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Thermal sensation during mild hyperthermia is modulated by acute postural change in

humans

Ryosuke Takeda1, Daiki Imai1,2, Akina Suzuki1, Akemi Ota1, Nooshin Naghavi1, Yoshihiro

Yamashina1, Yoshikazu Hirasawa1, Hisayo Yokoyama1,2, Toshiaki Miyagawa1,2, and

Kazunobu Okazaki1,2

1Department of Environmental Physiology for Exercise, Osaka City University Graduate

School of Medicine, Osaka, Japan, 2Research Center for Urban Health and Sports, Osaka

City University, Osaka, Japan

Running head: Altered thermal sensation with body posture and temperature

Key words: behavioral thermoregulation; passive heating; non-thermal factors; central blood

volume

Word count: 4096 Tables: 2 Figures: 2

Corresponding author

Kazunobu Okazaki, Ph.D.

Research Center for Urban Health and Sport, Osaka City University, and Department of

Environmental Physiology for Exercise, Osaka City University Graduate School of Medicine,

3-3-138 Sugimoto Sumiyoshi, Osaka 558-8585, Japan

TEL: +81-6-6605-2950 / FAX: +81-6-6605-2950

E-mail: okazaki@sports.osaka-cu.ac.jp

Conflict of Interest: None declared.

Source of Funding: This study was supported in part by a Grant-in-Aid for Young Scientists

A 23689014 and Challenging Exploratory Research 25560372 (to K. Okazaki) from the

Ministry of Education, Culture, Sports, Science and Technology of Japan.

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ABSTRACT (250 words)

Thermal sensation represents the primary stimulus for behavioral and autonomic

thermoregulation. We assessed whether the sensation of skin and core temperatures for the

driving force of behavioral thermoregulation was modified by postural change from the

supine (Sup) to sitting (Sit) during mild hyperthermia. Seventeen healthy young men

underwent measurements of noticeable increase and decrease (±0.1°C/sec) of skin

temperature (thresholds of warm and cold sensation on the skin, 6.25 cm2 of area) at the

forearm and chest and of the whole-body warm sensation in the Sup and Sit during

normothermia (NT; esophageal temperature (Tes), ~36.6°C) and mild hyperthermia (HT; Tes,

~37.2°C; lower legs immersion in 42°C of water). The threshold for cold sensation on the

skin at chest was lower during HT than NT in the Sit (P < 0.05) but not in Sup, and at the

forearm was lower during HT than NT in the Sup and further in Sit (both, P < 0.05), with

interactive effects of temperature (NT vs. HT) × posture (Sup vs. Sit) (chest, P = 0.08;

forearm, P < 0.05). The threshold for warm sensation on the skin at both sites remained

unchanged with changes in body posture or temperature. The whole-body warm sensation

was higher during HT than NT in both postures and higher in the Sit than Sup during both NT

and HT (all, P < 0.05). Thus, thermal sensation during mild hyperthermia is modulated by

postural change from supine to sitting to sense lesser cold on the skin and more whole-body

warmth.

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INTRODUCTION

Paragraph 1. Under various environments and body conditions, our body maintains

homeostasis of body temperatures by controlling heat production, and heat loss and gain

between the body and environment (Werner et al. 2008). When we are exposed to a hot

environment, our body activates heat loss mechanisms by enhancing autonomic

thermoregulatory responses (i.e., increased cutaneous vasodilation and sweating) (Werner et

al. 2008). In addition, the body activates behavioral thermoregulatory responses such as

removing clothes, escaping from the heat, turning on the air conditioner, and so on, which

increase heat loss from the body to the environment and/or decrease heat gain from

environment to body (Nagashima 2006). The thermoregulatory command center in the

preoptic area (POA) controls these autonomic and behavioral thermoregulatory responses

based on input signals from thermo-sensitive neurons in the POA and from the temperature

receptors in the skin and other deep body tissues (Simon et al. 1986; Morrison and Nakamura

2011; Egan et al. 2005; Nagashima 2006).

Paragraph 2. Autonomic thermoregulatory responses in humans are also modified by

non-thermal factors (Nagashima 2006). The levels of central blood volume have been known

to modify cutaneous vasodilation under hot conditions with non-thermal mechanisms. It has

been reported that increased central blood volume with intravenous isotonic saline infusion

(Nose et al. 1990) or continuous negative-pressure breathing (Nagashima et al. 1998) acutely

enhances forearm skin blood flow responses to increased esophageal temperature (Tes) during

exercise in a hot environment. On the other hand, decrease in central blood volume with

postural change from the supine to upright position attenuates cutaneous vasodilatation under

hot conditions. Johnson et al. (1974) reported that the rise of forearm blood flow was lower in

the upright than supine position when skin temperature was raised from 33–35°C to 38°C by

using water-perfused suits, although the rise of Tes was comparable in both postures. In

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contrast, it is not known whether behavioral thermoregulatory responses are modified as well

with the levels of changes in central blood volume. It has been reported in experimental

animals that behavioral thermoregulatory responses, i.e., heat escape and/or cold seeking

behaviors, during hot conditions are enhanced when autonomic thermoregulatory responses

are attenuated with non-thermal factors such as hyperosmolality in the plasma with

hypertonic saline infusion or salt loading to maintain homeostasis of body temperatures (Lin

et al. 2012; Nagashima et al. 2001).

Paragraph 3. With these lines of evidence as background, we hypothesized that an index

of behavioral thermoregulatory responses was enhanced while autonomic thermoregulatory

responses were attenuated by decreased central blood volume with acute postural change

from supine to sitting during mild hyperthermia in humans. In the present study, we assessed

warm and cold sensation thresholds on the skin surface at the forearm and chest and whole-

body warm sensation as indices of the central drive of behavioral thermoregulatory

responses. Additionally, we evaluated local sweat rate and skin blood flow at the forearm and

chest to increased Tes as the measure of autonomic thermoregulatory responses.

METHODS

Subjects

Paragraph 4. The study procedure was approved by the Institutional Review Board of

Osaka City University Graduate School of Medicine and conformed to the standards set by

the Declaration of Helsinki. After the experimental protocol was fully explained, 17 healthy

young male volunteers; age, 22.8 ± 3.2 years; height, 175 ± 7 cm; body weight, 64.7 ± 6.7

kg ; maximal oxygen uptake (VO2max), 50.9 ± 11.1 ml/kg/min (means ± SD) gave written,

informed consent before participating in this study. All subjects were non-smokers and had no

overt history of cardiovascular, metabolic, or pulmonary diseases. All experiments were

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performed in cool seasons (other than July, August, and September) in Japan. VO2max was

determined by a graded maximal cycling exercise test (Okazaki et al. 2009) performed at the

other day of the main experiment.

Experimental protocol

Paragraph 5. The subjects were instructed to refrain from consuming beverages

containing caffeine or alcohol, and to avoid vigorous exercise for 24 h before arriving at the

laboratory. In addition, they were required to refrain from consuming any food at least 2 h

after having a light breakfast. To avoid dehydration, they consumed more than 500 ml of

water at least 1 h before arriving at the laboratory. Upon arrival at the laboratory at 08:30-

09:30, subjects were familiarized with the measurements of noticeable increase and decrease

of skin temperature (thresholds of warm and cold sensation on the skin). They then voided

urine, were weighed in the nude, and asked to put on short pants. They then inserted an

esophageal thermistor through the external nares to measure Tes and thermistor probes were

applied to measure skin temperatures. Subsequently, they entered the climatic chamber

(TBR-6W2S2L2M; ESPEC Co., Osaka, Japan) with ambient temperature of 28.0 ± 0.1°C and

relative humidity of 40 ± 1% (mean ± range). The subjects sat for 20 min on a reclining chair

while other measurement devices were applied, and then the baseline data for 20 min were

collected in the sitting position.

Paragraph 6. Subjects then underwent the measurements in the sitting or supine position

with the order counterbalanced under the thermoneutral condition as normothermia (NT).

Positions of head-up by 0 for supine and 70 for sitting position were applied by changing

the angle of the backrest of the reclining chair. NT data were collected for 5 min in the

appropriate body position after 5 min of pre-conditioning. Then the subjects underwent

measurements for the threshold of warm and cold sensation on the skin. The skin warm

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threshold was measured then the skin cold threshold was measured at chest and forearm. The

degree of whole-body warm sensation was determined before and after the skin

measurements. Finally, stroke volume was determined by using echocardiography. All of the

procedures were performed again in the other body position. Then subjects placed their lower

legs in water controlled at 42°C in the sitting position. After 40 min, they underwent the

above measurements during mild hyperthermia (HT). We used immersion of the lower legs in

water at 42°C in order to avoid elevating the skin temperature at body parts used to measure

thermal sensation thresholds.

Measurements

Tes and skin temperatures:

Paragraph 7. Tes was measured with the esophageal thermistor inserted into a

polyethylene tube (LT-ST08-11; Gram Co, Saitama, Japan). The tip of the tube was advanced

to a distance of one-fourth the participant's standing height. Skin surface temperature were

measured at four sites using thermistors (LT-ST08-12; Gram Co) placed on the right side of

the chest (Tchest), upper arm (Tarm), forearm (Tforearm), thigh (Tthigh) and lower leg (Tleg). Mean

skin temperature (Tsk) was calculated as 0.3 × (Tchest + Tarm) + 0.2 × (Tthigh + Tleg), as previously

described (Ramanathan 1964).

Cardiovascular responses:

Paragraph 8. Heart rate (HR) was monitored using a bedside electrocardiogram monitor

(BSM-7201; Nihon Kohden Co., Tokyo, Japan). Systolic (SBP) and diastolic blood pressures

(DBP) were measured every minute by auscultation using a pressure cuff (STBP-780, Colin,

Komaki, Japan) applied to the left arm at the level of the heart. Pulse pressure (PP) was

calculated as SBP – DBP. Mean blood pressure (MBP) was calculated as DBP + PP/3. Stroke

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volume (SV) was measured from aortic flow, calculated as the product of beat-to-beat

measurements of the Doppler velocity time integral (VTI) and aortic root diameter (Vivid-i;

GE Healthcare, Tokyo, Japan) in a subset of subjects (n = 6). Aortic root diameter was

determined using two-dimensional echocardiogram imaging obtained in the left parasternal

long axis view with the subject; SV was calculated as SV = π (D/2) 2 × VTI.

Skin blood flow and sweat rate:

Paragraph 9. Skin blood flow (SkBF) was measured using laser-Doppler flowmetry (LDF

type ALF-21D; Advance, Tokyo, Japan) at the forearm (SkBFforearm) and chest (SkBFchest). The

laser probe was placed externally 1 cm away from the thermistor for Tforearm and Tchest, while

avoiding superficial veins. Sweat rate (SR) was measured by the ventilated capsule method

(SKN-2000; Nishizawa Electronic Measuring Instruments, Nagano, Japan) at the forearm

(SRforearm) and chest (SRchest). A 0.785 cm2 capsule was placed proximal to the laser probe at

each site. The air flow rate of the capsule was 300–600 ml·min-1.

Measurement of thresholds of warm and cold sensations on the skin:

Paragraph 10. The threshold for warm and cold sensations on the skin was measured on

the forearm and chest on the right side of the body, by using a skin sensation threshold

measurement device consisting of a thermo-electronic probe and a push-button switch

(Intercross-200, Intercross, Tokyo, Japan) (Kawano et al. 2009; Tochihara et al. 2014). The

surface area of the thermo-electronic probe in contact with the skin was 25×25 mm (6.25 cm2

of area). Figure 1 shows an example of a trend graph of skin temperature during the

measurement. After the thermo-electronic probe was applied on the skin surface,

measurement was started when heat flux was maintained at ±30 W/m2 for 4 s; this confirmed

that the temperature at the probe was equal to the surface temperature of the skin. The skin

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temperature was defined as the “Initial temperature”. The speed of warming and cooling of

the probe was set at 0.1C·s-1. All subjects were instructed to push the switch the moment they

felt a “slightly warm” or “slightly cool” sensation, and the skin temperature at which point

was defined as “Noticeable temperature”. We calculated the threshold for warm and cold

sensations on the skin using the following equation:

Skin warm and cold sensation threshold = Noticeable temperature – Initial temperature

Skin warm and cold sensation thresholds were measured 3 times each. The average value of

the two nearest measurements was calculated and reported. The typical errors for the

measurement of skin warm and cold sensation thresholds at the chest during mild

hyperthermia obtained from multiple analyses of 17 datasets were 0.19°C and 0.14°C, or

14.3% and 10.1% as coefficient of variation, respectively.

Measurements of warm sensation in the whole-body:

Paragraph 11. Warm sensation in the whole-body was determined by using a visual

analogue scale from “no warm sensation” at zero to “extreme warm sensation” at 100 with

100 mm scale (Strigo et al. 2000). An examiner moved a pen from zero to 100 and marked

where subjects nodded at they felt across the whole-body at the time. The measurement was

taken before and after the measurement of thresholds of warm and cold sensations on the

skin. The average value of these two measurements was then calculated and reported. The

typical error for the measurement of the whole-body warm sensation during mild

hyperthermia obtained from multiple analyses of 17 datasets was 3.4, and 7.9% as coefficient

of variation.

Data analysis

Paragraph 12. Data for Tes, skin temperatures, SkBFforearm, SkBFchest, SRforearm, and SRchest

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were collected at intervals of 1 s using a 16-channel computerized data acquisition system

(Intercross-310; Intercross Co, Tokyo, Japan) and stored on a laboratory computer. Percent

changes in cutaneous vascular conductance (%CVC) at the forearm (%CVCforearm) and chest

(%CVCchest) were calculated as SkBFforearm and SkBFchest divided by MBP, respectively, and

were expressed as the percent change from the baseline. The average data collected over 5

min was reported for each variable.

Statistics

Paragraph 13. The effects of body temperature (NT vs. HT) and body posture (supine vs.

sitting) on each variable were tested by using a two-way analysis of variance (ANOVA) with

repeated-measures. Subsequent post-hoc tests to determine significant differences in each

pairwise comparison were performed using the Student-Newman-Keuls test. The null

hypothesis was rejected at P < 0.05. Values are expressed as means ± SEM.

RESULTS

Paragraph 14. Table 1 shows cardiovascular responses. HR, SBP, DBP, and MBP were

significantly higher in sitting than supine position both during NT and HT. Heat stress

increased HR and SBP significantly in both postures, while DBP and MBP remained

unchanged. PP was significantly lower in sitting than supine position both during NT and HT.

Heat stress increased PP significantly in both postures. We found a trend but not significant

effect of posture (P = 0.104) and temperature (P = 0.16) on SV.

Paragraph 15. Table 2 shows the body temperatures and thermoregulatory responses. Heat

stress increased Tes and Tsk significantly in both postures. There were no significant

differences in Tes and Tsk between supine and sitting positions. Tchest was significantly lower

during HT than NT in both postures. There were no significant differences in T chest between

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supine and sitting positions during NT and HT. Tforearm remained unchanged. %CVC and SR at

both sites were increased significantly during HT compared with NT in both postures. The

effect of postural change on %CVC at both sites did not reach a significant level.

Paragraph 16. Figure 2 shows warm and cold sensation thresholds on skin at chest and

forearm. Skin warm sensation threshold at both sites remained unchanged with changes in

body posture and temperature. The threshold for cold sensation on the skin at chest was

significantly lower during HT than NT in the sitting but not in the supine position. The

threshold for cold sensation on the skin at the forearm was significantly lower during HT than

NT in the supine and further in the sitting positions. Most importantly, we found significant

or marginally significant interactive effects of temperature (NT vs. HT) × posture (supine vs.

sitting) (chest, P = 0.08; forearm, P < 0.05), indicating that decrease in skin cold sensation

threshold with mild hyperthermia was greater in sitting than supine position.

Paragraph 17. Figure 3 shows warm sensation in the whole-body. Whole-body warm

sensation during HT was significantly higher than NT in both postures. More importantly,

whole-body warm sensation was significantly higher in sitting than supine postures during

both NT and HT.

DISCUSSION

Paragraph 18. The major findings of the present study are that (1) the decrease in the cold

sensation threshold on the skin with mild hyperthermia was greater in the sitting than supine

position, and (2) whole-body warm sensation was higher in the sitting than supine position

during mild hyperthermia. These findings indicate that thermal sensation during mild

hyperthermia is modulated by postural change from supine to sitting positions such that our

body senses less skin cold and more whole-body warmth. The present study suggests possible

mechanisms to enhance behavioral thermoregulation during hyperthermia with postural

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challenge by which autonomic thermoregulation can be attenuated.

Paragraph 19. To the best of our knowledge, the present study is the first to suggest that

thermal sensation during hyperthermia is modulated by postural change in humans. As shown

in Figures 2 and 3, our body senses less skin cold and more whole-body warmth in the

sitting than supine position during mild hyperthermia. Although a method for quantitative

assessment of the behavioral thermoregulatory response in humans has not yet been

established, thermal perception can be used to estimate the driving force for the behavioral

thermoregulatory response (Nagashima 2006; Tokizawa et al. 2010). Therefore, the enhanced

whole-body warm sensation in the sitting compared with supine position indicates that

behavioral thermoregulatory responses during hyperthermia were enhanced in sitting

compared with supine positions.

Paragraph 20. In the present study, we observed that %CVC both at the chest and forearm

decreased in sitting compared with supine position as have been reported in previous studies

(Johnson et al. 1974; Yamazaki et al. 2006), although we failed to detect significant

differences with the postural change in %CVC at both sites (Table 2). The orthostatic

stimulus with postural change in the present study, from the supine to sitting positions, might

not be sufficient to induce significant reductions in cutaneous vasodilation. In contrast, the

present observations clearly demonstrated that thermal sensations were modulated by the

degree of orthostatic stimulus. Although it is a matter of speculation, thermal sensations and

therefore behavioral thermoregulatory responses are more sensitive to orthostatic stimulus

with postural change than autonomic responses. Several previous studies have suggested in

experimental animals that behavioral thermoregulatory responses during hot conditions

assessed by counting operant heat-escape and/or cold-seeking behavior are enhanced (Lin et

al. 2012; Nagashima et al. 2001) under the conditions that autonomic thermoregulatory

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responses can be attenuated with non-thermal factors rather than thermal factors (Horowitz

and Meiri 1985; Nakajima et al. 1998). We assumed but not proved that behavioral

thermoregulatory responses in humans are also enhanced when autonomic thermoregulatory

responses can be attenuated with non-thermal factors as in experimental animals. This is an

important physiological compensatory mechanism to maintain thermal homeostasis by

minimizing the effects of attenuated autonomic thermoregulatory responses with

hypohydration during hyperthermia. Further studies are required to elucidate whether there is

a reciprocal relationship between the responses in thermal sensations and those in autonomic

thermoregulatory responses to greater levels of hypohydration during hyperthermia.

Paragraph 21. One previous study assessed the effects of mild thermal dehydration,

induced by sweating with exercise in a hot environment, on ratings of thermal sensation as an

estimate of the driving force for behavioral thermoregulatory responses in humans (Tokizawa

et al. 2010). They reported that thermal sensation was not enhanced with thermal dehydration

and suggested that behavioral thermoregulatory response would not be activated by mild

thermal dehydration in humans (Tokizawa et al. 2010). However, they assessed thermal

sensation for increased skin temperature during a short-term and step-wise increment of

ambient temperature; therefore, the increase in core temperature was minimal (~0.2C). Thus,

their results do not represent the effects of dehydration on thermal sensation during

hyperthermia and do not conflict with our observations.

Paragraph 22. Our observations would suggest that postural change has an effect through

an influence on the thermosensory pathway (Nakamura and Morrison 2010). The whole-body

warm sensation assessed in the present study is basically influenced by information from the

skin and body core temperatures (Gagge et al. 1967; Gagge et al. 1969; Hall and Klemm

1969; Frank et al. 1999). Therefore, the increased whole-body warm sensation with mild

hyperthermia was caused by the elevated Tes and skin temperatures. In contrast, we confirmed

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that Tes and skin temperatures remained unchanged during postural change in both thermal

conditions (Table 2). It is supported that the observed modifications with postural change in

the whole-body warm sensation and the threshold for cold sensation on the skin are not

associated with thermal factors but with non-thermal factors. During postural change,

cardiopulmonary baroreflex contributes overall the arterial pressure adjustments and mainly

plays an important role in regulation of the central blood volume (Rowell 1993). More

importantly, decrease in central blood volume with postural change from the supine to upright

position attenuates cutaneous vasodilatation via the cardiopulmonary baroreflex during hot

conditions (Johnson et al. 1974; Yamazaki et al. 2006). We also observed a trend but not

significant effect of postural change on SV in the present study, indicating decrease in central

blood volume with postural change from the supine to upright position. With these evidences,

we speculate that the observed modifications in thermal sensations with postural change

during hyperthermia are also mediated by the cardiopulmonary baroreflex.

Paragraph 23. Cardiopulmonary baroreceptors are stretch receptors located in the atrium,

ventricle, and pulmonary blood vessels. The afferent nerve from cardiopulmonary

baroreceptors projects on the nucleus tractus solitarius (NTS) and ventrolateral medulla

(VLM) in the caudal medulla (Badoer et al. 1997). Unloading of the cardiopulmonary

baroreceptors from supine to sitting positions decreases afferent nerve activity and inhibits

the NTS and VLM activity (Shafton et al. 1999). Although this is a speculation, the

attenuated NTS and/or VLM activity with unloading of the cardiopulmonary baroreceptors

may decrease the input of cold-responsive neurons to the thalamus as well, which lead to

attenuated perception and discrimination of cutaneous temperature (Craig et al. 1994; Inoue

and Murakami 1976).

Paragraph 24. Mild hyperthermia induced the significant decrease in the skin cold

sensation threshold in both postures and at both sites except in the supine at the chest (Figure

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2), which is thought to be associated with the increased core temperature with passive

heating. Previous studies have reported that noxious skin thermal sensation (Strigo et al.

2000) and also hedonic quality of skin thermal sensation are influenced by core temperature

(Mower 1976; Attia et al. 1980) whereas innocuous skin thermal sensation is independent of

core temperature (Mower 1976; Strigo et al. 2000). Although little has been known whether

skin thermal sensation threshold is also influenced by core temperature, the present

observations clearly demonstrated that the skin cold but not warm sensation threshold was

decreased with the increased core temperature. Recently, several studies suggested that

analgesia associated with exposure to hot environment or with exercise attenuated the

magnitude of skin cold sensation (Strigo et al. 2000; Garrett et al. 2015) as well known as

reduced pain sensitivity by exercise induced analgesia which is thought to be associated with

an increased endogenous opioids (Koltyn 2000). Although we did not measure opioids in the

present study, the increased plasma β-endorphin levels has been reported in humans

following brief exposure to 47 °C hot-spring bath (Kubota et al. 1992). Thus, the decreased

skin cold sensation threshold during passive heating may be mediated by endogenous opioid

activation with the elevated core temperature.

Paragraph 25. The decreased local skin temperature at the chest with passive heating

might have the potential to influence the observations of the skin thermal sensation

thresholds, since previous studies have suggested that skin thermal sensations are influenced

by difference in local skin temperatures (Bartlett et al. 1998; Hilz et al. 1999). On the other

hand, Hagander et al. (2000) have suggested that local skin temperature within a range of 27–

37°C did not cause a significant effect on skin warm sensation threshold and had only a

minor effect on skin cool sensation threshold, and several previous studies have also reported

no effect of local skin temperature on thermal sensation threshold (Gelber et al. 1995;

Sosenko et al. 1989). The discrepancies in the previous studies would be associated with the

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differences in the methodology; body region(s) assessed, types of measures used, and the

types of stimuli (Guergova and Dufour 2011). We observed that the skin cold sensation

threshold was decreased significantly during mild hyperthermia at the forearm without

significant changes in local skin temperature. Therefore, the decreased local skin temperature

at the chest during mild hyperthermia might not associate with the observed decrease in the

skin cold sensation threshold but have a minor effect to reduce the effect of passive heating

on the skin cold sensation threshold.

Paragraph 26. The skin warm sensation threshold remained unchanged with mild

hyperthermia and postural change (Figure 2). One of the reasons would be lower sensitivity

to warm than cold sensations in every body part (Stevens and Choo 1998). Additionally, this

difference may also be related to the fact that cold sensation is transmitted by myelinated Aδ

fibers and unmyelinated C fibers whereas warm sensation is transmitted by unmyelinated C

fibers (Campero et al. 2001; Palmer et al. 2000). Our data suggest that the skin warm

sensation threshold was not affected at the levels of hyperthermia and orthostatic challenge

used in this study.

Limitations

Paragraph 27. Unlike previous studies (Johnson et al. 1974; Yamazaki et al. 2006), there

was no significant reduction in CVC and/or SV by a postural change during mild

hyperthermia in this study. This could result from the use of a reclining chair for the postural

change from supine to sitting positions and the use of lower legs immersion. This level of

orthostatic stimulus was possibly not sufficient to induce significant reduction in CVC and/or

SV, though it modified the warm sensation across the whole-body and the threshold for cold

sensation on the skin in the present study. We assessed the whole-body warm sensation to

estimate the driving force for the behavioral thermoregulatory response, though we did not

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assess the behavioral thermoregulatory response itself. In addition, the postural change

employed in this study was relatively short in duration, therefore different responses may be

observed with a prolonged duration of postural change or changes in central blood volume.

Finally, the present study includes a lot of speculations. Further studies are necessary to

determine both the physiological implications and the mechanisms of the increased thermal

sensations with postural change during hyperthermia in humans.

Paragraph 28. In conclusion, postural change from the supine to sitting positions enhances

the whole-body warm sensation and attenuates the sensation of cold on the skin without

altering the sensation of warmth on the skin during mild hyperthermia. Therefore, thermal

sensation during mild hyperthermia is modulated by a postural change from the supine to

sitting position to sense lesser cold on the skin and more whole-body warmth. The present

observations indicate that behavioral thermoregulatory responses in humans can be enhanced

when the autonomic thermoregulatory response is attenuated with non-thermal factors. This

is an important physiological mechanism to maintain thermal homeostasis by minimizing the

effects of attenuated autonomic thermoregulatory responses during multiple thermal and

postural challenges.

Paragraph 1.

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AUTHOR CONTRIBUTIONS

R.T. contributed to the design of the experiment, data collection, assembly, analysis and

interpretation, and drafted the article; D.I., A.S., A.O., N.N., Y.Y., and Y.H. contributed to

data collection, analysis and interpretation, and revised the article; H.Y. and T.M. contributed

to data interpretation and revised the article; K.O. contributed to the conception, the design of

the experiment, data interpretation, and revised the article critically for important intellectual

content.

All authors approved the final version of the manuscript.

ACKNOWLEDGMENTS

We are very grateful to the volunteers who participated in this study. We also thank Dr.

Takaaki Okumoto from our laboratory, and Dr. Shinya Matsumura from the department of

Sport Science and Medical Science, Osaka University of Health and Sport Science, for useful

comments and suggestions regarding this manuscript.

GRANTS

This study was supported in part by a Grant-in-Aid for Young Scientists A 23689014 and

Challenging Exploratory Research 25560372 (to K. Okazaki) from the Ministry of Education,

Culture, Sports, Science and Technology of Japan.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

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FIGURE LEGENDS

Figure 1.

An example of a trend graph of skin temperature during the measurement of threshold for

warm (left panel) and cold (right panel) sensations on the skin at chest of a representative

subject in sitting position during normothermia. Dashed lines indicate the start of the

measurement, and skin temperature at which point was defined as the “Initial temperature”.

Arrows indicate where the subject felt a “slightly warm” or “slightly cool” sensation, and

skin temperature at which point was defined as “Noticeable temperature”. The threshold for

warm and cold sensations on the skin was the delta change in the skin temperature during the

measurement.

Figure 2.

Thresholds of warm (A and B) and cold (C and D) sensations on the skin at chest and forearm

in supine (Sup) and sitting positions (Sit) during normothermia (NT) and mild hyperthermia

(HT). Values are means±SEM for 17 subjects. * P < 0.05.

Figure 3.

Warm sensation in the whole-body in supine (Sup) and sitting position (Sit) during

normothermia (NT) and mild hyperthermia (HT). Values are means±SEM for 17 subjects. * P

< 0.05.

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