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Home , Hypothermia, Motion sickness, Sopite syndrome

Effects of on Human Thermoregulatory Mechanisms

Gerard Nobel

Thesis for doctoral degree (Ph.D.)

Department of Environmental Physiology School of Technology and Health KTH (Royal Institute of Technology)

Academic dissertation which, with permission from KTH (Royal Institute of Technology) Stockholm, will be presented on Friday December 10, 2010, at 13.30, in lecture hall 3221, Alfred Nobels allé 10, Huddinge, Sweden.

TRITASTH Report 2010:6 ISSN: 16533836 ISRN: ISRN KTH/STH/2010:6SE ISBN: 9789174157956

© Gerard Nobel, Stockholm 2010

Cover photo: KODIAK, Alaska A life raft from the fishing vessel Alaska Ranger floats in the Bering Sea after the survivors were rescued by the Coast Guard. Photo by PA3 Richard Brahm, US Coast Guard. Note that these types of life rafts are notorious for causing motion sickness.

“Seasickness: at first you are so sick you are afraid you will die, and then you are so sick you are afraid you won't die.”

Allegedly by Mark Twain.

Abstract

The presented studies were performed to investigate the effects of motion sickness (MS) on human autonomic and behavioural thermoregulatory mechanisms during stress and in a thermoneutral environment. The roles of histaminergic and cholinergic neuron systems in autonomic and MSdependent dysfunction of autonomic thermoregulation were studied using a histaminereceptor blocker, (DMH), and a receptor blocker, (Scop). In addition, the effects of these substances on MSinduced and perceptual thermoregulatory responses were studied.

MS was found to lower core , during cold stress by attenuation of coldinduced and decreased shivering thermogenesis, and in a thermoneutral environment by inducing sweating and vasodilatation. The increased core cooling during cold stress was counteracted by DMH but not by Scop. In a thermoneutral environment, the temperature was perceived as uncomfortably warm during and after the MS provocation despite decreases in both core and . No such effect was seen during cold water immersion.

Both pharmacologic substances had per se different effects on autonomic thermoregulatory responses during cold stress. Scop decreased heat preservation, but did not affect core cooling, while DMH reduced the rate of core cooling through increased shivering thermogenesis. Both DMH and Scop per se decreased thermal discomfort during cold water immersion.

Findings support the notion of modulating roles of histamine (H) and acetylcholine (Ach) in autonomic thermoregulation and during MS. MS activates cholinergic and histaminergic pathways, thereby increasing the levels of H and Ach in several neuroanatomical structures. As a secondary effect, MS also elevates blood levels of several neuropeptides, which in turn would influence central and/or peripheral thermoregulatory responses.

In conclusion, MS may predispose to , by impairment of autonomic thermoregulation in both cold and thermoneutral environments and by modulation of behavioural thermoregulatory input signals. This might have significant implications for survival in maritime accidents.

Keywords: motion sickness, autonomic thermoregulation, behavioural thermoregulation, hypothermia, acetylcholine, histamine.

i

List of publications

The thesis is based on the following papers, which are referred to by their Roman numerals (IIV).

I. G. Nobel, A. Tribukait, I.B. Mekjavic and O. Eiken, Effects of motion sickness on thermoregulatory responses in a thermoneutral air environment (in manuscript).

II. G. Nobel, O. Eiken, A. Tribukait, R. Kölegård and I.B. Mekjavic, Motion sickness increases the risk of accidental hypothermia , Eur J Appl Physiol 98 (2006) 4855.

III. A. Tribukait, G. Nobel, I.B. Mekjavic and O. Eiken , Effects of anti- histaminic and anti-cholinergic substances on human thermoregulation during cold provocation , Res Bull 81 (2010) 100106.

IV. G. Nobel, A. Tribukait, I.B. Mekjavic and O. Eiken, Histaminergic and cholinergic neuron systems in the impairment of human thermoregulation during motion sickness , Brain Res Bull 82 (2010) 193200.

Publications protected by copyrights are reproduced with permission from the publishers.

ii

Table of contents

Abstract ………………………………………………………………………...... i

List of publications …………………………………………………………………… ii

Table of contents …………………………………………………………………….. iii

Abbreviations ………………………………………………………………………... v

Introduction ………………………………………………………………………….. 1

Aims …………………………………………………………………………………… 3

Methods and experimental procedures ……………………………………………... 4 Subjects……………………………………………………………………………. 4 Motion Sickness provocation……………………………………………………… 4 Cold provocation and passive rewarming…………………………………………. 5 Temperature perception and …………………………………….. 5 Body ………………………………………………………………… 5 Cardiovascular variables…………………………………………………………... 5 Mean Arterial and …………………………………….… 5 Forearm vs. fingertip temperature difference …………………………………. 6 Respiratory variables……………………………………………………………… 6 Sweating rate………………………………………………………………………. 6 Recording techniques……………………………………………………………… 6 Analysis of data…………………………………………………………………… 7 Experimental protocols……………………………………………………………. 8 Methodological considerations……………………………………………………. 9

Results ………………………………………………………………………………… 10 MS ratings…………………………………………………………………………. 10 Effect of MS and antiMS drugs on core temperature…………………………….. 10 Effect of MS and antiMS drugs on peripheral vasomotor tone…………………... 12 Effect of MS and antiMS drugs on skin temperature…………………………….. 13 Effect of MS and antiMS drugs on shivering…………………………………….. 14 Effect of MS and antiMS drugs on sweating rate………………………………… 15 Effect of MS and antiMS drugs on Tp and Tc…………………………………… 16

Discussion ……………………………………………………………………………... 19 Motion Sickness…………………………………………………………………… 20 Adrenocorticotropic (ACTH) in MS ………………………………… 21 Arginine vasopressin (AVP) in MS ……………………………………………. 21 Vasoactive intestinal polypeptide (VIP) in MS ………………………………... 21

iii Conclusions on MS ……………………………………………………………. 21 Thermoregulation………………………………………………………………….. 23 Autonomic thermoregulation ...... 23 Neural organization and pharmacology of thermoregulation ...... 23 Thermoregulation, central effects of Histamine ………………………………. 23 Thermoregulation, central effect of Acetylcholine …………………………….. 23 Behavioural thermoregulation ………………………………………………... 24 Conclusions on thermoregulation ……………………………………………... 24

MS and thermoregulation…………………………………………………………. 24 Neuropharmacological links between MS and thermoregulation…………….. 24 Vasomotor tone ………………………………………………………………... 25 Shivering ………………………………………………………………………. 26 Sweating ……………………………………………………………………….. 27 Effects of MS on behavioural thermoregulation/thermal perception …………. 28 Conclusions on MS and thermoregulation ……………………………………. 28

Practical implications……………………………………………………………… 29

Summary and conclusions …………………………………………………………… 32

Acknowledgements …………………………………………………………………... 34

References …………………………………………………………………………….. 35

Publications: I-IV

iv

Abbreviations

Ach Acetylcholine ACTH Adrenocorticotropic hormone AVP Arginine vasopressin CN Control DMH Dimenhydrinate H Histamine/Histaminic H1R Histamine1 receptor M Muscarine/Muscarinic MS Motion sickness MSCN Notion sickness control MSDMH Motion sickness dimenhydrinate MSP Motion sickness placebo MSScop Motion sickness scopolamine MSR Motion sickness rating POAH Preoptic anterior PVN Paraventricular nucleus Scop Scopolamine SWR Sweating rate SON Supraoptic nucleus Tc Thermal comfort TEMPSC Totally enclosed motor propelled survival craft TMN Tuberomammillary nucleus Tp Temperature perception VIP Vasoactive intestinal peptide

v

Introduction

Working in a maritime environment means that one is exposed to the elements of nature, which, in extreme conditions, may imply grave risks. The present work investigated thermoregulatory responses to a combination of two conditions related to the maritime environment: cold stress, by means of coldwater immersion, and motion sickness (MS) provocation, by means of crosscoupled Coriolis stimulation. There is a distinct difference between the risks associated with the two conditions. While cold stress obviously may have serious consequences in terms of hypothermia, MS is often regarded as a mere nuisance, which, in severe cases, may result in incapacitation. At the outset of these studies, information was scanty as to how MS might impinge on thermoregulation.

In the 19th century, the German physician Hesse [63] was one of the first to report a decreased body temperature in relation to MS. He noticed that sea sick passengers on a transatlantic voyage showed a lowered rectal temperature. Temperatures returned to normal levels concomitant with the abatement of MS symptoms, suggesting a causal relationship [63]. Hemmingway (1944) [62], Crampton (1955) [32] and Graybiel (1969) [52] also found a decrement in core temperature during or after MS provocation. These effects were however not discussed [52], or where attributed to either an increased heat loss due to both increased ventilation and evaporative heat loss [32], or to increased convective heat loss associated with the experimental procedures [62]. The question whether MS might influence survival during maritime accidents was raised by Keatinge [74] in 1965 and by Golden [45] in 1973, the latter reporting on a sailing accident where the combination of MS and cold exposure might have resulted in the of two young sailors. This report lead to an experimental study by Mekjavic et al. (2001) [97], who investigated the effect of MS on thermoregulation during exposure to lukewarm (28˚C) water, and showed that MS leads to an exaggerated decrease in core temperature, due to attenuation of the tone in the cutaneous vasculature, resulting in increased heat dissipation [97]. In the study by Mekjavic et al., immersion in 28˚C water was used to simulate the skin temperature and heat flux from the skin of survivors of maritime accidents, wearing immersion protective clothing in an open life raft, and being exposed to cold, wet and windy conditions [127]. Though the study revealed a predisposition of motion sick individuals to cool faster in such a scenario, whether such predisposition would sustain in the presence of a greater cold stimulus remained to be elucidated. Conceivably, a strong sympathetic stimulus, like immersion in 15˚C water would override any effects of MS.

MS is a condition that may be described as a combination of , cold sweat and nausea/. The single symptom that defines MS for an afflicted individual is nausea. The most widely accepted theory regarding mechanisms underlying MS is the sensory rearrangement, or mismatch, theory [11,106]. According to this theory, MS may be induced when information regarding motion, conveyed by the eyes, vestibular organs and non vestibular proprioceptors, is at variance with one another and/or with what is expected on the basis of previous encounters with a specific environment. This theory also suggests that the vestibular organs are always involved in the development of MS. The neurotransmitters

1 histamine (H) and acetylcholine (Ach) play distinct roles in the neural circuitry involved in MS, as demonstrated by the beneficial effects of antihistaminic and antimuscarinic drugs against MS [42,53,54,56,58,104,120,130,131]. These two neurotransmitters are also involved in the regulation of body temperature [18,25,60,116]. Conceivably, the effect of MS on thermoregulation is related to one or both of these neurotransmitters. In the study by Mekjavic et al. [97] there appeared to be a dissociation between nausea and autonomic dysfunction; upon immersion after the MS provocation, nausea rapidly subsided, whereas there still was an effect on thermoregulation.

Thermal balance in man is the result of both autonomic and behavioural responses. The autonomic effector mechanisms consist of peripheral vasomotor tone, regulating heat loss, shivering thermogensis, regulating heat production, and sweat secretion, regulating evaporative heat loss. Autonomic thermoregulatory responses are governed by information from central and peripheral cold and warm sensors. Information from these sensors is integrated in the , in particular in the hypothalamus [15]. Behavioural thermoregulatory responses are dependent on perception of temperature ( Tp ), as well as on thermal (dis)comfort ( Tc ) [38]. When exposed to cold, one will normally try to escape cold through behavioural modifications: for example by using clothes or taking shelter. This response may take place before the shivering response, thereby preventing a possible deviation from the state of thermal neutrality and reducing the strain on the autonomous thermoregulatory response [9]. Information is scarce as regards the effects of MS on autonomic and behavioural thermoregulatory responses.

2

Aims

Accordingly, the overall aim of the thesis was to study the effects of Motion Sickness (MS) on autonomic and behavioural thermoregulatory mechanisms.

This overall aim can be divided into more specific areas of interest:

 To determine effects of MS on thermoregulation in a thermoneutral (28˚C) air environment, in particular, whether MSinduced sweating and/or vasodilatation may affect core temperature. In addition, we wanted to establish whether temperature perception and thermal comfort are altered by MS under thermoneutral conditions.

 To determine whether the MSinduced impairment of autonomic thermoregulation observed during mild cold stress prevails even during pronounced cold stimulus (15˚C water). In particular, we wanted to elucidate the effect of MS on coldinduced vasoconstriction and shivering thermogenesis.

 To use histamine and muscarinereceptor blockers to elucidate the roles of histaminergic and cholinergic neuron systems in autonomic thermoregulation during cold stress.

 To use histamine and muscarinereceptor blockers to elucidate the roles of histaminergic and cholinergic neuron systems in MSdependent dysfunction of autonomic thermoregulation.

 To study the effect of MS and of histamine and muscarinereceptor blockers on temperature perception and thermal comfort during cold stress.

 To establish the relationship between nausea and autonomic dysfunctions following a MS provocation.

3

Methods and experimental procedures

The aim of the studies in this thesis was to investigate the effect of MS on temperature regulation. The effects were studied in two different conditions; in cold (15˚C) water and in a thermoneutral air environment (28˚C). The effect of antiMS drugs was only tested in the 15˚C condition. MS was induced by standardised head movements during rotation.

Subjects

A total of 22 healthy male subjects participated in the four studies, 2 of them participated in all four studies, 4 in three studies, 4 in two studies and 12 in only one study. Their mean (range) height, mass and age were 1.78 (1.661.90) m, 76 (58102) kg and 26 (2234) yrs. Prior to enrolment in the studies, each subject underwent a physical examination and received information on the procedures, MS provocation, and, if applicable, on risks of hypothermia and usual actions and potential sideeffects of the antiMS drugs used. Subjects were under medical supervision throughout each experiment and were free to withdraw at any time. The studies were in accordance with the standards set by the Declaration of Helsinki and approved by the Regional Human Ethics Committee in Stockholm, Sweden.

Motion Sickness provocation

MS was induced in a similar manner in all experiments (study I, II and IV). The subject was placed on a rotating chair (Stille CF10, AB Stille Werner, Stockholm, Sweden, in study I, and Stille RS3/22, AB Stille Werner, Stockholm, Sweden in study II, and IV). Rotation speed was increased stepwise, starting with twomin exposures to 10˚/s, 25˚/s and 50˚/s each, followed by fourmin exposures to rotation speeds of 75˚/s, 100˚/s, 125˚/s, and 150˚/s each. During rotation, in the MS condition, the subject was instructed to move his head in a standardised sequence; left, right, up, and down, changing the position every 15 seconds. In this manner MS was induced by a crosscoupled Coriolis stimulus. To avoid habituation to the MS provocation, tests were separated by at least 7 days [28,30,46].

During rotation, the subject rated the degree of perceived discomfort/nausea using a 5 graded scale (0, no discomfort; 1, slight discomfort/mild nausea; 2, discomfort/nausea; 3, very nauseous/almost vomiting; 4, extremely nauseous/vomiting). The rotation was terminated once the subject had reached a level 3 on the rating scale. In study IV the subject’s susceptibility to MS (MSS) was established in a similar manner. In the subsequent conditions in study IV, the subject was exposed to a MS provocation which, in terms of duration and rotation pattern, was identical to that of his MSS condition. This data on rotation duration was also used for some of the subjects in study I.

4 The main characteristic of MS is nausea and although several other have been used to score the severity of MS, most of these scores have been developed to distinguish between different phases or provide correlations between signs and symptoms [29,59,107]. One could argue that vomiting is the cardinal endpoint of MS. Since in our studies we were not interested in the different phases and development of symptoms but only in MS defined by nausea we used a simplified score with a focus on nausea. Both from a practical and an ethical perspective we did not want to reach the endpoint of the scale (vomiting, a score of 4), but provoked subjects until they were very nauseas almost vomiting (a score of 3). During the whole series of experiments only one subject actually vomited.

Cold provocation and passive rewarming

In study II, III and IV, each subject was exposed to a cold provocation. After a baseline period, the subject was lowered to the manubrium, in 15˚C water, and positioned in a reclined position, for a maximum of 90 min or until his rectal temperature had dropped by 2˚C relative to baseline rectal temperature or until it had reached 35˚C. The immersion was followed by a 45min passive warmup period during which the subject was lying supine in a sleeping bag equipped with an inner plastic lining.

Temperature perception and thermal comfort

The subject provided a rating of his perception or sensation of temperature (Tp ) on a 7 point scale (1, cold; 2, cool; 3, slightly cool; 4, neutral; 5, slightly warm; 6, warm; 7, hot) and of thermal (dis)comfort (Tc ) on a 4 point scale (1, comfortable; 2, slightly uncomfortable; 3, uncomfortable; 4, very uncomfortable).

Body temperatures

The procedure to measure temperatures was similar in all studies. Skin temperatures were measured at four locations, the calf, thigh, chest and upper arm with skin thermistors (Yellow Springs Instruments (YSI) Model 409AC, Yellow Springs USA) taped to the skin. Mean skin temperature ( Tskin ) was derived from the unweighted average of these four skin temperatures. Rectal temperature (Tre ) was measured with a rectal thermistor (YSI) placed in a protective sheath and inserted 10 cm beyond the anal sphincter.

Cardiovascular variables

Mean Arterial Pressure and Heart Rate Finger mean arterial pressure and heart rate were measured continuously, beatbybeat, using a volumeclamp technique (Finapres Ohmeda 23000, Ohmeda, USA), with the cuff placed at the midphalanx of the second or third finger of the right hand. In the immersion studies (study II, III and IV), the forearm was kept above water level. During immersion, these recordings were terminated after 15 (study II), resp. 25 min (study III and IV) because

5 increasing coldinduced vasoconstriction makes the measurements unreliable. In study II, III and IV, mainly for the purpose of medical surveillance, systolic and diastolic arterial pressure and heart rate were also measured at 5min intervals in the right brachial artery by means of sphygmomanometric techniques (Propaq monitor, Welch Allyn Inc, Skaneateles Falls, USA). Also for medical surveillance purposes, a precordial twolead ECG was recorded during immersion and passive rewarming.

Forearm vs. fingertip temperature difference (T ff ) The difference in skin temperature between the forearm and the tip of the second or third finger ( Tff ) was measured with two skin thermistors (YSI Model 409AC ) and used as an index of peripheral vasomotor tone [68,111]. During the immersion studies (study II, III and IV), the forearm was kept above water level.

Respiratory variables

Respiratory variables were recorded in study II, III and IV. In these studies, the subject breathed via a mouthpiece through a lowresistance valve (Hans Rudolf, MO, USA). Inspiratory minute ventilation ( Vi, l min 1) was measured with a turbine ventilation module (KL Engineering, USA). Expired air was directed via respiratory hosing to a 10 l mixing box. A sample of the expired air was drawn continuously from the mixing box at a rate of 0.2 l min 1 and analysed for the contents of (Applied Electrochemistry model S3A/I oxygen analyser, Pittsburgh, PA, USA) and carbon dioxide (Beckman model LB2, carbon dioxide analyser Fullerton, CA, USA), values being used for the subsequent calculation of oxygen uptake ( VO 2).

Sweating rate

Sweating rate was recorded from the forehead ( SWR , expressed in g m 2 min 1) using a ventilated capsule. The flow through the capsule was measured using a flow meter (Perflow Instruments LTD, London, UK) and set at approximately 100 ml min 1. The temperature and relative humidity of the air entering and exiting the capsule were measured with thermistors and resistance hygrometers, respectively (model Smart Reader 2, temperature and relative humidity logger, ACR Systems Inc., Canada). SWR was estimated from the difference in water vapour content of the outflowing and inflowing air, adjusting for the skin surface area covered by the capsule (467 mm 2). SWR was recorded prior to MS provocation (baseline) and during 5 min directly after provocation in studies II, III and IV. SWR was recorded continuously during baseline and rotation, and intermittently after rotation in study I.

Recording techniques

Temperatures, Vi and VO 2, values were recorded/calculated continuously with an acquisition system (Biopac Systems Inc., Santa Barbara, CA, USA) connected to two computers (Apple, Cupertino, USA and Dell D610, Dell Inc, USA). Online analysis was

6 provided by AcqKnowledge software (Biopac Systems Inc.) and mean values were calculated at 1min intervals.

Analysis of data

Because of the termination criteria in study II, III and IV (core temperature ≤ 35˚C or a drop in core temp ≥ 2˚C), the duration of immersion might differ between subjects, as well as between trials for a given subject. To make group level statistics possible for change in Tre ( Tre , i.e. Tre relative to the baseline value) and for VO 2 and Tff as functions of time, with a minimum loss of data, the following procedure was employed. For each individual only data corresponding to the time span of the shortest immersion was used, e.g. if the shortest immersion lasted 60 min, then, for all immersions in the study concerned, only data for the first 60 min were included. For the individual, this time span was defined as 100 per cent. For each individual, mean values were calculated for every 10 per cent interval (010 per cent, 1020 per cent, etc.). Group means were then calculated for comparable time intervals, i.e. 010 per cent, 1020 per cent, etc. While, for most subjects, 100 per cent corresponds to 90 min, for some it might correspond to only 60 min. A similar procedure was used to make group comparison during rotation in study I possible. For each individual only data corresponding to the time span of the shortest rotation duration was used, e.g. if the shortest rotation lasted 15 min, then, for the other condition, only data for the first 15 min were included. For the individual, this time span was defined as 100 per cent.

A similar procedure was also used when analysing the oxygen uptake ( VO 2) and peripheral vasoconstriction ( Tff ) responses to the change in rectal temperature ( Tre ). For any given individual, the final change in Tre might, naturally, not be the same in the different trials. The trial where the final Tre was smallest determined, for the individual, the interval from which data for VO 2 and Tff should be taken. This temperature interval was defined as 100 per cent. For the individual, mean values were calculated for each 10 per cent interval, 010 per cent, 1020 per cent, etc. Group means for Tff and VO 2 were calculated for comparable relative changes in Tre (i.e. 010 per cent, 1020 per cent, etc.) (see for instance Fig. 3).

The statistical significance of intercondition differences in the physiological variables was determined by oneway ANOVA, or ANOVA with repeatedmeasures design, and Fisher post hoc test. In the event that Tff or VO 2 showed an obvious saturation phenomenon, or a ceiling effect, when Tre exceeded a certain value, intercondition comparisons were restricted to the interval anteceding this value. Differences in Tp and Tc , and perceived MS were evaluated by Friedman ANOVA followed by Wilcoxon matched pairs test. Maximum SWR between pre and postMS provocation was evaluated by Student’s paired ttest (Statistica, StatSoft, Inc.).

7 Experimental protocols

A BL MSP Post-MSP Study I A BL Post-MSP

A BL MSP BL Immersion PI Study II A BL Immersion PI

Study III A BL Immersion PI

A BL MSP BL Immersion PI Study IV A BL Immersion PI

Figure 1 . Experimental protocols for the different studies. A: Acclimation at room temperature, BL; Baseline, MSP; Motion Sickness Provocation, PostMSP; Post Motion Sickness Provocation, PI; Post Immersion – passive rewarming.

The experimental protocols for the four studies are presented in Fig. 1 and Table 1. In all studies, the subject came to the laboratory ca 1 hour before immersion or rotation. After 30 min of acclimation ( A in Fig. 1), the subject changed into swim trunks and was then instrumented. Recordings obtained during the last 5 min (study II, III and IV) or the last 10 min (study I) of the acclimation period were used as baseline values ( BL in Fig. 1). (study III and IV) was administered in a doubleblind randomised fashion. A placebo (P) or dimenhydrinate (DMH) tablet (Amosyt®, 100 mg, Bioglan Pharma, Lund, Sweden) was administered 60 min prior to rotation and a scopolamine (Scop) (Scopoderm®; 1.5 mg, Novartis Consumer Health Ltd, Derbyshire, UK) or placebo (P) plaster was applied 1112 hours before rotation.

Study I (28˚C) Study II (15˚C) Study III Study IV (15˚C and drugs) (28˚C,drugs and MS) CN CN CN CN MS MS MSCN

MSP DMH

Scop MSDMH

MSScop

Table 1 . The different conditions in each of the studies. CN, control; MS, motion sickness; P, placebo; DMH, dimenhydrinate; Scop, scopolamine.

8 Methodological considerations

Subjects In order to avoid the effect of hormonal changes on temperature regulation during the menstrual cycle, only male subjects were used in these studies.

MS provocation In the MS studies, subjects were rendered motion sick by use of a rotating chair. Rotation will generate airflow over the skin that will increase with increasing rotation speeds. This airflow will lead to a convective cooling of the skin, which in turn may decrease core temperature. In study I, this issue was addressed; subjects were rotated with an equal duration in both a MS and a Control (CN) condition; in the CN condition, the subjects kept their head still during rotation to avoid, or minimise, MS provocation. It was shown that during rotation Tre decreased equally in both conditions, albeit minimal. Most likely this drop in Tre was indeed induced by convective cooling of the skin. During the postrotation period, Tre remained stable in the CN condition, while in the MS condition it continued to drop. The decrease in Tre in the MS condition can therefore not be explained merely by an effect of rotation.

Peripheral vasomotor tone The difference in skin temperature between the forearm and the tip of the second or third finger ( Tff ) was used as an index of peripheral vasomotor tone. This method was first introduced by Rubinstein and Sessler [111] and has since been verified as a robust index of cutaneous vasomotor tone also by other research groups; House and Tipton [68] conducted a study to determine if Tff could be used to identify the onset of vasodilatation and vasoconstriction. They compared Tff to skin bloodflow measurements, obtained with a laserDoppler technique, during immersion in cold and warm water, and showed that both vasoconstriction and vasodilatation could be predicted accurately by the inflicting points of Tff . They concluded that no predefined Tff should be used to describe when vasoconstriction or vasodilatation had occurred but to use the inflection point of Tff . Nevertheless, it is clear from their study that Tff represents changes in skin blood flow. It thus appears justified to use this method to compare the relative difference in vasomotor tone as in the present studies.

Sweating rate Sweating is not only an autonomic thermoregulatory response; it is also one of the signs of MS, as shown in numerous studies [29,32,47,52,62,93,94,100]. SWR , recorded as electrodermal activity, measured by skin conductance or by skin potential levels, has been considered useful as an indicator of MS [126] (see Golding [47] for more references). However, the validity of the method has been questioned and quantitative measurement of sweat secretion may be a more adequate method to determine SWR [47]. The recording site of sweating during MS provocation is of importance. Palmar sweating increases during emotion or arousal, and during the onset of MS [71,94], while sweating at the forehead provided a good correlation of MS onset and recovery [47]. Accordingly, SWR was measured at the forehead in the present studies. It should be noted that SWR may vary considerably between different regions of the body [27,89], also with regard to nonthermal sweating [87,88]. Thus, to be able to estimate the heatdissipation effects of MSinduced sweating, SWR should be measured at several sites.

9

Results

The following section is a summary of the results of the four studies (table 1). More detailed information on the different results can be found in the separate articles. Unless otherwise stated, all differences and/or changes given in the results chapter are statistically significant i.e. p≤ 0.05

MS ratings  By using an endpoint criterion during MS provocation, i.e. 3 very nauseous/almost vomiting, we ensured that all subjects reached the same perceived level of MS during the rotation (study I and II). Median (range) MS ratings at the end of rotation in the CN condition in study I was 0 (02). In study II, none of the subjects reported any MS symptoms in the CN condition.  In study I, MS ratings returned to baseline values (0) within 7 min of the post rotation period, while in study II, after about 5 min of immersion, MS ratings had decreased to 0.5 (01).  In study IV, MS ratings at the end of MS provocation were as follows: MSCN, 3 (23); MSP, 3 (13); MSDMH, 1 (03); and MSScop, 1 (03). Thus, there was no placebo effect, and both Scop and DMH reduced the MS ratings. After 5 min of immersion, ratings had decreased to 0 in all conditions.

Effect of MS and anti-MS drugs on core temperature (Tre ) (Fig. 2)

 In study I, Tre dropped by 0.1 ± 0.1˚C during rotation both in the CN and MS condition. During the 90 min after rotation, Tre dropped significantly in the MS condition (0.4 ± 0.1˚C) whereas it remained unaffected in the CN condition (0.1 ± 0.1˚C).  During immersion in cold water (15˚C), Tre was 33% greater in the MS than in the CN condition in study II (1.6 ± 0.2˚C vs.1.2 ± 0.1˚C) and 27% greater in the MS than in the CN condition in study IV (1.04 ± 0.05˚C vs. 0.82 ± 0.05˚C).  Study IV showed that the MSinduced exaggerated drop in Tre was counteracted by DMH ( Tre : 0.82 ± 0.05˚C) but not by Scop ( Tre : 0.99 ± 0.05˚C).  The use of DMH per se (without MS provocation) reduced core cooling by 23% ( Tre : 0.86 ± 0.19˚C) compared to in the CN condition (Tre : 1.11 ± 0.19˚C) and by 40% compared to in the Scop condition ( Tre : 1.20 ± 0.19˚C) (study III).

10 Study I Study II 0.0 0.0

-0.1 -0.4 -0.2

-0.3 -0.8

-0.4 -1.2 Trectal (˚C) Trectal Trectal (˚C) Trectal -0.5 * -1.6 -0.6 * -0.7 -2.0 CN MS CN MS

Study III Study IV 0.0 0.0

-0.2 -0.4 -0.4

-0.8 -0.6 Trectal(˚C) Trectal (˚C) Trectal

-0.8 -1.2 -1.0 ** -1.6 CN DMH Scop -1.2 CN * MS-P* MS-Scop MS-CN MS-DMH

Figure 2. Change in rectal temperature ( Tre ) relative to baseline values. CN, control; MS, motion sickness; DMH, dimenhydrinate; Scop, scopolamine; P, placebo. ∗denotes statistical significance (p≤ 0.05). Values are means (SEM). Study I (28˚C), n=11; Study II (15˚C), n=11; Study III (15˚C), n=10; Study IV (15˚C), n=9. Note: Mean immersion times differed in the three immersion studies; study II, 73 min; study III, 82 min; study IV, 79 min.

11 Effect of MS and anti-MS drugs on peripheral vasomotor tone (T ff ) (Fig. 3 and 4)

 MS attenuated cutaneous vasomotor tone in study I. Thus, for a given Tre there was a relative vasodilatation in the MS compared to the CN condition.  During coldwater (15˚C) immersion, the coldinduced peripheral vasoconstriction was attenuated in the MS conditions in both study II and IV. This attenuated vasoconstriction was completely counteracted by DMH and partly counteracted by Scop (study IV). During the last part of the immersion, when Tre had dropped by more than 0.4˚C, there was a stronger vasoconstrictor response in the MSDMH condition than in the MSCN, CN, and MSScop conditions (Fig. 3).  In study III, Scop per se attenuated coldinduced peripheral vasoconstriction when treated as a function of time. Also when treated as a function of Tre , there was a tendency (p=0.08) for an overall attenuation of the peripheral vasoconstriction in the Scop condition compared to vasoconstriction in the CN and DMH conditions; for Tre decrements less than 0.4˚C the difference between the Scop and DMH was significant (study III) (Fig. 4).

Tre (%) 0 10 20 30 40 50 60 70 80 90 100 110 10.0

9.0

8.0

7.0

6.0

(˚C) 5.0 ff T 4.0 CN 3.0 MS-CN 2.0 MS-DMH 1.0 MS-Scop

0.0 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1.0 -1.1 Tre (˚C)

Figure 3 . Study IV. The difference in temperature between forearm and fingertip ( Tff ) as a function of change in rectal temperature ( Tre ). CN, control; MS, motion sickness; DMH, dimenhydrinate; Scop, scopolamine. Values are means (SEM), n=7.

12 Tre (%) 0 10 20 30 40 50 60 70 80 90 100 110 9.0 8.0 7.0 6.0 C) o ( 5.0 ff T 4.0 3.0 CN SCOP 2.0 DMH 1.0 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1.0

Tre (˚C)

Figure 4. Study III. The difference in temperature between forearm and fingertip ( Tff ) as a function of change in rectal temperature ( Tre ). CN, control; MS, motion sickness; DMH, dimenhydrinate; Scop, scopolamine. Values are means (SEM), n=7.

Effect of MS and anti-MS drugs on skin temperature (T skin )

 Mean Tskin was derived from the unweighted average of skin temperature of the calf, thigh, upper arm and chest in study III and IV, whereas in study II the skin temperature of the right forearm (not immersed) was also included in the calculation of mean Tskin .  Tskin was not measured during rotation in study II, III and IV.  In study I, before rotation, mean Tskin was lower in the CN (32.8 ± 0.1˚C) than in the MS condition (33.0 ± 0.1˚C). In both conditions, Tskin dropped during the course of the rotation, by 0.8 ± 0.1˚C in the CN and by 0.7 ± 0.2˚C in the MS condition. During the postrotation period, the drop in T skin was substantially larger in the MS (1.0 ± 0.1˚C) than in the CN condition (0.5 ± 0.1˚C).  During immersion, there were no differences between conditions for Tskin (study II, III and IV). Tskin decreased rapidly upon immersion to reach asymptotic values. Mean Tskin during immersion in study II was 24.0 ± 0.2˚C (CN) and 23.8 ± 0.2˚C (MS). In study III, mean Tskin assumed asymptotic values between 15.5˚C and 15.6˚C with a SEM of 0.1˚C in all conditions. In study IV, mean Tskin reached values between 15.4˚C and 15.6˚C with a SEM of 0.1˚C in all conditions.  There was no difference in Tskin between conditions in study IV, before, or after MS provocation. However, Tskin dropped in all conditions after MS provocation, the Tskin being 0.4 ± 0.1˚C for MSCN condition and 0.6 ± 0.1˚C for MSDMH and MSScop conditions.

13 Effect of MS and anti-MS drugs on shivering (VO 2) (Fig. 5 and 6)

 In all immersion studies (study II, III and IV), VO 2 showed an instantaneous increase upon immersion. This cold response was followed by a rapid return of VO 2 values to levels close to those observed during the preimmersion period.  In study II, MS attenuated the shivering response for given decrements in Tre larger than 0.4˚C. The MS attenuation of shivering was no longer significant at the end of the immersion ( Tre : 0.9˚C). In study IV, MS did not affect the shivering response.  DMH per se increased the shivering response, compared to the response in the Scop and CN conditions, for given decrements in Tre less than 0.5˚C (study III) (Fig. 5). In study IV, the shivering response was stronger in the MSDMH condition than in the MSScop condition (Fig. 6).

Tre (%) 0 10 20 30 40 50 60 70 80 90 100 110 1.2

1.0

0.8 (l/min) 2

VO 0.6 CN 0.4 SCOP DMH 0.2 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1.0

Tre (˚C)

Figure 5. Study III. Oxygen consumption ( VO 2) as a function of change in rectal temperature ( Tre ). CN, control; MS, motion sickness; DMH, dimenhydrinate; Scop, scopolamine. Values are means (SEM), n=7.

14 Tre (%) 0 10 20 30 40 50 60 70 80 90 100 110 1.3

1.2

1.1

1.0

0.9 (l/min) 2 0.8 VO

0.7 CN MS-CN 0.6 MS-DMH 0.5 MS-Scop

0.4 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9

Tre (˚C)

Figure 6. Study IV. Oxygen consumption ( VO 2) as a function of change in rectal temperature(Tre ). CN, control; MS, motion sickness; DMH, dimenhydrinate; Scop, scopolamine. Values are means (SEM), n=8.

Effect of MS and anti-MS drugs on sweating rate (SWR)  SWR was recorded before, during and after rotation in study I, while in study II and IV, SWR was only measured before and after rotation.  In study I, rotation without head movements (CN) did not result in an increased SWR during, or after rotation. In the MS condition, SWR increased at the end of MS provocation and reached a peak (22.6 ± 2.0 g m 2 min 1) during the first minutes of the postrotation period. Thereafter SWR steadily declined, but after 10 min, values had not yet reached prerotation values (baseline values: 6.9 ± 0.2 g m 2 min 1, 10 min postrotation: 12.5 ± 1.3 g m 2 min 1) (study I). SWR increased after MS provocation compared to baseline recordings, from 10.5 ± 2.3 g m 2 min 1 to 16.8 ± 2.3. g m 2 min 1(study II), from 4.7 ± 0.4 g m 2 min 1 to 26.2 ± 6.1 g m 2 min 1 (study IV, MSCN) and from 6.3 ± 1.0 g m 2 min 1 to 21.6 ± 5.1 g m 2 min 1 (study IV, MSP).  SWR increased despite the use of DMH or Scop, from 4.5 ± 0.4 g m 2 min 1 to 18.7 ± 4.5 g m 2 min 1 in MSDMH and from 5.2 ± 1.9 g m 2 min 1 to 19.3 ± 3.6 g m 2 min 1 in the MSScop condition (study IV).  Except for a lower SWR in the CN condition, there were no intercondition differences in study IV.

15 Effect of MS and anti-MS drugs on Tp and Tc (Fig.7a and 7b)

 Tp and Tc ratings were recorded before and after, but not during the MS provocation in study II and IV, whereas in study I ratings were recorded throughout the entire experiment.  MS provocation affected both Tp and Tc ratings towards the end of rotation and during the first min of post rotation in study I. Subjects perceived temperature as being slightly warm ( Tp = 5) and uncomfortable ( Tc = 3). The changes in Tp and Tc followed MS ratings and returned to prerotation values within 7 min (Fig.7a and 7b).  There was no difference in Tp or Tc ratings before, or 5 min after MS provocation in study II and IV.  Both in study II and IV, Tc increased during the course of immersion. There were no intercondition differences during immersion.  Upon immersion, Tp ratings decreased to a median of 1 for all conditions and remained stable at a median of 1 during the entire immersion (study II and IV).  Both DMH and Scop per se affected Tc at the end of immersion; subjects judged temperatures to be uncomfortable (score of 3) compared to very uncomfortable (score of 4) in the CN condition (study III).

4 CN

Rotation MS 3 MSR

2 Thermal comfort/ Thermal 1 Motion Sickness Rating Sickness Motion

0 0 5 10 15 20 25 30 Time (min)

Figure 7a. Study I, ratings of thermal comfort ( Tc ) as a function of time in the control (CN) and motion sickness (MS) conditions during and after rotation, as well as of MS ratings (MSR) for the MS condition, as a function of time. Ratings at Time=0 are baseline ratings. Only ratings of the first ten minutes of the postrotation period are shown. Thereafter ratings showed no further changes. Values are medians (n=11). Note: increased Tc denotes increased discomfort.

16 7 Rotation CN

6 MS MSR 5

4

3

2 Motion Sickness Rating Sickness Motion Temperature perception/ Temperature 1

0 0 5 10 15 20 25 30 Time (min)

Figure 7b. Study I, ratings of temperature perception ( Tp ) as a function of time in the control (CN) and motion sickness (MS) conditions during and after the rotation, as well as MS ratings (MSR) for the MS condition, as a function of time. Ratings at Time=0 are baseline ratings. Only ratings of the first ten minutes of the postrotation period are shown. Thereafter ratings showed no further changes. Values are medians (n=11).

17

Study I (28˚C) Study II (15˚C) Study III (15˚C and drugs) Study IV(15˚C and drugs and MS) MS MS DMH Scop MS-CN MS-DMH MS-Scop MSDMH = CN DMH < CN Scop > DMH MS > CN MS > CN MSCN > CN MSScop = MSCN Tre DMH < Scop Scop = CN MSDMH < MSCN Partial vasodilatation Tendency to Unchanged compared to in CN vasodilatation compared to in CN Vasoconstriction compared to in CN Vasodilatation compared to in MSCN, Vasoconstriction Vasodilatation Vasodilatation Tff Vasoconstriction compared to in CN MSScop and CN compared to in MSCN Vasodilatation compared to in compared to in Scop Vasodilatation compared DMH to in MSDMH Scop < DMH MSDMH = CN MSScop = CN DMH > CN Not recorded MS < CN MSCN = CN MSDMH = MSCN MSScop = MSCN VO 2 DMH > Scop Scop = CN MSDMH > MSScop MSScop < MSDMH MSDMH > CN MSScop > CN SWR MS > CN MS > CN MSCN > CN MSDMH = MSCN MSScop = MSCN MSDMH = MSScop MSScop = MSDMH Less Less Uncomfortably No differences No differences between No differences between No differences uncomfortable uncomfortable Tp/Tc warm between conditions conditions conditions than in CN than in CN

Table 1. Differences, in qualitative terms, for the main variables recorded in study IIV. For study I and II, results obtained in the MS condition are compared with those of the CN condition. For study III and IV comparisons between respective conditions are given in the table. Tre , change in rectal temperature; Tff , temperature difference between forearm and finger, indicative of peripheral vasomotor tone; VO 2, oxygen uptake, indicative of shivering thermogenesis; SWR , sweating rate; Tp , temperature perception; Tc , thermal comfort .

18

Discussion

The present studies demonstrate that MS aggravates bodycore cooling during cold stress in terms of coldwater immersion (study II and IV), and lowers core temperature in a thermoneutral air environment (study I). The observed MSinduced drop in core temperature could be related to disturbances in heat preservation, heat dissipation, and in thermogenesis. The MS impairment of heat preservation was shown by an attenuation of the coldinduced peripheral vasoconstriction (study II and IV). Exaggerated heat dissipation, in terms of sweating, and hence increased evaporative heat loss, as well as in terms of vasodilatation, was found during MS in a thermoneutral air environment (study I). In study II, MS significantly attenuated shivering thermogenesis; this finding could, however, not be confirmed in study IV. Thus, MS may induce dysfunction of autonomic thermoregulatory mechanisms.

In humans, also behavioural responses play a significant role in maintaining core temperature. Behavioural modifications are initiated in response to the perception of the thermal environment (hot or cold), and an appreciation of its pleasantness, based on the central integration of thermoafferent information. We observed that, in a thermoneutral air environment, the ratings of Tp and Tc , were augmented by MS. Subjects felt uncomfortably warm during MS provocation, despite decreases in both core and skin temperatures (study I). It thus appears that MS may also affect behavioural thermoregulation, assuming that such misperceptions determine behaviour in certain scenarios. In study III, both Scop and DMH reduced the sensation of discomfort during cold stress.

In study III and IV we investigated how thermoregulatory responses to cold stress are affected by two pharmacological substances commonly used against MS, namely DMH, a H1receptor blocker, and Scop, a Mreceptor blocker. DMH reduced the drop in core temperature both in subjects exposed to MS provocation (study IV) and in those not exposed to MS provocation (study III). The exaggerated core cooling during MS was completely counteracted by DMH. DMH per se , i.e. in the nonMS condition, increased shivering thermogenesis. During MS, DMH not only prevented the MSinduced attentuation of the peripheral vasoconstriction but actually potentiated coldinduced vasoconstriction. By contrast, Scop did not prevent MSinduced core cooling, and Scop per se attenuated coldinduced vasoconstriction.

The present studies demonstrate that MS may induce dysfunction of autonomic and behavioral thermoregulatory mechanisms. These findings will be reviewed in the context of mechanisms underlying MS and thermoregulation.

19 Motion Sickness

MS is a combination of signs and symptoms that may arise during actual or perceived motion. The signs/symptoms are pallor, especially in the face, nonthermal sweating or “cold sweating”, and nausea/vomiting. In addition to these primary signs and symptoms, a wide variety of other signs and symptoms have been reported, including disturbances in cardiovascular [10,23,32,35,57,63,99] and gastrointestinal functions [32,63,69,99,102,103], yawning [100], drowsiness [55,84], and apathy [14,63] or mood changes [84]. Several of these signs and symptoms may still be present after the actual provocation stimulus has ceased [51]. Some of the MS effects, which are usually subclinical, may in certain conditions manifest themselves as dysfunctions with practical implications. One such example is the decrease in arterial pressure, which may result in orthostatic intolerance [115] and reduced capacity to withstand high gravitoinertial loads [35].

According to the “mismatch” or “sensory conflict” theory [11,106], MS is caused by conflicts between actual sensory input during motion or perceived motion, and expectations based on memories from previous sensory input regarding motion. During actual or perceived motion, signals from the proprioceptive, vestibular and visual systems converge in the cerebellum [92], vestibular nuclei [16] and parietal cortex [3]. Here input signals are integrated to form an image of the individual’s spatial orientation ( 1 in Fig. 8). The integrated signals of sensory impressions are then compared with stored information on previous experiences. The hippocampal system, encompassing the hippocampus and hippocampal field CA1 ( 2 in Fig. 8), is involved in spatial orientation [105], in the retrieval and formation of memories, and in relating information to a spatial context [19,81]. When the sensory information on present motion deviates from previous or expected motion, a mismatch signal is generated in the cholinergic neurons of the hippocampal system ( 3in Fig. 8) [41,61,132]. The generation of a mismatch signal has been confirmed by in vivo experiments in rats where conflicting sensory information increased the release of Ach in the hippocampus [66,122]. Accordingly, Scop would prevent MS either by blocking the generation of the cholinergic mismatch signal or by blocking transmission of this signal ( 4 in Fig. 8).

The mismatch signals from the hippocampal field CA1 activate histaminergic neurons in the tuberomammillary nucleus (TMN) [22] of the hypothalamus, resulting in signs and symptoms of MS. Histaminergic signals project from the TMN to several areas of the brain (5 in Fig. 8) [60,116]. Vestibular stimulation in the rat results in increased H transmission in the hypothalamus and vomiting centre, targeting H1 receptors, an effect blocked by DMH ( 6 in Fig. 8) [123]. In guinea pigs, neural activity in the paraventricular nucleus (PVN) of the hypothalamus was changed after caloric stimulation of the vestibular organs, an effect that could be modified by ( 7 in Fig. 8) [70]. In addition, there is a dense histaminergic innervation of parts of the hypothalamus that regulate, via H1 and H2 receptors, the secretion of pituitary like adrenocorticotropic hormone (ACTH), arginine vasopressin (AVP), and vasoactive intestinal polypeptide (VIP) (8 in Fig. 8) [60,116].

20 Adrenocorticotropic hormone (ACTH) in MS The release of ACTH is stimulated by H [60] and in humans it has been shown that this release can be blocked by meclastine, a selective H1receptor blocker [2]. In addition, the increased release of ACTH during MS is prevented by a H1receptor blocker but not by Scop [77]. Blood of ACTH increase during crosscoupled Coriolis stimulation but rotation without head movements does not result in increased ACTH levels [36].

Arginine vasopressin (AVP) in MS The of AVP is high in the PVN, and release of AVP is stimulated by H, an effect that can be blocked by H1receptor blockers [60,79,116]. Plasma levels of AVP increase during MS provocation [36,75,76] and increased plasma AVP correlates with the severity of nausea [110]. It is however uncertain wether AVP is the cause or the consequence of nausea. Considering the fact that H stimulates the release of AVP, it seems likely that the MSinduced increase in AVP is initiated via the histaminergic pathway and that DMH would block the release of AVP.

Vasoactive intestinal polypeptide (VIP) in MS H participates in the release of VIP [60], which, in humans, is colocated with AVP in neurons of the PVN and supraoptic nucleus (SON) of the hypothalamus [108]. During parabolic flight, plasma levels of VIP increase in motion sick but not in nonsick subjects [33].

Conclusions on MS There is ample evidence that MS activates cholinergic and histaminergic pathways, thereby increasing the levels of H and Ach in several neuroanatomical structures. As a secondary effect, probably through the increased release of H, MS also elevates blood levels of ACTH, AVP and VIP.

21

Figure 8. A schematic depiction of neural pathways envisaged to be involved in the development of MS, as well as of how such pathways may impinge on thermoregulatory functions. See also narrative text. Ach, acetylcholine; ACTH, adrenocorticotropic hormone; AVP, arginine vasopressine; DMH, dimenhydrinate; H1R/H2R, histamine1 or 2receptor, POAH, preoptic anterior hypothalamus; PVN, paraventricular nucleus; SON, supraoptic nucleus; TMN, tuberomammillary nucleus; VIP, vasoactive intestinal polypeptide.

22 Thermoregulation

Thermal , the maintenance of core temperature within a narrow range, is achieved by autonomic and behavioural responses.

Autonomic thermoregulation In thermoneutral environments, core temperature is regulated through fine adjustment of vasomotor tone (vasomotor zone or null zone) [96]. Cold exposure, or drop in core temperature below certain thresholds, will result in thermogenic and heatpreservation responses, which in humans consist of shivering and peripheral vasoconstriction, respectively. Heat exposure, or a rise in core temperature above certain thresholds, will result in heat dissipation, i.e. sweating and vasodilatation.

Neural organization and pharmacology of thermoregulation Temperature information from different regions of the body, including the skin and hypothalamus, is integrated in the preoptic anterior hypothalamus (POAH) which contains populations of cold and warm thermosensitive neurons ( 1 in Fig. 9). Based on temperature information from the skin and body core, these thermosensitive neurons will stimulate autonomic responses for heat production, heat preservation or heat loss, i.e. via shivering thermogenesis, regulation of peripheral vasomotor tone and sweating ( 2 in Fig. 9) (for review see [12,15]).

Thermoregulation, central effects of Histamine From the POAH there are projections to the histaminergic neurons of the TMN. The activity of these histaminergic neurons is increased by heating the body, which in turn activates heatloss mechanisms through H1 receptors on warm thermosensitive neurons in the POAH ( 3in Fig. 9) [40,124]. Injection of H in the hypothalamus of animals decreases body temperature [26]. In rats, systemic administration of H1receptor blockers prevents this effect [17]. The findings of study III, where DMH reduced the core cooling rate via an increased shivering thermogenesis, are in accordance with these animal studies. It thus appears that H affects thermal balance via reduced shivering thermogenesis.

Thermoregulation, central effects of Acetylcholine It is clear that the cholinergic system plays an important role in thermoregulation [31,39,49,91]. However, it cannot be deduced from the literature how Ach and the M receptor blocker Scop will affect human thermoregulation during exposure to cold. Responses not only differ between humans and animals [49,82], they also seem to depend on environmental temperature and dosage of Ach [13]. Studies have yielded conflicting results, some suggesting that Ach aggravates hypothermia [39] and others suggesting the opposite [13].

The present finding that Scop (study III) reduced peripheral vasomotor tone, agrees with results from animal studies, that demonstrated an excitatory cholinergic synapse between cold sensors and interneurons activating heatproduction mechanisms and inhibiting heat loss mechanisms (2 in Fig. 9) [12,13]. In other words, Scop would affect thermoregulatory mechanisms by inhibiting the signals from cold sensors to heatpreserving mechanisms.

23 Behavioural thermoregulation Behavioural thermoregulation refers to the activation of behavioural responses of an organism to establish a thermal environment that represents a preferred condition for heat exchange (adapted from [4]). Behavioural modifications are initiated in response to the perception of the thermal environment (hot or cold) and an appreciation of its pleasantness, based on central integration of thermoafferent information. Compared to autonomic thermoregulatory responses, behavioural responses are more efficient and energetically less costly in maintaining Tcore within the neutral zone [9].

In study III, an interesting observation was made in the Tc ratings. Immersion in cold water was less uncomfortable in both the DMH and Scop condition than in the CN condition. In the DMH condition the lower thermal discomfort could simply be the result of the smaller drop in core temperature, or, conceivably, it might be a consequence of the sedative effect of DMH [50]. In de Scop condition Tre dropped at a similar rate as in the CN condition and Scop is not associated with sedation [50,104]. Thus, it seems that the Scopinduced attenuation of Tc was inadequate, and such effect might, in a different scenario, impair the behavioural defence against cold. The mechanisms underlying this altered Tc should be elucidated.

Conclusions on thermoregulation Both H and Ach modulate autonomic thermoregulation. Histaminergic activity initiates heatloss mechanisms via stimulation of H receptors in the POAH. The findings of study III, where DMH reduced the core cooling rate via increased shivering thermogenesis are consistent with this notion. The role of Ach is less clear. It appears that during cold stress Scop reduces vasomotor tone. Both pharmacological substances attenuated the sensation of discomfort. For DMH this might be explained by a smaller drop in core temperature. However, the attenuation of the sensation of discomfort by Scop seems inadequate.

MS and thermoregulation

Both thermoregulation and the development of MS are critically dependent on histaminergic and cholinergic transmission. Apparently, this is the basis for interactions between the two phenomena. The present studies demonstrate that MS affects the regulation of core temperature, increasing core cooling during cold stress and initiating a drop in core temperature in a thermoneutral air environment. The effect on core temperature must be explained by a disturbance in autonomic thermoregulation, namely increased sweating, vasodilatation in a thermoneutral environment, attenuation of shivering thermogenesis and attenuation of coldinduced vasoconstriction during cold stress. Below, these findings are first briefly discussed in a neuropharmacological perspective. Then they will be reviewed in the context of each of the thermoregulatory effector mechanisms.

Neuropharmacological links between MS and thermoregulation The role of H in central nervous thermoregulation has been discussed previously. Increased histaminergic activity during MS would thus activate heatloss mechanisms through H1 receptors on warm thermosensitive neurons in the POAH ( 3in Fig. 9). Blocking the H1 receptors in the POAH would therefore prevent activation of heatloss mechanisms. In this context it is interesting to note that motion sick subjects prefer cool fresh air. Histaminergic

24 activity is increased by heating of the body [40,124]. Presumably, a cold stimulus may reduce MSinduced histaminergic activity. If this activity is linked to nausea, a decrease in activity might thus reduce nausea. Some of the subjects in our study actually reported such an effect on nausea during the first minutes of immersion.

The effect of increased cholinergic activity during MS on central thermoregulation is less straightforward. Matters are complicated by the fact that the cholinergic and histaminergic systems are closely interacting. H may either increase cholinergic activity via H1 receptors or decrease activity via H3 receptors [67], while Ach, via M1 receptors, inhibits the release of H [67]. Furthermore, both warm and coldsensitive neurons in the POAH receive cholinergic input and in several species injection of Ach has been shown to increase activity of both types of neurons (4in Fig. 9) [90,112].

Scop ameliorated nausea; yet, the drop in core temperature after MS provocation was not reduced by the use of Scop (study IV). Also the question arises as to why Scop per se showed a negative effect on heat preservation responses (study III), while no such effect was observed during MS (study IV). The results of study III and IV might be explained in two rather different ways:

(i) Scop does not block mismatch signals from the hippocampus to the hypothalamus and consequently does not prevent histaminergic activation. If so, the antiemetic effects of the antiMS drug Scop would be dependent on other mechanisms then those generally assumed [122]. Several studies do in fact suggest that a number of MSinduced Hdependent phenomena are not blocked by Scop [77,121,125]. The findings of these studies will be discussed in more detail in the sections below.

(ii) Alternatively, Scop may have thermoregulatory effects that are independent of those exerted by the histaminergic system, outbalancing any beneficial effects of preventing activation of histaminergic neurons. Cholinergic neurons are abundant throughout the CNS and are involved in several different functions of the thermoregulatory system. Thermoregulatory effects of cholinergic agonists and antagonists can therefore not readily be predicted.

Vasomotor tone Judging from the present studies, it seems that the most consistent thermoregulatory effect of MS during cold stress as well as in a thermoneutral environment is an attenuation of the peripheral vasomotor tone. In agreement with this notion, an effect of vestibular stimulation on vasomotor tone [10] has been reported previously by Arslan [5], who refers to several studies dating back to 1905, demonstrating vasodilatation after caloric stimulation of the vestibular organs. These findings have been confirmed by more recent studies, showing that vestibular stimulation increases skin blood flow in the limbs [23] and face [78] and increases blood flow in the limbs [72,119,121]. In the latter studies, however, no distinction was made between skin and muscle blood flow.

MS might hypothetically affect vasomotor tone on three different levels. (i) There is a central effect of H as discussed above [40,124]. Thus, MS would activate heat loss mechanisms via H1 receptors on warm thermosensitive neurons in the POAH (3 in Fig. 9). This was supported by study IV where the use of DMH prevented the MSinduced

25 attenuation of coldinduced vasoconstriction. Of particular interest is the study by Sunahara et al. [44], who found that prometazine, a H1receptor blocker, but not Scop, counteracted the MSinduced increase in forearm blood flow. This is in line with our present finding that DMH, but not Scop prevented the MSinduced attenuation of the coldinduced vasoconstriction.

(ii) Centrally released H stimulates the release of neuropeptides, e.g. AVP, ACTH and VIP, which in turn influence central thermoregulatory mechanisms. When AVP was injected into the lateral ventricle of rats, Tcore dropped and this drop was preceded by increased Tskin of the tail, suggesting vasodilatation [80]. AVP also plays a role as an endogenous antipyretic in rats [24,109], and administration of AVP in the hypothalamus of rabbits impairs the peripheral vasomotor response during ( 5 in Fig. 9) [34].

Also ACTH may affect vasomotor tone on a central level ( 5 in Fig. 9). Administration of ACTH in the hypothalamus of rabbits reversed vasoconstriction during induced fever [43]. Centrally or systemically administered ACTH induces hypothermia in rabbits and rats, probably via inhibition of heat conservation [24]. The mechanism for this induction of hypothermia is however unknown. It seems that several MSinduced Hdependent phenomena are not blocked by Scop. For instance, Kohl [25] showed that the release of ACTH induced by crosscoupled Coriolis stimulation was blocked by prometazine, but not by Scop.

(iii). The abovementioned neuropeptides might influence thermoregulatory mechanisms on a peripheral level ( 6 in Fig. 9). AVP is well known for its vasoconstrictive effects, but may in certain circumstances, by contrast, induce vasodilatation [1,8,64,85]. VIP may induce vasodilatation in the skin through direct binding to VIP receptors in skin blood vessels or via mastcell degranulation with subsequent local release of H [128], an effect that could be blocked by a H1receptor antagonist [128,129]. Increased blood concentrations of H following MS provocation have been found by Wang et al. [125]. In addition, they found that Scop did not diminish MSdependent blood levels of H, suggesting that Scop did not block this MSinduced Hdependent phenomenon. Present studies (study III and IV) suggest that the MS reduction of peripheral vasomotor tone is H mediated. However, the results do not permit conclusions as regards the relative importance of the aforementioned mechanisms for vasodilatation, since they are all clearly H dependent.

Results from animal studies indicate that there is an excitatory cholinergic synapse between the cold sensors and those interneurons which activate heatproduction mechanisms and inhibit heatloss mechanisms [12,13]. Scop would thus cause a reduction in peripheral vasomotor tone by inhibition of the signal from cold sensors to heatpreserving mechanisms, as found in study III. However, the finding that MS increases the drop in Tcore appears to be in conflict with the finding of an excitatory cholinergic synapse; an increased cholinergic activity during MS would activate heat production and inhibit heatloss mechanisms. However, while Scop will affect all M receptors throughout the CNS, the MS induced release of Ach is likely to be localized to certain brain areas.

Shivering The MSinduced attenuation of the shivering response found in study II was not confirmed in study IV. Yet, in study III it was found that DMH per se reduced the rate of core cooling,

26 seemingly due to increased shivering thermogenesis. This suggests that H, besides playing a role during heat stress [40] also plays a role during cold stress. The decreased shivering response in motion sick subjects in study II suggests that H not only increases heat dissipation, but also, through cross inhibition, decreases shivering thermogenesis. Under thermoneutral conditions such crossinhibition mechanism would not be revealed [12]. In study IV, shivering thermogenesis was significantly greater in the DMHMS condition than in the ScopMS condition, which supports the notion that H is involved in the regulation of heat production; however, it cannot be excluded that also Ach has an influence on shivering thermogenesis. That H may act as a modulator of shivering thermogenesis is further supported by the observation that administration of VIP the release of which is induced by H in rats, immersed in cold water, decreases shivering thermogenesis ( 6 in Fig. 9) [73].

Sweating Another MSrelated thermoregulatory phenomenon is the increased sweating ( 7 in Fig. 9). During heat stress, sympathetic cholinergic neurons activate eccrine sweat glands, initiating evaporative heat loss. The MSinduced sweating increased in study I and IV, although neither skin nor core temperature increased. In fact, the environmental temperature was neutral, and both Tcore and Tskin showed a decrease during MS provocation (study I). Sweating during MS is not related to an elevation of Tskin or Tcore and is best defined as non- thermal sweating instead of cold sweating. The occurence of sweating during MS, and in the absence of any elevations in skin and/or core temperature, is a clear sign of MS, and has often been used as an index of the occurrence of MS [93,94], and in rating the severity of MS [59,98]. Thus, prevention of MS by antiMS drugs would also be reflected in the absence or reduction of nonthermal sweating. In study IV there was, however, no such effect on sweating. Thus, although antiMS drugs were effective against nausea, they did not decrease the MSinduced sweating. In agreement, other studies have shown increased sweating even when medication was used. Golding and Stott [48] showed that hyoscine (scopolamine) reduced skin conductance, indicating reduced sweating during MS, yet, SWR was still higher than in the control condition. A similar finding was presented by Sebel et al. [117] who observed a reduction in MSinduced sweating following administration of DMH. Nevertheless, SWR remained significantly higher than in the control condition.

That neither Scop nor DMH prevented sweating during MS provocation suggests a dissociation between the mechanisms inducing nausea and sweating during MS, and hence that skin conductance not always constitutes a valid index of MS. Furthermore, it was a conspicuous finding that DMH compared to Scop increased vasomotor tone and increased shivering thermogenesis during MS but did not affect MSrelated sweating. It should also be noted that the Mreceptor blocker Scop had no effect on MSsweating, despite the fact that thermal sweating is mediated by descending sympathetic pathways to preganglionic cholinergic neurons. These contradictory findings may act as a reminder of the complexity of the thermoregulatory mechanisms.

There are other conditions where nonthermal sweating occurs, such as during mental stress (63, 64). The hippocampus may play a role in mental sweating, i.e. sweating in response to emotions and/or mentally stressful tasks [65,87]. Although it is generally assumed that mental sweating is limited to glabrous skin, it has also been observed on the forehead [118] and in certain other regions of the body [87,88]. Hcontaining neurons, originating in the

27 TMN innervate the hippocampus [116], but it remains to be elucidated whether MS induced sweating is due to histaminergic influence on the hippocampus resulting from mental stress or MS provocation, or due to histaminergic excitation of warmsensitive neurons in the thermoregulatory centre of the hypothalamus.

Although sweating also increased in study II and IV this probably did not affect evaporative heat loss once subjects were immersed. However, since the head constitutes about 9 % of the total surface area of the body and SWR is highest at the head [89], MSinduced sweating may still have enhanced cooling to some extent during the beginning of immersion.

Effects of MS on behavioural thermoregulation/thermal perception Thermal information from both skin and core may alter thermoregulatory behaviour [20,21,37,113,114]. The relative contribution of Tskin and Tcore to the initiation of behavioural responses in humans remains unclear. Frank et al. [38] showed that Tskin and Tcore have a relatively equal contribution to Tc , while Mower et al. [101] , on the other hand, concluded that the hedonic scale ( Tc ) is influenced by internal temperature alone, and that Tp depends only on peripheral stimulation. Irrespective of the relative contribution of Tskin and Tcore to the initiation of behavioural responses, the decreasing Tcore and Tskin during MS provocation would call for opposite responses than those observed in study I; subjects felt uncomfortably warm during rotation and the first minutes of the postrotation period. Remarkable is also the fact that Tre continued to decrease in motion sick subjects, during the post rotation period, while Tc and Tp returned to baseline values during this period. This suggests that the changes in Tp and Tc during MS provocation are not governed by signals from peripheral or central thermal sensors ( 8 in Fig. 9).

Thermal hedonic responses are not only influenced by Tskin or Tcore . Nonthermal factors like [6] and mild narcosis [95] and also prior experience or expectations seem to affect Tc [7]. In study I, the perception of uncomfortable warmth during MS provocation coincided with a significant increase in sweating. Perhaps, to some extent, the inadequate thermal sensations were due to the fact that the subjects sweated profoundly, a response usually related to being warm or being in a warm environment.

In study I, the time course for Tc and Tp , following MS provocation, was similar to the time course of change in MS ratings. Although we cannot rule out a “spillover” effect from the unpleasant sensation of nausea, i.e. subjects might not have differentiated between nausea and thermal unpleasantness, it seems unlikely that subjects would confuse Tp , i.e. warm cold, with the sensation of nausea.

Conclusions on MS and thermoregulation Both H and Ach play significant roles in the disturbance of thermoregulation during MS. The MSinduced increase in core cooling might be related to central and/or peripheral H dependent functions. There is indirect evidence that several neuropeptides would influence central or peripheral thermoregulatory responses and that the release of these neuropeptides is induced by H during MS provocation. The finding that DMH reduces MSinduced heat loss might be explained by blocking H receptors on warmsensitive neurons in the POAH. It is also possible that DMH prevents the release of neuropeptides that may affect thermoregulation during MS. Finally, DMH may block H1 receptors in skin blood vessels, thereby preventing the VIPdependent increase in blood flow. The role of Ach/Scop is less

28 clear; our results indicate that H plays a more dominant role in MSdependent dysfunction of autonomic thermoregulation. Study III suggests that blocking cholinergic transmission might reduce the sensation of discomfort during cold stress.

Figure 9 . A schematic depiction of neural pathways envisaged to be involved in thermoregulatory functions, as well as of how MS may impinge on such pathways. See also narrative text. Ach, acetylcholine; ACTH, adrenocorticotropic hormone; AVP, arginine vasopressine; POAH, preoptic anterior hypothalamus; TMN, tuberomammillary nucleus; VIP, vasoactive intestinal polypeptide.

Practical implications

That MS predispose individuals to hypothermia by impairing autonomic heatpreservation mechanisms, by stimulating autonomic heat dissipation and by inducing a false impression of warmth, may be of practical importance when humans are exposed to environments that are cold and MSprovoking. There are several anecdotal accounts in the literature implicating MS to fatalities in maritime accidents. Keatinge [74] investigated the causes of death of 124 passengers, who had to enter the water when the vessel Lakonia was abandoned at sea in December 1963. Water temperature at the time was 17.9 ˚C and air temperature was 15.7 ˚C. He concluded that most were due to hypothermia. Keatinge further observed that most of those who died had their face coated with vomit, presumably due to seasickness, and he continued by speculating on the effect of vomiting

29 on vasomotor function, an effect that might have led to an increased heat loss in cold water. A somewhat similar observation is described by Golden [45], who reported on a sailing accident where MS might have decreased survivability. Also reports on WW II incidents suggest that MS may affect survivability. Llano [86] drew the conclusion that MS indirectly contributed to deaths; repeated vomiting would have caused and facilitated hypothermia and apathy. However, information from controlled investigations on the effect of MS on human thermoregulation in cold environments is limited. Present results confirm and extend those of Mekjavic et al. [97], who found that MS increased core cooling in a scenario simulating immersion in cold water while wearing a survival suite. It should be noted that in a reallife scenario, MS effects on autonomic and behavioural thermoregulation are likely to be more pronounced than those observed in the present studies and in that of Mekjavic et al. (70), since in all these studies merely residual effects of MS, following a relatively brief MS provocation, were examined. More realistic stimulus conditions might comprise sustained MS provocation in a cold environment.

MS still constitutes a problem in survival situations. Analysis of 5 offshore oil rig disasters, where subjects were evacuated with a totally enclosed motor propelled survival craft (TEMPSC), showed high incidences of MS, ranging from 75 to 100%, with a rapid onset within 1530 min (one individual even became motion sick within 2 min) [83]. The accidents took place in cold weather conditions with air temperature ranging from 3˚C to 19˚C and water temperature ranging from 1˚C to 15˚C. Occupants not only reported MS, but also increased sweating and a sense of uncomfortable warmth which lead some individuals to remove their survival suits [83]. The temperature inside the TEMPSC was not recorded. It is therefore uncertain to what extent MS contributed to the thermal discomfort. However, in at least one of those incidents, most occupants suffered from MS and hypothermia at the time of rescue [83]. In the present experiments, MS induced core cooling even in a 28˚C air environment. Thus, even though these survival vessels offer protection against the elements, considering the high incidence of MS, occupants might still be at risk of developing hypothermia.

In a reallife scenario, MS might have an additional effect on survivability. Although not part of the present studies, it might be of interest to briefly mention some observations of MSinduced apathy. Bohemier [14] gives an account of his experiences as an instructor of extreme cold water survival training, during which as many as 3040 % of the students may become totally incapacitated from seasickness: “ By totally incapacitated, I mean that without our rescue swimmers or indeed assistance from other students on the course, those students suffering from seasickness would perish. ” Thus, MS may lead to a change in behaviour, to an extent that an individual is no longer capable of taking appropriate actions in order to survive.

A practical issue is whether, or to what extent, the MSinduced nonthermal sweating observed in the present and in numerous previous studies [28,29,32,47,52,57,62,93,94,100] might affect thermal homeostasis in a coldair environment. There is undoubtedly a threshold skin temperature below which MS no longer induces sweating [93]. The Tair at which MS no longer induced sweating, despite the development of nausea, has been shown to have a wide variation, ranging from 12.8˚C to 22˚C, whereas temperature thresholds for sweating before MS provocation was started, i.e. thermal sweating, ranged from 24.4˚C to 32.2˚C [93]. Crampton [32] and Hemmingway [62] made similar observations, that MS

30 induced sweating is potentiated by high Tair and attenuated by low Tair . Despite a low number of subjects in the study by McClure [93], it is evident that MS may induce sweating at Tair as low as 12.8˚C. It thus appears reasonable to assume that MSinduced sweating may result in significant heat dissipation even at relatively low ambient temperatures.

The present studies showed that DMH completely abolished the MSinduced exaggeration of core cooling, whereas Scop, despite being equally efficient against nausea as DMH, did not have any beneficial effects on thermoregulation during cold provocation. A conspicuous finding of study III was that coldwater immersion was perceived as less uncomfortable in the Scop condition, which suggests that Scop also may have a negative influence on the behavioural defence against cold. Accordingly, it appears that in scenarios where cold stress and MS provocation are imminent features, antihistaminics would be more adequate antiMS drugs. The discrepancy between Scop and DMH as regards their effects on the thermoregulatory disturbances also shows that the nausea of MS cannot be used as a marker of MSrelated autonomic dysfunctions. This notion was also supported by the finding (study I, II, IV) that MSinduced thermoregulatory dysfunctions prevailed after MS provocation, in the absence of subjective symptoms.

As regards medication, another lesson from TEMPSC accidents is the rapid onset of MS and the inadequate effect of antiMS drugs [83]. Since Scopoderm should be applied 1012 hours before MS provocation, and, according to the results of study IV, does not protect against the MSinduced increase in core cooling, this medication is a less suitable candidate in situations where there is a considerable risk for hypothermia or in an emergency situation. The antiH DMH, by contrast, prevents the MSinduced increased core cooling, and sufficient plasma levels are attained within 3060 min after intake. Yet, as MS onset can be rapid, intramuscular injection of antihistaminic drugs might be an option.

In conclusion, the results of our studies I to IV, combined with accounts implicating MS to hypothermiarelated fatalities in maritime accidents [44,74], suggest that under certain circumstances MS is a far more serious malady to the mariner than hitherto realised. Present results demonstrate (studies III and IV) that it is possible to prevent the hypothermic effect of MS by the use of an antihistaminic drug.

31

Summary and conclusions

The effects of motion sickness (MS) on autonomic and behavioural thermoregulatory mechanisms during cold stress (immersion in 15˚C water), and in a thermoneutral environment (exposure to 28˚C air) were studied, as were the relationship between nausea and autonomic dysfunctions following MS provocation. The studies were carried out in healthy male subjects, and MS was induced by standardised head movements during rotation, causing crosscoupled Coriolis stimulus. Histamine (H) and muscarine (M) receptor blockers were used to study the roles of histaminergic and cholinergic neuron systems in autonomic thermoregulation during cold stress, and in MSdependent dysfunction of autonomic thermoregulation. H and Mreceptor blockers were further used to study, if, or to what degree, these drugs influenced temperature perception ( Tp ) and thermal comfort ( Tc ) and nausea during cold stress. The main results and conclusions were as follows:

(i) During a pronounced cold stimulus, i.e. immersion in 15˚C water, MS was found to attenuate coldinduced vasoconstriction and shivering thermogenesis, resulting in an increased corecooling rate. It thus appears that the MSinduced impairment of autonomic thermoregulation, previously observed during mild cold stress, prevailed during pronounced cold stimulation.

(ii) Also in a thermoneutral air environment, MS attenuated peripheral vasomotor tone, which, in combination with MSinduced sweating, resulted in a lowered core temperature. During and after the MS provocation in thermoneutral air, subjects transiently perceived the temperature as warmer and more uncomfortable, despite decreases in both core ( Tcore ) and skin temperature (Tskin ). It thus appears that, also in an environment normally regarded as thermoneutral, individuals suffering from MS may be predisposed to core cooling due to dysfunction of autonomic thermoregulation and to altered perceptions of temperature and Tc .

(iii) The Mreceptor blocker scopolamine (Scop) and the Hreceptor blocker dimenhydrinate (DMH) exhibited different effects on thermoregulatory responses during cold stress. Scop had a deteriorating effect on heat preservation, but did not significantly affect core cooling, while DMH reduced the rate of core cooling through increased shivering thermogenesis. Findings support the notion of modulating roles of H and acetylcholine (Ach) in autonomic thermoregulation, histaminergic activity initiating heat loss mechanisms, presumably via stimulation of H receptors in the preoptic anterior hypothalamus. The role of Ach is less clear, it appears that during cold stress cholinergic activity may increase peripheral vasomotor tone.

(iv) DMH but not Scop prevented the MSinduced increase in core cooling; DMH prevented the MSinduced attenuation of the coldinduced vasoconstriction. The vasoconstrictor response was stronger in the MSDMH condition than in the control (CN), MSCN and MSScop conditions. Also the shivering response was greater in the MSDMH

32 than in the MSScop condition. It is known that MS activates cholinergic and histaminergic pathways, thereby increasing the levels of H and Ach in several neuroanatomical structures. As a secondary effect, probably through the increased release of H, MS also elevates blood levels of adrenocorticotropic hormone (ACTH), arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP). There is indirect evidence that these neuropeptides would influence central and/or peripheral thermoregulatory responses. Thus, the finding that DMH reduces MSinduced heat loss might be related to central and/or peripheral Hdependent functions. The role of Ach/Scop is less clear; results indicate that H plays a more dominant role in MS dependent dysfunction of autonomic thermoregulation.

(v) MS did not affect Tc or Tp during coldwater immersion. However, coldwater immersion was perceived as less uncomfortable both in the MSDMH and MSScop conditions. For DMH, the blunted thermal discomfort might be explained by a smaller drop in core temperature. However, the attenuation of the sensation of discomfort by Scop seems inadequate. To what extent such influence on a perceptual function might also impair behavioural defence against cold remains to be established.

(vi) The subjects’ perception of MS declined rapidly after cessation of the MS provocation, while autonomic dysfunctions persisted long after subjective symptoms had abated, both during cold stress and in a thermoneutral environment. In particular, the MSdependent reduction of peripheral vasomotor tone prevailed throughout the 90min postrotation periods. Therefore, and because Scop and DMH were equally efficacious in ameliorating nausea, whereas only DMH counteracted the MSinduced exaggeration of core cooling, it appears that nausea cannot be used as marker of MSrelated autonomic dysfunction.

33

Acknowledgements

Completing a thesis is no one-man’s job; it is therefore my pleasure to thank those who made this thesis possible.

I’m very thankful to Ola Eiken , my supervisor, coach, and mentor. Some six years ago you took in a stranger from the Netherlands, without knowing what you got yourself into. Thank you for your friendship, for sharing your scientific knowledge, critical thinking and the on and oftopic discussions. It has been enjoyable, both at work and after work. Thanks for helping out in rough seas. One day I will have more holes in my trousers than you.

I would also like to express my gratitude to Igor B. Mekjavic , cosupervisor, great host in Slovenia, and for showing the fun in science, conferences and experiments.

Arne Tribukait , your support helped me stay on track and reach the finish. I enjoyed our “philosophical” discussions, from art to conspiracy theories, thank you for being the person you are.

Mikael Gennser , your connection with the Navy made it possible, thanks.

Roger Kölegård , it always helps to have someone ahead of you! Thank you, it was fun.

Of course, Björn Johannesson , who, more than once, saved me at the last moment.

The people at FOI; Mikael Grönkvist, Eddie Bergsten, Oskar Frånberg, Lena Nordin, Ulf and Ulf . I felt welcome from day one.

All subjects, you did the job, while I still need to take a bath.

Boris, Hielke, Nienke and Shirly, words are not enough.

My Dad .

I have been able to start and finish this thesis thanks to the support of:

The Royal Netherlands Navy , in particular; Harry Hofkamp and Remco Blom.

Scania CV AB, who provided me with time when I most needed it .

The studies were supported by grants from the Swedish Armed .

34

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