Skin thermal pain modeling—A holistic method

Pain sensation has been studied extensively, over a range of scales, from the molecular level to the entire human neural system. Thermal stimulation of pain has been widely used in the study of pain sensation. Skin thermal pain is induced through both direct (an increase/decrease in temperature) and indirect (thermomechanical and thermochemical) ways, and is governed by complicated thermomechanical–chemical–neurophysiologic responses. This paper is focused on the theoretical modeling of the underlying mechanisms in the process of skin thermal pain. A holistic model has been developed, which is composed of three sub-models, namely, transduction, transmission, and modulation and perception. The model can contribute to the understanding of thermally related pain phenomena in skin tissue and to improvements in a range of thermal therapeutic methods.     

Temperature and the two-point threshold

Studies dating back to 1834 have shown that the temperature of objects contacting the skin can substantially intensify their apparent pressure on the skin. Later research demonstrated qualitatively that object temperature can also sharpen the spatial acuity of the skin as revealed by gap perception (two-point and two-edge thresholds). Pressure intensification and sharpening probably relate intimately. The present experiments sought to provide several more accurate and parametric extensions of thermal sharpening: (1) sharpening can improve tactile spatial acuity by as much as 60%, but the degree of sharpening is graded as a function of deviation of stimulator temperature from normal (neutral) skin temperature; (2) thermal sharpening seems to characterize the body surface since it takes place freely in forearm, forehead, and palm; local differences do, however, become apparent; (3) large thermal sharpening can even occur when one tip of the stimulator is warm, the other cold; and (4) thermal sharpening is easily captured by experiment and is basically the same in magnitude whether assessed by modern forced-choice procedure (controlled criterion) or by the more traditional procedures (uncontrolled criterion) used for more than a century before the advent of signal detection theory. Various arguments are put forth here and elsewhere to suggest that both thermal intensification of pressure sensation and thermal sharpening of gap perception result from direct thermal stimulation of mechanoreceptors and/or polymodal nociceptor networks; neither phenomenon yeilds readily to a "cognitive" interpretation.     

Temperature and the Two-Point Threshold

Studies dating back to 1834 have shown that the temperature of objects contacting the skin can substantially intensify their apparent pressure on the skin. Later research demonstrated qualitatively that object temperature can also sharpen the spatial acuity of the skin as revealed by gap perception (two-point and two-edge thresholds). Pressure intensification and sharpening probably relate intimately. The present experiments sought to provide several more accurate and parametric extensions of thermal sharpening: (1) sharpening can improve tactile spatial acuity by as much as 60%, but the degree of sharpening is graded as a function of deviation of stimulator temperature from normal (neutral) skin temperature; (2) thermal sharpening seems to characterize the body surface since it takes place freely in forearm, forehead, and palm; local differences do, however, become apparent; (3) large thermal sharpening can even occur when one tip of the stimulator is warm, the other cold; and (4) thermal sharpening is easily captured by experiment and is basically the same in magnitude whether assessed by modern forced-choice procedure (controlled criterion) or by the more traditional procedures (uncontrolled criterion) used for more than a century before the advent of signal detection theory. Various arguments are put forth here and elsewhere to suggest that both thermal intensification of pressure sensation and thermal sharpening of gap perception result from direct thermal stimulation of mechanoreceptors and/or polymodal nociceptor networks; neither phenomenon yields readily to a “cognitive” interpretation.     

TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents

TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain.     

A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice

There is great interest in discovering new targets for pain therapy since current methods of analgesia are often only partially successful. Although protein kinase C (PKC) enhances nociceptor function, it is not known which PKC isozymes contribute. Here, we show that epinephrine-induced mechanical and thermal hyperalgesia and acetic acid-associated hyperalgesia are markedly attenuated in PKCepsilon mutant mice, but baseline nociceptive thresholds are normal. Moreover, epinephrine-, carrageenan-, and nerve growth factor- (NGF-) induced hyperalgesia in normal rats, and epinephrine-induced enhancement of tetrodotoxin-resistant Na+ current (TTX-R I(Na)) in cultured rat dorsal root ganglion (DRG) neurons, are inhibited by a PKCepsilon-selective inhibitor peptide. Our findings indicate that PKCepsilon regulates nociceptor function and suggest that PKCepsilon inhibitors could prove useful in the treatment of pain.     

Pain TRPs

Transient receptor potential (TRP) ion channels are molecular gateways in sensory systems, an interface between the environment and the nervous system. Several TRPs transduce thermal, chemical, and mechanical stimuli into inward currents, an essential first step for eliciting thermal and pain sensations. Precise regulation of the expression, localization, and function of the TRP channels is crucial for their sensory role in nociceptor terminals, particularly after inflammation, when they contribute to pain hypersensitivity by undergoing changes in translation and trafficking as well as diverse posttranslational modifications.     

The mechano‐activated K+ channels TRAAK and TREK‐1 control both warm and cold perception

The sensation of cold or heat depends on the activation of specific nerve endings in the skin. This involves heat‐ and cold‐sensitive excitatory transient receptor potential (TRP) channels. However, we show here that the mechano‐gated and highly temperature‐sensitive potassium channels of the TREK/TRAAK family, which normally work as silencers of the excitatory channels, are also implicated. They are important for the definition of temperature thresholds and temperature ranges in which excitation of nociceptor takes place and for the intensity of excitation when it occurs. They are expressed with thermo‐TRP channels in sensory neurons. TRAAK and TREK‐1 channels control pain produced by mechanical stimulation and both heat and cold pain perception in mice. Expression of TRAAK alone or in association with TREK‐1 controls heat responses of both capsaicin‐sensitive and capsaicin‐insensitive sensory neurons. Together TREK‐1 and TRAAK channels are important regulators of nociceptor activation by cold, particularly in the nociceptor population that is not activated by menthol.     

TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction

TRPA1, a member of the transient receptor potential (TRP) family of ion channels, is expressed by dorsal root ganglion neurons and by cells of the inner ear, where it has proposed roles in sensing sound, painful cold, and irritating chemicals. To test the in vivo roles of TRPA1, we generated a mouse in which the essential exons required for proper function of the Trpa1 gene were deleted. Knockout mice display behavioral deficits in response to mustard oil, to cold ( approximately 0 degrees C), and to punctate mechanical stimuli. These mice have a normal startle reflex to loud noise, a normal sense of balance, a normal auditory brainstem response, and normal transduction currents in vestibular hair cells. TRPA1 is apparently not essential for hair-cell transduction but contributes to the transduction of mechanical, cold, and chemical stimuli in nociceptor sensory neurons.     

Incorporating neurophysiological concepts in mathematical thermoregulation models

Skin blood flow (SBF) is a key player in human thermoregulation during mild thermal challenges. Various numerical models of SBF regulation exist. However, none explicitly incorporates the neurophysiology of thermal reception. This study tested a new SBF model that is in line with experimental data on thermal reception and the neurophysiological pathways involved in thermoregulatory SBF control. Additionally, a numerical thermoregulation model was used as a platform to test the function of the neurophysiological SBF model for skin temperature simulation. The prediction-error of the SBF-model was quantified by root-mean-squared-residual (RMSR) between simulations and experimental measurement data. Measurement data consisted of SBF (abdomen, forearm, hand), core and skin temperature recordings of young males during three transient thermal challenges (1 development and 2 validation). Additionally, ThermoSEM, a thermoregulation model, was used to simulate body temperatures using the new neurophysiological SBF-model. The RMSR between simulated and measured mean skin temperature was used to validate the model. The neurophysiological model predicted SBF with an accuracy of RMSR?<?0.27. Tskin simulation results were within 0.37 °C of the measured mean skin temperature. This study shows that (1) thermal reception and neurophysiological pathways involved in thermoregulatory SBF control can be captured in a mathematical model, and (2) human thermoregulation models can be equipped with SBF control functions that are based on neurophysiology without loss of performance. The neurophysiological approach in modelling thermoregulation is favourable over engineering approaches because it is more in line with the underlying physiology.     

Body surface temperature distribution in relation to body composition in obese women

Adipose tissue levels and human obesity are known to be associated with increased heat production. At the same time, subcutaneous adipose tissue provides an insulating layer that impedes heat loss. The energy implications of obesity and body thermoregulatory mechanisms remain relatively poorly understood. This study attempted to examine the potential relationship between body composition (subcutaneous and visceral fat) determined by bioimpedance as well as BMI (body mass index), and skin surface temperature distribution recorded at rest.One specific aim of this study was to draw a thermal map of body areas in obese women and compare this with women of normal body mass, and thus to identify body regions within which heat transfer is particularly impeded. As high fat content is a good insulator, it could reduce the body‘s ability to respond effectively to changes in environmental temperature, which would be problematic for thermal homeostasis. Our results showed that core temperature did not differ between obese and normal body mass participants, while skin temperature of most body surfaces was lower in obese subjects.The results of regression analysis showed that the mean body surface temperature (T_mean) decreased with increasing percentage of body fat (PBF) of the abdominal area. The opposite relationship was observed for the front area of the hand (simultaneous increase in T_mean and PBF). We also found a negative correlation between BMI and T_mean of the thigh areas, both the front and the back. From this it could be concluded that the mean body surface temperature is dependent on body fat.     

Modeling the thermal responses of the skin surface during hand-object interactions

The objective of this research is to analyze and model the decreases in skin temperature when the hand makes contact with an object at room temperature so that thermal feedback can be incorporated into haptic displays. A thermal model is proposed that predicts the thermal responses of the skin and object surface as well as the heat flux exchanged during hand-object interactions. The model was evaluated by comparing the theoretical predictions of temperature changes to those experimentally measured using an infrared thermal measurement system. The thermal measurement system was designed to overcome the limitations imposed by contact thermal sensors, and was able to measure skin temperature during contact, together with the contact area and contact force. The experimental results indicated that over the pressure range of 0.73-10.98 kPa, changes in skin temperature were well localized to the contact area and were affected by contact pressure. The pressure in turn influenced both thermal contact resistance and blood flow. Over the range of contact forces typically used in manual exploration, blood perfusion and metabolic heat generation do not appear to have a significant effect on the skin's thermal responses. The theoretical predictions and the measured data were consistent in characterizing the time course and amplitude of the skin temperature change during contact with differences typically being less than 1 degrees C between the two for pressures greater than 4 kPa. These findings indicate that the proposed thermal model is able to characterize and predict the skin temperature responses during hand-object interactions and could be used in a thermal display that simulates the properties of different materials.     

A study of direct moxibustion using mathematical methods

Direct moxibustion is an important and widely used treatment method in traditional medical science. The use of a mathematical method to analyse direct moxibustion treatment is necessary and helpful in exploring the new direct moxibustion instruments and their standardisation. Thus, this paper aims to use a mathematical method to study direct moxibustion in skin to demonstrate a direct relationship between direct moxibustion and skin stimuli. In this paper, the transient thermal response of skin layers is analysed to study direct moxibustion using the data got from standardised method to measure the temperature of a burning moxa cone. Numerical simulations based on an appropriate finite element model are developed to predict the heat transfer, thermal damage and thermal stress distribution of barley moxa cones and jujube moxa cones in the skin tissue. The results are verified by the ancient literatures of traditional Chinese medicine and clinical application, and showed that mathematical method can be a good interface between moxa cone and skin tissue providing the numerical value basis for moxibustion.     

Thermal insulation and body temperature wearing a thermal swimsuit during water immersion

This study evaluated the effects of a thermal swimsuit on body temperatures, thermoregulatory responses and thermal insulation during 60 min water immersion at rest. Ten healthy male subjects wearing either thermal swimsuits or normal swimsuits were immersed in water (26 degrees C or 29 degrees C). Esophageal temperature, skin temperatures and oxygen consumption were measured during the experiments. Metabolic heat production was calculated from oxygen consumption. Heat loss from skin to the water was calculated from the metabolic heat production and the change in mean body temperature during water immersion. Total insulation and tissue insulation were estimated by dividing the temperature difference between the esophagus and the water or the esophagus and the skin with heat loss from the skin. Esophageal temperature with a thermal swimsuit was higher than that with a normal swimsuit at the end of immersion in both water temperature conditions (p<0.05). Oxygen consumption, metabolic heat production and heat loss from the skin were less with the thermal swimsuit than with a normal swimsuit in both water temperatures (p<0.05). Total insulation with the thermal swimsuit was higher than that with a normal swimsuit due to insulation of the suit at both water temperatures (p<0.05). Tissue insulation was similar in all four conditions, but significantly higher with the thermal swimsuit in both water temperature conditions (p<0.05), perhaps due to of the attenuation of shivering during immersion with a thermal swimsuit. A thermal swimsuit can increase total insulation and reduce heat loss from the skin. Therefore, subjects with thermal swimsuits can maintain higher body temperatures than with a normal swimsuit and reduce shivering thermo-genesis.     

A study of direct moxibustion using mathematical methods

Direct moxibustion is an important and widely used treatment method in traditional medical science. The use of a mathematical method to analyse direct moxibustion treatment is necessary and helpful in exploring the new direct moxibustion instruments and their standardisation. Thus, this paper aims to use a mathematical method to study direct moxibustion in skin to demonstrate a direct relationship between direct moxibustion and skin stimuli. In this paper, the transient thermal response of skin layers is analysed to study direct moxibustion using the data got from standardised method to measure the temperature of a burning moxa cone. Numerical simulations based on an appropriate finite element model are developed to predict the heat transfer, thermal damage and thermal stress distribution of barley moxa cones and jujube moxa cones in the skin tissue. The results are verified by the ancient literatures of traditional Chinese medicine and clinical application, and showed that mathematical method can be a good interface between moxa cone and skin tissue providing the numerical value basis for moxibustion.     

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.     

Estimating outdoor thermal comfort using a cylindrical radiation thermometer and an energy budget model

A mathematical model to estimate outdoor thermal comfort for humans from micrometeorological data has been formulated using the energy balance concept and the simultaneous satisfaction of four criteria for comfort from the literature: (a) a comfortable perspiration rate, (b) a comfortable core body temperature, (c) a comfortable skin temperature, and (d) a near-zero energy budget. A cylindrical modification of the globe thermometer is proposed as a simple monitor of outdoor radiation absorption for a person, and the effect of windspeed on the thermal resistance of clothing is considered. Results show a correlation coefficient of 0.91 between model output and subjective comfort ratings of 59 different situations with a variety of temperatures, insolations and windspeeds.     

Effects of the neurotrophic factor artemin on sensory afferent development and sensitivity

Artemin is a neuronal survival and differentiation factor in the glial cell line-derived neurotrophic factor family.Its receptor GFRα3 is expressed by a subpopulation of nociceptor type sensory neurons in the dorsal root and trigeminal ganglia(DRG and TG).These neurons co-express the heat,capsaicin and proton-sensitive channel TRPV1 and the cold and chemical-sensitive channel TRPA1.To further investigate the effects of artemin on sensory neurons,we isolated transgenic mice(ARTN-OE mice) that overexpress art...     

Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain

Mechanical probes of various sizes and shapes were used to determine thresholds for the perception of pressure, sharpness, and pain on the human finger. As force increased, perception changed from dull pressure to sharp pressure to sharp pain. With the smallest probe (0.01 mm2), sharpness threshold was very close to pressure threshold. As probe size increased, sharpness and pain threshold expressed in terms of force) increased in proportion to probe circumference (not probe area), whereas pressure threshold increased relatively little. Pain and sharpness thresholds also increased as probe angle became obtuse. There was a statistically significant increase in both thresholds with a probe angle change of 15 degrees. Thus, both size and shape are necessary to describe a mechanical stimulus adequately, and pressure (force/area) is not a sufficient metric for pain studies. Thresholds varied at different skin sites on the finger. The dorsal surface had lower thresholds than the volar surface, but the difference between the two areas was not always statistically significant. The compliance of the skin (e.g., the amount of indentation produced by a given force) exhibited no relation to sharpness or pain threshold, whether considered within subjects at various skin sites, or across subjects at the same skin site. Comparison of the perceptual thresholds with the thresholds for nociceptors determined in electrophysiological studies indicates that the sensation of nonpainful sharpness is likely to be mediated by nociceptors. Furthermore, considerably more than threshold activation of nociceptors is necessary for normal pain perception.     

Heat transfer analysis of skin during thermal therapy using thermal wave equation

Specifying exact geometry of vessel network and its effect on temperature distribution in living tissues is one of the most complicated problems of the bioheat field. In this paper, the effects of blood vessels on temperature distribution in a skin tissue subjected to various thermal therapy conditions are investigated. Present model consists of counter-current multilevel vessel network embedded in a three-dimensional triple-layered skin structure. Branching angles of vessels are calculated using the physiological principle of minimum work. Length and diameter ratios are specified using length doubling rule and Cube law, respectively. By solving continuity, momentum and energy equations for blood flow and Pennes and modified Pennes bioheat equations for the tissue, temperature distributions in the tissue are measured. Effects of considering modified Pennes bioheat equation are investigated, comprehensively. It is also observed that blood has an impressive role in temperature distribution of the tissue, especially at high temperatures. The effects of different parameters such as boundary conditions, relaxation time, thermal properties of skin, metabolism and pulse heat flux on temperature distribution are investigated. Tremendous effect of boundary condition type at the lower boundary is noted. It seems that neither insulation nor constant temperature at this boundary can completely describe the real physical phenomena. It is expected that real temperature at the lower levels is somewhat between two predicted values. The effect of temperature on the thermal properties of skin tissue is considered. It is shown that considering temperature dependent values for thermal conductivity is important in the temperature distribution estimation of skin tissue; however, the effect of temperature dependent values for specific heat capacity is negligible. It is seen that considering modified Pennes equation in processes with high heat flux during low times is significant.     

Leptin Signaling Is Required for Adaptive Changes in Food Intake,but Not Energy Expenditure,in Response to Different Thermal Conditions

Survival of free-living animals depends on the ability to maintain core body temperature in the face of rapid and dramatic changes in their thermal environment. If food intake is not adjusted to meet the changing energy demands associated with changes of ambient temperature, a serious challenge to body energy stores can occur. To more fully understand the coupling of thermoregulation to energy homeostasis in normal animals and to investigate the role of the adipose hormone leptin to this process, comprehensive measures of energy homeostasis and core temperature were obtained in leptin-deficient ob/ob mice and their wild-type (WT) littermate controls when housed under cool (14°C), usual (22°C) or ∼ thermoneutral (30°C) conditions. Our findings extend previous evidence that WT mice robustly defend normothermia in response to either a lowering (14°C) or an increase (30°C) of ambient temperature without changes in body weight or body composition. In contrast, leptin-deficient, ob/ob mice fail to defend normothermia at ambient temperatures lower than thermoneutrality and exhibit marked losses of both body fat and lean mass when exposed to cooler environments (14°C). Our findings further demonstrate a strong inverse relationship between ambient temperature and energy expenditure in WT mice, a relationship that is preserved in ob/ob mice. However, thermal conductance analysis indicates defective heat retention in ob/ob mice, irrespective of temperature. While a negative relationship between ambient temperature and energy intake also exists in WT mice, this relationship is disrupted in ob/ob mice. Thus, to meet the thermoregulatory demands of different ambient temperatures, leptin signaling is required for adaptive changes in both energy intake and thermal conductance. A better understanding of the mechanisms coupling thermoregulation to energy homeostasis may lead to the development of new approaches for the treatment of obesity.