunteers had warming (WDT) and cooling detection thresholds (CDT) measured at four different rates of temperature change (0.3, 0.5, 0.7 and 1.0 degrees C s(-1)) from the thenar and/or mental regions using a contact thermode. With the Method of Limits, CDT increased linearly with rate of temperature change suggesting increments were due to RT artefacts. This was further supported by threshold assessment with the Method of Levels which showed CDT were unaffected by the rate of change in the RT exclusive method (P > 0.1). In contrast, WDT did not increase linearly with rate of stimulus temperature change when the Method of Limits was used and threshold assessment with the Method of Levels showed WDT assessed using a 0.3 degrees C s(-1) ramp rate were significantly higher than those measured with a 1 degrees C s(-1) rate of change (P < 0.05). This study indicates that adaptation to a warming stimulus can occur at faster rates of stimulus change than previously anticipated and identifies differences in warming and cooling pathways in sensitivity to adaptation.     

Interaction of hyperalgesia and sensory loss in complex regional pain syndrome type I (CRPS I)

Background

Sensory abnormalities are a key feature of Complex Regional Pain Syndrome (CRPS). In order to characterise these changes in patients suffering from acute or chronic CRPS I, we used Quantitative Sensory Testing (QST) in comparison to an age and gender matched control group.

Methods

61 patients presenting with CRPS I of the upper extremity and 56 healthy subjects were prospectively assessed using QST. The patients'' warm and cold detection thresholds (WDT; CDT), the heat and cold pain thresholds (HPT; CPT) and the occurrence of paradoxical heat sensation (PHS) were observed.

Results

In acute CRPS I, patients showed warm and cold hyperalgesia, indicated by significant changes in HPT and CPT. WDT and CDT were significantly increased as well, indicating warm and cold hypoaesthesia. In chronic CRPS, thermal hyperalgesia declined, but CDT as well as WDT further deteriorated. Solely patients with acute CRPS displayed PHS. To a minor degree, all QST changes were also present on the contralateral limb.

Conclusions

We propose three pathomechanisms of CRPS I, which follow a distinct time course: Thermal hyperalgesia, observed in acute CRPS, indicates an ongoing aseptic peripheral inflammation. Thermal hypoaesthesia, as detected in acute and chronic CRPS, signals a degeneration of A-delta and C-fibres, which further deteriorates in chronic CRPS. PHS in acute CRPS I indicates that both inflammation and degeneration are present, whilst in chronic CRPS I, the pathomechanism of degeneration dominates, signalled by the absence of PHS. The contralateral changes observed strongly suggest the involvement of the central nervous system.     

Age-related differences in cutaneous warm sensation thresholds of human males in thermoneutral and cool environments

The purpose of this study was to investigate age-related differences in cutaneous temperature thresholds for warm thermal sensitivity in a thermoneutral (28 °C) and in a cool environment (22 °C). Peripheral warm thresholds were measured on nine body regions (cheek, chest, abdomen, upper arm, forearm, hand, thigh, shin, and foot) using a thermal stimulator in 12 young (22±1 years) and 13 elderly male subjects (67±3 years). The results showed that: (1) mean skin temperature did not differ by age in both environments; (2) the cutaneous warm thresholds for the hand, shin, and foot were significantly higher for the elderly than for the young in both environments (p<0.01), whereas the remaining body parts showed no age difference; (3) the most insensitive region for elderly males was the shin for both environments (p<0.01), while for young there was no statistical significant difference with T_a 28 °C; (4) the shin of the elderly was seven and nine times less sensitive to warmth when compared to those of the cheek at T_a 28 and 22 °C, respectively; and (5) warm thresholds were 3-4 °C greater at T_a 22 °C than at 28 °C, only for the elderly males' shin and foot (p<0.05), while for young the difference between T_a 22 and 28 °C was not statistically significant. The results indicate that age-related differences in cutaneous warm perception appear to be non-uniform over the body and significant on extremities; there is a greater bluntness of warm sensitivity in the cool environment for elderly males.     

Cutaneous thermal thresholds of tropical indigenes residing in Japan

The purpose of this study was to examine the deacclimatization of the cutaneous thermal sensations of tropical indigenes residing in temperate climates. Tropical indigenes (n=13) who were born and raised in tropics but had resided in Japan for 5–61 months participated in this study, along with temperate indigenes (n=11). Their cutaneous thermal thresholds for warm, cool, hot, and cold sensations were measured in 12 body regions using a thermal stimulator controlled by a Peltier element and a push button switch. Subjects pressed the button-switch as soon as they perceived a feeling of being ‘slightly warm’, ‘slightly cool’, ‘hot’, or ‘cold’ from a neutral thermal state. Our results showed that: (1) among the tropical indigenes, no significant relationship was found between the duration of their stay in Japan and their cutaneous thermal thresholds; (2) the tropical indigenes were, on average, 3.3, 3.5, 4.2, and 7.3 °C less sensitive to warm, hot, cool, and cold sensations, respectively, than the temperate indigenes (P<0.05); and (3) the inter-threshold sensory zones between cutaneous warmth and coolness, and hot and cold sensations were wider among the tropical indigenes than among the temperate indigenes. It was concluded that the nature of the heat acclimatization of the cutaneous thermal thresholds for the tropical indigenes was retained despite their residence in a temperate climate for up to 61 months, indicating that they had more blunted perceptions of both warming and cooling than the temperate indigenes.     

Estimation of regional cutaneous cold sensitivity by analysis of the gasping response.

Regional cutaneous sensitivity to cooling was assessed in males by separately immersing four discrete skin regions in cold water (15 degrees C) during head-out immersion. The response measured was gasping at the onset of immersion; the gasping response appears to be the result of a nonthermoregulatory neurogenic drive from cutaneous cold receptors. Subjects of similar body proportions wore a neoprene "dry" suit modified to allow exposure to the water of either the arms, upper torso, lower torso, or legs, while keeping the unexposed skin regions thermoneutral. Each subject was immersed to the sternal notch in all four conditions of partial exposure plus one condition of whole body exposure. The five cold water conditions were matched by control immersions in lukewarm (34 degrees C) water, and trials were randomized. The magnitude of the gasping response was determined by mouth occlusion pressure (P0.1). For each subject, P0.1 values for the 1st min of immersion were integrated, and control trial values, although minimal, were subtracted from their cold water counterpart to account for any gasping due to the experimental design. Results were averaged and showed that the highest P0.1 values were elicited from whole body exposure, followed in descending order by exposures of the upper torso, legs, lower torso, and arms. Correction of the P0.1 response for differences in exposed surface area (A) and cooling stimulus (delta T) between regions gave a cold sensitivity index [CSI, P0.1/(A.delta T)] for each region and showed that the index for the upper torso was significantly higher than that for the arms or legs; no significant difference was observed between the indexes for the upper and lower torso.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Reliability study of thermal quantitative sensory testing in healthy Chinese

Background: Test–retest reliability is important to establish for any diagnostic tool. The reliability of quantitative sensory testing (QST) in the trigeminal region has recently been described in Caucasians as well as differences in absolute thresholds and responses between Caucasians and Chinese. However, the test–retest reliability has not been determined in a Chinese population.

Objective: To provide novel information on the test–retest reliability of thermal QST in the trigeminal and spinal system in healthy Chinese.

Methods: Twenty healthy volunteers (10 women and 10 men) participated. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), and heat pain threshold (HPT) were measured at two sites: the surface of the left hand and the left masseter. The testing was performed over three consecutive stimuli trials, three sessions conducted on one day and repeated one week later. Data were analyzed with intra-tester reliability test and four-way analysis of variance (ANOVA) for repeated measures.

Results: There was a tendency for the first trial in CDT (p?=?0.005), CPT (p?=?0.02), and HPT (p?p?=?0.003) and HPT (p?=?0.045) with higher sensitivity at the masseter muscle. There were significant gender differences with higher sensitivity in women for CPT (p?=?0.001) and HPT (p?=?0.001).

Conclusion: Test site and gender affect thermal thresholds substantially. The test–retest reliability of most thermal threshold measures were acceptable for assessing somatosensory function, however, innocuous thresholds appear to be associated with larger variability than noxious thresholds in a Chinese population.     

Spatial variation in sensitivity as a factor in measurements of spatial summation of warmth and cold

Perception of cutaneous heating and cooling depends strongly on stimulus size. Although this dependence has been attributed solely to spatial summation, topographical variations in temperature sensitivity may also play a role. These variations, which differentially affect perception of small stimuli, may have led to overestimation of spatial summation. This possibility was investigated by measuring detection thresholds and perceived intensity for heating and cooling on the volar surface of the forearm using a multiple-thermode stimulus array. By keeping the array in place throughout each testing session we were able to measure threshold sensitivity and suprathreshold responsiveness at eight individual sites and for combinations of these sites having total stimulus areas of 0.64-5.12 cm2. When spatial summation was calculated in the traditional way by averaging the data for all stimuli of each size, the results agreed closely with previous estimates of summation for warmth and cold. When calculations were based instead on the most sensitive test site for each stimulus size, estimates of summation were reduced by about two-thirds. This outcome indicates that the spatial heterogeneity of thermal sensitivity likely contributed to estimates of spatial summation reported in earlier psychophysical studies. A schematic model of cutaneous thermoreception is presented that shows how neural summation and the density of innervation may combine to produce the psychophysical effects of increasing stimulus size (spatial enhancement).     

Cutaneous Warm and Cool Sensation Thresholds and the Inter-threshold Zone in Malaysian and Japanese Males

The purpose of this study was to investigate ethnic differences in cutaneous thermal sensation thresholds and the inter-threshold sensory zone between tropical (Malaysians) and temperate natives (Japanese). The results showed that (1) Malaysian males perceived warmth on the forehead at a higher skin temperature (T_sk) than Japanese males (p<0.05), whereas cool sensations on the hand and foot were perceived at a lower T_sk in Malaysians (p<0.05); (2) Overall, the sensitivity to detect warmth was greater in Japanese than in Malaysian males; (3) The most thermally sensitive body region of Japanese was the forehead for both warming and cooling, while the regional thermal sensitivity of Malaysians had a smaller differential than that of Japanese; (4) The ethnic difference in the inter-threshold sensory zone was particularly noticeable on the forehead (1.9±1.2 C for Japanese, 3.2±1.6 °C for Malaysians, p<0.05). In conclusion, tropical natives had a tendency to perceive warmth at a higher T_sk and slower at an identical speed of warming, and had a wider range of the inter-threshold sensory zone than temperate natives.     

Spatial variation in sensitivity as a factor in measurements of spatial summation of warmth and cold

Perception of cutaneous heating and cooling depends strongly on stimulus size. Although this dependence has been attributed solely to spatial summation, topographical variations in temperature sensitivity may also play a role. These variations, which differentially affect perception of small stimuli, may have led to overestimation of spatial summation. This possibility was investigated by measuring detection thresholds and perceived intensity for heating and cooling on the volar surface of the forearm using a multiple-thermode stimulus array. By keeping the array in place throughout each testing session we were able to measure threshold sensitivity and suprathreshold responsiveness at eight individual sites and for combinations of these sites having total stimulus areas of 0.64-5.12 cm². When spatial summation was calculated in the traditional way by averaging the data for all stimuli of each size, the results agreed closely with previous estimates of summation for warmth and cold. When calculations were based instead on the most sensitive test site for each stimulus size, estimates of summation were reduced by about two-thirds. This outcome indicates that the spatial heterogeneity of thermal sensitivity likely contributed to estimates of spatial summation reported in earlier psychophysical studies. A schematic model of cutaneous thermoreception is presented that shows how neural summation and the density of innervation may combine to produce the psychophysical effects of increasing stimulus size (spatial enhancement).     

Seasonal changes in thermal responses of urban residents to cold exposure

To determine whether urban circumpolar residents show seasonal acclimatisation to cold, thermoregulatory responses and thermal perception during cold exposure were examined in young men during January-March (n=7) and August-September (n=8). Subjects were exposed for 24 h to 22 and to 10 degrees C. Rectal (T(rect)) and skin temperatures were measured throughout the exposure. Oxygen consumption (VO(2)), finger skin blood flow (Q(f)), shivering and cold (CDT) and warm detection thresholds (WDT) were assessed four times during the exposure. Ratings of thermal sensations, comfort and tolerance were recorded using subjective judgement scales at 1-h intervals. During winter, subjects had a significantly higher mean skin temperature at both 22 and 10 degrees C compared with summer. However, skin temperatures decreased more at 10 degrees C in winter and remained higher only in the trunk. Finger skin temperature was higher at 22 degrees C, but lower at 10 degrees C in the winter suggesting an enhanced cold-induced vasoconstriction. Similarly, Q(f) decreased more in winter. The cold detection threshold of the hand was shifted to a lower level in the cold, and more substantially in the winter, which was related to lower skin temperatures in winter. Thermal sensations showed only slight seasonal variation. The observed seasonal differences in thermal responses suggest increased preservation of heat especially in the peripheral areas in winter. Blunted vasomotor and skin temperature responses, which are typical for habituation to cold, were not observed in winter. Instead, the responses in winter resemble aggravated reactions of non-cold acclimatised subjects.     

Reliability of the method of levels for determining cutaneous temperature sensitivity

Determination of the thermal thresholds is used clinically for evaluation of peripheral nervous system function. The aim of this study was to evaluate reliability of the method of levels performed with a new, low cost device for determining cutaneous temperature sensitivity. Nineteen male subjects were included in the study. Thermal thresholds were tested on the right side at the volar surface of mid-forearm, lateral surface of mid-upper arm and front area of mid-thigh. Thermal testing was carried out by the method of levels with an initial temperature step of 2°C. Variability of thermal thresholds was expressed by means of the ratio between the second and the first testing, coefficient of variation (CV), coefficient of repeatability (CR), intraclass correlation coefficient (ICC), mean difference between sessions (S1-S2diff), standard error of measurement (SEM) and minimally detectable change (MDC). There were no statistically significant changes between sessions for warm or cold thresholds, or between warm and cold thresholds. Within-subject CVs were acceptable. The CR estimates for warm thresholds ranged from 0.74°C to 1.06°C and from 0.67°C to 1.07°C for cold thresholds. The ICC values for intra-rater reliability ranged from 0.41 to 0.72 for warm thresholds and from 0.67 to 0.84 for cold thresholds. S1-S2diff ranged from -0.15°C to 0.07°C for warm thresholds, and from -0.08°C to 0.07°C for cold thresholds. SEM ranged from 0.26°C to 0.38°C for warm thresholds, and from 0.23°C to 0.38°C for cold thresholds. Estimated MDC values were between 0.60°C and 0.88°C for warm thresholds, and 0.53°C and 0.88°C for cold thresholds. The method of levels for determining cutaneous temperature sensitivity has acceptable reliability.     

Male sterility thermal thresholds in Drosophila: D. simulans appears more cold-adapted than its sibling D. melanogaster

Numerous different criteria may be used for analysing species thermal adaptation. We compared male sterility thresholds in the two most investigated cosmopolitan siblings, D. melanogaster and D. simulans. A survey of various populations from Europe and North Africa evidenced consistent differences between the two species, and a detailed analysis was made on flies from Marrakech. Sharp sterility thresholds were observed in both species but at different temperatures: D. simulans appeared more tolerant to cold than its sibling (difference 1°C) but more sensitive to heat (difference 1.5°C). When transferred to an optimum temperature of 21°C, D. simulans males, sterilized by a low temperature, recovered more rapidly than males of D. melanogaster; the reverse was true on the high temperature side. The analysis of progeny number also revealed the better tolerance of D. simulans males to cold but a lesser tolerance to heat. From these observations, we might expect that D. simulans should be more successful in cold temperate countries than its sibling, while ecological observations point to the contrary. Our data clearly show the difficulty of comparing ecophysiological data to field observations, and also the need of extensive comparative life history studies in closely related species.     

Cutaneous thermal thresholds—the reproducibility of their measurements and the effect of gender

The present study evaluated the reproducibility of measurements of the forearm thresholds for warm (WT) and cold (CT) sensation, and their dependence on gender. The Middlesex Thermal Testing System was used for this purpose. CT did not differ between the five consecutive trials, whereas WT fell significantly. A minimum of two trial tests are therefore recommended prior to the assessment of WT. Furthermore, CT and WT were induced by significantly smaller skin temperature changes (lower thresholds) in females as compared to males. Should this gender specific difference in thermosensitivity also be observed in other skin regions, then females would be more sensitive to thermal stimulation than males.     

Regional distribution of thermal sensitivity to cold at rest and during mild exercise in males

Although several studies have compared thermal sensitivity between body segments, little is known on regional variations within body segments. Furthermore, the effects of exercise on the thermal sensation resulting from a cold stimulus remain unclear. The current experiment therefore aimed to explore inter- and intra-segmental differences in thermal sensitivity to cold, at rest and during light exercise. Fourteen male participants (22.3±3.1 years; 181.6±6.2 cm; 73.7±10.3 kg) were tested at rest and whilst cycling at 30% VO_2 max. Sixteen body sites (front torso=6; back=6; arms=4) were stimulated in a balanced order, using a 20 °C thermal probe (25 cm²) applied onto the skin. Thermal sensations resulting from the stimuli were assessed using an 11-point cold sensation scale (0=not cold; 10=extremely cold). Variations were found within body segments, particularly at the abdomen and mid-back where the lateral regions were significantly more sensitive than the medial areas. Furthermore, thermal sensations were significantly colder at rest compared to exercise in 12 of the 16 body sites tested. Neural and hormonal factors were considered as potential mechanisms behind this reduction in thermal sensitivity. Interestingly, the distribution of cold sensations was more homogenous during exercise. The present data provides evidence that thermal sensitivity to cold varies within body segments, and it is significantly reduced in most areas during exercise.     

Sex differences in thermal detection and thermal pain threshold and the thermal grill illusion: a psychophysical study in young volunteers

Background

Sex-related differences in human thermal and pain sensitivity are the subject of controversial discussion. The goal of this study in a large number of subjects was to investigate sex differences in thermal and thermal pain perception and the thermal grill illusion (TGI) as a phenomenon reflecting crosstalk between the thermoreceptive and nociceptive systems. The thermal grill illusion is a sensation of strong, but not necessarily painful, heat often preceded by transient cold upon skin contact with spatially interlaced innocuous warm and cool stimuli.

Methods

The TGI was studied in a group of 78 female and 58 male undergraduate students and was evoked by placing the palm of the right hand on the thermal grill (20/40 °C interleaved stimulus). Sex-related thermal perception was investigated by a retrospective analysis of thermal detection and thermal pain threshold data that had been measured in student laboratory courses over 5 years (776 female and 476 male undergraduate students) using the method of quantitative sensory testing (QST). To analyse correlations between thermal pain sensitivity and the TGI, thermal pain threshold and the TGI were determined in a group of 20 female and 20 male undergraduate students.

Results

The TGI was more pronounced in females than males. Females were more sensitive with respect to thermal detection and thermal pain thresholds. Independent of sex, thermal detection thresholds were dependent on the baseline temperature with a specific progression of an optimum curve for cold detection threshold versus baseline temperature. The distribution of cold pain thresholds was multi-modal and sex-dependent. The more pronounced TGI in females correlated with higher cold sensitivity and cold pain sensitivity in females than in males.

Conclusions

Our finding that thermal detection threshold not only differs between the sexes but is also dependent on the baseline temperature reveals a complex processing of “cold” and “warm” inputs in thermal perception. The results of the TGI experiment support the assumption that sex differences in cold-related thermoreception are responsible for sex differences in the TGI.

     

Is there modal opponency in the thermal senses?

1. 1.The sensations evoked by pairs of distinct thermal stimuli applied to the back of the hand were studied in 17 volunteer subjects. Four stimulus combinations were used; neutral-cold (NC), neutral-neutral (NN), neutral-warm (NW), and cold-warm (CW).

2. 2.The subjects were first asked to estimate the magnitude of the thermal sensations evoked by the thermal stimuli. On average, the four pairs were reported as increasing magnitude in the following order: NC, CW, NN, and NW, seeming to suggest that the subjects experienced the cold-warm combination as a composite sensation of cold and warmth intermediate between pure cold and pure warmth.

3. 3.When asked only to detect the presence of a cold stimulus, the subjects performed as well for the CW combination as for the CN combination. This second result indicates that the reported composite magnitude of CW does not result from a true opponency of cold and warmth but from a cognitive combination of distinct sensations of cold and warmth.