REM sleep related increase in brain temperature: a physiologic problem

The roles of metabolic heat production, arterial blood flow and temperature in the genesis of the brain temperature increase related to REM sleep occurrence in several mammalian species are discussed on the basis of available experimental evidence. The experimental data show that only changes in arterial blood flow and temperature consistently underlie the rise in brain temperature in presence (cat) or absence (rabbit) of the carotid rete. The alteration of cardiovascular regulation in REM sleep is the remote cause of such rise. The proximate causes are decrease in carotid blood supply and increase in vertebral blood supply to the brain and related depression of systemic and selective brain cooling.     

Selective Brain Cooling Reduces Water Turnover in Dehydrated Sheep

In artiodactyls, arterial blood destined for the brain can be cooled through counter-current heat exchange within the cavernous sinus via a process called selective brain cooling. We test the hypothesis that selective brain cooling, which results in lowered hypothalamic temperature, contributes to water conservation in sheep. Nine Dorper sheep, instrumented to provide measurements of carotid blood and brain temperature, were dosed with deuterium oxide (D₂O), exposed to heat for 8 days (40◦C for 6-h per day) and deprived of water for the last five days (days 3 to 8). Plasma osmolality increased and the body water fraction decreased over the five days of water deprivation, with the sheep losing 16.7% of their body mass. Following water deprivation, both the mean 24h carotid blood temperature and the mean 24h brain temperature increased, but carotid blood temperature increased more than did brain temperature resulting in increased selective brain cooling. There was considerable inter-individual variation in the degree to which individual sheep used selective brain cooling. In general, sheep spent more time using selective brain cooling, and it was of greater magnitude, when dehydrated compared to when they were euhydrated. We found a significant positive correlation between selective brain cooling magnitude and osmolality (an index of hydration state). Both the magnitude of selective brain cooling and the proportion of time that sheep spent selective brain cooling were negatively correlated with water turnover. Sheep that used selective brain cooling more frequently, and with greater magnitude, lost less water than did conspecifics using selective brain cooling less efficiently. Our results show that a 50kg sheep can save 2.6L of water per day (~60% of daily water intake) when it employs selective brain cooling for 50% of the day during heat exposure. We conclude that selective brain cooling has a water conservation function in artiodactyls.     

Absence of selective brain cooling in unrestrained baboons exposed to heat

To test whether baboons are capable of implementing selective brain cooling, we measured, every 5 min, the temperature in their hypothalamus, carotid arterial bloodstream, and abdominal cavity. The baboons were unrestrained and exposed to 22 degrees C for 7 days and then to a cyclic environment with 15 degrees C at night and 35 degrees C during the day for a further 7 days. During the latter 7 days some of the baboons also were exposed to radiant heat during the day. For three days, during heat exposure, water was withheld. At no time was the hypothalamus cooler than carotid arterial blood, despite brain temperatures above 40 degrees C. With little variation, the hypothalamus was consistently 0.5 degrees C warmer than arterial blood. At high body temperatures, the hypothalamus was sometimes cooler than the abdomen. Abdominal temperature was more variable than arterial blood and tended to exceed arterial blood temperature at higher body temperatures. Hypothalamic temperature cooler than a warm abdomen is not evidence for selective brain cooling. In species that can implement selective brain cooling, the brain is most likely to be cooler than carotid arterial blood when an animal is hyperthermic, during heat exposure, and also dehydrated and undisturbed by human presence. When we exposed baboons to high ambient temperatures while they were water deprived and undisturbed, they never implemented selective brain cooling. We conclude that baboons cannot implement selective brain cooling and can find no convincing evidence that any primate species can do so.     

Non-thermal signals govern selective brain cooling in pigs

We used implanted miniature data loggers and fine thermistors to measure arterial blood and brain temperatures in four female pigs, to a resolution of 0.04 °C, every 5 min, for 4 weeks. Within that period, pigs were exposed on different days, and in random order, to a cold (5 °C) or hot (38 °C) environment. In the thermoneutral environment of the pigs' home pens, brain temperature was usually lower than blood temperature. Such selective brain cooling was absent for 2 days after surgery, during handling and transport stress, and on waking. The magnitude of selective brain cooling was greatest when pigs were sleeping and body temperatures were low, and was smallest, or even absent, during hyperthermia and natural fever. Our results showed that selective brain cooling was present in pigs, but there was no clear relationship between blood temperature and the magnitude of selective brain cooling. Instead, the degree of selective brain cooling in pigs was governed by non-thermal factors, especially those associated with high sympathetic nervous system activity. Our results further support the concept that selective brain cooling does not serve to protect the brain from thermal damage during heat stress. Accepted: 14 September 1999     

Adaptive heterothermy and selective brain cooling in arid-zone mammals

Adaptive heterothermy and selective brain cooling are regarded as important thermal adaptations of large arid-zone mammals. Adaptive heterothermy, a process which reduces evaporation by storing body heat, ought to be enhanced by ambient heat load and by water deficit, but most mammals studied fail to show at least one of those attributes. Selective brain cooling, the reduction of brain temperature below arterial blood temperature, is most evident in artiodactyls, which possess a carotid rete, and traditionally has been considered to protect the brain during hyperthermia. The development of miniature ambulatory data loggers for recording body temperature allows the temperatures of free-living wild mammals to be measured in their natural habitats. All the African ungulates studied so far, in their natural habitats, do not exhibit adaptive heterothermy. They have low-amplitude nychthemeral rhythms of temperature, with mean body temperature over the night exceeding that over the day. Those with carotid retes (black wildebeest, springbok, eland) employ selective brain cooling but zebra, without a rete, do not. None of the rete ungulates, however, seems to employ selective brain cooling to prevent the brain overheating during exertional hyperthermia. Rather, they use it at rest, under moderate heat load, we believe in order to switch body heat loss from evaporative to non-evaporative routes.     

一种硬膜外局部低温方法的降温效能和安全性研究

目的应用自制降温线圈发展一种硬膜外局部低温治疗方法,对其降温效能和安全性进行评估。方法SD大鼠随机分为常温对照组（Nor组）、硬膜外局部低温组（LH组）和全身低温组（SH组）,对LH组和SH组分别实施硬膜外局部降温和全身降温,观察降温前后同侧脑温、对侧脑温、肛温以及呼吸、心率、血压变化,降温后24h对各组大鼠进行神经功能评测,取脑组织标本行光镜、电镜检查,并检测脑组织水、钠、钾离子含量和血脑屏障通透性。结果降温后,LH组大鼠的降温侧脑温在数分钟内从（36．5±0．3）℃下降到（31．4±0．4）℃并维持稳定,其对侧脑温和肛温无明显下降,R、HR和MABP无明显变化;SH组降温后双侧脑温、肛温均出现降低,降温后HR下降。降温后,LH组和SH组大鼠神经功能评分正常,光镜和电镜下脑组织无损伤表现,其脑组织水、钠、钾离子含量和血脑屏障通透性与常温对照组比较无统计学差异。结论应用这种硬膜外局部低温方法可以达到与全身降温一样的效果,且不会引起生命体征波动及对脑组织产生急性损害。     

Dehydration increases the magnitude of selective brain cooling independently of core temperature in sheep

By cooling the hypothalamus during hyperthermia, selective brain cooling reduces the drive on evaporative heat loss effectors, in so doing saving body water. To investigate whether selective brain cooling was increased in dehydrated sheep, we measured brain and carotid arterial blood temperatures at 5-min intervals in nine female Dorper sheep (41 +/- 3 kg, means +/- SD). The animals, housed in a climatic chamber at 23 degrees C, were exposed for nine days to a cyclic protocol with daytime heat (40 degrees C for 6 h). Drinking water was removed on the 3rd day and returned 5 days later. After 4 days of water deprivation, sheep had lost 16 +/- 4% of body mass, and plasma osmolality had increased from 290 +/- 8 to 323 +/- 9 mmol/kg (P < 0.0001). Although carotid blood temperature increased during heat exposure to similar levels during euhydration and dehydration, selective brain cooling was significantly greater in dehydration (0.38 +/- 0.18 degrees C) than in euhydration (-0.05 +/- 0.14 degrees C, P = 0.0008). The threshold temperature for selective brain cooling was not significantly different during euhydration (39.27 degrees C) and dehydration (39.14 degrees C, P = 0.62). However, the mean slope of lines of regression of brain temperature on carotid blood temperature above the threshold was significantly lower in dehydrated animals (0.40 +/- 0.31) than in euhydrated animals (0.87 +/- 0.11, P = 0.003). Return of drinking water at 39 degrees C led to rapid cessation of selective brain cooling, and brain temperature exceeded carotid blood temperature throughout heat exposure on the following day. We conclude that for any given carotid blood temperature, dehydrated sheep exposed to heat exhibit selective brain cooling up to threefold greater than that when euhydrated.     

Activity, blood temperature and brain temperature of free-ranging springbok

We used miniature data loggers to record temperature and activity in free-ranging springbok (Antidorcas marsupialis) naturally exposed to severe nocturnal cold and moderate diurnal heat. The animals were active throughout the day and night, with short rests; the intensity of activity increased during daylight. Arterial blood temperature, averaged over many days, exhibited a circadian rhythm with amplitude <1 °C, but with a wide range which resulted from sporadic rapid deviations of body temperature. Peak blood temperature occurred after sunset. Environmental thermal loads had no detectable effect on blood temperature, even though globe temperature varied by >10 °C from day to day and >20 °C within a day. Brain temperature increased approximately linearly with blood temperature but with a slope <1, so that selective brain cooling tended to be activated at high body temperature, but without a precise threshold for the onset of brain cooling. Low activity attenuated selective brain cooling and high activity abolished it, even at high brain temperature. Our results support the concept that selective brain cooling serves to modulate thermoregulation rather than to protect the brain against heat injury. Accepted: 7 January 1997     

Brain thermal inertia,but no evidence for selective brain cooling,in free-ranging western grey kangaroos (<Emphasis Type="Italic">Macropus fuliginosus</Emphasis>)

Marsupials reportedly can implement selective brain cooling despite lacking a carotid rete. We measured brain (hypothalamic) and carotid arterial blood temperatures every 5 min for 5, 17, and 63 days in spring in three free-living western grey kangaroos. Body temperature was highest during the night, and decreased rapidly early in the morning, reaching a nadir at 10:00. The highest body temperatures recorded occurred sporadically in the afternoon, presumably associated with exercise. Hypothalamic temperature consistently exceeded arterial blood temperature, by an average 0.3°C, except during these afternoon events when hypothalamic temperature lagged behind, and was occasionally lower than, the simultaneous arterial blood temperature. The reversal in temperatures resulted from the thermal inertia of the brain; changes in the brain to arterial blood temperature difference were related to the rate of change of arterial blood temperature on both heating and cooling (P < 0.001 for all three kangaroos). We conclude that these data are not evidence for active selective brain cooling in kangaroos. The effect of thermal inertia on brain temperature is larger than might be expected in the grey kangaroo, a discrepancy that we speculate derives from the unique vascular anatomy of the marsupial brain.     

Absence of selective brain cooling in pyrogen-induced fever in rabbits

In 9 rabbits the effect of intravenous administration of E. coli pyrogen 0.5 microgram/kg on the reaction of selective brain cooling was studied at ambient temperatures of 20, 30 and 40 degrees C. In the freely moving animals the temperatures of the brain, carotid artery and nuchal muscles were measured with an accuracy down to 0.05 degree C and the temperatures of the ear pinna and nasal mucosa were measured accurate to 0.5 degree C. The respiratory rate was measured as well. It was found that the spontaneous febrile reaction without the component of passive hyperthermia failed to cause selective brain cooling, even if its temperature reached higher values than in case of brain temperature rise caused only by high ambient temperature. On the other hand, when the high ambient temperature caused thermal panting, pyrogen administration at an ambient temperature of 30 degrees C could reduce panting, while at an ambient temperature of 40 degrees C intense panting initiated prior to the appearance of the febrile reaction and was associated with the fever and outlasted it.     

Long-term Survival From Muscleinvasive Bladder Cancer With Initial Presentation of Symptomatic Cerebellar Lesion: The Role of Selective Surgical Extirpation of the Primary and Metastatic Lesion

A 59-year-old man was diagnosed with urothelial carcinoma involving an isolated cerebellar metastasis after presenting to the emergency department for headache complaints. After selective surgical excision of the symptomatic brain lesion and delayed cystectomy due to intractable hematuria, he survived 11 years without evidence of recurrence or subsequent systemic chemotherapy. He eventually expired after delayed recurrence in the lung, supraclavicular lymph node, and brain. To our knowledge, this is the only case of prolonged survival from urothelial carcinoma after selective surgical extirpation of the primary and metastatic lesion without subsequent systemic chemotherapy.Key words: Bladder cancer, Cystectomy, Metastasis, Urothelial carcinomaUsually, brain metastasis of bladder urothelial carcinoma is associated with widespread systemic disease and/or multiple brain lesions. It is exceedingly rare to have bladder cancer metastasize to the brain without evidence of additional systemic manifestations.¹ As with other forms of distant urothelial carcinoma metastasis, brain metastasis is associated with poor prognosis, with survival often less than 14 months in those with solitary brain lesions.² We report an isolated bladder urothelial carcinoma metastasis to the cerebellum with an 11-year survival fol-lowing extirpative therapy of both the primary lesion and brain metastasis.     

Behavioral state-dependent thermal feedback influencing the hypothalamic thermostat

The experimental evidence on the behavioral state-dependent compartmentalization of temperature in the central nervous system of three homeothermic species has been reviewed to address the question of how selective brain cooling influences hypothalamic temperature regulation.     

Regional blood flow changes in response to thermal stimulation of the brain and spinal cord in the Pekin duck

Summary In conscious Pekin ducks, carotid and sciatic blood flows, respiratory rate, core and skin temperatures were measured during selective thermal stimulations of the spinal cord and rostral brain stem in thermoneutral (20 °C) and warm (32 °C) ambient conditions.At thermoneutral ambient temperature selective heating of the spinal cord by 2–3 °C (to 43–44 °C) increased the carotid blood flow by 138% and the sciatic blood flow by 46%. Increase in blood flows was correlated with increased breathing rate and beak and web skin temperatures.Selective cooling of the spinal cord at warm ambient temperatures and panting reduced the blood flow in both arteries and decreased the breathing rate.Heating or cooling of the brain stem showed generally very weak but otherwise similar responses as thermal stimulation of the spinal cord. In one duck out of six there was a marked effect on regional blood flow during brain stimulation.The results show that thermal stimulation of the spinal cord exerts a marked influence on regional blood flow important in thermoregulation, whereas the lower brain stem shows only a weak thermosensitivity, and stimulation caused only small cardiovascular changes of no major consequence in thermoregulation.     

Tympanic temperatures during hemiface cooling

In adult men the left half of the head was covered with thick heat insulation, and the right hemiface was cooled by spraying a mist of water, and vigorous fanning. The subjects were immersed up to the waist in warm water (42 degrees) to achieve hyperthermia. In control sessions the subjects were rendered slightly hypothermic by preliminary exposure to cold. Under the hypothermic condition during right skin cooling, the right Tty remained low as compared with oesophageal temperature, while the left Tty was raised. Under the hyperthermic condition right hemiface cooling maintained not only the right Tty lower than oesophageal but also, to a lesser extent the left Tty, while the skin on the left side was close to core temperature. This latter result cannot be explained by conductive cooling from the skin to the tympanic membrane and implies a vascular cooling of the left Tty originating from the other side of the head. It is concluded that selective cooling of the brain takes place during hyperthermia. The main mechanism is forced vascular convection, but conductive cooling also occurs.     

Brain temperature and limits on transcranial cooling in humans: quantitative modeling results

Selective brain cooling (SBC) of varying strengths has been demonstrated in a number of mammals and appears to play a role in systemic thermoregulation. Although primates lack obvious specialization for SBC, the possibility of brain cooling in humans has been debated for many years. This paper reports on the use of mathematical modeling to explore whether surface cooling can control effectively the temperature of the human cerebrum. The brain was modeled as a hemisphere with a volume of 1.33 1 and overlying layers of cerebrospinal fluid, skull, and scalp. Each component was assigned appropriate dimensions, physical properties and physiological characteristics that were determined from the literature. The effects of blood flow and of thermal conduction were modeled using the steady-state form of the bio-heat equation. Input parameters included core (arterial) temperature: normal (37°C) or hyperthermic (40°C), air temperature: warm (30°C) or hot (40°C), and sweat evaporation rate: 0, 0.25, or 0.50 l · m⁻² · h⁻¹. The resulting skin temperatures of the model ranged from 31.8°C to 40.2°C, values which are consistent with data obtained from the literature. Cerebral temperatures were generally insensitive to surface conditions (air temperature and evaporation rate), which affected only the most superficial level of the cerebrum (≤1.5 mm) The remaining parenchymal temperatures were 0.2–0.3°C above arterial temperatures, regardless of surface conditions. This held true even for the worst-case conditions combining core hyperthermia in a hot environment with zero evaporative cooling. Modeling showed that the low surface-to-volume ratio, low tissue conductivity, and high rate of cerebral perfusion combine to minimize the potential impact of surface cooling, whether by transcranial venous flow or by conduction through intervening layers to the skin or mucosal surfaces. The dense capillary network in the brain assures that its temperature closely follows arterial temperature and is controlled through systemic thermoregulation independent of head surface temperature. A review of the literature reveals several independent lines of evidence which support these findings and indicate the absence of functionally significant transcranial venous flow in either direction. Given the fact that humans sometimes work under conditions which produce face and scalp temperatures that are above core temperature, a transcranial thermal link would not necessarily protect the brain, but might instead increase its vulnerability to environmentally induced thermal injury. Accepted: 11 March 1998     

Effect of warm rearing on temperature regulation in resting and exercising rats

1. 1.|Hypothalamic and rectal temperatures were recorded in 8 warm-reared (wr) and in 12 warm-acclimated control rats during resting in the heat and during 30 min running under thermoneutral conditions.

2. 2.|Brain and body temperatures of wr rats were significantly higher (P < 0.001) than control rats, both in normothermia as well as in hyperthermia; at rest, and also during exercise.

3. 3.|Warm-reared rats were more tolerant to heat.

4. 4.|During normothermia a weak selective brain cooling was present in control but absent in wr rats. During hyperthermia, however, the cooling intensified in control and occurred in wr rats.

5. 5.|The main strategy of adaptation to heat in wr rats is an upward resetting of the temperature set-point and increased passivity.

The vagus is inhibitory of insulin secretion under fasting conditions

The involvement of the vagus in the insulin response during the early phase of absorption of a meal has been demonstrated recently. The extent of this vagal influence was investigated during fasting in an anesthetized porcine model. Portal and systemic insulin were evaluated together with glycemia during cooling and sectioning of both cervical vagal trunks in 12 splanchnicotomized or sham-operated pigs. In sham-operated animals, portal and systemic insulin were significantly and reversibly increased by cooling (173 and 123%, respectively). Portal insulin peaked 20 min after the onset of cooling but declined slowly while cooling was still activated. In contrast, systemic insulin was increased evenly along cooling. Section of the vagus was also associated with a portal and systemic insulin increase (144 and 117%) but to a lesser extent than cooling. In both treatments, portal and systemic insulin increases were either reduced (vagal cooling) or eliminated (vagal section) in splanchnicotomized animals. We conclude that the vagus exerts an inhibitory activity on interdigestive insulin secretion that is partly mediated by the splanchnic nerves.     

Competition for cool nasal blood between trunk and brain in hyperthermic goats

An influence of brain and trunk temperatures controlled independently of each other by means of artificial heat exchangers, on the intensity of natural selective brain cooling (SBC) was studied in 6 conscious goats. Intensity of SBC was markedly enhanced by increasing brain temperature. On the other hand, a rise of trunk temperature with the cerebral temperature clamped at 39 degrees C or 40 degrees C, reduced SBC intensity in spite of a simultaneous increase in the respiratory evaporative heat loss. When brain temperature was clamped at 41 degrees C, the magnitude of SBC was essentially independent of trunk temperature. These results suggest that during hyperthermia a competition exists between trunk and brain for cool nasal blood.     

Partial Inhibition of Brain Succinate Dehydrogenase by 3-Nitropropionic Acid Is Sufficient to Initiate Striatal Degeneration in Rat

Abstract: Chronic inhibition of succinate dehydrogenase (SDH) by systemic injection of the selective inhibitor 3-nitropropionic acid (3NP) has been used as an animal model for Huntington's disease (HD). However, the mechanisms by which 3NP produces lesions in the striatum are not fully characterized. A quantitative histochemical method was developed to study the level of regional SDH inhibition resulting from intraperitoneal injection of 3NP or chronic intoxication using osmotic pumps. The results showed that (a) 3NP was an irreversible SDH inhibitor in vivo, (b) the level of SDH inhibition in the striatum (the brain region most vulnerable to 3NP) was similar to that observed in other brain regions not affected by the toxin, such as the cerebral cortex, and (c) the neurotoxic threshold of SDH inhibition in the brain was 50–60% of control levels. The present study demonstrates that the selective degeneration in the striatum observed after chronic 3NP administration cannot be ascribed to a preferential inhibition of SDH in this particular brain region. This work also suggests that the partial decrease in the activity of the respiratory chain complex II–III reported in HD patients may be sufficient to induce the selective striatal degeneration observed in this disorder.     

Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo

Neuronal activity regulates the catabolism of specific structural proteins in adult mammalian brain. Pharmacological stimulation of rat hippocampal neurons by systemic or intraventricular administration of the excitatory amino acids kainate or N-methyl-D-aspartate induces selective loss of brain spectrin and the microtubule-associated protein MAP2, as determined by quantitative immunoblotting, but not of actin, the high molecular weight neurofilament polypeptide, or glial fibrillary acidic protein. The spectrin decrease occurs primarily by enhanced proteolysis, as levels of the major breakdown products of the alpha-subunit increase more than 7-fold. This proteolysis may occur from activation of the calcium-dependent neutral protease calpain I. The immunopeptide maps produced by alpha-spectrin degradation, selective loss of spectrin and MAP2, and decrease in calpain I levels are all consistent with calpain I activation accompanied by autoproteolysis. We propose that calcium influx and calpain I activation provide a mechanism by which neuronal activity regulates the degradation of specific neuronal structural proteins and may thereby modify neuronal morphology.