Brain temperature fluctuations during physiological and pathological ...

Eur J Appl Physiol (2007) 101:3–17 DOI 10.1007/s00421-007-0450-7

REVIEW ARTICLE

Brain temperature Xuctuations during physiological and pathological conditions Eugene A. Kiyatkin

Accepted: 16 March 2007 / Published online: 12 April 2007 © Springer-Verlag 2007

Abstract This review discusses brain temperature as a physiological parameter, which is determined primarily by neural metabolism, regulated by cerebral blood Xow, and aVected by various environmental factors and drugs. First, we consider normal Xuctuations in brain temperature that are induced by salient environmental stimuli and occur during motivated behavior at stable normothermic conditions. Second, we analyze changes in brain temperature induced by various drugs that aVect brain and body metabolism and heat dissipation. Third, we consider how these physiological and drug-induced changes in brain temperature are modulated by environmental conditions that diminish heat dissipation. Our focus is psychomotor stimulant drugs and brain hyperthermia as a factor inducing or potentiating neurotoxicity. Finally, we discuss how brain temperature is regulated, what changes in brain temperature reXect, and how these changes may aVect neural functions under normal and pathological conditions. Although most discussed data were obtained in animals and several important aspects of brain temperature regulation in humans remain unknown, our focus is on the relevance of these data for human physiology and pathology. Keywords Brain metabolism · Neural activity · Hyperthermia · Addictive drugs · Brain edema · Neurotoxicity

E. A. Kiyatkin (&) Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, DHHS, 333 Cassell Drive, Baltimore, MD 21224, USA e-mail: [email protected]

Introduction Mammals, including humans, maintain internal temperatures within strict limits under widely varying environmental temperatures. While it is generally believed that body temperature remains stable in the healthy organism under quiet resting conditions in a temperature-neutral environment, a relatively small increase in body temperature (fever) is an important index of disease. In contrast to wellestablished ideas of central regulation of body temperatures via adjustments in heat production and dissipation (Berner and Heller 1998; Boulant 2000; Gordon and Heath 1986; Mekjavic and Eiken 2005; Nadel 2003; SatinoV 1978), knowledge on brain temperature, its normal and pathological Xuctuations, and mechanisms underlying these Xuctuations remains less clear. In contrast to other physiological parameters, brain temperature in humans remains generally unknown because of virtually no direct experimental studies. Although it is known that temperature aVects multiple chemical and physical processes in the brain and that relatively weak hyperthermia may damage neural cells, many basic questions regarding brain temperature Xuctuations and their regulation in normal and pathological conditions remain unanswered. The Wrst measurements of brain temperatures in animals were conducted more than 140 years ago (SchiV 1870, cited by James 1892), long before the Wrst recordings of the brain’s electrical activity or even the realization that neural cells have electrical activity. Moritz SchiV described “neural activation” manifested as »1°C brain temperature elevation in hungry dogs after the presentation of meat and showed that this response depends on the animal’s motivational state (i.e., hunger). Based on these Wndings and results of early thermal recordings from the human scalp (Amidon 1880; Lombard 1879; cited by James 1892),

123

4

James (1892) concluded that “brain-activity seems accompanied by a local disengagement of heat” and speculated that cerebral thermometry may be valuable for experimental psychology to correlate brain activity with psychic functions. This pioneering work, however, did not receive adequate development during the next century, despite a plethora of new experimental data and approaches for understanding brain functions. Brain temperature, as a physiological parameter that provides information on the activity and functions of the brain, was generally forgotten until it became clear that slight changes in its temperature are able to dramatically aVect the outcome of stroke and other pathological conditions in humans (Busto et al. 1987; Maier and Steinberg 2003; Miyazawa et al. 2003; RosomoV 1957). The goal of this review is to discuss brain temperature as a parameter that provides information on normal brain functions and the development of brain pathology. First, we consider basic issues related to the brain’s thermogenic activity and mechanisms involved in brain temperature homeostasis. Second, we consider how brain temperature Xuctuates under normal physiological and behavioral conditions and the mechanisms underlying these Xuctuations. Here we discuss the role of temperature in modulating normal neuronal functions and the role of hyperthermia in damaging neural cells and potentiating neurotoxicity induced by other factors. Third, we consider alterations in brain temperature induced by drugs that aVect brain metabolism and/or heat dissipation. Our focus here is on psychomotor stimulant drugs, which are widely abused by humans and may induce pathological brain hyperthermia and lifethreatening health complications. We review data suggesting the importance of associated environmental factors in modulating the thermogenic eVects of psychomotor stimulants and in the development of pathologies resulting from drug use under adverse experimental conditions. Finally, we summarize our views on regulation of brain temperature and its role in normal brain functions and pathology in humans.

Brain as a thermogenic organ Although the brain represents »2% of human body mass, it accounts for »20% of the organism’s total oxygen consumption (Schmidt-Nielsen 1997; Siesjo 1978). Neurons require several orders of magnitude more energy than other cells under resting conditions; the power consumption of a single neuron is about 0.5–4.0 nW, 300–4,000 times more than the average body cell (1.0–1.6 pW) (Gerasimov 1998). Most energy used for neuronal metabolism is spent restoring membrane potentials after electrical discharges (Hodgkin 1967; Ritchie 1973; Laughlin et al. 1998; Siesjo 1978;

123

Eur J Appl Physiol (2007) 101:3–17

SokoloV 1999; Shulman et al. 2004), suggesting a relationship between metabolic and electrical neural activity. Energy is also used on other neural processes not directly related to electrical activity, particularly for synthesis of macromolecules and transport of protons across mitochondrial membranes. Since all energy used for neural metabolism is Wnally transformed into heat (Siesjo 1978), intense heat production appears to be an essential feature of brain metabolism. To maintain temperature homeostasis, thermogenic activity of the brain needs to be balanced by heat dissipation from the brain to the body and then to the external environment. Because the brain is isolated from the rest of the body and protected by the skull, cerebral circulation provides the primary route for dissipation of brain-generated metabolic heat. The simpliWed analogy of the cooling of an internal combustion engine may be valid. Similar to the working, heat-producing engine, which receives a liquid coolant, the brain receives arterial blood, which is cooler than brain tissue (Delgado and Hanai 1966; Feitelberg and Lampl 1935; Hayward and Baker 1968; Kiyatkin et al. 2002; McElligott and Melzack 1967; Nybo et al. 2002; Serota and Gerard 1938). Similar to the coolant, which takes heat from the engine, arterial blood removes heat from brain tissue because venous blood is warmer. After warm venous blood from the brain is transported to the heart and mixed with blood from the entire body (cooler blood from skin surfaces and warmer blood from internal organs), it travels to the lungs, where it is oxygenated and cooled by contact with air. This oxygenated, cooled blood travels to the heart again and is then rapidly transported to the brain. While brain temperature homeostasis is determined primarily by intra-brain heat production and dissipation by cerebral blood Xow, it also depends on the organism’s global metabolism and the eYciency of heat dissipation to the external environment via skin and lung surfaces. At rest total energy consumption in humans is about 100 W and may increase up to 10–12 times (>1 kW) during intense physical activity such as running, cycling or speed skating (Margaria et al. 1963). While this enhanced heat production is generally compensated by enhanced heat loss via skin and lung surfaces, physical exercise increases body and arterial blood temperatures (Nybo et al. 2002), thus aVecting brain temperatures. While it is diYcult to separate brain and body metabolism, it was suggested that physical activity also increases brain metabolism (Ide and Secher 2000; Ide et al. 2000), enhancing brain thermogenesis. In contrast, Nybo et al. (2002) explained a weak, »7% rise in metabolic heat production found in the brain during intense physical exercise in humans as an eVect entirely dependent upon rise in brain temperature. Because heat from the body dissipates to the external environment, body temperature is


5

also aVected by the physical parameters of the external environment. Humans have eYcient mechanisms for heat loss, which depend on a well-developed ability to sweat and on a dynamic range of blood Xow rates to the skin, which can increase from »0.2 to 0.5 l/min in thermally neutral conditions to 7–8 l/min under maximally tolerable heat stress (Rowell 1983). Under these conditions sweat rates may reach 2.0 l/h, providing a potential evaporative rate of heat loss in excess of 1 kW, i.e., more than the highest possible heat production. These compensatory mechanisms, however, become less eVective in hot, humid conditions, resulting in progressive heat accumulation in the organism. For example, body temperatures measured at the end of a marathon run on a warm day were found to be as high as 40°C (Schaefer 1979), and cases of fatigue during marathon running were associated with even higher temperatures (Cheuvront and Haymes 2001). While intense cycling at normal ambient temperatures increased body temperature less than 1°C, 2.0–2.5°C (up to 40°C) increases were found when cycling is performed in waterimpermeable suits that restricted heat loss via skin surfaces (Nybo et al. 2002). Therefore, changes in brain temperature may be determined not only by thermogenic activity of the brain, but also by thermogenic activity of the body and the physical parameters of the environment.

Physiological Xuctuations in brain temperature and their mechanisms Although brain temperature may either increase or decrease due to physical body heating or cooling, or during pathological conditions (i.e., fever, stroke, etc.), it also Xuctuates in healthy animals at normal, stable ambient temperatures following somato-sensory environmental challenges, changes in activity state, and during natural motivated behavior (Abrams and Hammel 1964; Blumberg et al. 1987; Delgado and Hanai 1966; Kovalzon 1972; McElligott and Melzack 1967; Moser et al. 1993; Serota and Gerard 1938). High-speed thermorecording in behaving rats reveal that brain temperature Xuctuates within »3°C under normal physiological conditions (Kiyatkin 2005). Following a rat’s exposure to various arousing stimuli (e.g., light, sound, smell, new environment, tail-pinch, presentation of another rat, saline injection), brain temperature transiently increases along with behavioral activation (Fig. 1). These increases in brain temperature have relatively short onset latencies (10– 20 s), variable magnitude (0.2–2.0°C) and duration (10– 90 min), and they are accompanied by similar, but delayed temperature changes in arterial blood, muscle, and body core. These brain and body hyperthermic responses are accompanied by transient skin hypothermia, apparently reXecting acute peripheral vasoconstriction (Baker et al.

Fig. 1 Changes in nucleus accumbens (NAcc), muscle (musculus temporalis) and skin temperatures (a) as well as locomotion (b) following subcutaneous injection of saline (0.15 ml). Filled symbols show values signiWcantly diVerent from the last pre-injection value (P < 0.05)

1976), which decreases heat dissipation from the body. Brain temperature responses to arousing environmental challenges are also dependent on animal experience, showing progressive habituation to repeated exposure of simple sensory stimuli (i.e., light, sound) and relative day-to-day stability to salient stimuli (i.e., tail-pinch, social interaction with another animal, placement in new environment). Finally, brain temperature increases induced by sensory stimuli are aVected by learning (conditioning), showing no habituation or sensitization, when these stimuli become cues and trigger motivated behavior. To clarify the source of physiological brain hyperthermia, we simultaneously recorded temperatures from several brain structures and arterial blood in awake, unrestrained rats (Kiyatkin et al. 2002). To provide a reliable measure of arterial temperature, a miniature thermocouple probe was inserted into a polyethylene catheter chronically implanted into the abdominal aorta via the caudal artery (Kiyatkin 1988; Kiyatkin and Stein 1993). Carotid artery would seem to be a better site for evaluating the temperature of arterial blood inXow to the brain and this approach was used in cats

123

6

and monkeys (Delgado and Hanai 1966; Hayward and Baker 1968; McElligott and Melzack 1967), but in rats it has important disadvantages. Although the catheter can be implanted in carotid artery in rats, it will either fully block or signiWcantly decrease blood Xow, thus aVecting both arterial brain inXow and measured blood temperature (it will be lower because of heat loss to the adjacent neck tissue). In contrast, heat loss will be minimized if the catheter is in the abdominal aorta, which is located in the warmest area of the body. With this approach, moreover, surgery is much less traumatic and interruption of blood Xow is minimal. This study resulted in several Wndings. First, it conWrmed previous work conducted in cats, dogs, monkeys, and humans, which demonstrated that aortal temperature during quiet rest in normal laboratory conditions (23°C, low humidity) is lower than the temperature of any brain structure (Fig. 2). Second, temperature increases occurring in brain structures following salient stimuli are more rapid and Fig. 2 Temperature changes in nucleus accumbens (NAcc), striatum, cerebellum) and arterial blood following 3-min social interaction with females and 3-min tail-pinch. a Absolute temperatures; b relative temperatures; c brain–arterial blood temperature diVerences

123


stronger than those in arterial blood, suggesting intra-brain heat production rather than delivery of warm blood as the primary cause of brain hyperthermia. Therefore, metabolic brain activation appears to be the primary cause of intrabrain heat production and a factor determining, via various neuroeVector mechanisms, subsequent body hyperthermia. Third, this and our later studies (Kiyatkin 2005) conWrmed classic observations (Serota 1939; Delgado and Hanai 1966) that brain temperature increases are qualitatively similar in diVerent brain structures, although there are some important between-structure diVerences in both basal temperature and the pattern of changes with respect to diVerent stimuli. Consistent with the dorso-ventral brain temperature gradient reported in both animals (Delgado and Hanai 1966; Hayward and Baker 1968; Horvath et al. 1999; Serota 1939) and humans (Mellergard and Nordsrom 1990), more dorsally located structures (i.e., hippocampus, dorso-medial thalamus) have lower basal temperatures than


more ventrally located structures (i.e., nucleus accumens, ventral tegmental area of midbrain, hypothalamus). Finally, we found that rats, under quiet resting conditions, have basal temperatures in body core that are similar or slightly less (0.2°C) than those in deep brain structures and higher (0.4–0.6°C) than those in more superWcially located structures (i.e., hippocampus). These diVerences, however, became altered during physiological activation and following the administration of drugs, which can either decrease or increase brain metabolism (see below). Increased brain metabolism is accompanied by increased cerebral blood Xow (CBF; Fox and Raichle 1986; Raichle 2003; Trubel et al. 2006). However, the relationships between brain temperatures and interrelated changes in metabolism and CBF are complex and currently poorly understood. Although some consider brain temperature a passive parameter that depends entirely upon the ability of CBF to remove metabolic heat from brain tissue (Sukstanskii and Yablonskiy 2006; Yablonskiy et al. 2000), direct relations between temperature and blood Xow have been established in peripheral tissues. An increase in local temperature is accompanied by strong blood Xow increases in skin (Charkoudian et al. 2003; Ryan et al. 1997), muscle tissue (Oobu 1993), the intestine (Nagata et al. 2000), and the liver (Nakajima et al. 1992). This relationship is also observed in the brain tissue of monkeys (Moriyama 1990), rats (Uda and Tanaka 1990), and humans (Nybo et al. 2002). Therefore, increased local brain temperature resulting from increased neural metabolism can increase local blood Xow. This factor may contribute to the blood Xow increases that exceed the metabolic activity of brain tissue (Fox and Raichle 1986). As a result, the brain is able to increase blood Xow more and in advance of actual metabolic demands (“anticipatory” metabolic activation), thus providing a crucial advantage for successful goal-directed behavior and the organism’s adaptation to potential energetic demands. By increasing blood Xow above current demand, more potentially dangerous metabolic heat is removed from intensively working brain tissue. To examine brain temperature Xuctuations during natural motivated behavior, we used sexual behavior in male and female rats (Kiyatkin and Mitchum 2003; Mitchum and Kiyatkin 2004). This behavior was interesting for several reasons. First, it is a natural, biologically important, and highly energy-consuming behavior (Bohlen et al. 1984; Goldfarg 1970). The energy equivalent of this behavior in human males is about 420–840 kJ, resulting in »419 W. While the time-course of energy consumption and temperature Xuctuations within this complex behavior are unknown, it is accompanied by robust physiological changes. For example, the largest Xuctuations in arterial blood pressure have been described in male volunteers during sexual intercourse (Masters and Johnson 1966).

7

Second, it is a cooperative behavior that includes two individuals, and can be easily quantiWed in both sexes (e.g., lordosis, mounts, intromissions, ejaculation). Third, although there is abundant information about sexual behavior per se and its psycho-emotional accompaniments, physiological information is very limited both in humans and animals. Finally, because of powerful physiological activation, sexual behavior represents a medical problem since many pathological processes (i.e. stroke) may manifest during sexual behavior. Both male and female rats showed robust and relatively similar changes in brain and body temperature during sexual behavior. Males and females, however, had some important diVerences. As shown in Fig. 3, in both males and females brain temperature robustly increased during

Fig. 3 Original records of changes in temperature (nucleus accumbens NAcc; medial-preoptic area of hypothalamus MPAH and muscle) during sexual behavior in experienced male and female rats. The Wrst two vertical lines mark the moments when the rat of the opposite sex was placed in the cage, Wrst behind a non-transparent barrier (A1), then a transparent barrier with holes that allow limited interactions (A2). The third vertical line shows the moment when the rats were allowed to interact freely. Each next hatched line shows either mount or intromission and solid line the moment of ejaculation (black triangles with numbers). The last vertical line shows the moment when the rat of opposite sex was removed from the cage

123

8

sexually arousing stimulation and further increased during copulatory behavior, peaking around male ejaculation. Then, temperature physically decreased and showed several similar increases during subsequent copulatory cycles. The point of ejaculation marked the highest absolute temperatures in males (in hypothalamus and nucleus accumbens »39.0–39.8 or 2.5–3.0°C above quiet rest baseline) and was preceded by robust temperature acceleration (up to 0.05°C/min), indicating an intense heat production not seen under any other physiological conditions. Although females showed similar dynamics, they diVered from males in the peak of brain activity. In males, maximal increases in brain–muscle diVerentials occurred immediately before ejaculation, while in females they occurred within one minute after this event. Both males and females were aVected by learning (conditioning), showing an increased locomotion and temperature increases when placed in the environment of previous sexual interaction. These diVerences were equally strong in both sexes.

Brain temperature as a factor aVecting neural functions Heat release is an obvious “by-product” of metabolic activity, but the changes in brain temperature it triggers may aVect various neural processes and functions. While it is generally believed that most physical and chemical processes governing neuronal activity are aVected by temperature with the average Van’t HoV coeYcient Q10 = 2.3 (i.e., doubling with 10°C change, Swan 1974), experimental evaluations, using in vitro slices, revealed widely varying eVects of temperature on passive membrane properties, single spike and spike bursts, as well as the neuronal responses (i.e., EPSP and IPSP) induced by electric stimulation of tissue or its aVerents (Lee et al. 2005; Thompson et al. 1985; Tryba and Ramirez 2004; Volgushev et al. 2000). While conWrming that synaptic transmission is more temperaturedependent than the generation of action potentials (Katz and Miledi 1965), these studies showed that temperature dependence varies greatly for each parameter, the type of cells under study, and the nature of aVerent input involved in mediating neuronal responses. Although temperature-sensitive neurons were Wrst described in the preoptic/anterior hypothalamus (Berner and Heller 1998; Boulant 2000; Nadel 2003), cells in many other structures (i.e., visual, motor and somato-sensory cortex, hippocampus, medullary brain stem, thalamus) also show dramatic modulation of impulse activity by temperature. Many of these cells, moreover, have a Q10 similar to classic warm-sensitive hypothalamic neurons. In the medial thalamus for example, 22% of cells show a positive thermal coeYcient >0.8 imp/s per °C (Travis et al. 1995), exceeding the number of temperature-modulated cells found in

123


both anterior (8%) and posterior (11.5%) hypothalamus. About 18% of neurons in the superchiasmatic nucleus are warm-sensitive (Burgoon and Boulant 2001), while >70% of these cells decrease their activity rate with cooling below physiological baseline (37–25°C) (Ruby and Heller 1996). Finally, electrophysiologically identiWed substantia nigra dopamine neurons in vitro are found to be highly temperature-sensitive (Guatteo et al. 2005). Within the physiological range (34–39°C), their discharge rate increases with warming (Q10 = 3.7) and dramatically decreases (Q10 = 8.5) during cooling below physiological range (34–29°C). While the eVects on discharge rate and evoked synaptic responses suggest that transmitter release is also strongly temperature-dependent, and these data agree with direct evaluation of stimulated release of diVerent neuroactive substances (i.e., Q10 = 3.6–5.5 for K+-induced glutamate release; Q10 = 3.5–6.3 for GABA release, and Q10 = 11.3– 37.7 for K+- and capsaicin-induced release of calcitonin gene-related peptide; Nakashima and Todd 1996; Vizi 1998), in vivo these changes in release are compensated for by increased transmitter uptake. For example, within the physiological range (24–40°C) DA uptake almost doubles with a 3°C temperature increase (Q10 = 3.5–5.9, Xie et al. 2000), a Xuctuation easily achieved in the brain under conditions of physiological activation. The fact that temperature has strong eVects on various neural parameters, ranging from the activity of single ionic channels to such integrative processes as transmitter release and uptake, has important implications. First, it suggests that naturally occurring Xuctuations in brain temperature aVect various parameters of neural activity and neural functions. While in vitro experiments permit individual cells to be studied and individual components of neural activity and synaptic transmission to be separated, neural cells in vivo are interrelated and interdependent. Therefore, their integral changes may be diVerent from those of individual components assessed in in vitro experiments. For example, increased transmitter uptake should compensate for temperature-dependent increase in transmitter release, thus limiting Xuctuations in synaptic transmission. By increasing both release and uptake, however, brain hyperthermia makes neurotransmission more eYcient and neural functions more eVective at reaching behavioral goals. Therefore, changes in temperature may play an important integrative role, involving and uniting numerous central neurons within the brain.

Brain hyperthermia as a factor inducing and potentiating neural damage The brain is the most heat-sensitive organ in the human body (Dewhirst et al. 2003). While neurons tolerate low


temperatures (at least to 30°C; Arai et al. 1993; Lucas et al. 1994), irreversible changes of neural cells start at »40°C (Iwagami 1996; Lepock 2003; Lepock et al. 1983; Willis et al. 2000), only about 3°C above quiet rest baseline. Destructive inXuence increases exponentially with slight increases above that level. The most temperaturesensitive cellular elements are mitochondrial and plasma membranes. Although all brain cells are aVected by high temperature, destruction of endothelial cells of the brain and leakage of serum proteins across the brain–blood barrier (Sharma and Hoopes 2003) are important factors in determining brain edema, the most dangerous acute complication of pathological brain hyperthermia (Dewhirst et al. 2003; Sharma 2006). Heat-induced damage occurs in diVerent brain structures, but the damage is stronger within the edemateous areas of the brain, suggesting swelling as an important co-factor of heat-induced damage of brain tissue (Sharma et al. 1998). Heat-induced brain injury is not limited to the neurons but includes glial cells and cerebral microvessels. In addition to water accumulation in the brain, hyperthermia-related leakage of the blood–brain barrier results in alterations of ionic environment and travel of some toxic substances (i.e., glutamate) to brain tissue. Although high temperature and leakage of the brain– blood barrier per se may be important for cellular damage, more often they are potentiating factors. An increase in temperature ampliWes neural damage induced by experimental hypoxia, ischemia, and cerebral trauma, while hypothermia is neuroprotective (Busto et al. 1987; Maier and Steinberg 2003; Miyazawa et al. 2003; Olsen et al. 2003). For example, hyperthermia potentiates the cytotoxic eVects of reactive oxygen species in vitro (Lin et al. 1991) and glutamate-induced neurotoxicity (Suehiro et al. 1999). While prevention of fever and mild hypothermia may be important therapeutic tools to minimize the extent and severity of neural damage associated with these pathological conditions, it is unknown how brain temperature is changed during these conditions.

Brain hypothermia during general anesthesia Barbiturates have a strong inhibitory eVect on brain metabolism and temperatures (Crane et al. 1978; Hayward and Baker 1968; Michenfelder 1988), an action related to their ability to induce general anesthesia (Sessler 2000). To study brain–body temperature homeostasis during barbiturate anesthesia, we examined changes in brain (anterior hypothalamus and hippocampus), body core, and skin temperature following sodium pentobarbital (50 mg/kg) injected under normal conditions (23°C) and during body warming (37°C) (Kiyatkin and Brown 2005).

9

At 23°C pentobarbital decreased temperatures in each recording location (Fig. 4a–c). Although basal temperatures in the hypothalamus and body core were similar and higher than in hippocampus and skin (a), the decrease, as a relative change, was stronger in both brain structures than in body core (b, c), suggesting metabolic brain inhibition and diminished heat production as a primary factor of brain hypothermia. In contrast, the decrease was weaker in skin than in body core, resulting in a rapid and prolonged increase in skin–body temperature diVerential. This relative skin warmth is associated with enhanced heat release via skin surfaces, contributing to hypothermia. While body warming (applied at 10 min after drug administration) decreased pentobarbital-induced hypothermia (a, b), it was unable to compensate for it completely. Decreases in brain– body core diVerentials became greater and more prolonged with body warming, suggesting that this procedure is less eVective at inXuencing brain than body temperatures. Figure 5 shows changes in absolute and relative temperatures as well as between-site temperature diVerentials during the initiation of anesthesia (left panel; hatched line is drug injection) and awakening from anesthesia (right panel; hatched line is the Wrst head movement), analyzed at higher temporal resolution. Immediately after pentobarbital administration, brain and body temperature increased, reXecting the arousing eVect of the procedure of injection. From the fourth minute, however, brain temperature decreased rapidly and brain–body diVerentials became inverted, reXecting the drug’s action. Similar to other arousing stimuli, skin temperature, as a relative change, decreased after pentobarbital injection, but it began to increase from »4 min, reXecting drug-induced peripheral vasodilatation and enhanced heat loss. Awakening from anesthesia was preceded by a gradual increase in temperature with the greatest acceleration at the time of the Wrst movement. These data complement observations suggesting selective brain cooling during anesthesia induced by diVerent drugs. While in the awake animals and humans brain temperatures in diVerent locations are similar, or slightly higher, than body temperature (Hayward and Baker 1968; Mariak et al. 1998, 1999, 2000), these relationships become inverted during anesthesia. In cats, for example, during halothane and pentobarbital anesthesia with body warming cortical tissue was, respectively, 1.0 and 1.8°C colder than body core (Erikson and Lanier 2003). Similar negative brain–body temperature diVerentials were found during pentobarbital anesthesia in dogs (Wass et al. 1998), urethane anesthesia in rats (Moser and Mathiesen 1996), and anesthesia induced by alpha-chloralose and chloral hydrate in rats (Zhu et al. 2004). In the latter study, when alphachloralose was combined with body warming, the diVerence between cortex and core body reached 4.3°C. In

123

10


Fig. 4 Changes in temperature in brain sites (MPAH medial preoptic area of hypothalamus; Hippo hippocampus), skin and body core (a absolute; b relative; c between-site diVerences) during pentobarbital anesthesia (50 mg/ kg, ip injected at 0 min). Filled symbols show values signiWcantly diVerent from the last preinjection value (P < 0.05)

contrast to our study, these evaluations were performed in acute experiments often with an open skull and electrodes that were not properly thermo-isolated. Although these experimental conditions would result in brain cooling and undervalued brain temperatures, especially in superWcial recording sites and on small animals, these Wndings suggest that anesthesia may invert normal brain–body temperature homeostasis. Barbiturate anesthesia also decreases brain and rectal temperatures in humans, making the positive brain–body temperature diVerence smaller than in drug-free conditions (Rumana et al. 1998). Although the diVerences between brain and body core temperatures in awake animals and humans are minimal and the brain may become cooler than body during general anesthesia, it is unclear whether arterial blood arriving to the brain can be warmer than brain tissue during anesthesia. To test this possi-

123

bility, we simultaneously recorded brain (hypothalamus and hippocampus) and arterial blood temperatures during pentobarbital anesthesia (unpublished observations). As shown in Fig. 6, hypothalamic temperature is about 0.5°C higher than aortal temperature under quiet resting conditions, and the diVerence increases during activation (placement in the cage, 3-min tail-pinch and social interaction with a female). After pentobarbital injection, the temperature diVerence between the hypothalamus and arterial blood decreases rapidly, reaching its minima (»0.1°C) at »90 min after drug injection. The diVerence, however, remains positive within the entire period of anesthesia. Awakening from anesthesia is preceded by a gradual increase in hypothalamus–blood diVerential, which peaks at the time of the Wrst head movement. Although changes in hippocampal temperature mirror those in hypothalamus, basal temperature in hippocampus is equal to that in


11

Fig. 5 Changes in temperature during the initiation of pentobarbital anesthesia (Wrst 10 min after injection of sodium pentobarbital at 0 min) and awakening from anesthesia (ten minutes before and after the Wrst head movement). Filled symbols show values signiWcantly diVerent from the last pre-injection (left) or pre-movement (right) values (P < 0.05)

Fig. 6 Original records of temperature changes in two brain structures (Hpt medial-preoptic area of hypothalamus; Hip hippocampus), skin and arterial blood during tail-pinch (TP, 3min), social interaction with female (SI 3-min), and pentobarbital anesthesia (50 mg/kg, ip). The last vertical line shows the moment of awakening. Top graphs show absolute temperatures and lower graphs show temperature diVerences between each of the brain strictures and arterial blood

123

12

abdominal aorta. During physiological activation, hippocampal temperature becomes higher than in arterial blood but is lower during anesthesia.

Drug-induced brain hyperthermia Methamphetamine (METH) and MDMA (ecstasy) are widely used psychomotor stimulant drugs. Production of amphetamine-like stimulants (i.e. amphetamine, METH and MDMA) is estimated at 500 t a year, with more than 40 million people using them in the past 12 months (Ecstasy and amphetamines 2003). The prevalence of abuse among youth is higher than that in the general population, and much higher than that for heroin and cocaine. In recent years abuse continues to spread in terms of geography, age, and income. Although METH is the most widely abused drug, MDMA shows the largest increases in abuse in recent years. MDMA is usually used in pill form as part of recreational, leisure time activities, thus becoming part of a “normal” lifestyle for certain groups of young people, with more than 1.4 billion tablets consumed annually. METH, in contrast, is typically injected, snorted or smoked, and is associated with heavy abuse, severe psychological problems, and addiction (Ecstasy and amphetamines 2003). Both these drugs increase metabolism and induce hyperthermia (Green et al. 2003; Mechan et al. 2001; Sandoval et al. 2000), which is an important contributor to pathological changes associated with both acute intoxication and

Fig. 7 Temperature changes (a absolute, b brain–muscle diVerence) after sc administration of meth-amphetamine (9 mg/kg, sc, n = 8) and MDMA (9 mg/kg, sc, n = 7). Filled symbols show values signiWcantly diVerent from the last pre-injection value (P < 0.05)

123


chronic abuse (Ali et al. 1996; Davidson et al. 2001; Kalant 2001). Both METH and MDMA are considered club drugs typically used under conditions of physical and emotional activation and often in warm and humid environment. While the eVects of any drug may be modulated by environmental conditions and speciWc activity states of the individual, these factors may be especially important for METH and MDMA because, in addition to metabolic activation, they induce peripheral vasoconstriction (Gordon et al. 1991; Pederson and Blessing 2001), thus diminishing heat dissipation from the body to the external environment. To assess how these drugs aVect brain temperature and how their eVects are modulated by environmental conditions that mimic human use, we examined temperature changes in NAcc, hippocampus and temporal muscle induced in male rats by METH and MDMA (1–9 mg/kg, sc) in quiet resting conditions at normal laboratory temperatures (23°C), during social interaction with female, and at moderately warm ambient temperatures (29°C) (Brown et al. 2003; Brown and Kiyatkin 2004, 2005). Both METH and MDMA (9 mg/kg, sc) induce hyperthermia both in brain and muscle (Fig. 7a). In both cases, the increases are stronger in brain sites than the muscle (b). Therefore, intra-brain heat production associated with metabolic brain activation appears to be the primary cause of brain hyperthermia and a factor behind more delayed and weaker body hyperthermia. While hyperthermia is stronger for METH (>3°C) than MDMA (»1.4°C), in both cases changes are prolonged and highly variable.


Hyperthermic eVects of METH and MDMA became stronger when the drugs are injected during social interaction and in a moderately warm environment (29°C), which is close to normothermy in rats (Romanovsky et al. 2002). As shown in Fig. 8, mean temperatures after METH administration increases rapidly in all animals, resulting in some animals in clearly pathological values (>41°C) and death in four of six animals. Similar changes occur with MDMA (Fig. 8). In this case, Wve of six tested animals that showed maximal temperature increases (>41°C) died within 7 h. In each case, at the moment of death, brain–muscle diVerentials rapidly inverted and the brain became relatively cooler than the body. A similar phenomenon of selective brain cooling has been described in patients with brain death (Lyson et al. 2006). Although all temperatures decreased by 2–4°C, the decrease was maximal in the brain, and brain temperature, in fact, was the lowest temperature of the body. Apparently, brain temperature lower than temperature in arterial blood

13

appears to be incompatible with ongoing brain metabolism and such temperature proWle might be speciWc to brain death. Classic features of neurotoxicity induced by amphetamine-like substances (i.e., neuronal necrosis and apoptosis) are usually linked to some toxic products (i.e., nitric oxide, catechol–quinones, peroxynitrite) of abnormally increased metabolism of endogenous neurotansmitter substances (Cadet et al. 2001; Kuhn and Geddes 2000). While these factors contribute to neural damage following chronic use of these substances, brain overheating appears to be an important factor in fatal decompensation of vital functions due to acute drug overdose. While the rise in brain temperature above certain limits (>40–41°C) may per se have direct destructive eVects on brain cells (Iwagami 1996; Lepock 2003; Willis et al. 2000), high temperatures induce progressive leakage of the brain–blood barrier with gradual water accumulation within the brain (Kiyatkin et al. unpublished observations). Both the water content and albumin immunostaining

Fig. 8 Temperature changes (a relative changes; b brain–muscle diVerentials; c NAcc changes in each rat) after administration of meth-amphetamine (METH 9 mg/kg, sc, n = 6) and MDMA (9 mg/kg, sc, n = 6) at 29°C. In both groups, NAcc temperature gradually increased after drug administration and grew to pathological levels (>41–42°C), resulting in death of most animals. Within 8 h, 5/6 animals of MDMA and 5/6 METH group died

123

14

seen in METH-treated animals are related tightly to brain temperature increases. These data conWrm previous observations that METH induces breakdown of the brain–blood barrier (Bowyer and Ali 2006; Sharma and Ali 2006), supporting the role of this mechanism in the development of brain edema—the most dangerous complication of pathological brain hyperthermia (Kalant 2001; Dewhirst et al. 2003; Sharma 2006). A powerful modulation of drug-induced toxicity by environmental conditions may explain exceptionally strong, sometimes fatal, responses of some individuals to amphetamine-like substances. Although 9 mg/kg of MDMA is a two–threefold larger dose than that typically used by humans, it corresponds to only one-sixth of the LD50 in rats (Davis et al. 1987) and does not result in lethality in normal environmental conditions. The same dose, however, is lethal for most animals in a moderately warm environment. Therefore, one (1.5 mg/kg) or two tablets of MDMA may be highly toxic in predisposed individuals if consumed in adverse environmental conditions.

Neurobiological and human implications While the brain plays an essential role in sensing Xuctuations in environmental temperature, altering heat production and loss, it is unclear whether the idea of regulation can be applied to the brain itself. This review suggests that brain temperature of the rat Xuctuates within 3°C under normal physiological conditions. It is not known yet whether these Xuctuations occur in the human brain but, based on similarities found between rats and monkeys (Hayward and Baker 1968), it appears likely. Although recording of brain temperature in humans is possible only in patients, available data suggest that this temperature is consistently higher than in the body (Mariak et al. 1994, 1998, 1999, 2000; Mcilvoy 2004; Mellergard and Nordstrom 1990; Rumana et al. 1998). These data also suggest the existence of dorso-ventral temperature gradient, with more ventrally located structures being warmer than more dorsally located structures. The degree of this gradient, however, varies depending upon the functional state of the individual and technical aspects of temperature recording. This work also suggests that human brain has no speciWc cooling mechanism (Bringelmann 1993 vs. Cabanac 1993 for alternative points of view) and brain temperature always remains higher than temperature of arterial blood during external temperature impact and hyperthermia. This review suggests that physiological brain hyperthermia is a part of normal brain functioning rather than an index of disease. Since arterial blood is cooler than brain tissue, metabolic neural activation, accompanied by intrabrain heat production, may be viewed as the primary cause

123


of physiological brain hyperthermia. CBF, therefore, not only provides oxygen and nutrients for enhanced brain metabolism but also removes potentially dangerous metabolic heat from neural tissue. While brain heat production is an obvious by-product of cerebral metabolism, physiological Xuctuations in brain temperature aVect various neural parameters ranging from the activity of single ionic channels to transmitter release and uptake. Thus, brain hyperthermia may have adaptive signiWcance, changing the dynamics of neural functions and making them more eYcient for reaching behavioral goals. Brain hyperthermia may also result from impaired heat dissipation during intense physical activity in a hot, humid environment. While under these conditions temperature in arterial blood remains cooler than in brain tissue, heat is accumulated in the brain because of progressive body warming due to an inability to dissipate metabolic heat to the external environment. While this deWcit remains compensated under quiet resting conditions, it may result in dramatic changes in temperature responses following exposure to various activating stimuli and pharmacological drugs. Brain hyperthermia may be induced also by various addictive drugs, which increase brain metabolism and impair heat dissipation. Such frequently used psychomotor stimulants as METH and MDMA induce dose-dependent brain hyperthermia, which is enhanced during physiological activation and under conditions that restrict heat dissipation. Because high temperature exacerbates drug-induced toxicity and is destructive to neural cells and brain functions, pathological brain hyperthermia (>40°C) is an important contributor to both acute life-threatening complications and chronic destructive CNS changes induced by psychomotor stimulants. Although humans have more eVective mechanisms for heat dissipation than rats, this drug-activity-environment interaction is important for understanding potential health hazards of these drugs of abuse, which are typically taken during high-energy activity in a hot, humid environment that prevents heat dissipation from the brain and body. Brain hyperthermia may develop during several pathological conditions (head trauma, ischemic and necrotic damage), which are accompanied by neural cell damage, inXammation and impairment of venous blood outXow from the brain, even under conditions of decreased brain metabolism and relatively normal body temperatures. These abnormalities in brain–body temperature homeostasis make these patients especially sensitive to fever and environmental over-heating, which both increase the extent of neural damage and mortality. This review indicates that monitoring of brain temperatures in animals is a valuable tool for assessment of alterations in metabolic neural activity induced by environmental


stimuli or drugs and occurring during the development and performance of motivated behaviors. Although heat production is a basic feature of neural metabolism, locally released metabolic heat is continuously re-distributed within brain tissue and aVected by a variable inXow of cooler arterial blood, determining a similar pattern of temperature Xuctuations in diVerent brain structures. Rapid time-course temperature monitoring and determining temperature gradients between brain structures and body, muscle, or arterial blood allow one to reveal between-structure diVerences and peaks of neural activation. Brain temperature Xuctuation, however, is a diVerent reXection of neural activity than a change in neuronal electrical discharges. While the relationships between these parameters remain unclear and need to be clariWed in the future, similar to neuronal discharges brain temperatures are aVected by various salient sensory stimuli and drugs, show consistent changes during learning, and Xuctuate during motivated behavior, tightly correlating with key behavioral events. Acknowledgments I would like to thank Paul Leon Brown and David Bae for valuable comments regarding this manuscript. This research was supported by the Intramural Research Program of the NIH, NIDA.

References Abrams R, Hammel HT (1964) Hypothalamic temperature in unanesthetized albino rats during feeding and sleeping. Am J Physiol 206:641–646 Ali SF, Newport GD, Slikker W (1996) Methamphetamine-induced dopaminergic toxicity in mice: role of environmental temperature and pharmacological agents. Ann NY Acad Sci 801:187–198 Arai H, Uto A, Ogawa Y, Sato K (1993) EVect of low temperature on glutamate-induced intracellular calcium accumulation and cell death in cultured hippocampal neurons. Neurosci Lett 163:132–134 Baker M, Cronin M, Mountjoy D (1976) Variability of skin temperature in the waking monkey. Am J Physiol 230:449–455 Berner NJ, Heller HC (1998) Does the preoptic anterior hypothalamus receive thermoaVerent information? Am J Physiol 274:R9–R18 Blumberg MS, Mannella JA, Moltz H (1987) Hypothalamic temperature and deep body temperature during copulation in the male rat. Physiol Behav 39:367–370 Bohlen JG, Held JP, Sanderson MO, Patterson RP (1984) Heart rate, rate-pressure product and oxygen uptake during four sexual activities. Arch Intern Med 144:1745–1748 Boulant JA (2000) The role of preoptic-anterior hypothalamus in thermoregulation and fever. 31, Suppl 5:S157–S161 Bowyer JF, Ali S (2006) High doses of methamphetamine that cause disruption of the blood–brain barrier in limbic regions produce extensive neuronal degeneration in mouse hippocampus. Synapse 60:521–532 Brengelmann GL (1993) Specialized brain cooling in humans? FASEB J 7:1148–1153 Brown PL, Kiyatkin EA (2004) Brain hyperthermia induced by MDMA (“ecstasy”): modulation by environmental conditions. Eur J Neurosci 20:51–58 Brown PL, Kiyatkin EA (2005) Fatal intra-brain heat accumulation induced by meth-amphetamine at normothermic conditions in rats. Intern J Neuroprot Neuroregen 1:86–90

15 Brown PL, Wise RA, Kiyatkin EA (2003) Brain hyperthermia is induced by methamphetamine and exacerbated by social interaction. J Neurosci 23:3924–3929 Burgoon PW, Boulant JA (2001) Temperature-sensitive properties of rat suprachiasmatic nucleus neurons. Am J Physiol 281:R706– R715 Busto R, Dietrich WD, Globus MYT, Valdes I, Scheinberg R, Ginsberg MD (1987) Small diVerences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:729–738 Cabanac M (1993) Selective brain cooling in humans: “fancy” or fact? FASEB J 7:1143–1147 Cadet JL, Thiriet N, Jayanthi S (2001) Involvement of free radicals in MDMA-induced neurotoxicity in mice. Ann Med Intern 152(Suppl. 3):IS57–IS59 Charkoudian N (2003) Skin blood Xow in adult human thermoregulation: how it works, when it does not, and why? Mayo Clin Proc 78:603–612 Cheuvront SN, Haymes EM (2001) Thermoregulation and marathon running: biological and environmental inXuences. Sports Med 31:743–762 Crane P, Braun L, Cornford E, Cremer J, Glass J, Oldendorf M (1978) Dose-dependent reduction of glucose utilization by pentobarbital in rat brain. Stroke 9:12–18 Davidson C, Gow AJ, Lee TH, Ellinwood EH (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Rev 36:1–22 Davis WM, Hatoum HT, Walters IW (1987) Toxicity of MDA (2,4methylenedioxyamphetamine) considered for relevance to hazards of MDMA (ecstasy) abuse. Alcohol Drug Res 7:123–134 Delgado JMR, Hanai T (1966) Intracerebral temperatures in free-moving cats. Am J Physiol 211:755–769 Dewhirst MW, Viglianti BL, Lora-Michiels M, Hanson M, Hoopes PJ (2003) Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia. Int J Hyperthermia 19:267–294 Ecstasy and amphetamines. Global survey 2003. United Nations Publication, New York Erikson K, Lanier W (2003) Anesthetic technique inXuences brain temperature, independently of core temperature, during craniotomy in cats. Anesth Analg 96:1460–1466 Feitelberg S, Lampl H (1935) Warmetonung der Grosshirnrinde bei Erregung und Ruhe. Functionshemmung Arch exp Path Pharmak 177:726–736 Fox RT, Raichle ME (1986) Focal physiological uncoupling of cerebral blood Xow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci 83:1140– 1144 Gerasimov V (1998) Information processing in human body. http://vadim.www.media.mit.edu/MAS862/Project.html Goldfarg AN (1970) Energy cost of sexual activity. Arch Intern Med 126:526 Gordon CJ, Heath JE (1986) Integration and central processing in temperature regulation. Ann Rev Physiol 48:595–612 Gordon CJ, Watkinson WO, O’Callaghan JP, Miller DB (1991) EVects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat. Pharmacol Biochem Behav 38:339–344 Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463– 508 Guatteo E, Chung KK, Bowala TK, Bernardi G, Mercuri ND, Lipski J (2005) Temperature sensitivity of dopaminergic neurons of the substantia nigra pars compacta: involvement of transient receptor potential; channels. J Neurophysiol 94:3069–3080

123

16 Hayward JN, Baker MA (1968) Role of cerebral arterial blood in the regulation of brain temperature in the monkey. Am J Physiol 215:389–403 Hodgkin AL (1967) The conduction of the nervous impulse. Liverpool University Press, Liverpool Horvath TL, Warden CH, Hajos M, Lombardi A, Goglia F, Diano S (1999) Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 19:10417–10427 Ide K, Secher NH (2000) Cerebral blood Xow and metabolism during exercise. Prog Neurobiol 61:397–414 Ide K, Schmalbruch IK, QuistorV B, Horn A, Secher NH (2000) Lactate, glucose, and oxygen uptake in human brain during recovery from maximal exercise. J Physiol 522:159–164 Iwagami Y (1996) Changes in ultrastructure of human cell related to certain biological responses under hyperthermic culture condition. Human Cell 9:353–366 James W (1892) Psychology. Briefer course. Henry Holt, New York Kalant H (2001) The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. Can Med Assoc J 165:917–928 Katz B, Miledi R (1965) The eVect of temperature on the synaptic delay at the neuromuscular junction. J Physiol 181:656–670 Kiyatkin EA (1988) Functional properties of presumed dopamine-containing and other ventral tegmental area neurons in conscious rats. Intern J Neurosci 42:21–43 Kiyatkin EA (2005) Brain hyperthermia as physiological and pathological phenomena. Brain Res Rev 50:27–56 Kiyatkin EA, Brown PL (2005) Brain and body temperature homeostasis during sodium pentobarbital anesthesia with and without body warming in rats. Physiol Behav 84:563–570 Kiyatkin EA, Mitchum R (2003) Fluctuations in brain temperatures during sexual behavior in male rats: an approach for evaluating neural activity underlying motivated behavior. Neuroscience 119:1169–1183 Kiyatkin EA, Stein EA (1993) Behavior-associated changes in blood pressure during heroin self-administration. Pharmacol Biochem Behav 46:561–567 Kiyatkin EA, Brown PL, Wise RA (2002) Brain temperature Xuctuation: a reXection of functional neural activation. Eur J Neurosci 16:164–168 Kovalzon VM (1972) Brain temperature variations during natural sleep and arousal in white rats. Physiol Behav 10:667–670 Kuhn DM, Geddes TJ (2000) Molecular footprints of neurotoxic amphetamine action. Ann NY Acad Sci 914:92–103 Laughlin SB, de Ruyter van Steveninck RR, Anderson JC (1998) The metabolic cost of neural information. Nature Neurosci 1:36–41 Lee JCF, Callaway JC, Foehring RC (2005) The eVects of temperature on calcium transients and Ca2+-dependent afterhyperpolarizations in neocortical pyramidal neurons. J Physiol 93:2012–2020 Lepock JR (2003) Cellular eVects of hyperthermia: relevance to the minimum dose for thermal damage. Int J Hyperthermia 19:252–266 Lepock JR, Cheng K-H, Al-Qysi H, Kruuv J (1983) Thermotropic lipid and protein transitions in Chinese hamster lung cell membranes: relationship to hyperthermic cell killing. Can J Biochem Cell Biol 61:421–427 Lin PS, Quamo S, Ho KC, Gladding J (1991) Hyperthermia enhances the cytotoxic eVects of reactive oxygen species to Chinese hamster cells and bovine endothelial cells in vitro. Radiat Med 126:43–51 Lucas JH, Emery DG, Wang G, Rosenberg-SchaVer LJ, Jordan RS, Gross GW (1994) In vitro investigation of the eVect of nonfreezing low temperatures on leasoned and uninjured mammalian spinal neurons. J Neurotrauma 11:35–61 Lyson T, Jadeszko M, Mariak Z, Kochanowicz J, Lewko J (2006) Intracerebrain temperature measurements in brain death. Neurol Neurosurg Pol 40:269–275

123

Eur J Appl Physiol (2007) 101:3–17 Maier CM, Steinberg GK (2003) Hypothermia and cerebral ischemia. Humana Press, New York Margaria R, Cretelli P, Aghemo P, Sassi G (1963) Energy cost of running. J Appl Physiol 18:367–370 Mariak Z, Lewko J, Luczaj J, Polocki B, White MD (1994) The relationship between directly measured human cerebral and tympanic temperatures during changes in brain temperature. Eur J Appl Physiol Occup Physiol 69:545–549 Mariak Z, Jadeszko M, Lewko J, Lebkowski W, Lyson T (1998) No speciWc brain protection against thermal stress in fever. Acta Neurochir (Wien) 140:585–590 Mariak Z, Lebkowski W, Lyson T, Lewko J, Piekarski P (1999) Brain temperature during craniotomy in general anesthesia. Neurol Neurochir Pol 33:1325–1327 Mariak Z, Lyson T, Peikarski P, Lewko J, Jadeszko M, Szydlik P (2000) Brain temperature in patients with central nervous system lesions. Neurol Neurosurg Pol 34:509–522 Masters WH, Johnson VE (1966) Human sexual response. Little, Brown and Co., Boston McElligott JC, Melzack R (1967) Localized thermal changes evoked in the brain by visual and auditory stimulation. Exp Neurol 17:293–312 Mcilvoy L (2004) Comparison of brain temperature to core temperature: a review of the literature. J Neurosci Nurs 36:23–31 Mechan AO, O’Shea E, Elliot JM, Colado MI, Green AR (2001) A neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) to rats results in a long-term deWcit in thermoregulation. Psychopharmacology 155:413–418 Mekjavic IB, Eiken O (2005) Contribution of thermal and nonthermal factors to the regulation of body temperature in mammals. J Appl Physiol 100:2065–2072 Mellergard P, Nordstrom CH (1990) Epidural temperatures and possible intracerebral temperature gradients in man. Br J Neurosurg 4:31–38 Michenfelder J (1988) Anesthesia and the brain: clinical, functional and vascular correlates. Churchill Livingstone, New York Mitchum R, Kiyatkin EA (2004) Brain hyperthermia and temperature Xuctuations during sexual interaction in female rats. Brain Res 1000:110–122 Miyazawa T, Tamara A, Fukui S, Hossmann KA (2003) EVects of mild hypothermia on focal cerebral ischemia: review of experimental studies. Neurol Res 25:457–464 Moriyama E (1990) Cerebral blood Xow changes during localized hyperthermia. Neurol Med Chir (Tokio) 30:923–929 Moser E, Mathiesen L (1996) Relationships between neuronal activity and brain temperature in rats. Neuroreport 78:1876–1880 Moser E, Mathiesen I, Andersen P (1993) Association between brain temperature and dentate Weld potentials in exploring and swimming rats. Science 259:1324–1326 Nadel E (2003) Regulation of body temperature. In: Boron WF, Boulpaep EL (eds) Medical physiology. Saunders, Philadelphia, pp 1231–1241 Nagata Y, Katayama K, Manivel CJ, Song CW (2000) Changes in blood Xow in locally heated intestine of rats. Int J Hyperthermia 16:159–170 Nakajima T, Rhee JG, Song CW, Onoyama Y (1992) EVect of a second heating on rat liver blood Xow. Int J Hyperthermia 8:679– 687 Nakashima K, Todd MM (1996) EVects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke 27:913–918 Nybo L, Secher NH, B. Nielson B (2002) Inadequate heat release from the human brain during prolonged exercise with hyperthermia. J Physiol 545:697–704 Olsen TS, Weber UJ, Kammersgaard LP (2003) Therapeutic hypothermia for acute stroke. Lancet Neurol 2:410–416

Eur J Appl Physiol (2007) 101:3–17 Oobu K (1993) Experimental studies on the eVect of heating on blood Xow in the tongue of golden hamsters Fukuoka Igaku Zasshi 84:497–511 Pederson NP, Blessing WW (2001) Cutaneous vasoconstriction contributes to hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy) on conscious rabbits. J Neurosci 21:8648– 8654 Raichle ME (2003) Functional brain imaging and human brain functions J Neurosci 23:3959–3962 Ritchie JM (1973) Energetic aspects of nerve conduction: the relationships between heat production, electrical activity and metabolism. Prog Biophys Mol Biol 26:147–187 Romanovsky AA, Ivanov AI, Shimansky YP (2002) Ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality. J Appl Physiol 92:2667–2679 RosomoV HL (1957) Hypothermia and cerebral varcular lesions. II. Experimental interruption followed by induction of hypothermia. Arch Neurol Psych 78:454–464 Rowell LB (1983) Cardiovascular aspects of human thermoregulation. Circ Res 52:367–376 Ruby NF, Heller HC (1996) Temperature sensitivity of the suprachiasmatic nucleus of ground squirrels and rats in vitro. J Biol Rhythms 11:126–136 Rumana CS, Gopinath SP, Uzura M, Valadka AB, Robertson CS (1998) Brain temperatures exceeds systemic temperatures in head-injured patients. Clin Care Med 26:562–567 Ryan KL, Taylor WF, Bishop VS (1997) Arterial baroreXex modulation of heat-induced vasodilation in the rabbit ear. J Appl Physiol 83:2091–2097 Sandoval V, Hanson GR, Fleckenstein AE (2000) Methamphetamine decreases mouse striatal dopamine transporter activity: roles of hyperthermia and dopamine. Eur J Pharmacol 409:265–271 SatinoV E (1978) Neural organization and evolution of thermal regulation in mammals. Schence 201:16–22 Schaefer CF (1979) Possible teratogenic hyperthermia and marathon running. JAMA 241:1892 Schmidt-Nielsen K (1997) Animal physiology. Adaptation and environment, 5th edn, Cambridge University Press, Cambridge Serota HM (1939) Temperature changes in the cortex and hypothalamus during sleep. J Neurophysiol 2:42–47 Serota HM, Gerard RW (1938) Localized thermal changes in cat’s brain. J Neurophysiol 1:115–124 Sessler D (2000) Perioperative heat balance. Anesthesiology 92:578– 596 Siesjo B (1978) Brain energy metabolism. Wiley, New York Sharma HS (2006) Hyperthermia-induced brain aedema: current status and future perspectives. Indian J Med Res 123:629–652 Sharma HS, Ali SF (2006) Alterations in blood–brain barrier function by morphine and methamphetamine. Ann NY Acad Sci 1074:198–224 Sharma HS, Hoopes PJ (2003) Hyperthermia-induced pathophysiology of the central nervous system. Int J Hyperthermia 19:325–354 Sharma HS, Alm P, Westman J (1998) Nitric oxide and carbon monoxide in the pathophysiology of brain functions in heat stress. Prog Brain Res 115:297–333

17 Shulman RG, Rothman DL, Behar KL, Hyder F (2004) Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci 27:489–495 SokoloV L (1999) Energetics of functional activation in neural tissues. Neurochem Res 24:321–329 Suehiro E, Fujisawa H, Ito H, Ishikawa T, Maekawa T (1999) Brain temperature modiWes glutamate neurotoxicity in vivo. J Neurotrauma 16:285–297 Sukstanskii AL, Yablonskiy DA (2006) Theoretical model of temperature regulation in the brain during changes in functional activity. Proc Natl Acad Sci 103:12144–12149 Swan H (1974) Thermoregulation and bioenergetics. Elsevier, New York Thompson SM, Musakawa LM, Rince DA (1985) Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro. J Neurosci 5:817–824 Travis KA, Bockholt HJ, Zardetto-Smith AM, Johnson AK (1995) In vitro thermorensitivity of the midline thalamus. Brain Res 686:17–22 Trubel HKF, Sacolick LI, Hyder F (2006) Regional temperature changes in the brain during somatosensory stimulation, J Cereb Blood Flow Metab 26:68–78 Tryba AK, Ramirez J-M (2004) Hyperthermia modulates respiratory pacemaker bursting properties. J Neurophysiol 92:2844–2852 Uda M, Tanaka Y (1990) Arterial blood Xow changes after hyperthermia on normal liver, normal brain, and normal small intestine. Gan No Rinsho 36:2362–2366 Vizi ES (1998) DiVerent temperature dependence of carrier-mediated (cytoplasmic) and stimulus-evoked (exocytotic) release of transmitter: a simple method to separate the two types of release. Neurochem Int 33:359–356 Volgushev M, Vidyasagar TR, Chistiakova M, Eysel UT (2000) Synaptic transmission in the neocortex during reversible cooling. Neuroscience 98:9–22 Wass C, Cable D, SchaV H, Lanier W (1998) Anesthetic technique inXuences brain temperature during cardiopulmonary bypass in dogs. Ann Thorac Surg 65:454–460 Willis WT, Jackman MR, Bizeau ME, Pagliassotti MJ, Hazel JR (2000) Hyperthermia impairs liver mitochondrial functions. Am J Physiol 278:R1240–R1246 Xie T, McGann UD, Kim S, Yuan J, Ricaurte GA (2000) EVect of temperature on dopamine transporter function and intracellular accumulation of methamphetamine: implications for methamphetamine-induced dopaminergic neurotoxicity. J Neurosci 20:7838–7845 Yablonskiy DA, Ackerman JH, Raichle ME (2000) Coupling between changes in human brain temperature and oxidative metabolism during prolonged visual stimulation. Proc Natl Acad Aci 97:7603–7608 Zhu M, Nehra D, Ackerman J, Yablonskiy DA (2004) On the role of anesthesia on the body/brain temperature diVerential in rats. J Thermal Biol 29:599–603

123