The Hot Brain - Survival, Temperature, and The Human Body
The Hot Brain - Survival, Temperature, and The Human Body
Aristotle was completely wrong when he said that the brain was a cold
and bloodless organ, and therefore could not be the seat of thoughts and
feelings. However, he was correct in his intuition that to have thoughts
and feelings, a hot organ was needed. His mistake was to think that this
organ was the heart . Today we know that the brain is responsible for
maintaining a constant core body temperature .
Nature took almost 500 million years to achievethis physiological ca-
pacity , which evolved in mammals at a time when marked changes oc-
curred in the size and functions of the brain . Was a constant brain
temperature in part responsible for its further evolution ? We do not have
an answer to this question . However , with a constant core body temper -
ature, mammals were able to change their habitats. This brought about
new genetic -environmental conditions to which the brain responded ,
thus showing the plasticity of this organ.
Feeding, drinking , and sexual reward-basedbehavior are basic to sur-
vival of the individual and of the species. The control of temperature by
the brain is coded along with thesereward-basedmechanisms. Emotion,
motivation , and a sophisticated sensorimotor integration seemto form
the basis of these behaviors. But they cannot occur unless the brain is
functioning properly, and for it to do so, a constant brain temperature is
essential. In addition to these basic survival behaviors, body and brain
temperatures are implicated in many more physiological functions not
restricted to the " warm bed" of " essential" functions. They are even
tightly related to sleep. Could it be that at least one of the functions of
sleepis to prevent the brain from becoming too hot ?
x Preface
mental stress , the brain , evolution , and survival , will benefit from its con -
tent .
This excerpt from
~
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:I: J LIGHT
ENERGY
VOLCANOS
PHOTIC
ZONE
NATURAL
WATER
Figure 1.1
Illustration of a protocell suspendedin a convecting fluid heated from below,
cooled at the top, and subjected to cyclic illumination . Under these conditions,
the protocell will be thermally cycled and is the best-known example of self-
organization by a dissipative structure. (Modified from Muller 1995.)
(a)
Figure 1.2
Reactions of paramecia to changes in ambient temperature . At (a) the paramecia
were at a temperature of 19 C. In (b ) a temperature gradient was established be-
tween 26 and 38 C. In (c) the temperature gradient was from 10 to 25 C.
(Jennings 1906 .)
These experiments clearly show that unicellular organisms have the ca-
pacity to select a preferred temperature behaviorally, and therefore to
protect themselves from environmental extremes .
Thus , environmental heat was a source of deleterious stimulation " but
-- ~- -
ground
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Figure1.3
Drawingof a skunkcabbagewith the spadixin the center.(FromKnutson1974.)
The Protoneuron
25
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Figure 1.4
(A ) Temperatures of skunk cabbage spadices at various air temperatures. (B)
Oxygen uptake of skunk cabbage spadicesmeasuredin the field at available air
temperatures. (From Knutson 1974.)
In the Beginning 7
Probably one of the earliest theories about the origin of the nervous
system is that of Kleinenberg (1872), who proposed that the neuromus-
cular cells of the hydra contained the three elementary components of
the nervous system: the receptor, the conductor, and the effector.
However, based on researchperformed on " primitive " nervous systems
such as those in coelenterates, medusae, and others, severaltheories have
been proposed to explain the origin of the nervous system. Among the
most relevant are those of Parker (1919), Pantin (1956), and Passano
(1963).
For Parker, " The most primitive nerve cell, from the standpoint of ani-
mal phylogeny, is the sense-cell or receptivecell, as it occurs in the sensory
epithelium of the coelenterates" (1919, p. 210). Therefore, for Parker, the
proto neurons initially emergedas individual sensorycells or cells for de-
tecting changesin the immediate surroundings of the pluricellular organ-
ism. Thereafter, motor nerve cells developed.
Pantin has a more globalized conception of the primitive nervous sys-
tem: " The metazoan behavior machine did not evolve cell by cell and re-
flex by reflex. From its origin it must have evolved the structure of the
whole animal, and it must have been complex enough and organized
enough to meet all the varied requirements of behavior" (1956, p. 173).
In contrast with Parker, Pantin places emphasison the simultaneous de-
velopment of nondifferentiated nerve cells coordinating the whole organ-
ism in both sensoryand motor responses. He further emphasizesthat the
primitive nervous cell was not just a single sensorycell controlling a sin-
gle effector cell becausea meaningful responsecould not be initiated by
the innervation of a single muscle cell by a single receptor cell.
Passanoproposed the following theory (seefigure 1.5):
Individualprotomyocytesfirst evolvedinto assemblages of independentcontrac-
tile cells, permittingmore extensivemovementsthan thoseresultingfrom con-
tractionsof individualmyocytes . Certainof thesecellsbecameendogenous activity
centersor pacemakers by developingunstablespecialized membraneareascapa-
ble of activedepolarization. Suchlocal pacemakers synchronizedcontractionsof
adjacentcellsby passivedepolarizationspreadaffectingthe contractilemecha-
nisms, perhapsutilizing intercellularbridges. Groupsof musclecellsresponding
to pacemakerswould permit the evolution of recurrentfeedingmovements .
8 Chapter 1
Differentiation of these two cell types would have thus proceeded together , with
what was to become nerve becoming specialized for activity initiation . Initially
both would become specialized for passive conduction of depolarization . The spe -
cialization of the nerve cell for the conduction rather than the repetitive initiation
pp . 307 - 308 )
nerve rings and sensory cells accumulated in organs associated with the
ganglia .
R.
8.
c .
Figure 1 . 5
into one single organism , one or more protomyocytes developed unstable mem -
brane potentials ( black protomyocyte ) so that they could depolarize the adjacent
cells .
10 Chapter 1
came more efficient through learning and memory . In summary , the basic
Regulation
cust , for example , which has a marked torpor in the morning , orients itself
Other insects ( like bees and large moths ) generate internal heat to regu -
for flight , when they approach the period of activity , they begin shivering
insects must be near or above 40 C before they can start a free flight . This
these insects are covered with a dense layer of pile that prevents heat loss .
B
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EvolutionaryPerspectives
behavioral means. More than that , this dramatic event put tremendous
pressure on these animals to develop different behavioral strategies (im -
plicating brain and body ) to adapt to constantly changing environmental
conditions . For instance , the fins used for swimming were now adapted to
walking on land . Would this not require important changes in the motor
programming of the brain ? And what about changes in brain program -
ming of behavioral temperature regulation ?
The second important event in the evolution of thermoregulation was
the development of homeothermy , which seems to have occurred in prim -
itive nocturnal animals . Under conditions of poor solar radiation , these
animals lost their capacity to gain heat from the environment ; as a conse-
quence, one could envisage them behaving torpidly . Over time , these ani -
mals developed a remarkable capacity to produce significant amounts of
heat internally . These changes must have been produced by changes in the
brain as well as in the body to allow them not only to cope with the new
sensorial situation (absence of light ) but also to have autonomic control
of body temperature . How could this have occurred ?
Before entering into these general considerations , however , in order to
have a better understanding of a phylogeny of thermoregulation , let 's
trace the geochronology and geobiology of vertebrates since they began
to appear, most probably in the middle to late Ordovician period , about
500 million years ago. Today , there are approximately 46 ,000 living
species vertebrates and 1,250 ,000 species of invertebrates . Table 2 .1
shows the biogeological time scale.
Outside the area of physiology , the terms " cold -blooded animals " and
" warm -blooded animals " involve two rather confusing concepts . Do
cold -blooded animals really have cold blood ? And if so, what about the
rest of the body ? The same questions could be posed for warm -blooded
animals . Because these are vague concepts used throughout the literature
of thermoregulation , for the sake of clarity they will be described here be-
fore discussing evolution .
Cold -blooded animals (invertebrates , fish , frogs , and reptiles ) are poor
heat generators . That is, they produce internal heat , but not in quantities
Evolution and the Control of Body Temperature 17
Table 2 .1
Geologic periods after the time when fossils first becameabundant
Estimated
time since
beginning
of each
period (in
Era millions of
(and duration ) Period years) Epoch Life
Cenozoic ( age Quarter - 2 + Holocene Modern species and sub -
about 65 man .
ners ; decimation of
spread glaciation .
mals .
families of mammals ;
evolution of grazing
mammals .
of mammals .
mals .
mammals .
dotherms , from " endo " and " thermal " (internal and temperature ). This
refers to the fact that heat is produced internally. Becauseof a high meta-
bolic heat production , the thermal state of the endothermic animal is such
that body temperature is maintained almost constant over a wide rangeof
environmental temperatures and despite effective heat-loss mechanisms.
Animals in this category are also called homeotherms , from the Greek
homos (fairly equal) and thermos (temperature), and regulators.
However , as mentioned in chapter 1, some invertebrates developed dif -
ferent strategies to allow them to thermoregulate as if they were en-
dotherms. And there are vertebratesthat thermoregulate like ectotherms.
For instance, a kind of homeothermy and even real endothermy has been
achieved in fish such as the tuna . Also , in reptiles such as dinosaurs , a
kind of homeothermy has been proposed because of their enormous
mass/surface area ratio . This last condition has been called gigan -
tothermy, ectothermic homeothermy, inertial homeothermy, or mass
homeothermy. And mammals (at least primitive mammals), considered
without exception to be homeotherms , have exceptions among them . For
instance , marsupials and monotremes are considered not to have a con -
stant body temperature although they are not hibernators . Some mam -
Chapter 2
snssoI6A4 ~e.l
sn4 ~uA4JO4'.J.!UJO
_ _ 1111-
snJnAsea
e!DUOU98
Mammals
sniJ.eeln ~e
SnU!leUe
Amphibia
Reptiles
snln ::>!un ::>
Ilonb
Figure 2 .1
Variations in the range of active body temperature among ectotherms and en-
dotherms. Some ectotherms (reptiles) experience temperatures as high as, or
higher than , those of some endotherms . (Modified from Ostrom 1980 .)
.
Evolution and the Control of Body Temperature 21
400
Night
..-_____L______ -
Figure 2 .2
Body temperature as a function of ambient temperature in an active Central
American opossum , Metachirus , during day and night . (Modified from Morrison
and Ryser 1952 . )
mals have dormancy or hibernating periods during which their body tem -
perature decreases markedly in accordance with the temperature in their
surroundings (figure 2 .2 ) .
ation , wind velocity , relative humidity , size and shape of the animal , qual -
ity and quantity of insulation , and metabolic rate .
thermal niches or climatic spaces . Spotila ( 1980 p . 251 ) stated , " We can
ceeding sequentially from one evolutionary level to the next , but rather as
---Insulation
+ metabolism
---> MAMMALS
. BIRDS
----Largesize+ metabolism
---> TUNAFISH
----Largesize
------------> DINOSAURS
. ELEPHANTS
POIKILOTHERMI
C
ANCESTORS
----Metabolism
----------------> INSECTS
----Special
heatexchangers
---> DIMETRODON
STEGOSAURUS
----Behavior
-----------------> SMALL
LIZARDS
Figure2.3
Evolutionarystrategiesemployedby poikilothermicancestorsin their transition
to homeothermicand poikilothermic present -day animalsto increaseand/or
maintainbodytemperature . (Modified from Spotila1980.)
Figure 2.4 shows the main evolutionary trends leading to modern mam-
mals. Six main stepscould be envisagedin this general trend:
1. Ancestral protochordates gave rise to the Agnathans (ostracoderms),
or fish without jaws. These archaic fish first appeared in the Ordovician
period of the Paleozoic era, around 500 million years ago. There are fos-
sil records of these fish. They also have present-day representatives, the
(cyc/ostomes). Examples include hagfish and lamprey.
2. The Agnatha gave rise to the placoderms, jawed fish. Living represen-
tatives of placoderms are the elasmobranchs(sharks and skates) and the
holosteans(sturgeon, gar) and teleosts(perch).
3. Chondrichthyes and Osteichthyes evolved from the placoderms. The
Chondrichthyes are cartilaginous fish. The Osteichthyes are bony fish.
The latter class gave rise to the actinopterygians and sarcopterygians.
Descendedfrom sarcopterygians are the crossopterygians (from which
land animals appear to have descended). Thesehave a living descendent,
the coelacanths (Latimeria ). The dipnoans (lungfish), also descended
from the sarcopterygians, have living descendantsin the tropical regions
of Australia, Africa , and South America.
Evolution and the Control of Body Temperature 23
(ostracoderms
)
Amphioxus t
"....- - - - - - --- - AncestraI *
Protochordates
*Extinct
Figure2.4
Schematic diagramillustratingvertebrateevolution. (FromRomer1970.)
24 Chapter
2
that appeared at the end of the Devonian period , around 400 million
years ago . Descended from these primitive amphibians are the urodeles
Archosaurs also evolved from the primitive reptiles and gave rise to prim -
itive birds .
Is there any evidence that during the Paleozoic ( 340 million years ago )
and Mesozic ( 165 million years ago ) eras , up to the appearance of primi -
worth considering .
Present - day fish , frogs , and reptiles are cold - blooded animals .
However , that doesn ' t mean they were unable to maintain a body temper -
ing ice - laden seas swam without freezing in waters that had a temperature
creases when green sunfish ( Lepomis cynauellus ) are moved from 2Soc to
higher metabolic rate , and therefore acclimation of these fish to the new ,
cold environment . Thyroxine not only can alter the behavioral response
of fish to temperature changes but also can influence their general level of
Evolution and the Control of Body Temperature 25
cult to assesshow they dealt with varied thermal environments. All verte-
brates alive today, however primitive their structure, have had a long time
to evolve specializedphysiological capabilities. However, if we investigate
many living vertebratesfrom varied classesand inhabiting various envi-
ronments , and we find that they all exhibit certain characteristics , we can
26 Chapter
2
A B
Olfactory lobe
Epiphysis
External nostril
Olfactory capsule Cerebrum
Diencephalon Forebrain Ig t. a enu a
TelencePhalon
Pineal organ } R. h h bIII I
ventricle
Ventricle III
MesencePhalon } Midbrain Midbrain
Lateral lobe
, Ventricle IV Hind
tl Medulla oblongata brain Optic lobe
~ Cerebellum (metencePhalOn)}
(myelencephalon) ventricle
Spinal cord Cerebellum
Medulla
oblongata
Ventricle IV
Figure 2 .5
(A ) Reconstruction of the brain of an extinct jawless fish (Heterostraci ). (B)
Dorsal view of the brain of a lamprey (Petromyzon ). (A from Jerison 1973 ; B
from Romer 1970 .)
Evolution and the Control of Body Temperature 27
Bony Fish
ACTINOPTERYGII SARCOPTERYGII
J Collacants
Illatimeria
II
CROSSOPTERYGIANS
~
PRIMITIVE
t
AMPHIBIANS
Lungfish
Figure 2 .6
Simplified evolutionary tree of bony fish. (Modified from Romer 1970.)
28 Chapter 2
( 1973 ) have described a simple model in which a " reflex circuitry " lo -
cated in the anterior part of the brain stem of fish could subserve these
brain stem and subserving reflex activity could have served the survival of
fish for millions or years . Nonetheless , fish have a certain degree of inter -
internal milieu . For example , during winter starvation , certain fish select
clude hormones that interact with the brain . Under these conditions , fish
have a reduced metabolic rate and therefore require less food . An obvious
Crossopterygians
the Devonian period , 400 million years ago , these ferocious and preda -
ceous fish were the most common bony fish ( figure 2 . 8 ) . They showed
structural features that made them suitable for life on land . They had
lungs ( as did some of their ancestors the placoderms ) and sturdy fins that
evolved . In the Carboniferous period , 350 million years ago , these fish ,
There is evidence that in the Devonian period there were dry periods
fish became extinct . Under these conditions , the survival of fish with lungs
and strong fins was substantial . Fish with these characteristics could
breathe and move over land from one pool of water to another .
Moreover , the rhipidistians were carnivores , living upon other fish , and in
because nothing was on land for a carnivorous fish to eat until insects be -
have lived on other fish for a long time before they evolved into amphib -
Evolution and the Control of Body Temperature 29
optic tectu m
optiC chiasma
Figure2.7
(A) Schematicdiagramof the fish brain. (B) Anterior portion of the brainstem
,
enlarged
. (C) Simplifiedneuronalnetworkillustratinga negativefeedbackloop.
Stimulationof cutaneouswarm or cold receptorsactivatesa behavioralresponse
to counter the deviation in environmentaltemperature . (Modified from
Crawshawet al. 1981.)
I~
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Chapter 2
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Figure
2.8
Examples of crossopterygians
. (A) Devonian
form. (B) Livingcoelacanth
(Latimeria
). (Taken
fromRomer1970.)
As Romer (1970 p. 60) pointed out, " Greatest, perhaps, of all ventures
made by the vertebratesduring their long history was the developmentof
tetrapods in the invasion of the land" (figure 2.9). The derivation of four-
leggedwalking animals from fish resulted in structural changesin every
anatomical and physiological systemof the body. In contrast, the brain of
both amphibians and reptiles did not changein any meaningful way from
the generalizedand primitive vertebrate pattern of their predecessors , the
crossopterygians. In fact, present studies of frogs, crocodiles, and turtles
suggestthat they have undergonevery small changeswith respectto their
predecessorsin the Triassic period (Jerison 1973).
Myhre and Hammmel (1969) stressedthat in reptiles, as in fish and
frogs, the anterior brain stem plays an important role in temperature reg-
ulation . Frogs and reptiles, like fish, are poikilothermic . Their internal
temperature fluctuates several degreescentigrade daily and from season
to season. They do not produce enough internal heat, nor do they have ef-
32 Chapter 2
To mammals
Lizardsandsnakes
t
Rulingreptiles Advanced mammal -like reptiles
(dinosaurs
) t
Primitive mammal -like reptiles
Turtles
(laberinthodonts )
t
Ancestral c rossopteryrians
Figure 2 .9
seeking shade ) , they can control and maintain body temperature above
tion to the cold by a reptile . These turtles can maintain a constant body
Spotila ( 1994 p . 261 ) explain that " This dramatic ability to maintain
of peripheral circulation , and extensive insulation due to large body size ."
Evolution and the Control of Body Temperature 33
Dinosaurs lived on Earth for more than 150 million years. Compared
with the existence of other species, including humans (with only about 2
million years), they were a extremely successfulexperiment of nature.
Unfortunately , because dinosaurs have been extinct for more than 65 mil -
lion years, there is no way of determining the real lifestyle or physiology
of these large reptiles . Regarding temperature regulation , only through
inferences obtained from fossilized bones, the anatomy of complete skele-
tons , reconstructions of the brain , and comparative studies with present
living reptiles can we obtain any clues about the many fascinating aspects
of these creatures .
provides different indirect arguments for and against dinosaurs being ec-
tothermic or endothermic (Thomas and Olson 1980). Although most of
34 Chapter
2
the literature supports the idea that dinosaurs were ectothermic, Robert
Bakker (1986) pioneered the idea that dinosaurs, in particular the large
Cretaceousdinosaurs, were endotherms. Paladino and Spotila (1994, pp.
263- 264) summarized the factors supporting endothermy as follows :
1. Fossil evidence indicates that late Cretaceous dinosaurs lived in the
polar more seasonal areas where there might have even been snow.
Dinosaurs had to be endothermsto accomplish this;
2. Oxygen 18 isotope analysis for the bones of dinosaurs indicates they
maintained high, constant body temperatures even in their extremities,
like modern birds;
3. Dinosaurs had complex social behaviors such as herding, communal
nesting, and long distance migrations which required them to be en-
dothermic;
4. Dinosaurs appear to have richly vascularized, dense haversian bone
with growth plates similar to those of birds;
5. Birds evolved from small bipedal dinosaurs that diverged from the di-
nosaurian lineage more than 90 million years ago; thus all dinosaurs (a
monophyletic group) must also have been endotherms since they are the
direct precursors of birds;
6. Sincedinosaurs were very active, they neededan increasedaerobic ca-
pacity that necessitatedthe development of endothermy [the increased
aerobic capacity hypothesis for the evolution of endothermy].
The truth probably lies somewhere between endothermy and ec-
tothermy. Researchin living speciesstrongly supports the possibility of
dinosaurs having beenectothermic homeotherms, a condition also called
gigantothermy. This condition is reached by animals that gain most of
their body heat from the environment (ectotherms) but, becauseof their
mass/surface area ratio , maintain a constant high body temperature
(homeotherms) (Spotila 1980). This possibilit)Thas received strong theo-
retical and experimental support from comparative studieson large living
reptiles (Paladino and Spotila 1994).
To complicate matters, Barrick (1994) suggeststhat large dinosaurs
were (1) endotherms throughout their life; (2) endotherms as juveniles
and masshomeotherms as adults; or (3) ectotherms as juveniles and mass
homeotherms as adults. Added to this is the recent suggestion, basedon
isotope composition of bone, that becausedinosaurs were relatively fast-
paced, grew rapidly, and probably had a high metabolism, most of them
Evolution and the Control of Body Temperature 35
Table2.2
Quantitativebrain and bodyrelationsin ten dinosaurs
Body volume Endocast volume Expected brain
Genus (metric tons) (ml ) volume (ml )
4 . Camptosaurus 0.4 46 38
5. Diplodocus 11.7 100 360
6. Iguanodon 5.0 250 200
7. Protoceratops 0 .2 30 24
8. Stegosaurus 2 .0 56 * 110
9 . Triceratops 9 .4 140 310
10 . Tyrannosaurus 7 .7 404 270
tient (EQ ). This is the ratio of actual brain weight to expected brain
weight . The expected brain weight is an " average " for living species that
takes into account body weight. Consider the following example from
Jerison. A squirrel monkey with a body weight of 1000 grams has a brain
weight of 24 grams . What is its expected brain weight ?
..
..-.~ .
w. . ~ ' .
' . -
. . I. . . .~ .
" . . ~ . . .
. ,
. . .
. .
.'
Figure 2 .14
Reconstruction of an early mammal (Megazostrodon rudmerae ) from the late
Triassic period , about 200 million years ago . (Taken from Crompton et ale
1978 .)
steps . First came the acquisition of a constant body temperature that was
10 C lower than 37 C . Two families of insectivores , the Tenrecidae and
Erinaceidae , that live in nocturnal niches and appear to have lived there
( 1978 p . 334 ) suggest that " a low body temperature coupled with a low
metabolic rate restricted the first mammals to their nocturnal niches en -
abling them to survive on much less energy . " The second step would have
been the acquisition of a higher metabolic rate by some of these nocturnal
mammals .
Evolution and the Control of Body Temperature 43
Virtually all previous interpretations of the metabolical status of extinct taxa have
centered on speculative and/or circumstantial evidence, including predator-prey
ratios, fossilized trackways, fossil bone oxygen isotope ratios and paleoclimato-
logical inferences, or on correlations with mammalian or avian morphology, such
as posture , relative brain size, and bone histology . These arguments are equivocal
at best. Furthermore, the majority of the morphological arguments used previ-
ously, including specially bone histology data, are basedpredominantly on appar-
ent similarities to the mammalian or avian condition , without a clear functional
correlation to distinctly endothermic process. . . . this situation has changedwith
the discovery that the nasal respiratory turbinate bonesin mammals and possibly
birds, are tightly and causall}"' linked to high ventilation rates and endothermy in
these taxa .
That mammals and birds, but not reptiles, have special anatomical
arrangements in their nasal cavities (turbinates ) can be traced in fossil
records. This is a fascinating story. From theserecords, physiological in-
ferencesfor endothermy have beenmade. The turbinates are highly com-
plex structures located in the nasal cavities that provide a countercurrent
exchange mechanism to preserve heat and water . Thus , during inspira -
tion , cool external air enters the respiratory tract and takes up heat and
moisture from the turbinate linings . During expiration , this process is re-
versed and warm air is cooled as it passes over the turbinates . In this way
water and heat are preserved in the organism . These turbinates are pre -
sent in the nasal cavities of almost all mammals and birds , but are com -
pletely absent in all extinct reptiles (including dinosaurs ) (figure 2 .15).
Therefore , it seems that turbinates evolved in parallel with the evolution
of mammalian and bird endothermy. Of enormous interest are the studies
on cranial fossils which showed that the bony structures to which
turbinates attach were present in some therapsids and early mammals .
This suggests that some advanced mammal -like reptiles already had high
ventilation rates, high metabolic rates, and , supposedly , endothermy - a
hypothesis advanced by Van Valen (1960 ) but not shared by Heath
44 Chapter 2
ABC
Figure2.15
Turbinatesin mammals(A), birds (B), andreptiles(C).
(1967), and inconsistent with the findings obtained from the brains of
therapsids.
But what has the brain to do with this ? When trying to explain the
achievement of endothermy by primitive mammals, only body changes
such as muscle activity , circulatory improvement , metabolic activity ,
and changesin the surface of the body to diminish heat loss (including
the development of hair or fur in the skin) have been considered.
However, for mammals to have achieved a constant body temperature,
a balance between heat production and heat loss had to be maintained
and controlled by the brain , a capacity that has not been achieved in ec-
tothermic animals (fish, amphibians, and reptiles). What do we know
r.bout the brain of therapsids and primitive mammals compared with
the brain of their ancestors, the reptiles? Is there a significant anatomi-
cal difference in brain morphology that could justify the appearanceof
endothermy? If so, what in the brain changed to allow small mammals
to becomeendothermic?
Heath (1968) believesthat the changein limb position in therapsidsled
not only to the development of endothermy but also to fundamental
changestoward reorganization of the brain, in both the motor and the so-
matosensory areas. In therapsids, changesin the cerebellum have clearly
been observed that fit well with better motor coordination and finer
motor control in theseanimals. The fact that the somatotopy of the pyra-
midal system in the cerebral cortex is found in marsupials, monotremes,
Evolution and the Control of Body Temperature 45
Although fish , frogs , and reptiles do not have a high metabolic rate and
require solar radiation to raise body temperature , they do thermoregu -
late . Like mammals , these lower vertebrates possess a spinal cord , brain
stem, and hypothalamus . When these areas of the brain are stimulated or
destroyed , disturbances in the capacity of these animals to thermoregu -
late occurs , thus indicating that these structures do participate in the con -
trol of body temperature . However , these animals are unable to maintain
the fine control of core temperature observed in mammals .
In the preceding chapter , we noted that the brain of mammals is signif -
icantly larger in relation to body weight , compared with brain size of
their predecessors, the lower vertebrates . Is the achievement of homeo -
thermy in mammals linked in some way to brain size? From lesion stud -
ies, we know that the mammalian hypothalamus is the primary area
within the central nervous system (CNS ) controlling body temperature .
Is there a significant change in the structure of the hypothalamus of mam -
mals , compared with lower vertebrates , to explain the narrow range
within which mammalian body temperature is maintained ? Is the hypo -
thalamus in mammals the sole structure controlling body temperature ?
What do we know of the chemical substances, neurotransmitters and
neuromodulators , within thermoregulatory pathways of the mammalian
brain that control body temperature ?
Until the mid - 1960s , the hypothalamus was considered by most inves-
tigators in the field to be the only structure able to detect core body tem -
.
50 Chapter
3
perature. This concept was abandoned when Simon and his colleagues
(see Simon et al . 1986 for review ) demonstrated that the spinal cord is ca-
pable of eliciting all of the thermoregulatory responsesevoked by the hy-
pothalamus. Subsequent studies provided evidence for other areas of
control , and Satinoff (1978 ) suggested that the control of body tempera -
ture by the CNS in higher mammals was acquired , during evolution ,
through the developmentof different hierarchically arranged parallel sys-
tems . Rather than a single integrator with multiple inputs and outputs ,
the proposed model includes integrators for all thermoregulatory re-
sponses at several levels of neural control that can facilitate or inhibit
upper and lower levels of control . In fact , considerable evidence points to
the involvement of many areas of the CNS in the control of body temper -
ature (Hardy 1961; Zeisberger 1987). If this theory is correct, it would
imply that a sudden jump from poikilothermic to endothermic animals
did not occur , in the sense that endotherms acquired a unique set-point
absent in poikilotherms . It suggests, instead , that throughout evolution ,
all living systems had inputs , thermostats , and outputs , however simple ,
and that nature developedmore and more sophisticatedsystemssuperim-
posedon those already developed. Theseideasfollow the Jacksoniancon-
cept of evolution that nature superimposes new neural structures on
preexisting systems rather than replacing them . The added structure
would control the existing structure. In mammals, the hypothalamus usu-
ally controls the activity of thermoregulatory effector mechanismsalong
the neuraxis . This latter arrangement , reached in primitive mammals and
birds, was probably so efficient that it was retained without modification
for about 150 million years .
An example of this process would be the following senario . A high in -
ternal heat production was proposed by Heath (1968 ) as a by -product of
primitive reptiles changing posture from a sprawling position to standing
erect . However , as the capacity to produce internal heat improved , it
probably became a thermal stressover time, and required the develop-
ment of internal thermodetectors and a mechanism of heat loss . Because
Ka
. . .
K ; ~
brain stem, and hypothalamus, but only birds and mammals are
homeotherms. Since the mammalian hypothalamus exhibits large
anatomical differences from the hypothalamus of all other vertebrates,
and since the hypothalamus is the seat of higher and finer temperature
control , would comparative cytoarchitectural studies of the hypothala-
mus provide insight into the developmentof homeothermy?
regulation in mammals. (Redrawn from figure 3.1.) (B) shows the transition
from poikilothermic to endothermic animals and the corresponding narrowing
of the range of temperature regulation. This could be interpreted as a gross indi -
cation of the phylogenetic development of temperature regulation during evolu-
tion . (Redrawn from figure 2.1.)
The Mechanics of Our Environmental Independence 55
56 Chapter 3
Posterior Hypothalamus
1. Posterior hypothalamic nucleus (dorsal)
2. Mammillary nuclei: ventral, intercalary, and lateral (ventral)
For comparative gross anatomical purposes , this brief account of the
main nuclei of the hypothalamus is sufficient as a reference . In fact , only
the three main parts of the hypothalamus will be comparatively analyzed
through evolution . Moreover , despite the fact that the hypothalamus is an
area of the brain that integrates the function of many brain areas (brain
stem, limbic system) and information from peripheral and central ther -
moreceptors, as well as vegetativeinput , neuropharmacologistsand neu-
rochemists often speak in such vague terms as " anterior hypothalamus "
and " posterior hypothalamus ."
B. Amphibian(Amb/ystoma :
after C. J. Herrick.
C. Reptile(Chelone
).
Hyp.
D. Mammal(Opossum
).
Figure 3.4
A systematicview of the extent of the hypothalamus through the saggital sections
of the brains of a fish, an amphibian, a reptile, and a mammal. a, anterior com-
missure; C, cerebral hemisphere; Cb, cerebellum; Hyp , hypophysis; L, lobus infe-
rior ; M , mamillary body; Op, optic chiasm; S, saccusvasculossus; T, tectum of
midbrain . (From LeGros Clark 1938.)
58 Chapter 3
thalamic area , which includes the posterior hypothalamic nucleus and the
tics of this hypothalamic area . Has this observation any special signifi -
mals were ten times higher than those of normal dogs . The analysis of
these initial observations led Hardy ( 1961 ) to hypothesize that the func -
prevents pyrogenic action in most cases . If pyrogens elevate the set - point
The Mechanics of Our Environmental Independence 63
the neural circuitry responsible for the set - point . Additional support for a
set - point function within the posterior hypothalamus comes from the hi -
Myers and Veale ( 1970 ) reported that the posterior hypothalamus , but
Gisolfi and Wenger ( 1984 ) subsequently concluded that the set - point for
When all of these data are taken together , and when they are consid -
Thermal information reaches the central controlling areas of the brain via
thermo receptors are stimulated when the skin of the body is warmed or
cooled . This afferent information enters the spinal cord , synapses with a
tract ) . Collaterals from this pathway reach the reticular formation in the
brain stem . From the basal complex , thermal information reaches the
to warm and cold have been found . Also , neurons in the midbrain can re -
back to the brain stem (H . Sato 1984 ). Serotonin neurons and noradren -
ergic neurons from the brain stem may participate in conducting or mod -
ulating thermal information to the hypothalamus (Hellon 1975 ; Hinckel
and Schroder -Rosenstock 1981 ).
As proposed at the beginning of this chapter , thermal information is in -
tegrated at various levels of the neuraxis in a hierarchically organized
fashion : spinal cord , brain stem, and hypothalamus . Presumably an inte -
grator receiving input and transmitting output signals exists at each of
these levels. However , it is generally accepted that the hypothalamus is
the highest station acquired through evolution for thermoregulation .
Moreover , it is in this area of the brain that research has been concen -
trated and considerable knowledge has accumulated . How are thermal
inputs organized in the hypothalamus to activate thermoregulatory re-
sponses to heat and cold stimuli ? The answer is complex and not entirely
known . The first neuronal model of hypothalamic thermoregulation was
presented by Hammel (1965 ). Since then , numerous models have been
proposed to explain how a balance between heat production and heat
loss is achieved within neural structures of the brain (see chapter 7 for dis-
cussion ) (Bligh 1972 ; Boulant 1980 ; Myers 1980 ). Figure 3.7 illustrates
our current understanding of hypothalamic thermosensitivity and neu-
ronal firing rates in response to peripheral and central thermal stimuli .
Important characteristics that should be represented in any neuronal
model of thermoregulation are the following : (a) synaptic inhibition by
temperature -insensitive neurons of warm -sensitive neurons ; (b ) warm -
and cold -receptors in the POAH receive afferent signals from cutaneous
and spinal thermal sensors, which means that a thermosensor can act as
an integrator ; and (c) changes in peripheral temperature can alter the sen-
sitivity and firing rates of POAH thermo sensitive neurons . For example ,
warming the skin increases heat loss but reduces the sensitivity of hypo -
thalamic warm receptors . On the other hand , cooling the skin decreases
the firing rate of warm -sensitive neurons but enhances their sensitivity .
In figure 3.7, Boulant (1996 ) depicts a model to explain how different
groups of temperature -sensitive neurons (based on differences in ther -
mosensitivity ) can elicit different thermoregulatory effector responses. He
proposes 4 types of thermo sensitive neurons ; 3 are warm -sensitive (a, b,
and c) and 1 is cold -sensitive . Thermosensitive warm -neuron " a" has a
The Mechanics of Our Environmental Independence 65
a ~
,lJL
~.:~ ;.- / Pant,
W - - ---- '\ Sweat
.
Peripheral F =/ HEAT
WARM /f RETENTION
W Skin Blood
Flow
J7 -
. .
l:t=
~ ~~ ~
F / r--
=:E-<Shivcr
jn9I
f :
PerIpheral
c
~ )~~:=:r=~
~
..../
'(D
.
e , C~
(t) C9
Non -shiver
Tt"'termo -
genesis
COLD
Recepbt' s
Figure 3 .7
tive neurons are depicted : warm (W ) neurons ( a , b , and c ) and cold ( C ) neurons .
The cold and warm inputs to these neurons are depicted as excitatory ( + ) and in -
temperature (T ) .
low spontaneous firing rate and responds only when the animal is hyper -
thermic (when hypothalamic temperature is above the thermoneutral
zone ). It is postulated that these neurons most likely control heat loss
(sweating or panting ). The low firing rate is attributed to inhibition from
peripheral cold -receptors and/or limited input from peripheral warm -re-
ceptors .
Warm -receptors labeled " b " are thermo sensitive above and below nor -
mal hypothalamic temperature and therefore are most likely to control
heat retention , that is, skin blood flow and behavioral thermoregulatory
responses. These neurons receive moderate inputs not only from ascend-
ing pathways but also from limbic structures such as the hippocampus ,
which participates in functions including emotion and motivation , learn -
ing and memory (see chapter 4 ). This is most interesting because it has
been suggested that " b " neurons playa role in behavioral thermoregula -
tion (rewards and pains ) and skin blood flow ( a response that is often in -
fluenced by emotion ).
66 Chapter 3
Warm - sensitive " c " neurons have the highest spontaneous firing rate .
This is attributed to the fact that they receive the greatest amount of af -
creased glucose , and so on . Because these neurons have such a high spon -
taneous firing rate , it is unlikely that they would increase their firing rate
heat loss . Cold - sensitive neurons receive direct input from cutaneous cold
through POAH warm - sensitive neurons . The latter neurons exert a nega -
tive influence on POAH cold - sensitive neurons . Thus , with a cold skin ,
input from cutaneous cold - receptors and the removal of negative input
from cutaneous warm - receptors . This analysis fits well with in vivo stud -
duction than heat loss ( Benzinger et ale 1963 ; Hellstrom and Hammel
1967 ) .
Since the mid - 1960s , a multitude of studies have reported the effects of
ulators .
The Mechanics of Our Environmental Independence 67
have been proposed to playa role in the CNS . Evidence supporting nora -
ters soon followed that for Ach . These neurotransmitters , once released ,
Much has been learned about the molecular machinery responsible for
nals and glia that participate not only in terminating the synaptic action
know the true physiological role of neuropeptides in the CNS , all recep -
action of neurotransmitters .
One of the most interesting findings since the late 1970s has been the
same neuron ( Lundberg and Hokfelt 1985 ) . Most often , this coexistence
Table 3 .2
Coexistence of neurotransmitters and neuromodulators
ModifiedfromCooper
, Bloom
, andRoth1991.
has been reported to change body temperature when injected into the
cerebral ventricles or directly into the brain . In addition to this list , recent
experiments indicate that the gas NO may also playa role in thermoregu -
latory pathways .
However , evidence supporting a role for any of these substances ' trans -
ocal ( Bla tteis 1981 ; Myers and Lee 1989 ) . This is so because the vast
B7- B9, using the original terminology of Dahlstrom and Fuxe (1964 ).
Many pharmacological experiments have shown that 5-HT injected ICV
or into the POAH at certain doses produces hyperthermia . However , at
other doses it produces hypothermia . Myers (1980 ), using push -pull per -
fusion , found an increase in 5-HT in perfusates from the PO AH when the
animals were cooled , but not when they were heated .
Again , as for NE , recordings from single -unit activity reported contra -
dictory results : 5-HT seems to produce nonspecific effects (excitation or
inhibition of spontaneous activity of thermo sensitive or thermoinsensi -
tive neurons ). In fact , Watanabe et al. (1986 ) reported that of the total
number of warm -sensitive neurons recorded in the hypothalamus , 91 per -
cent were activated by 5-HT and 85 percent were inhibited by NE . Of the
58 percent that were thermally insensitive , 71 percent were inhibited by
NE and 37 percent were excited by 5-HT . In contrast , other studies have
suggested that 5-HT increases the inhibitory input from central ther -
mosensors to effector neurons , thus activating the increase of vasomotor
tone and thermoregulatory heat production , whereas NE suppresses this
inhibitory input . The increased heat conservation and production that
may increase body temperature in a thermoneutral environment are the
result of NE activation . Increased heat loss and reduced heat production ,
leading to a decrease in body temperature , are the result of activating the
5-HT system. These changes were observed in the guinea pig and rat
(Bruck and Zeisberger 1990 ).
From the preceding paragraph , it is clear that species differences con -
tinue to plague any unified understanding of the role that NE and 5-HT
play in thermoregulatory pathways . Moreover , to think that they are the
sole mediators of warm and cold information in hypothalamic pathways
is unrealistic . That thermal information could reach the hypothalamus
after specific spinal fibers reach the midbrain and activate cell bodies of
the ascending NE and 5-HT fibers is very likely . However , the role these
monoamines play in the anterior hypothalamus -preoptic area remains
unclear .
Another prominent amine thought to participate in hypothalamic tem -
perature regulation is dopamine (DA ). Lee et ale (1985 ) reviewed the lit -
erature in this field and concluded that in rats , rabbits , and other species
(including humans ), DA plays a role in the thermoregulatory pathways
The Mechanics of Our Environmental Independence 73
SUBSTANTIANIGRA
. 0 .4
+02 - APO
t
0 r
I.
r T T
-0.2 T rA ----i- -
1/ 1 .. 1
U -0.4 T/ 1 1
0 T/ f .
uj -06 T /r ~
a: 1/ 1
:) -0.8 - r r. / i- ..
~
~ - 1.0
UJ
\ T T/ ~"""'I 1
- -. . .
T/ -
.1.
~ - 12
w
11
~ - 1 .4
u PREOPTIC / ANTERIOR HYPOTHALAMUS
~ +0.4 APO T
0..J +02 . TI~ I
u r Vi - I
, ..
0 '-
Z '
~
~
_02
.
T
.
/ l
z /!
- < - 0 .4 T T . ./ '"
I T Vi - :- l
U -0.6 . T 1, ;--1 1
-08 \ . T/ :1
.:.-
./ ~
, -
~ I
.. 1
J.
- 10
- 12
- , . .5 . ~ . . ~ - . , I -
0 10 20 30 40 50 60 70
TIME IN MINUTES
Figure 3 . 8
evolution ? Patients with Parkinson ' s disease who have a lesion in this
Lee et ale ( 1985 ) suggest that the circuitry through which these structures
( figure 3 . 9 ) .
ANTERIOR
HYPO
THALAMUS
Figure 3.9
Diagrammatic
- representation
- of anatomical connections between the anterior
hypothalamus and the substantia nigra .
lamp (Weiss and Laties 1961). Rats placed in a warm environment learn
to press a bar for cold air . Under these conditions , heat or cold will be re -
warding , if the animal works to obtain the desiredtemperature.
Supposedly the brain circuits for reward described above are part of the
brain circuitry that participates in the specific rewards provided by cold
or heat when the animal is placed in a hot or cold environment . It is not
known if there are specificcircuits for specificrewards or simply a unique
circuit recognizing reward and other circuits, with further specificity, for
the different rewards that subserve different motivated behaviors .
The POAH is at least one brain area that integrates autonomic and be-
havioral thermoregulation (Satinoff 1964; Corbit 1969). Satinoff (1964)
was one of the first investigators to show that a rat can be motivated to
work by pressing a bar to provide heat (turning on an infrared lamp)
when the POAH is cooled directly through a thermode implanted in it
(figure 4 .3 ). Rats also will turn on a draft of cool air when hypothalamic
temperature is elevated (Corbit 1969 ). Most interesting is that rats will
work to produce changesin their own hypothalamic temperatureswhen
either skin or hypothalamic temperature is increased above neutrality . In
this case, by pressing a bar, rats changed the temperature of the water per -
fusing a hypothalamic thermode, causing an abrupt change in skin tem-
perature and hypothalamic temperature (Corbit 1969). This last study
supports previous findings, and further demonstratesthat discomfort re-
sulting from deviations in skin or hypothalamic temperature can be alle -
viated by changing hypothalamic temperature .
Unfortunately , experiments have not been done to demonstrate the
reward areas of the limbic system most relevant to behavioral thermoreg -
ulation . Three areas of the limbic system- the lateral hypothalamic -me-
dial forebrain bundle , the nucleus accumbens , and the septum - are
tightly interconnected with the POAH , and are involved in both reward
and temperature regulation (Boulant 1980; Dean and Boulant 1989;
Wang et ale1994). Moreover, the hippocampus, another area of the limbic
systeminvolved in learning and memory, has been shown to send impor-
tant afferent connections to thermosensitive neurons (type " b " of Boulant ;
see Chapter 3) in the preoptic area. Boulant (1996 ) has suggested that
these neurons may participate in behavioral thermoregulation .
82 Chapter 4
(/ ) -
COOlin91 -+-COOlin91 -+-COOlin91
"' C
C
0
Co)
Q)
U>
0
0' )
(/)
"' C
-+-COOlin91 ..-Cooling4 -+-Cooling4
c
0
Co)
Q)
U>
0
0' )
Heat Lamp
~~~~
Figure 4.3
Schematicof a rat bar-pressingto turn on a heat lamp in responseto cooling the
POAH . Also shown is the cumulative record of the amount of bar-pressing be-
fore and during (labeled cooling) hypothalamic cooling in a neutral (24 :t 3 C)
and cold (5 :t 2 C) environment. The amount of heat the animal worked for was
greater in the cold environment. (Modified from Satinoff 1964.)
More About the Brain and Temperature 83
BF~ B D
66 ~ ~ ~ ~
6t:i.A~
t:;.~ ~~
~ ~--......"""6 ~ MRF
POAH
Figure 4 .5
brain and body induces NREM sleep . Increased body and brain temperature will
increase the firing rate of warm - sensitive neurons in the preoptic anterior hypo -
thalamus , which in turn will activate neurons in the basal forebrain . These basal
forebrain neurons will produce an inhibitory input to neurons in the cerebral cor -
tex and the medial reticular formation , giving rise to NREM sleep . C , cortex ; BF ,
Does sleep function , in part , to keep the brain cool , or is it just a biologi -
cal consequence of the cyclicity that all events in nature have ? An intrigu -
lism and activates heat loss by increasing skin blood flow and by initiating
that , compared with being awake , NREM sleep decreases the slope of the
phins , which basically have two brains and show unihemispheric sleep ,
ing temperature in mammals and birds could not be sustained without the
vigorous exercise during the day increases NREM sleep at night ; however ,
performing the same exercise but reducing the rise in brain temperature
by cooling the body prevents the increase in NREM sleep . These observa -
tions led to the speculation that the brain somehow stores information
about how long brain temperature is elevated during the day and then
compensates for this " awake heat load " by sleep - related cooling ( Mc -
humans lower their body temperature during the day ( Froberg 1977 ) .
1993 ) .
Nurses who work in intensive care units are keenly aware of the labile na -
those with low birth weight ) do not have mature neural structures con -
trolling endothermy .
vironment . Their tissue insulation also is less than adults ' ( Hey and Katz
1970 ) , and they have a low metabolic rate ( when normalized for surface
a cold environment .
During the period of time that newborns are acquiring autonomic con -
My husband now sleepsin the living room, but at least I have my hot Hashesto
keep me warm . (Kronenberg 1990 p . 52 )
10
a
0
26.0 -6
12.5
DO
f~
90
75
~
eo
400
3eD
200
37.5 ()
-
30 37D
~
.0
~ 28
26
ftr
~ T8I1
~ ,t
I=~ ~~ ia ~ . ~
0 6 10162026SO864046
Tt. Crrt1Jtee
>
~ ~=~~~~~t~ :: . ~!~r:J
IIII~ ~ ~ ~.1111 -
Figure 4 . 6
Physiological and perceived changes during a typical hot flash in a neutral envi -
ronment ( 28 C ) . Sensation , finger blood flow , heart rate , skin resistance on the
V';"-'. :._
chest , vaginal temperature , and skin temperatures on the forehead and finger are
cates that they are not random , but occur with some regularity
[~~ ~ .=.] ~ ]
odicity . They usually are more intense at night than during the day ", and
are more frequent in a warm environment than under cool ambient con -
Wlr
HOTFLASH
( Neutral To)
Fever On. . t of Endof
Breaks Hot Floah - Hot Flash
t t t
Tcor .
Tsset"
et r.r- .. ~; :::"'.I~
- . -., ~j .
W"III
~~~~'-/ " L _.~~ ...--
.I_Tset
'W
~
I~;!,-
-_.~:~;:'Tcore
L..J :.~
..-
"J Err
0r
fcold
~ _~+ J ""- - l ...........-::~
- f. ~
. 1
hot
Signa I ~ ~ \/ j ..",,~ __~feel
feel
hot
- cold
Figure 4 .7
Schematic diagram comparing the effects of fever and a hot flash on set-point ,
core temperature , effector mechanisms , and sensation . (Modified from
Kronenberg and Downey 1987 .)
More About the Brain and Temperature 93
temperature that allows for animal life is only about 0 to 50 C ( the tem -
23 C ( 73 F ) .
dict the body or brain temperature that humans " regulate . " The different
mechanisms for surviving the " straitjacket " are varied and intriguing . For
example , some animals " supercool " or actually allow part of their body
During those early times , and for periods lasting more than a billion
were cold - blooded and were classified as " ectotherms " because they re -
96 Chapter 5
IKY THERMAL
1,..pintOfY
~'"""""'"'"' AADIATION
R RADIATION
Ea
...t~""~ """'-
SKINBLOODfLOW
CONVECTION
AIR TEMPERATURE
AIR HUMIDIT ~
CONVECTION
RA
WORK
CONDU CONTRACTING
Q MUSCLE
Figure 5.1
Schematic diagram showing human heat production , transfer, and loss. Heat
produced within working musclesis carried by the blood to the body core (ab-
dominal, thoracic, cranial cavities), thus elevating core temperature. This rise in
core temperature results in the transfer of blood from the core to the skin and the
initiation of sweating. Heat is lost from the surface of the skin by radiation , con-
vection, conduction, and evaporation. (From Gisolfi and Wenger 1984.)
The ThermoregulatoryComputer
What Is Regulated ?
The term " body temperature " is a misconception . When humans are
placed in an environmental chamber and ambient temperature is slowly
raised from a level that is cold to one that is hot , skin temperature changes
with the environment , but the temperature of other parts of the body ,
such as the heart , remain constant (figure 5.2 ). It is as if we had , from a
thermoregulatory viewpoint , two bodies in just one organism , that is, the
reptilian or poikilothermic body as a shell and a homeothermic core . In
humans , the core consists of the abdominal , thoracic , and cranial cavities ;
the shell comprises the skin , subcutaneous tissue, and muscles. Therefore ,
what we typically refer to as body temperature (Tb ) is a composite of the
core (T c) and the shell (T s) temperatures :
Tb = 0.65 Tc + 0.35 T s.
The numbers in the above equation representthe magnitudes of these
two bodies in a neutral environment. In fact, these two bodies are not
fixed anatomical entities becausethey changewith ambient temperature,
and therefore they can get larger or smaller. Thus, the concept of core and
shell is more physiological than anatomical. In a sense, anatomy and
What"'s So Important About a Body Temperatureof 37 C? 99
~Q
,~
)+ 35
40
:c~
QJ').30
-a
,E o ~
Core Temp .
25
Figure 5 . 2
creases as ambient temperature increases , heat transfer from core to skin is main -
tained by an increasing skin blood flow as ambient temperature rises . Heat loss is
orative heat loss as ambient temperature rises compensates for the decrease in ra -
flow to the skin plays a crucial role . By changing cutaneous blood flow
and cutaneous blood volume , the insulative value of the shell can be re -
ducedorincreased .
which increases the insulative value of the skin . Thus , the skin assumes a
ture :
Tb = O . 6T c + O . 4T s .
fer heat from the core . As a result , the insulative value of the shell de -
Tb = D . 8T c + D . lT s '
100 Chapter
5
Non-ThtmBlInput
Figure 5.3
Schematicdiagram illustrating the elementsthat control the temperature regula-
tory effector responses. Basic thermal input is transmitted from skin (T s) and
core (T c) thermoreceptors. This information is integrated and a " weighted sum"
(T ws) of this activity is then compared with basal neural activity (T ref) within the
regulatory circuiting to form a " command signal" that impinges on all integra-
tors for regulating brain temperature. The ratio of filIal is 9/ 1. (From Gisolfi
and Wenger 1984.)
These elements of the control system are depicted in figure 5.3. Each
box in the diagram consists of multiple neuronal circuits that receive
excitatory and inhibitory inputs resulting from the releaseof chemical
substancescalled neurotransmitters . (A hypothesis explaining the ac-
quisition of this machinery through the evolution of the brain in mam-
mals is developed in chapters 2 and 3.) As illustrated in the diagram, the
integrative circuits compare the thermal and nonthermal input that they
receivewith basal neuronal activity , then generatewhat is described as a
" command signal." This command signal, in turn , servesas the input to
separate populations of neurons controlling sweat rate, shivering,
blood flow to the skin, and behavior. In addition to this command sig-
nal, these separate neuronal pools subserving the thermoregulatory ef-
fectors receive nonthermal input that can influence their ultimate
responSIveness .
102 Chapter
5
input from the core and the shell . The equation below describes the con -
R - RO = O - lTc + a2Ts - b .
These include the sweating response and alterations in blood flow to the
more by mean skin temperature . In both men and women , skin tempera -
temperature , rather than the entire core , which includes the abdominal
that seems to drive sweating , shivering , and skin blood flow responses .
ture , often are observed to lag well behind a change in sweating or skin
blood flow , which suggests that these temperatures are the consequence
sponse .
rons are not functionally specific ; they do not respond only to tempera -
ture . In some sense , we could call them " polymodal . " For example , low
glucose excites warm - sensitive neurons and inhibits cold - sensitive neu -
part , why the typical alcoholic with a low plasma glucose concentration
Survivingthe TemperatureStraitjacket
Table 5 .1
Ion concentrations of body fluids
Ion ICF Plasma Sweat Urine
Na + 10 140 50 128
Cl - 4 103 50 134
K + 140 4 4 60
Mg ++ 58 3 2 15
Heat Acclimatization
Imagine what would happen if a person driving from an air -conditioned
office in Los Angeles to Las Vegas in an air -conditioned car suddenly
stopped because the engine overheated , and decided to walk in the desert
for the next 2 to 3 hours . Without prior exposure to such conditions , this
person would experience marked elevations in core and skin tempera -
tures , heart rate would approach maximal values of 200 beats/min , and
symptoms of syncope , including dizziness , nausea, and pounding head-
ache, most likely would appear in less than 60 minutes . These physiolog -
ical responses would occur even if the person had access to sufficient
fluids to drink . A heat-acclimatized person ingesting sufficient fluids
would be able to walk the 2 to 3 hours in the desert without ill effects . In
fact , the rise in core body temperature during such a desert walk would be
106 Chapter
5
no higher than during a similar walk in the cool of the evening , when am -
bient temperature is only 50 F, compared with 120 F during the day (fig -
ure 5.4 ).
How does one become acclimatized to the heat ? The process is simple
and fast , especially in physically active or endurance -trained individuals .
It only requires walking in desertlike conditions 2 to 3 hours per day for 5
to 10 days. At the end of this period , not only does core temperature not
rise any higher than it would during the same walk in a cool room , but it
is accomplished with a cooler skin , owing to greater evaporative cooling
from increased sweating , and a heart rate of only 100 beats/min instead
of 200 beats/min (figure 5.4 ). This is perhaps the most remarkable physi -
ological adjustment that humans are capable of making and is attributed
in large part to the evolution of the sweat gland .
As a result of acclimatization , these glands not only are more sensitive
to a rise in core temperature , but also secrete a sweat that is almost like
distilled water , that is, it has very little salt (NaCI ). This is most beneficial
because the acclimatized person therefore retains more salt , which stimu -
lates drinking and helps to prevent dehydration . What a marvelous ex-
ample of physiological brinkmanship ! (Additional information regarding
the mechanisms of heat acclimatization are presented in chapter 6.)
UNACCLIMATIZED
(SOCheat
)
EXHAUSTED
HR = 200 beatYmin
NAUSEA
, DIZZY
, HEADACHE
ACCLIMA
TIZED(SOCheat
)
UNACCLIMATIZED
(20C)
I I I I
0 1 2 3
Time it Hours
Figure 5.4
Graph of the remarkable physiological adjustments associatedwith heat acclima-
tization . Initially , the unacclimatized person can walk only approximately 60 min
in desertlike heat (50 C, 120 F) before becoming exhausted. After only 5 to 10
days of repeat exposures, core temperature rises to a plateau no higher than ob-
(It')
f"'"
ness suit . Interestingly , the insulation of the head does not change with en-
tt")
~
~o'a.lnJ'B.ladma~ a.I J
lete who has 10 percent body fat and is a competitive swimmer , or the rel -
atively sedentaryperson who has 20 percent body fat ?At first glance, one
is tempted to answer that the competitive swimmer survives, because
when swimming, he can produce a considerable amount of heat through
muscle contraction . However , in the cold , it is not how much heat you
can produce , but the amount of subcutaneous fat that you have, that de-
termines survival (figure 5.5). The fall in core body temperature is directly
related to mean skinfold thickness . The greater the skinfold thickness , the
~ .
.--c
- .
u0.
. .
Figure 5 . 5
neous fat when men were exposed to water at 15 C for 30 min . In cold water ,
oration , wet skin cools faster than dry skin . However , this faster cooling
rate does not explain the higher incidence of freezing . Apparently what
The practical lesson here is to keep your hands out of water ifexposure to
cold is anticipated .
Lewis ( 1941 p . 870 ) wrote : " It has been found that supercooling dis -
plays itself in greater degree in skin that remains unwashed . Washing the
skin encourages , while rubbing the skin with spirit and anointing it with
well known that Arctic explorers leave their skins unwashed . "
What 's So Important About a Body Temperature of 37 C ? 111
Figure 5.6
Insulation of winter fur. The insulation of fur on different animals is comnared
-
with the insulationof 2.5 in of blubberin an arctic seal. (From Scholanderet al.
In Folk 1974.)
which is very comparable with the best insulating fur of animals ( figure
air .
compare this insulation with the fur and feathers of animals . To deter -
1 = 3 . 1 ( Ts - Ta ) '
314M
6
Mean Radiant Temp . = Air Temp .
(~
z:/))
5
Relative Humidity = 50 %
Air Velocity = 0.5 m/s
9
u ~
4
0
w
a-:
3
- 30 - 25 - 20 -15 -10 -5 0 5 10
AMBIENT TEMPERATURE , C
Figure 5 .7
exercise intensity increases from 70 to 232 watts per meter square of surface area
heat can be produced to balance heat loss . Under these conditions IREQ
vided by the clothing worn is less than that required to maintain thermal
Cold Acclimatization
Humans can be acclimatized to the cold . In fact , one of the most amazing
human capacities is that of sleeping " like a baby," completely nude , at al-
most freezing ambient temperatures . (This is one of the examples that will
be discussed, along with other forms of cold acclimatization , in chapter 6.)
114 Chapter 5
nores the fact that more than 50 percent of the body tissues , representing
Moreover , the recent discovery of " hyperthermophiles " that can live at
ature better than the core temperature can adapt to a temperature for op -
Arrhenius , is often expressed as the " Q10 effect " - the increase in reac -
tion rate for a 10 C rise in temperature . For most living cells , heat pro -
and that x is body temperature , the difference between core and ambient
and core body temperatures , heat loss will increase in the ratio of [ ( x -
and heat loss would be 37 C . This temperature assumes that heat transfer
to the skin from the core is constant and that the heat transfer coefficients
for the different avenues of heat loss are constant . However , this approx -
heat loss is proportional to the thermal gradient from the skin to the envi -
that proof of this theory would not withstand careful scrutiny , but the ex -
ercise does suggest that the core temperature of homeotherms may have
Consider the fluid balance problem that would be created if core body
and the only avenue of heat loss would be evaporation . The sweating
polypeptide chains uncoil , become tangled with one another , and cannot
activity would produce severe thermal stress , and high intensity exercise ,
even for short periods of time , would likely result in thermal injury " ( heat
stroke ) . Sports like tennis , football , basketball , field hockey , and soccer
What-'s So Important About a Body Temperatureof 37 C? 117
Minut ~ of Runnng
Figure 5 .8
Rise in core temperature during exhausting exercise in the heat . This figure illus -
trates the effect of a competitive 3 mile run on a humid day when the ambient
temperature was 87 P. Core temperature was elevated by warm - up before the
race . Competitor A achieved a much higher core temperature than competitor B
at the end of the race , in part because he had a higher core temperature at the end
of his warm - up . ( Modified from Robinson 1963 .)
:>a' H
30 'a.lD1e.ladwa~ 1R1
with a high relative humidity , core temperature will rise at the rate of
will elevate core temperature and contribute to its marked rise during the
. .
competItIon .
fever , which is discussed in chapter 8 , but aside from fever , is there a tem -
Neurons are exquisite and delicate cells that require constant and unper -
turbed surroundings to perform their job . They require chemical constancy
and , above all , a warm environment . Neurons are very hardworking cells .
They do not seem to complain about their hard and tiring work , but they
need help . In fact , for this purpose neurons have their maids , the glia ,
which are in charge of cleaning up and maintaining their extracellular
surroundings .
In the brain of poikilotherms , the neuronal environment was constant
with regard to chemicals and hormones , but not temperature . For these
animals , neurons in the brain worked hard when temperature was ele-
vated , but slowed their activity when temperature fell . During the transi -
tion from reptiles to mammals , these animals had to cope with a new
problem , that of producing excess internal heat . Solving this problem re-
quired the development of mechanisms for losing heat , and with these
mechanisms , a machine , a computer in the brain , to control it . With this
computer , and with a constant temperature in the brain , neurons became
continually active .
It looks as if in the final stages of mammalian evolution , in the late
Cretaceous and Eocene times , the final stage of development of tempera -
ture regulation took place . Precisely, it was at the time of growing and
further elaboration of the cortical mantle . It has been hypothesized that
the evolution of a more complex brain brought a greater need for a con -
stant brain temperature . Recall that the Law of Arrhenius states that re-
action rates are a function of temperature . More important , each reaction
What's So Important About a Body Temperatureof 37 C? 119
in the body has an " activation energy " that is temperature -dependent .
Activation energy is the energy required to initiate a reaction rather than
the energy (or heat ) produced by a reaction . Moreover , activation energy
can vary markedly from one reaction to another .
Imagine the difficulty of performing coordinated movements and com -
plex thought processes if the millions of reactions (with their different ac-
tivation energies) required to perform these tasks occurred at different
times as a function of varying brain temperatures . The emerging concept
therefore is that the organizational complexity of the brain and the need
for complex interaction of neuronal activity require homeothermy . In
support of this concept , it is common knowledge that hypothermia is as-
sociated with drowsiness and confusion ; and that elevations in brain tem -
perature significantly impair mental performance (Engel et ale 1984 ;
Hancock 1981 ). Although fever is associated with impaired mental pro -
cessing, even a nontoxic rise in core temperature produced by exercising
in the heat significantly increases the frequency of errors on an attention -
stress test . Further evidence supporting the importance of homeothermy
for normal brain function is the poor temperature regulation (as an ex-
ample of neuronal processing ) in the newborn compared with an adult
(see chapter 4 ).
This excerpt from
Ducks walk on ice without freezing their feet, rats can live in refrigera -
tors , and some humans can sleep virtually nude at near freezing tempera -
tures without shivering or discomfort . On the other hand , desert ants can
maintain body temperatures over 50 C, and elite marathon runners can
sustain brain temperatures between 40 and 42 C without heatstroke .
How is this possible ? One of the most remarkable characteristics of
homeotherms is their ability to adapt to changing environments through
physiological adjustments and, with more prolonged exposure, anatomi-
cal changes. The term used to describe the physiological responsesto
chronic exposure to environmental stressis acclimatization, whereasac-
climation is used when an organism is exposedto a single stress, usually
in a specifically designedenvironmental chamber where temperature, hu-
midity, oxygen tension, and so on can be controlled and varied indepen-
dently. During the process of acclimatization or acclimation, if a
particular physiological responsediminishes compared with the unaccli-
matized or unacclimated state, the term habituation is used. The term
adaptation usually is reservedfor genetic effects produced by natural se-
lection. Often the ability to acclimate to one stressimproves one's ability
to cope with other stresses . This is called crossacclimation. A good exam-
ple of crossacclimation is the effect of endurance training on heat and
cold acclimation.
Cold Acclimatization
adaptive response . With this notion in mind , (a ) are there any human
populations that expose their whole body to the cold sufficiently to pro -
example , if your hands are usually exposed to the cold , do they exhibit
greater cold tolerance than the hands of someone who usually wears
gloves ?
made to the cold : ( a ) decreased heat loss , achieved by reducing the surface
area of skin exposed to the cold , growing hair for insulation , and / or de -
several or all bodily tissues . Is there any evidence for whole - body cold ac -
climatization in humans ?
The concept that humans are incapable of acclimatizing to the cold is sup -
viewpoint , these responses should not come as a great surprise , since both
groups maintain virtually the same skin temperature despite the fact that
the Eskimo lives in the Arctic . Eskimos simply wear appropriate clothing
to protect their skin from the cold . On the other hand , Eskimos generate
is attributed to the high - protein diet consumed by the Eskimo and not to
cold exposure . When the diet of the Eskimo is limited in protein content
Although Eskimos do not expose their whole body to the cold , they do
example , Eskimos have a much greater capacity to keep their hands warm
pecially to the fingers , than the Europeans . Even Eskimo children , with a
smaller hand volume and greater surface - to - mass ratio than their elders ,
edly have their hands in cold water , and is attributed to a blunted vaso -
posed limb but also in the contralateral nonexposed hand , indicating that
In contrast to the Eskimo , the women of Korea and japan who dive to
harvest plant and animal life year round in waters that reach 10 C during
When physiologist Suki Hong studied these women in the early 1960s ,
their basal metabolic rate during the winter months , when they were div -
ing in very cold water , was significantly elevated above values observed
during warmer months ; this provided the crucial evidence for cold ac -
What happened ?
Traditional Divers
TheseKorean and Japanesewomen divers are called ama. They begin div-
ing at the age of 11 or 12, and may continue to the age of 65 (Hong and
Rahn 1967). They dive both winter and summer and, if pregnant, are
known to work up to the day of delivery. In the late 1950s, when Hong
124 Chapter 6
Figure 6.1
Korean diving woman wearing a traditional bathing suit made of light cotton.
(From Hong and Rahn 1967.)
From Siberia to Africa 125
began his classical studies, these women wore only cotton bathing suits
(figure 6.1), even during the winter , when the air temperature was near
freezing and seawatertemperature was only 10 C. In the winter, a diver
worked 1 or 1 15 - to lO -min shifts ; even this short time was sufficient to
lower rectal temperature from 37 C to 34 .8 C (Hong et ale 1987 ). This
level of hypothermia also has been observed in Australian Aborigines (see
below ) and Channel swimmers . A typical dive lasted about 60 sec and
consisted of a 30 -sec dive followed by a 30 -sec rest interval in the water .
During the summer , when air temperature is 25- 30 C and water temper -
ature is 22 - 27 C , divers worked 2 1 - hour shifts and 1 2 - hour shift . Each
35
Figure 6 .2
Basal metabolic rate of ama women (A ) increases in winter and decreases in sum -
mer . In nondiving women (B ), basal metabolic rate is constant throughout the
(JnoH/Ja~all\l aJenbs/sa!JOle::>ol!>t) a~e~ ::>!loqe~all\llese8
year . Curve (C ) shows the mean seawater temperature in the diving area of Pusan
harbor for the period covered by the other measurements . (Modified from Hong
and Rahn 1967 .)
nondivers , yet they lose less heat under conditions of cold exposure . How
is this possible ? The answer relates to the control of peripheral blood
~
0
several hours and recording their core temperature and heat produc -
tion . Using these results , maximal body insulation is calculated from the
equation
% 31
75 CONTROLS
:.;:.1 29
0
.
9
; 0
28 .
;2 0 AMA
I
, :I ::
~ -/c-))50
'(>
.~ Q %...
25
%
0 320310 300
Figure 6.3
Woter
Bath )290
Temp
.(O .-28
C
Shivering threshold of Korean diving women is shifted from 32 C to 31 C . The
difference between control groups (men , nondiving women ) and the ama is more
apparent at 50 percent shivering . The ama become cold -acclimatized in winter
and shiver at a lower temperature than nondivers and men . (From Hong 1973 .)
without shivering , and the rate of skin heat loss is equal to metabolic rate
(corrected for respiratory heat loss) plus net loss of stored heat during
submersion . The outcome of these experiments indicated that the ama (a)
experience less heat loss than nondivers with the same thickness of subcu -
taneous fat ; (b) lose about half of their subcutaneous fat in the winter ,
presumably becausetheir caloric intake does not keep pace with their
heat loss; and (c) shiver at a significantly lower water temperature than
nondivers . The water temperature at which 50 percent of the ama shiv -
ered was 28.2 C, compared with 29.9 C for nondivers, and 31.1 C for
men (figure 6.3). This greater insulative shell of the ama is attributed to
the suppression of shivering , but , it could be a vascular response. The lat -
ter could be due to an enhanced vascular constriction of the limbs and / or
a more effective countercurrent heat exchange in the limbs . Because there
are no significant differences in heat flux from the limbs or in limb blood
flow when comparing the ama with nondivers , it has been concluded that
the greater insulation is due to a more efficient countercurrent heat ex -
change system (Hong et al.1969 ).
In addition to the response to whole -body submersion , another test
of cold tolerance is to submerge the hand in 6 C water and to monitor
the local vascular response. Contrary to the attenuation of finger va so-
128 Chapter6
Contemporary Divers
In 1977 , the ama began wearing wet suits to combat the cold stress . This
change provided the rare opportunity to study the time course of the
the divers more comfortable and productive . Rectal temperature fell only
2 . 2 C when the ama wore a cotton bathing suit . In a wet suit , mean skin
only 37 percent of what it was when the ama wore a cotton bathing suit .
critical water temperature between the ama and nondivers in the 1960s
tional divers was lost . This supports the notion that the latter response of
was associated with whole - body cold exposure rather than cooling of the
hands alone . Thus , the ama who lost their cold acclimatization blunted
zatIon .
From Siberia to Africa 129
Table 6 .1
Traditional divers
Contemporary divers
1980 0 0 - 20 - 2
1981 0 0 0 - 1
1982 0 0 0 - 0 .2
1983 0 0 0 0
Note : Basal metabolic rate , maximal body insulation , and Qfinger ( finger blood
flow during immersion of hand in 6 C water ) are expressed as percent deviations
from respective control values ( + and - denote higher and lower than control , re -
spectively ) . Critical water temperature indicates absolute value relative to con -
trol ( - denotes lower than control values ).
From Hong et ale 1987 .
There are a number of ways to test human tolerance for cold exposure .
Perhaps the most widely used is to submerge the subject in cold water or
expose the subject to cold air , and to determine the threshold skin tem -
perature for the onset of shivering . A less popular and more time - con -
suming test is the " cold bed test . " Basically , the individual is confined to
tests ; the most important one is whether the person is able to sleep . When
white Caucasians are tested , they feel cold , shiver , toss and turn , cannot
other hand , sleeps like a baby . Most interestingly , when noncold - acclima -
tized white Caucasians participate in long - term aerobic training , they dis -
Aborigine . What are these physiological adjustments , and how are they
metabolism during cold exposure . Thus , their ability to tolerate the cold
130 Chapter 6
38
36::~~~;::::::::::::::-. 0
.
CONTROL
ABORIGINE
-0
u-
3 ~ ~~ "'-O~~::
3
3 Tsk
I I I I I
0 2 4 6 8
HOURS HOURS
Figure 6.4
Averagethermal and metabolic responsesof sevenAustralian Aborigines and six
3:)N't/13nONO:) lVWH3Hl
METABOLICRATE
11a
I~ _ ~
group changed ver )lTlittle , but the heat content of the Aborigines fell
continuously throughout the night . The rate at which heat content fell
diminished as the gradient between skin temperature and air tempera -
ture decreased . The conductance of heat from the body core to the skin
was about 30 percent less in the Aborigines than in the controls , even
though mean skinfold thickness (3.04 mm ) and percent body fat (17 .3
percent ) were considerably lower in the Aborigines than in the whites .
From Siberia to Africa 131
C ,Esophageal
37
/ ----0------0-- - - -0-- - - 0
36
~
w
..- Ir~:'-: ::~~::=:::~:=: :==:~::=
-5 0 5 10 15 20 25 30
AMBIENT TEMPERATURE , C
% O2 Uptake
200
hLveiin.9 Ih ~ s.DJ.d-
100
34 35 36 37
I" 1
Threshold
Shift
MEANBODYTEMPERATURE
, C
Figure 6.5
Comparison of esophagealtemperature and oxygen uptake responsesof one sub-
ject to cold exposure before (e) and after 1 year (0 ) and 1.5 years (l:!) of
marathon training . Upper panel shows the change in esophagealtemperature as
ambient temperature was reduced from 29 C to - SoC. Lower panel shows the
corresponding change in ox)lTgenuptake as a function of mean weighted body
temperature. Although it appearsthat the threshold for an increasein 2 uptake
did not change, note the decreasein shivering threshold and diminished rise in
oxygen uptake with endurancetraining . (Redrawn from Baum et al. 1976.)
Corresponding values for the controls were 5.36 mm and 22.3 per-
cent, respectively (Hammel 1964). This form of cold acclimatization ,
whereby (a) heat content of the body decreases , allowing core tempera-
ture to fall , and (b) conductanceof heat to the skin is diminished, thereby
increasing the thickness of the body shell, has been referred to as " insu-
~mIJ' ~l:~r=1
Mean Body
38 I 0 Before1 35
I . After J
34
33
37
32
0 30 60 90 120
36
0 30 60 90 120
Figure 6 .6
Rectal , esophageal , mean body , and mean skin temperatures of a lean subject ex -
posed to 10 C air for 2 h , before and after training . ( Redrawn from Kollias et al .
1972 .)
take did not reach 200 percent until mean body temperature had fallen al -
temperature at rest and at the onset of shivering and sweating were all
derstood and can vary with different neurotransmitters , brain sites , and
animal size , age , development , and species . Based on data from guinea
pigs of the same strain , age , and sex , the body temperature threshold for
from nuclei in the lower brain stem ( Zeisberger and Roth 1996 ) . In fact ,
mated , but not in warm - acclimated , animals . On the other hand , block -
Heat Acclimatization
son was stranded in the desert during the summer and had to walk for
secreting sweat over the general body surface . However , even if this per -
son had adequate water to drink , the consequences of such a trek could
ox } Tgen to the legs to continue walking and blood to the skin to dissipate
result , heart rate rises to 200 beats / min and core temperature to 40 C or
symptoms and signs of severe stress are abated with repeated short - term
From Siberia to Africa 135
w 180
t.~ -c-140
..~
!8 S
120
-~ C
-.
!100
~
. -
-.JC )80
39
o
-wC ~
W
~ j
t~ w
Q
W 38
.t-37
~
. . . .
' "
~.. t
38
- 37
(J
! .. . 36
ZUJ
- a: 35
~ ~
(/) t - 34
z <
< a: 33
UJUJ
~ Q. 32
~
UJ
t -
31
COOL 1 2 3 4 5 6 7 8 9 10 COOL
CONTROL ACCLIMATION CONTROL
TIME (days )
Figure 6.7
Changesin heart rate and rectal and mean skin temperaturesin a cool room be-
fore and after a 10-day regime of heat acclimation to a hot, dry environment
(50 C). Each day, activity consisted of 5 10-min periods of treadmill exerciseal-
ternated with 2-min rest periods. The initial value each day is indicated by a
large dot and the end of each exerciseperiod by a small dot. The final values of
each day are connectedby a dotted line. (Taken from Eichna et ale 1950.)
136 Chapter
6
80 .
.
0 . .
50
40
.
30 ,
0 UNACCLIMA
TED
.
20 . ACCLIMATED
10
Figure 6.8
Effect of heat acclimation on sweat sodium concentration as a function of sweat
rate. (Modified from Alan and Wilson 1971.)
retaining sodium from the kidneys and the sweat glands causing a dilute
sweat (figure 6.8), which helps to maintain extracellular fluid volume and
: ri'i~i
the drive to drink . If the effects of aldosterone are blocked by the drug
It1Ii[ .J..~ ' 71
heart rate and skin temperatures also decline . The decline in skin temper -
ature is the result of an increasein evaporative cooling. It increasesthe
core-to-skin temperature gradient, which facilitates heat transfer to the
skin and heat loss , so that core temperature declines . The decrease in core
a
c .
IIIII
II!
Tes
. .C
SU8J .8RS
Tsk. 33. C
. PRE -EXERCISE
.8
D POST - EXERCISE
. POST - HEAT
'380.:1
( U!UJ."" 00 / ) / "'" M07,d00078 W8V
.4
.2
Figure 6.9
Effects of two weeks of training and heat acclimation on forearm blood flow and
sweating on the chest (as a function of esophagealtemperature, T es). (Taken
from Roberts et al. 1977.)
From Siberia to Africa 139
A.
B.
w
0
a:
I.0
0
(I)
5 4
From Siberia to Africa 141
AT x I" g
-I
/ J. T 10 pO
Figure 6 . 11
Dose - response curve for norepinephrine microinjected into the preoptic anterior
hypothalamus before ( closed circles ) and after ( open circles ) heat acclimation in
the rat . The change in colonic temperature with each dose of norepinephrine has
been normalized by dividing the change in temperature with each dose by the
~. Significantly greater ( P < O . OS ) than control response at that dose . t Linear por -
tion of dose - response curves significantly different ( P < 0 . 001 split - plot analysis of
Figure 6 . 10
( A ) Sweat glands from biopsy specimens of poor sweaters ( open symbols ) ( a ) and
gland size and sensitivity are associated with the level of fitness of these subjects .
sweaters ( closed circles ) and 3 subjects who were poor sweaters ( open circles ).
(b) 40.5
CAROTID
BLOOD
BRAIN
V//////////////////////
i I I . I . I . I I I
.
From Siberia to Africa 143
Rats, Cats, Dogs, and Humans: Who Can Cool the Brain ?
It 's a hot summer day on the Mojave Desert. A jackrabbit , with an im-
planted radio telemeterto measurebody temperature, is observedto have
a resting core temperature of 41 C. A dog spots the rabbit and immedi-
ately gives chase. In 10 min, the body temperature of the jackrabbit ,
which is sprinting to avoid the dog, rises to 43 C. Unable to hide, it con-
tinues to run and elevatesits body temperature to 44 C, then suddenly
dies. Why didn't the dog also become hyperthermic and die? The dog,
being much larger, you reason, must have produced more heat and prob-
ably had a higher body temperature than the rabbit . The answer, at least
in part, is that the dog was able to cool its brain. How is this possible?
In 1966, a group of investigators discovered that when goats became
hyperthermic, their brain temperature rose lessthan the rest of their body
(Taylor 1966). They termed this phenomenon " selectivebrain cooling"
(SBC). Subsequentstudiesrevealedthat SBCoccurs in artiodactyls (even-
toed mammals with hooves: pig, hippopotamus [4 toes], antelopes,
camels, deer, giraffe, cow [2 toes], dogs, cats, and other species. The
mechanism that allows SBC to occur is attributed primarily to the pres-
ence of a carotid rete (figure 6.12), a network of medium-sized arteries
embeddedin the cavernoussinus at the baseof the brain. The cavernous
Figure 6 .12
(A ) Schematicdiagram of countercurrent exchangein the brain of an antelope.
Venous blood draining the nasal and buccal cavities flows back to the heart
through the cavernous sinus, cooling arterial blood destined for the brain. The
magnification shows the carotid rete as a network of small arteries formed from
the carotid artery within the cavernous sinus. (B) Carotid blood (Tbl ) and brain
temperature of a goat during exercise, illustrating selectivebrain cooling (SBC).
Inset shows SBC (the difference between blood and brain temperatures ). The
cross -hatched bar represents 60 min of level treadmill exercise at 4 .8 km8h - 1 .
(Modified from Taylor and Lyman 1972; Baker 1993; Baker and Nijland 1993.)
144 Chapter 6
o.I2."5
E
'--
"0
oX
'
0.005 '
5
40.5
u
0
30 B. x
x x x
25 x x
x
20 x x
. x x
(U!W/ D)f / IW) MO13 aOO18
.~0
15
0 0
.0 0 00
10 . - .0o~ .00 000 0
. . . aX :] eoo. ------.- ' . RESTING
v.oo00 CD C8
0 0HYP
. HEAT
a::v
- ~ O
5 ~ .-a'.-_._- .,- x EXERCISE
. - - ' ..-
. . .. -
0 0.05 0.10 0.15 0.20
WATERLOSS(g/ kg/ min)
Figure 6.13
Relationship between cephalic blood flo\\Tand upper respiratory evaporation in
the dog. (A ) Carotid blood flow (implanted ultrasonic probe), evaporative water
loss (flow -through mask), rectal temperature, and brain (hypothalamic) tempera-
ture during exercise. In the period marked RUN (between the vertical arrows),
the dog ran at 7.5 kmlhr on a 20 percent slope. Ambient temperature was 25 C.
(B) Steady-state levels of carotid blood flow and evaporative water loss in a dog
at rest at ambient temepraturesfrom 25 C to 45 C (black circles), during heating
.!1Dm
of the hypothalamic thermosensitive zone (white circles), and during the last
.I
11 _ ; E
m
m
.
I
Chapter 6
ArteriaJ
B
Ttrunk
bfoodtemperature
(OC)
B
.
- 0 m 00
"'If' ...,. t' ) tI') .
From Siberia to Africa 147
mechanism similar to shivering and sweating , with the reservation that its
free - roaming antelopes showed that SBC occurred during the day under
( REHL ) was reduced because the brain temperature was lower than the
1993 ) .
would nature evolve a system that cools this area of the brain , thus pre -
stated in chapter 3 , thermo sensors are located in the spinal cord and
throughout the body core . Afferents from these trunk sensors contribute
equally to the control of respiratory heat loss if brain and trunk tempera -
tures are identical ( Jessen and Feistkorn 1984 ) . When brain and trunk
exclusive control over SBC ( Kuhnen and Jessen 1991 ) . The combination
ing but not SBC . On the other hand , the combination of a high brain tem -
perature and a low trunk temperature produces SBC but not panting .
Figure 6 . 14
Schematic diagram illustrating when SBC is turned " on " or " off " in an animal
under free - ranging conditions . ( A ) At rest or during moderate activity under con -
ditions of low environmental heat stress , SBC is evoked ( middle ) , which inhibits
trunk temperature sensors and the rise in REHL with increasing body tempera -
running for its life - SBC is suppressed , that is , brain temperature equals trunk
temperature ( middle ) , and REHL rises with a steeper slope because it is now dri -
ven by both trunk and brain temperature sensors . ( From Jessen 1998 . )
148 Chapter 6
Thus , in the hyperthermic animal , the brain can offset ( separate ) its own
temperature from the rest of the body . SBC can reduce the drive on ther -
moregulatory effectors that are activated by input from the core and
brain . However , when SBC is active and brain temperature is lower than
trunk temperature , REHL is reduced and the trunk contributes more than
the animal is running for its life and a maximal drive for REHL is desir -
is that SBC is not mandatory ; that is , cool venous blood from the
nasobuccal cavities can return to the heart via the angularis oculi vein
through the cavernous sinus and lead to SBC , or it can return through
the facial vein directly to the jugular vein and prevent SBC ( figure 6 . 12 )
( Johnsen et ale 1987 ) . These veins contain sphincters that are richly en -
dowed with sympathetic fibers . Thus , it may be possible for the sympa -
flow via these two routes because the angularis oculi sphincter has
Thus , low sympathetic activity could promote cool venous flow through
could constrict the angularis oculi sphincter , dilate the facial sphincter ,
and direct cool venous blood away from the cavernous sinus , thereby
preventing SBC .
What can we conclude from these findings ? How can we reconcile the
observations in the wild with those in the laboratory ? Jessen and col -
leagues ( Jessen 1998 ) have elegantly shown in field studies that antelope
appear to turn off SBC under " fight or flight " conditions . However , the
mal speeds . SBC under these conditions could have been overwhelmed by
intense heat production and thus not have been apparent . When exercise
studies using the same species were performed under laboratory condi -
tions , the intensity of the exercise was not maximum and the animals
were not subjected to the emotional stress associated with being chased in
From Siberia to Africa 149
not pant , but some investigators believe that significant cooling of the
brain can occur nevertheless(Cabanac 1986). This possibility is a contro-
versial issuethat dependson whether or not brain temperature can be es-
timated accurately (Nadel 1987 ; Wenger 1987 ; Brengelmann 1993 ;
Cabanac 1993 ). The temperature that has been used to estimate brain
temperature
has beentympanicmembrane
temperature
(Ttym). The
question is " Does T tym track esophagealtemperature (T es)' which is usu-
ally acknowledged as the best measureof core body temperature, or does
T tym fall below T esunder conditions of heat stressand during manipula-
tions such as face-fanning, and in so doing provide evidence of SBC?"
Before answering , it is critical that T tym be measured accurately . If it is
not , spurious data will be collected and incorrect interpretations will be
made . If the temperature -sensing device employed to measure T tyro is not
150 Chapter 6
A
...-- - - - ------- Copper /constantan
thermocouple sensor
soldered to steel wire loop
~ - Insulating paint
- Thermocouple cables
Sponge rubber
Polyethylenetube
(4 mm diameter)
34
Figure 6.15
(A) Tympanic membranethermocouple. (B) Effect of fanning the right side of the
face on tympanic membrane temperature (T ty ) in both ears and on esophageal
temperature (T es). (Modified from Sato 1996.)
From Siberia to Africa 151
Bra in
Figure6.16
Potentialsitesfor countercurrentcooling of arterial blood supplyingthe hypo-
thalamus and tympanic membrane . Site I: cavernoussinus- internal carotid
artery. Site II: internal jugular vein-common carotid artery. Site III: external
jugularvein- externalcarotid artery. (FromNielsen1988.)
Eachyearapproximately 2 millionpeoplefromover80nationsgatherto
makethegreatpilgrimage to Mecca , thehajj. Thisis not simplya visitto
a holyplace.EveryMuslim, everywhere in theworld, unless physically or
economically unableto do so, is obligatedto performthe hajj at least
oncein a lifetime.It is thefifth of thefivefundamental "Pillarsof Islam"
(Long1979). In the Quranit is writtenthat the first houseof worship
foundedfor mankind , theStanding Placeof Abraham , is in Mecca(Long
1979). Thetimingof thehajjis absolutely fixedontheeighth,ninth, and
tenthdaysof thelastmonthof theMuslimcalendar . Because thehajjoc-
cursaccording to theMuslimlunaryear,whichis 11daysshorterthan
thesolaryear,at theendof abouta 34-yearperiodit hasfallenin eachof
the12solarmonths . Thus, it fallsin thesummer(April- September ) and
winterin 17-yearcycles . Asidefromcholera , heatis themajorsourceof
curablemedicalproblems . This is because of the desertclimatefound
throughout theHejaz.In thesummer , maximumtemperature in theshade
hasbeenrecordedat 52.2 C (126F) (Long1979). Evenin the winter,
whentheclimateis balmy , constantexposure to thesuncanbedebilitat-
ing, especiallyfor theagedandyoung.In theJune1959hajj, 454people
diedof heatillness(Long1979). Heatstroke is a completely preventable
condition , butthecircumstances surrounding thehajjcontinueto makeit
a majorchallenge for thoseresponsible for administering this annual
event . This type of heatstrokeis known medicallyas "classicalheat
stroke" (table7.1).
Let'sconsider a verydifferentscenario thatcanleadto greatermorbid-
ity andmortalitythan classicalheatstroke . Imaginetrying to run 135
milesbeginningat 6:30 in the morning , whenambienttemperature is
156 Chapter 7
Table 7 .1
Characteristics of classica]l and exertion-induced heatstroke
skeletal muscle for oxygen delivery and blood flow to the skin for heat
these competitors are sweating profusely and must sustain blood flow to
muscle and skin when dehydrated , which reduces circulating blood vol -
Recall the staggering finish of Gabriella Andersen Scheiss during the first
medically as " exertion - induced heatstroke . " Both forms of this multior -
gan system injury can be fatal , although exertional heat stroke usually is
stroke from sepsis , and exertional heat stroke from less severe heat - in -
The Burning Brain 157
Is heatstroke the result of a " burning brain," that is, the direct effect of
heat on brain tissue, causing lesions and denaturation of protein ? Or is
heat stroke the result of primary damageto body tissuesthat ultimately
affects the brain ? Historically , it has beenattributed to either a central or
a peripheral event. In the former case, Malamud et ale (1946) hypothe-
sized that heat had a direct effect on the hypothalamus that led to ther-
moregulatory failure, the cessation of sweating, inadequate peripheral
circulation , and shock (a " burning brain" ). Thus, the brain could be the
primary target of heat injury . Adolph and Fulton (1923- 119-24) were the
first investigators to attribute heatstroke to a peripheral dysfunction, that
is, circulatory failure leading to shock. Acute circulatory failure was
shown to precededeath in more than 80 percent of 100 heatstroke cases
(Austin and Berry 1956). Basedon this knowledge, the critical question
seemsto be What causessystemichypotension during heat stress? Is the
critical target organ the gut or the brain ?
STAGE
ONE
STAGE
TWO
Figure7.1
Flow diagramillustrating a hypothesisto explain the etiology of heatstroke
.
The Burning Brain 159
Or Is It in the Brain ?
The brain is especially vulnerable to hyperthermia-induced dysfunction
(Brinnel et ale 1987). In fact, the reaction of the brain to thermal injury is
complex and multifactorial . The sequenceof eventsprobably beginswith
general circulatory failure produced by the events in the gut. Moreover,
the direct effectsof heat on brain tissuemay play an important role in the
final pathological outcome of this process. It is a well known that during
ischemia, or any other pathological insult to the brain, an increasein tem-
perature can potentiate neural damage. But before starting with the brain,
let's see what the neurological symptoms of heat stroke are, and then
speculateon how the brain is involved.
The presentation of heatstroke usually is acute. Clinically, the loss of
consciousnessis a constant feature. However, about 20 percent of the pa-
tients have prodromal symptoms (those which precede the loss of con-
sciousness ) lasting minutes to hours and including dizziness, weakness,
and nausea. A clinical picture of heat stroke can be seenin table 7.2.
Symptoms besidesthose listed above include seizures, stupor, delirium ,
irritability , and aggressiveness. In a smaller percentageof patients, symp-
toms include fecal incontinence, flaccidity, and hemiplegia. Prominent
symptoms that could persist after recovery are cerebellar deficits, such as
dysarthria and ataxia. Other symptoms that could remain after recovery
are hemiparesis, aphasia, and mental deficiency. Thus, the general symp-
tomatology, apart from the cardinal feature- the loss of consciousness -
is variable and dependson individual characteristics.
Malamud (Malamud et ale 1946) reported in a clinical study of 125
fatal heatstroke casesthat the most prominent pathological findings in
the brain during autopsy were general edemaand microhemorrhages. He
reported swollen neurons and dendrites in the cerebral cortex (particu-
162 Chapter7
r1'able7.2
Clinicalfeaturesof heatstroke
Dry skin 26
Rectal temperature 41 C 55
Vomiting 71
Diarrhea 44
larly the frontal cortex) and basalganglia. But the most dramatic damage
in the central nervous systemappearedin the cerebellum. This consisted
of edema of the Purkinje layer and a reduction in the population of
Purkinje cells. The Purkinje cells remaining were swollen, pyknotic , or
disintegrated. Moreover, there was a notable increase in glial mass. In
contrast to thesepathological findings, and despite a careful pathological
analysis, no significant alterations were observed in the hypothalamus.
Nor were there any demonstrable changes in the midbrain , pons,
medulla, or spinal cord; mild damageand slight gliosis were found in cells
of the inferior olivary nuclei and in the reticular formation .
Unfortunately, the above findings were observedin fatal casesand could
have developed during many hours preceding death. Therefore, they do
not necessarilyindicate the initial cascadeof eventsleading to the damage
reported.
Researchin experimental animals has provided insight into the bio-
chemistry, physiology, and histological changesoccurring in the brain at
the onset of heatstroke. Experimentally, in the rat, during the onset of
heatstroke (time at which mean arterial blood pressure beginsto decline
from its peak level during exposure to an ambient temperature of 42 C),
subjects display arterial hypotension, intracranial hypertension, de-
creasedcerebral perfusion, degenerationof neurons with replacementby
microglia proliferation , and neuronal loss (Kao and Linn 1996). Also, ev-
The Burning Brain 163
curs in many parts of the brain has accumulated . This deterioration can
teins , and other substances from the vascular compartment into the brain .
Despite these events , the primary cause of brain damage during heat -
1992 ) . Most probably the combined effects of hypotension and its conse -
quent reduction of cerebral blood flow , together with the direct effect of
cellular space . That is the case for at least glutamate and dopamine ,
today and play crucial roles in circuits of the brain coding for behaviors
particular , glutamate has been considered one of the most important neu -
AMP A , and meta botropic . Among these , the NMD A receptors are the
most relevant .
The Burning Brain 165
HYPOXIA HYPERTHERMIA
,~
ENERGY DEPLETION
, .
t UPTAKE
OFGLUTAMATE
"" EXTRACELLULAR
GLUT
AMATE
~
Figure 7.3
Hypoxia and hyperthermia share a common mechanism of neuronal injury me-
diated by glutamate toxicity .
especially the case for glutamate and dopamine in the neostriatum . The
circuitry involved in this interaction , which also includes ')' -aminobutyric
acid (GABA ) and acetylcholine (Ach), is being deciphered (Segoviaet al.
1997 ).
As mentioned above , serotonin participates in the neuronal damage
produced by ischemia. Destruction of serotonergic neurons significantly
attenuates the neuronal damage associated with heatstroke , thus support -
~
111 -
I
168 Chapter
7
Figure7.5
Speculativeflow diagramillustrating how the combinedeffectsof a leaky gut
andhot brain canproduceheatstroke .
In the 1950s and 1960s , there were numerous cases of heatstroke among
the Bantu laborers who worked in the gold mines of South Africa . It was
only after instituting the policy that everyone who worked in the mines
were heat - intolerant were identified and prevented from working under
such hot , humid conditions . Heat intolerance has been defined as the in -
heat - intolerant individuals have not been defined . The factors underlying
for age , height , weight , surface area , and VO2 max ( Shapiro et ale 1979 ) .
heart rate rose to 160 bpm , and the subjects stopped . Control subjects
exposure . Sweat rate was the same in both groups . The investigators con -
cluded that the heatstroke victims had difficulty transferring heat to the
Table 7 .3
a. General Factors
Dehydration
Unfitness
Heavy clothing
No acclimation
Previous heatstroke
Old age
Fatigue
b . Diseases
Cardiovascular diseases
Infectious diseases
Ectodermal dysplasia
Table 7 .4
Observed and derived results on the first com petitors ; finishing the Whitney
Marathon
Order of Finishing 1 2 3 4
0 bservations
treadmill for 6 weeks . Tissue damage and percent mortality were the
same in the trained and control sedentary animals , but the trained sur-
vivors (a) continued the test 44 percent longer, (b) performed significantly
more work , and (c) sustaineda 120 percent larger thermal load (product
of time and colonic temperature above 40 C ) than sedentary survivors .
Mortality first occurred at a core temperature range of 40 .6- 41 .0 C in
the sedentary animals , compared with a range of 41 .6- 42 .0 C in trained
animals (figure 7.6). Thus, training enabledrats to run longer in the heat,
The Burning Brain 173
.--~
-KX
)
~=80
60
0
. Sedentary
~e
c
"u40
A Trained
.20
~
0
I ~ I J I I I IJ
40 .1 - 40 .6 . 41 .1 - 41 .6 - 42 .1 - 42 .6 - 43.1+
40 .5 41 .0 41 .5 42 .0 42 .5 43 .0
Tc at exhaustion C
Figure 7.6
Percent mortality during work -heat tolerance test in trained and sedentary ani -
mals . Numbers above data points indicate the number of animals in each group .
(From Fruth and Gisolfi 1983 .)
Neonatally
Induced
Thermotol
erance : UniqueBlendof Head
AcclimatizationandAcquiredThermotolerance
?
How Does Heat Affect Cells , and What Is the Function of HSP ?
Heat increases metabolic rate and , as shown in figure 7.1, can uncouple
oxidative phosphorylation , leading to ATP depletion . Moreover , the
metabolic products of ATP breakdown can produce reactive oxygen
176 Chapter7
0 0
Figure 7 .7
Survival after whole - body heating at an ambient temperature of 42 .5 C for 24
(curve 1 ) , 96 (curve 2 ) , and 144 (curve 3 ) hours after a conditioning heat expo -
sure at 41 . 8 C for 60 min . The curves represent best - fit plots determined by the
logistic regression method . Horizontal bars indicate 95 percent confidence inter -
vals for the LD 50 . Curve 0 represents survival of previously unheated rats (con -
trol ) following heating at 42 . 5 C . ( From Weshler et al . 1984 .)
teins can induce the synthesis of HSP . One function of HSPs is to bind
ases " to restore them to their normal tertiary structures ( see figure 7 . 8 ) or
-
~ c~.Memb
Ribosomes
@~ \
~
_d Recovery
.S ~tress
~ ~
te
"'
S ~
- S
~ = HSP70
~-t!'-
~~ "
i't ~ ~ @ = HSC70
- - + = ATP
ADP
- .
+ Pi .
Figure7.8
Schematicdiagramillustratingthe possiblechaperonefunctionsof the 70-kDa
heat-shockprotein (HSP70). Membersof this family, when expressed constitu-
tively (HSC70), bind to proteinsto assisttheir properfolding and assembly(a).
Wrongly folded proteinsor denaturedproteinsare refoldedor transportedto
lysosomesfor degradation(b). HSPalso assistsin transportingproteinsacross
membranes into variouscellularcompartments(c). Heat andotherstressesdena-
ture proteinsand induceHSP70synthesis . Newly formedHSP70bindsto dena-
turedproteinsto keepthemsolubleandassistsin their renaturation(d). Proteins
arereleasedfrom HSC70/ HSP70with the aid of ATPhydrolysis. (Modifiedfrom
JaattelaandWissing1992.)
53- 55 C (Gehring and Wehner 1995). This remarkable capacity for ther-
mal stressis associatedwith the ability of these insects (a) to synthesize
HSP at up to 45 C, compared with only 39 C for Drosophila , and (b) to
accumulate HSP prior to heat exposure .
In addition to thermotolerance , formation of HSPs may contribute to
heat adaptation of whole organisms by their effect on (a) maintenanceof
epithelial barrier integrity and (b) their ability to enhance endotoxin tol -
erance. Recall from figure 7.1 that heat stroke was hypothesized to result
from an increase in intestinal permeability leading to endotoxemia and an
increasein circulating cytokines. If the intestinesare prophylactically ster-
ilized , or if antiendotoxin antibodies are administered to experimental
animals, they can tolerate higher core body temperatures and their sur-
vival in the heat improves (Gathiram et ale 1987a , 1987b ). In an epithelial
monolayer grown in culture, a reversible increasein permeability occurs
with a rise in culture temperature . If these culture cells are allowed to ac -
An English physician once commentedthat the only real threat to life dur-
ing exercise is the possibility of suffering a fatal heatstroke. However,
when a fit but untrained and unacclimatized healthy man or woman en-
gagesin hard exercise, even in a hot environment, heatstroke rarely oc-
curs. Why ? The answer is that the man or woman stops exercising before
reaching heatstroke conditions. Are there specific signals telling the per-
son to stop, thereby providing a natural defenseagainst such injury ?
The increaseddemand for blood flow to the skin during exercisein the
heat is met in part by redistributing the cardiac output . Blood flow to
splanchnic and renal vascular beds, reduced during exercisein a cool en-
vironment, is reduced further (figure 7.9). The question is whether or not
blood flow to working muscle is reduced as as well , as proposed by
The Burning Brain 181
hot
40 C HR
hot
40 C
1 = min -1
,,
0 10 20 30 0 10 20 30 40 50 60
Time,min
Figure7.10
Esophageal temperature(Tes)' heartrate (HR), and leg blood flow measuredas
femoralvein flow during 30 min of walking in cool environmentimmediately
followedby up to 60 mill of walking in a hot environment . Tesand HR are for
onerepresentativesubject;valuesfor blood flow are means:t SEfor 7 subjects .
(Modified from Nielsenet al. 1990.)
182 Chapter7
circulatory failure, was the critical factor leading to exhaustion during ex-
ercisein the heat. In this study, subjectsexercisedto exhaustion at 50 per-
cent VO2 max for 9- 12 consecutivedays at an ambient temperature of
40 C with 10 percent relative humidity (figure 7.11). They were highly
motivated, and cycled to exhaustion eachday without any cluesas to how
long they had worked. Evidence of acclimatization included increased
sweating rate, and a lower rate of rise of core temperature and heart rate.
Endurance time increasedfrom 48 to 80 min. The intriguing observation
was that exhaustion occurred each day at a core temperature of about
40 C, despite no reduction in cardiac output and muscle blood flow, no
changesin substrateutilization or availability, and no accumulation of fa-
tigue substances(figure 7.11). Moreover, there was no changein the abil-
ity to recruit motor units. As an index of local or central fatigue, maximal
isometric force with the elbow flexor and knee extensor was measured; it
was found to be the samebefore and after exercise.
In contrast to the data of Nielsen et al. (1990) in humans, when dogs
were made hyperthermic by running with hot pack, they showed meta-
bolic changessuggestingthat a high muscle temperature limited skeletal
muscle performance. Hales (1983), using sheep as an experimental
model, showed a decreasein muscle blood flow during exercise in the
heat. Rowell (1986) argued that the increase in cardiac output and the
reductions in splanchnic and renal blood flows during exercise in the
heat are insufficient to account for the estimated increase in skin blood
flow in exercising humans during heat exposure (figure 7.12). If the res-
olution of the thermodilution technique in the studies by Nielsen et al.
(1990, 1993) is only 10 percent, and muscle blood flow during exercise
is as high as 18 l/min, the measurementof muscle blood flow could be off
by. 1.8 l/min .
The mechanismresponsiblefor reducing blood flow to working skele-
tal muscle during exercise in the heat is unclear. Increased sympathetic
drive directed at skeletal muscle may be involved. Exercise in the heat
produces the most marked increase in circulating catecholamines, and
contracting skeletal muscle can vasoconstrict during direct sympathetic
nervous stimulation (Donald et ale 1970). Intact adrenergic nervesare re-
quired for the decreasein muscle blood flow observed in resting heat-
stressedsheep(Hales 1983). Thus, the issueof what limits performance in
The Burning Brain 183
~ 39 .0
u
0
~
~ 38 .0
B
-
u
~ 39 .0
~
Figure 7 . 11
Core temperature (T c ) as a function of time . Representative data from a control
subject during exercise at 40 C during the first and final experiments , and during
9 intervening rides on a cycle ergometer in a cool environment ( 18 - 20 C ) . (B )
Representative data from an acclimatizing subject during 10 consecutive days of
cycle exercise in the heat (40 C ) until exhausted .
the heat remains unresolved . The data of Nielsen et ale ( 1990 , 1993 ) are
impressive , but the arguments put forth by Rowell ( 1986 ) for a reduction
cle blood flow ; there is considerable room for increasing hind limb oxy -
gen extraction in the event of a fall in muscle blood flow ( Bird et ale
1981 ) . Thus , in the end , it may be the brain that indeed limits perfor -
22
18
14
10
OXYGENUPTAKE (1 min-l ) 2 .2 2 .1 2 .2
CARDIAC
OUTPUT (1 min- l ) 16 .4 16 .0 J, 21 .0 i
STROKE
VOLUME (ml) 110
[ =~~~J J, 110
Figure 7.12
Two possible means of increasing skin blood flow during moderate exercise in a
hot (43 .3 C ) environment . Comparison is with normal responses at 25 .6 C (col -
umn A ). Listed below columns A and B are measured variables and estimated skin
blood flow (boxes are for emphasis ). Column C shows a hypothetical maximal
adjustment achieved by raising heart rate to 190 bpm , while stroke volume and
distribution of cardiac output remain as they were at 25 .6 C . Skin blood flow
could reach 6 .3 lImine This would lower systemic arteriovenous oxygen difference
to 10 .3 mUI00 mI . Column B shows that the actual fall in stroke volume (com -
pensated by rise in heart rate to 176 bpm) prevented a rise in cardiac output .
(t- U!W L) ~nd~no ::>e!pJeJ
Thus skin blood flow could be increased to 3 Umin only by additional visceral
vasoconstriction and mainly by reducing muscle blood flow to make its oxygen
extraction 100 percent . The slightly lower oxygen uptake at 43 .3 C (2 .1 Umin )
could reflect such a change . (From Rowell 1986 ).
The Burning Brain 185
to the brain that details the thermal status of the body could be exertional
heat injury . Many athletes, especially in high stakes competition (the
Olympics), can push themselvesbeyond their physiological limits and
consequentlysuffer heat injury .
Are women less tolerant of the heat than men? Becausethey sweat less
than men, doesthis mean they are more susceptibleto thermal injury and
heatstroke? Early comparisons of thermoregulation in men and women
showed that women had lower sweat rates, higher core temperatures, and
higher heart rates than men during exercise, and did not tolerate the heat
as well as men (Drinkwater 1986). However, subsequentstudies revealed
that thesedifferences, as well as those associatedwith age, may be attrib -
uted to differencesin fitness.
If a group of men and women are askedto exerciseat three different in-
tensitiesand their steady-state core temperature is plotted as a function of
exerciseintensity, the lines representingthe men and women are scattered
(figure 7.13A). On the other hand, if each exerciseintensity is converted
to a percentageof VOl max for each subject and the steady-state core
temperature is plotted as a function of each individuals' percent VOl
max, the data converge(figure 7.13B). In other words, if all subjectswork
at 50 percent of their aerobic capacity, eventhough somewill be working
significantly harder than others, core temperature is the same. Back in the
1960s, when the first comparisonswere made of thermal tolerance in men
and women, both sexeswere exercisedat the sameabsolute workload . If
the women in thesestudieswere lessfit than the men, and in all likelihood
they were, they would have beenexercisingat a higher percentageof their
aerobic capacity, which would explain their higher core temperaturesand
heart rates.
lated deaths. In humans, old age has been associatedwith a reduced core
temperature at rest, hyperthermia in responseto heat stress, reduced ca-
pacity to sensetemperature extremes, and inadequate thermoregulatory
responsesto environmental challenge. Does aging truly result in tempera-
ture regulatory dysfunction and heat intolerance, or are thesefunctional
deficits the result of preexisting diseaseprocessesand/or differences in
aerobic power, heat acclimatization, and body composition ?The two pri -
mary effector mechanismsfor regulating body temperature during heat
challenges are skin blood flow and sweating. Is either of these mecha-
nisms compromised with advancing age?
In a review of the thermoregulatory responsesof healthy older adults at
rest and during exercise, the elderly (defined as men and women over 65
yearsof age) did not have lower core body temperaturesat rest compared
with young (20- 30 years of age) men and women, and had normal circa-
dian temperature rhythms (Kenney 1997). Moreover, the number of
sweat glands that responded to pharmacological stimulation was the
samein older and younger individuals, but the amount of sweat produced
per gland was reduced in the elderly. However, this age-related deficit in
drug-activated sweating does not necessarilytranslate to a lower sweat
rate during exercisein the heat. As illustrated in figure 7.14A, sweating
rate was not different in young and old groups in a hot, humid environ-
ment, but was significantly lower in the older subjectsduring exercisein a
hot, dry environment. This latter responsewas attributed to less sweat
produced per gland rather than a reduction in the number of heat-acti-
vated sweat glands (figure 7.14B).
The ability of the elderly to transfer heat to the skin by increasingcuta-
neous blood flow is limited . Figure 7.15 shows that the threshold for va-
sodilation during exercisein a warm environment is not altered by age,
but the rate at which blood flow increasesas core body temperature rises
is reduced. Moreover, the highest skin blood flow that can be attained is
reduced in the elderly. The mechanism responsible for this decreasein
skin blood flow is not understood . It is not the result of greater vasocon -
A Humid Hot-Dry
300 2
0
175
150
forearm chest back
v-.. J
* * *
( -r"1A
Time, min
Figure 7.14
(A ) Local sweating rates on three skin sites for two age groups of post -
menopausal women exercising in warm -humid (37 C, 60 percent r.h .) and hot -
dry (48 C, 15 percent r.h .) environments . (B) The age difference in sweating rate
observed in the hot -dry environment shown in (A ) is attributed to a lower sweat
output per gland, not fewer activated glands. Women (n=8 per group) were
matched for VO2max and exercisedat 35- 40 percent VO2 max. HASG is heat-
activated sweat glands . (Modified from Kenney 1997 .) * Significantly lower sweat
rates compared with young subjects.
The Burning Brain 189
Illllrl
111lillllll
l 1T1TTT
r. ~ T
~ ?f~
1Tl . age20-25
:J<
r<r~ I *
0 age60-74
I
Figure 7 . 15
Increase in forearm vascular conductance ( forearm blood flow / mean arterial pres -
Kenney 1997 .)
and thermoregulatory function among the aged are most probably attrib -
At the beginning of the twentieth century, William Osler wrote that the
three great scourges of humanity were fever, famine , and war (Atkins
1991 ). " For much of history the word 'fever ' has been used almost syn-
onymously with disease itself as various epidemics have ravaged the civi -
lization of East and West alike " (Atkins and Bodel1972 p .27 ). Fever was
recognized as a sign of illness several thousand years before the birth of
Christ (figure 8.1), but the ancient Greeksalso believedfever to be benefi-
cial. This concept had its origin in the theory of Hippocrates that health
and sicknesswere direct consequencesof the interrelationships among
the four body " humors"- blood, phlegm, yellow bile, and black bile.
Galen is credited with the idea that fever derived from the accumulation
A B
~~~~~~ )= -...
./
c
Figure 8 . 1
( A ) Akkadian words meaning " fever " and " inflammation , " um + mu . ( B ) Ummu
ummu appears inside a frame . When traced back to a Sumerian pictogram , the
translation is " inflammation inside the chest . " ( Modified from Majno 1975 . )
Interestingly , the idea that fever is harmful prevails today , despite the his -
pointed out by Kluger ( 1979 ) , this belief may be attributed to the fact that
most antipyretic ( fever - reducing ) drugs also are analgesics ( pain - reduc -
ing ) . Hence , feeling better after taking two aspirins may have little to do
Evolution of Fever
triguing questions immediately emerge : How did fever evolve ? Does fever
As Kluger ( 1979 ) said , we can not address the question of how fever
servation that primitive animals alive today can develop fevers when in -
[Phylum
e Porifera
.gmarine
sponge
] ,/
EUMETAZOA
~ ACOELOMATA
Phylum
Platyhelminthes
RADIATA
PhylumCnidaria
[e.g.tlatworms
-
~planarians
~tapeworms
]
[e.g. hydra
~jellyfish; PSEUDOCOELOMATA
seaanemones ]
PhylumNematoda
[e.g.hookworms
; pinworms
~plantparasites
]
DEUTE
R0STOM
IA PROT0STOM IA"""""" ""-~
I.II..
/ \ [e .g.clams ;mussels
Phylum ,octopus
Mollusca,
oysters ,snails
,squid
]
Phylum Echinoderrn
~ta. Phylum Annelida *
sea
[e.gcucumbers
.starfish
;sea
] urchins, [e.g.earthworms ;leeches
]
Phylum Chordata
* Phylum Arthropoda *
[e
.g.sharks
birds ~fish
;mammals];amphibians
,reptiles
; [e
.g.spiders
horseshoe,mite
crabs ~,scorpions
;Insects
] ;
Figure 8.2
How fever evolved. Starred (* ) phyla contain species that develop fever.
(Modified from Kluger 1991.)
primarily because the elevated temperature increases the rates of all bio -
fever did not have some adaptive value , it is probable that such an " ex -
pensive " process would have been eliminated ages ago . The fact that fever
has such a long evolutionary history strongly suggests that it was impor -
tant in ameliorating disease . What is the evidence that fever has survival
value ?
If fever evolved over hundreds of millions of years , does that mean it nec -
essarily benefits the host ? If pathogen and host coevolved , one could
argue that fever benefits the pathogen , not the host . How could we tell if
Aside from mammals and birds , all other vertebrates and invertebrates
have low rates of intrinsic heat production and therefore regulate their
temperature .
A Temperature
Recorder
30 C
t
Heating Coils
B 42
- 41
u
0
-Q) 40
' -
:J
~ ~
39
Q)
0. 38
E
~ 37 t
Inject
36 Bacteria
35
- nme - +-
Figure 8.3
(A ) Lizard (Dipsosaurus dorsalis) in a shuttle box maintained at 30 C at one end
and SO C at the other, with a bridge in the center. A thermocouple was inserted
into the cloaca of the lizard to monitor body temperature continuously. (B)A
continuous recording of the lizard's body temperature over time. Under control
conditions, body temperature cycled between 39 and 37.SoC as the animal
moved from the warm to the cool side of the box. This resulted in an average
body temperature of about 38 C. When the animal was inoculated with patho-
genic bacteria, body temperature rose to 41 C as a result of moving to the heated
side of the box. Again the animal showed cycling behavior, but body temperature
was now maintained at about 41 C. (From Kluger 1979.)
What CausesFever?
DOTO
A
MACROPHAGE
/ t ~
PROTEINS OXYGEN FREE LIPIDS
RADICALS
B Tumor Necrosis
. Factor 0 xygen (0 2 ) Prostaglandin 6
Interleuk~n-1 Hydrogen Thromboxane A2
Interleukln " -6 P eroxi "d e (H 2 0 2 ) Platelet -Activation
Interleukln -8 Nitric Oxide ( NO ) Factor
c
MODERATE FEVER HIGH FEVER
GENERALIZED STIMULATION HYPOTENSION
OF IMMUNE SYSTEM ( LOW BLOOD PRESSURE )
MICROBIAL KILLING DISSEMINATED
BLOOD CLOTTING
LETHAL SHOCK
Figure 8.4
Endotoxin stimulation of macrophages(A ) produces a variety of effects (B) me-
diated by the synthesisof proteins, oxygen free radicals, and lipids . Thesemedia-
tors may act in concert, independently, or in sequenceto produce beneficial or
harmful results (C). Mediator synthesisis enhancedby tumor necrosisfactor and
inhibited by prostaglandin E2. (Modified from Rietschel and Brade 1992.)
Fever, Survival, and Death 201
tem , the substantia nigra , and the recticular formation . Because such le -
terior hypothalamus ( POAH ) , because heat loss and heat gain mecha -
nisms are so readily elicited when this area of the brain is heated or
cooled , respectively . However , even lesions in this area of the brain do not
loss and heat gain centers in the brain is no longer tenable ; nor is it clear
areas of the brain different from those that control autonomic responses
in the human body , do we have any idea of where EP acts in the brain to
produce fever ?
As you might expect from the discussion above , lesioning the POAH
does not impair one 's ability to develop a fever . In humans , an adult
sence of the medial preoptic area ( MPOA ) were able to develop fevers
fevers followi ..1g the destruction of the MPOA . Moreover , rats that had
their MPOA separated from the rest of the brain by bilateral knife cuts
trol animals . Thus , it appears that the MPOA is not essential for the
generation of fever .
FEVER
Endogenous
Pyrogen
..Cytoki
Vagus nes
PGs
.Others
(Macrophage
kupffer
cells
) ( 0" Exogenous
Pyrogen
Figure 8 .5
fever . Exogenous pyrogens gain access to the circulatory system and cause the re -
lease of cytokines from Kupffer cells in the liver . These cytokines activate vagal
afferents that terminate on noradrenergic cell groups in the nucleus tractus soli -
tarius ( NTS ) . The signal is then communicated to the preoptic anterior hypo -
which causes body temperature to rise . ( Modified from Blatteis and Sehic 1997 .)
tude as the distance from the POAH increases ( Blatteis 1984 ) . Interest -
ingly , behavioral responses are elicited when EP is injected into the POAH
and lateral hypothalamus , but not when it is injected into the pons or
medulla oblongata , thus suggesting discrete brain loci for behavioral and
cuts separating different areas of the brain indicated that such a distinc -
Figure 8.6
The effects of endogenouspyrogen (P) on the firing rate (FR) of warm (W )-sen-
sitive (A ) and cold (C)-sensitive (B) neurons and whole-body heat production
(C). Under normal (N ) conditions, increasing hypothalamic temperature (Th ) in-
creasesthe FR of warm-sensitive neurons; some of these synaptically inhibit (-)
other neurons, making them respond as if they were cold-sensitive (negative
slope). By inhibiting (-) the FR of warm-sensitiveneurons, endogenouspyrogens
increasethe FRs of cold-sensitiveneurons and heat production . (Modified from
Mackowiak and Boulant 1996.)
The term " glass ceiling " is taken from an intriguing paper by Mackowiak
and Boulant (1996 ). The question is " Does fever have a relatively " fixed "
ceiling that can not be exceeded, or can this presumed upper limit be pen-
etrated , resulting in excessively high temperatures that can be fatal ? The
206 Chapter
8
upper limit for a " regulated " fever is 41 C - 42 C ( DuBois 1949 ) , but this
upper limit varies among mammals , the body site where temperature is
notorious for producing high fevers , whereas HIV results in little if any
fever . The need for an upper limit seems obvious - above the upper limit ,
the pathogenic microorganisms die , but so may the host . Kluger found
that when lizards were infected with a natural pathogen that afflicts them ,
there was a correlation between temperature and survival rate when body
Imagine having hot and cold chills , a runny nose , a headache , and an oral
scription : drink plenty of fluids , take two aspirins , and go to bed . You
proceed to the medicine cabinet , remove the bottle of aspirin , and pop
two tablets in your mouth . Have you just made a mistake ? Aspirin sup -
( Mackowiak 1994 ) . These beneficial effects of fever and its mediators are
limited and are directed primarily against localized infection . This evi -
cial and that the use of antipyretics (e.g., aspirin) may not be the most ef-
fective treatment for diseasesthat produce fever. In some instances, fever
perhaps should be allowed to run its natural course, or even be elevated.
The febrile responsealso has beenviewed as harmful . For example, ad-
ministration of an anti-interferon antibody significantly reducesmortality
in responseto the induction of septic shock; and bacterial sepsiscan be at-
tenuated by pretreating animals with IL -1 antagonists and monoclonal
antibodies directed against TNF. Thus, there is growing interest in devel-
oping agentsto combat the effects of pyrogenic cytokines.
If fever is beneficial, what are the mechanismsresponsiblefor its adap-
tive value? Figure 8.7 illustrates a number of possibilities. First, the bene-
ficial effect may simply be that a high temperature kills the invading
microorganisms. For example, the bacteria that causegonorrhea, pneu-
mococci bacteria, and spirochetesthat causeneurosyphilis are destroyed
by elevationsin temperature to 41 C (Kluger 1979). In addition to this di-
rect effect, there are several indirect effects of fever that can benefit the
host. These effects include increased lysosomal function , inhibition of
viral growth and synthesis by increased release of interferon, and in-
creasedleukocyte function . Leukocytes are white blood cells that playa
crucial role in immune function . Neutrophils , which are a form of while
blood cell, move through cell membranesmore effectively, phagocytize,
and kill bacteria more effectively at fever temperaturesthan at 37 C.
There also is some evidencethat antibody production and lymphocyte
transformation are enhanced by fever temperatures. Although there
clearly is much to be learned about immune function and how it is af-
fected by fever, the evidencesupports a positive role for fever in the man-
agement of disease. Evidence also indicates a role for cytokines in host
defense. Although they are not fever-dependent, febrile temperatures do
enhancethe effect of IL -1 and TNF or T lymphocyte proliferation , and
the effect of IL -1 on reducing serum iron concentration. Becausealmost
all bacterial pathogens require iron , hypoferremia is considered a host-
defensemechanismand has beentermed " nutritional immunity ," to char-
acterize the attempt of the host to deprive invading pathogens of needed
.
iron .
In the final analysis, is fever a blessingor a curse? Mackowiak (1994)
offers a unifying hypothesisthat requires the febrile responseto be viewed
208 Chapter 8
FEVER
DIRECT
EFFECT TEMP
~I: TURE " INDIRECT
EFFECT
' GROWTH
RATE
OR +LYSOSOME LEUKOCYTE
KILLS MICRORGANISM BREAKDOWN FUNCTION CYTOKINES
~
+NEUTROPHIL
MOBILITY II +PHAGOCYTOSIS
Tt' MA\JULI j V:)!:) II +INTRACELLULAR
KILLING J' "SERUMIRON
CONCENTRATION
PROLIFERATION OF
HELPER & CYTOTOXIC
T - CELLS
Figure 8.7
Potential mechanisms of host defense and survival. (Modified from Kluger
1979 .)
If we accept the concept that fever has an upper limit , then regulatory
processesthat prevent T c from exceeding 41 C to 42 C must exist.
Does the brain produce aspirin-like drugs (antipyretics or endogenous
cryogens) that can antagonize the temperature-elevating effects of pyro -
gens? " Antipyretics " are defined as substancesthat reduce febrile tem-
peratures but have no effect on normal core body temperatures. The
story of antipyretics began with observations made on periparturient
ewes and their newborn lambs. Five days before term, the pregnant
ewes showed an attenuated response to endotoxin -induced fever, and
Fever, Survival, and Death 209
Is the rise in body temperature during exercisea fever? Before we can ad-
dress this question , it is critical to define " fever " and distinguish it from
" hyperthermia."
210 Chapter 8
Core body temperature rises during both fever and exercise, but as a
fever develops , we shiver, whereas during exercise we sweat . How is this
possible? In both situations we becomehyperthermic (body temperature
rises). How can the sameelevation in body temperature produce opposite
responses? To understand this phenomenon , body temperature can be
placed in one of four categoriesdepending upon the concept of set-point
(Snell and Atkins 1968), which was describedin detail in chapter 2. These
categories are (1) normothermia- measured body temperature and the
set-point coincide ; (2 ) hypothermia - measured body temperature is
below the set-point , which mayor may not be normal; (3) hyperther-
mia - measured body temperature is above the set-point , which mayor
ma y not be normal ; (4 ) fever- the set-point is raised , but measured body
temperature mayor may not be raised to the same level . Set-point is de-
fined as that value of the controlled variable at which the control action is
zero (Hensel 1981 ). Thus , core temperature (the controlled variable ) is at
its set-point when the organism is neither heating nor cooling (controlled
action ) itself . During the development of a fever, heat production , heat
conservation , and behavioral mechanisms are activated until core tem -
. - - - - Set - point
Time
Figure 8 . 8
Effect of pyrogens on the set - point and the mechanisms responsible for the gen -
eration of fever . Note that following the rise in set - point , mechanisms to increase
that when the fever breaks ( crisis ) or following the ingestion of aspirin , the ele -
vated temperature is perceived as hot and the patient activates heat loss mecha -
75 F . How can this be ? In the cold , mechanisms for conserving and pro -
creases and skin blood flow decreases , whereas in the heat , sweating and
skin blood flow decrease . During the onset of a fever , a room temperature
that was comfortably warm , feels cold . This signifies that the perception
during a fever is regulated at a new set - point . And , unlike other forms of
pirin - like drugs , which presumably block the effects of pyrogen in the
212 Chapter
8
brain , reduce the set-point , which subsequently allows the body to lower
its temperature back to its normal control condition . Giving aspirin to an
athlete has no effect on the rise in body temperature during vigorous ex-
ercise. The only method of lowering body temperature during the hyper-
thermia of exerciseis by whole-body cooling.
During exercise, the rise in core body temperature often has beencom-
pared with turning up the thermostat in a house. Such a description
would be analogousto the effect of pyrogen. Are pyrogensproduced dur-
ing exercise ? Some recent data suggest that this may occur . Can exercise
produce endotoxemia , and if so, what effect might this have on brain
function , especiallyareasconcernedwith thermoregulation ?
Figure 8.9 compares the hyperthermia caused by fever and exercise.
During fever, the elevation in temperature is actively produced and regu -
lated at a new set-point . During exercise, the increase in body tempera -
ture occurs passively, from the accumulation of heat in the working
skeletal muscles; blood flow to the skin increases, and we begin sweating.
During exercisethe set-point does not change. Body temperature rises to
a plateau when heat production equals heat loss, but this new elevated
body temperature is not regulated .
If the same intensity of exercise (and therefore heat production ) is per -
formed in cooled stirred water and in air at the same temperature , the rise
in body temperature in the water will be much less because water has a
much greater capacity to remove heat from the body by conduction . This
simple experiment illustrates that body temperature during exercise is not
regulated, but is simply the result of the balancebetweenheat production
and heat loss. In fact, if exerciseis performed in cold water and heat loss
exceeds heat production , body temperature will fall during exercise.
If the rise in body temperature during exercise were the result of fever,
taking aspirin should prevent this rise . Taking aspirin prior to or during
exercise has no effect on the rise in body temperature in humans , which
convincingly demonstrates that the set-point does not rise during exer -
cise. Are there any circumstances under which exercise might release cy-
tokines and produce fever ? Yes, there are. During ultraendurance events
such as the triathlon , there have been reports of exercise initiating an
acute phase response, endotoxemia , and a decrease in anti -LPS im -
munoglobulin G (seeKluger 1991b: 115). The question of whether exer-
Fever, Survival, and Death 213
FEUED EHEACISE
Tc
40 0 Tc
u
39 :I
NOIIJnOOUdlU3H
I
I
38 I
I SET - POINT
I!-'~~
37 SET-POINT
I
L- - L ______- -
~ J~III =J rll ~..
0
:. ~I ~ ~..
. . L!!8~I ~ID! JJ.!!J1l1! !l
3 @
[111. 1[11111
2
-
. c 1
.
...J
0 - - - - - - - - - - - - - -
. 11
90 @ / HEAT
-PRODUCTION
...
] UrnUU] d~ ] l ] UOJ
225 / / \
/ \
/, - - \
15 / ~ --......... \
/ HEAT LOSS "
75
0 1 2 3 0 1 2 3
TIME IN HOURS
Figure 8.9
Fever increasesthe set-point , and body temperature must rise to reach a new
thermal balance. During exercise, the set-point does not change. Body tempera-
ture is elevated by increasedheat production until the rate of heat loss rises suf-
ficiently to achievea new thermal balance.
214 Chapter8
Human neonates (first month of life ) can only maintain a stable body
temperature within only very narrow environmental conditions and , in -
terestingly , usually do not develop fevers in response to infection .
However , under severe conditions - very high doses of the infecting or -
ganisms- they becomefebrile (Moltz 1993), indicating they have an ele-
vated fever threshold . How can we explain this phenomenon ? Could it be
that neonates produce less endogenous pyrogen in response to endo -
toxin ? Or perhaps the immune system must first be sensitized to EP be-
fore fever can develop . In other words , an initial dose of EP may not
produce fever, but a subsequent dose will . Because leukocytes from
neonates incubated with endotoxin produce similar amounts of EP as
adult leukocytes , and because some neonates develop fever when initially
exposed to endotoxin , these possibilities seem unlikely .
Could the explanation be the brain ? Is the thermoregulatory machinery
responsible for producing fever insensitive to cytokines and/or PGE?
Most of the experimental work on neonateshas beenconducted on lambs
Fever, Survival, and Death 215
and guinea pigs. In lambs, infusing PGE into the brain failed to produce
fever, but aspirin was effective in reducing fever produced by endotoxin,
suggestingthat PGE is involved in neonatal fever. Thus the evidence is
confusing. It is not clear where in the brain PGE may be acting to produce
fever.
Another intriguing possibility is that the neonate possesseshigh con-
centrations of its own endogenousantipyretic. As mentioned above, AVP
is a potent antipyretic, and in the neonatal brain, the concentrations are
exaggerated.
Stress-Induced Hyperthermia
hours without causing thermal injury . How is this possible ? Why do such
patients not suffer heatstroke ? What is the role of synthesizing heat shock
The use of heat to treat disease has been practiced for centuries . Recall
blood flow to a tissue cools the tissue , tumors or regions of tumors with
reduced blood flow will become hotter than normal tissue and more sus -
222 Chapter 9
rect induction of DNA strand breaks ( Streffer 1995 ) . The use of hyper -
The reader with interest in this area is referred to the text by Field and
as a therapeutic modality and the use of whole - body heating in the treat -
ment of cancer .
grees above normal is based on early reports of tumor regression and even
1982a , 1982b ) .
techniques such as hot air , hot water , or hot wax , radiation , or a combi -
critical target tissues , such as the heart and lungs , liver , and brain . The
not destroy all tumor cells ; as stated earlier , the best results occur when
called " thermotolerance " ( see chapter 4 ) , and is attributed to the expres -
sion of heat shock proteins in virtually all cells that have been tested .
Temperatureand the Strugglefor Life 223
DNA
Strand
Break
Energy
Depletion
~
Acidosis
.Cell
Death
"------~
BFlo
~'loo i
NutritionDeficiency
Hypoxia
Figure 9.1
Hyperthermia-induced cell death and related physiological and metabolic factors.
Seealso figure 7.4 for cell death mechanismsduring an ischemic/hypoxic episode.
(Modified from Streffer 1995.)
In Iowa, during a frigid night in March 1987, a two -year-old toddler, per-
haps in his sleep, wandered out of his parents' mobile home. About three
hours after his mother found him gone , he was discovered facedown in an
ice-covered puddle in a cornfield a half -mile away . His pajamas were
frozen to his body and ice had begun to form around his face. He had no
heartbeat, he was not breathing, and his body temperature was about
15 C. Clinically speaking, he was dead.
When a police officer came upon the scene, there appeared to be no life
in the boy 's eyes or face: " he looked like one of those dolls where the eyes
roll back in their head " (Ryberg 1987 pp . lA , 7A ). He immediately began
cardiopulmonary resuscitation. For 90 minutes there was no response.
Then, miraculously, a muscle twitched, a faint heartbeat was felt, and the
boy began to breathe on his own. Doctors claimed that a major factor in
the boy's favor was that his body temperature was reduced gradually.
This lowered his metabolism and reduced the activity of his major organs ,
thereby lessening the amount of oxygen they needed. Thus , major dam -
age was prevented when his heart stopped . The fact that he stopped
breathing the instant his face contacted the water prevented him from
drowning in the puddle (Gooden and Elsner 1985). Although he required
major physical therapy and had to learn how to walk again, one year later
it appearedthat the boy had made a complete recovery.
Hypothermia is defined as a reduction in body temperature below
35 C. The rationale for its use is illustrated in figure 9.2. The point to
which body temperature can be lowered with survival is not known , but
hypothermia can be lethal at any level below 35 C . The young , especially
infants , appear to be more tolerant than the elderly . The reason for this in
not known , but has been related to the ease with which infants slip into a
state of poikilothermy (Blair 1964 ). Hypothermia is not artificial hiberna -
tion , which is impossible in homeotherms . Another form of hypothermia
is that produced by drugs . It is called clinical hypothermia , and does not
. involve shivering.
The initial interest in hypothermia during cardiac surgery was fueled by
the successexperienced with cyanotic infants. Infants are remarkably
cold-tolerant . Mothers who are cooled to a moderate level of hypother-
Temperature and the Struggle for Life 225
HYPOTHERMIA
- - -REDUCE
2NEED
~- - - - - LOWER
TEMP
.
REDUCE BLOOD
AUGMENT VENTILATION
- INCREASE EffiCIENCY
SLOW RATE
MOBILI ZE - - - -'!);- ~ ,-
BLOOD - - REDUCE STRESS
.. .. ...
Figure 9.2
The rationale for hypothermia is related to the reduced oxygen requirement (by
about one-third ), sustainedarterial blood pressureproduced by the pressor effect
of cold, reduced heart rate, and enhancedcardiac efficiency. Augmented breath-
ing improves alveolar ventilation , reflex mechanismsare enhanced, and cerebral
inflammatory reactions are reduced. Renal flow may be improved, and blood se-
questeredin the splanchnic vascular bed may be mobilized. Finally, the stressre-
sponseof the adrenal cortex may be alleviated. (From Blair 1964.)
226 Chapter 9
Table 9 . 1
Safety limits for arrested brain blood flow during increasing levels of
hypothermia
C 37 30 28 25 20 10
of 99 88 82 77 68 50
Min 3 6 8 - 10 12 - 15 20 40
HEART
RATE
. . . .
. .
METABOLISM
0
Figure 9.3
Woodchuck entering dormancy. Note the dissociation of physiological responses.
Heart rate drops, first followed by oxygen uptake and then body temperature.
(Taken from Lyman 1958 .)
hibernation ; (c) stable, deep hibernation; and (d) 2 phasesof body tem-
perature during arousal (figure 9.4). Statistical analysis selected brain
sitesthat showed a similar pattern acrossall phasesof hibernation . Three
factors were identified that accurately discriminated among thesevarious
phases. Factor 1 (the hypothalamic factor) was associatedwith brain re-
gions that showed a trend for increased2-deoxyglucoseuptake as a func-
tion of the depth of hibernation . Factor 2 (the cortical factor ) was
characterized by regions showing a rapid decreasein 2-deoxyglucose
uptake early in hibernation; and factor 3 (the raphe factor) was character-
ized by regions exhibiting a pattern including factors 1 and 2. Thirty -three
brain regions exhibited a relatively high correlation on factor 1, including
almost all hypothalamic regions. To show the relationship between the
factor score for factor 1 and 2-deoxyglucose for a particular brain
region, figure 9.4B shows the 2-deoxyglucoseprofile for the suprachias-
matic nucleus, a hypothalamic structure that reflected a pattern of 2-de-
oxyglucose that was inversely associatedwith the depth of hibernation .
Figure 9.4C shows the 2-deoxyglucoseprofile for the cingulate cortex, a
brain region that reflecteda pattern of rapidly decreasing2-deoxyglucose
early in entrance into hibernation .
The analysis revealed that neuronal activity in the cerebral cortex
decreased, and hypothalamic activity increased, during entrance into hi-
bernation, whereas during arousal the opposite occurred. The suprachi-
asmatic nuclei were the main hypothalamic nuclei participating in the
entrance into hibernation, and the cingulate cortex was a major cortical
area that becameactive in arousal.
Disinhibition of structures such as the frontal and cingulate cortexes,
which are mainly inhibitory to limbic structures, seemsto playa crucial
role in this initial phaseof hibernation . As a consequence, the limbic cor-
tex is highly sensitive to stressful environmental stimuli (Gabriel et ale
1977). Arousal from hibernation seemsto be triggered by'"a different pat-
tern of neuronal activity. In this case, suprachiasmatic and paraventricu-
lar nuclei of the hypothalamus, as well as the medial preoptic area, play
major roles (figure 9.5). These results support the hypothesis that hiber-
nation is an active orchestration of integrated neurophysiological events
rather than a passiveprocess(Kilduff et ale1990).
Temperatureand the Strugglefor Life 231
A 20
- -- { } - Factor 1: Hypothalamic
. Factor 2 : Cortical
10
- 10
EU EE ME LE HB EA LA
Figure9.4
~ l:[1}lJ- .:[I] . l'~I
~
VENTROMEDIAL CTOR
HYPOTHALAMIC
N. OTHALA
ANTERIOR
HYPOTHALAMIC
H.
B BRAIN
STRUCTURES
THAT
MAYMEDIA
TE
VENTROMED
HYPOTHALAM
N
MEDIAL"
" CTOR
,
-/PARA
N.
AROUSAL
FROM
HIBERNA
TION
.""'-~ OTHALA
PREOPTIC
N ~$UHIAS
PRA
TIC N.
Figure 9.5
(A ) Schematicdiagram illustrating hypothalamic and cortical involvement in the
entrance into hibernation . (B) Schematic diagram illustrating hypothalamic in-
vol ,Tement in the arousal from hibernation . (Taken from Kilduff et al . 1990 .)
Hypothermia
Many fantasies and literary tales have reported the revival of people after
they were frozen solid. For example, the imagination of many was stimu-
lated by the tale of a French soldier who, during the retreat of Napoleon's
forces from Russia , became frozen and was revived years later without
damage to his body except the accidental loss of an ear during his reani -
mation . But true stories like that of Johnny Stevens, the young child who
recovered completely after having a body temperature of 17 .8 C and a
respiratory rate of 3 breaths /min , have made some people rethink the pos-
sibility of cooling and reviving a human . An obvious application of such
a procedure would be traveling through space. However , despite isolated
cases like the one described above , the adult human body cannot be
cooled below 25 C (Folk 1974 : 212 ). Therefore , the idea of freezing a
Temperatureand the Strugglefor Life 233
human for prolonged travel in space remains in the realm of science fic -
tlOll.
Hibernation
on Thermoregulation
For more than 500 million years the function of the brain has been coded
with time . The brain has served the rest of the body by responding to
time . Survival of the species depended on the time of response to the stim -
mals were well adapted . There was limited capacity in the brain for
was little time to think . For lower vertebrates ( fish , frogs , and reptiles ) to
develop and perform survival behaviors such as seeking food and water ,
and mating , warming of the brain from external sources was essential .
Brain activity , and hence body activity ( behavior ) , was impossible with -
out the brain and body achieving a certain range of temperature . In this
case , and since the beginning of life , radiation from the sun was the main
source of heat . Thus , the primary event required for life , even before ac -
for processing information from the environment and was able to provide
Krantz ( 1968 ) suggested that hunting behavior in its more primitive form ,
" persistence hunting , " could have been the basis of the selective pressures
essence of this type of hunting is persisting in the chase of the prey for as
long as one or two days , which obviously requires the hunter to focus
constantly on the task at hand . This is a kind of brain - mind training that
clearly could be relevant for the development of the brain . That the aus -
The idea that this kind of primitive hunting could be relevant for devel -
oping bigger brains within a species is based on the assumption that indi -
viduals who were anatomically adapted to run and who also had bigger
brains would have better memories than individuals with smaller brains .
This clearly would have important survival value . Krantz describes his
The idea of persistence hunting permits the following hypothesis as to the selec -
tive forces that brought about the transformation from Australopithecus to
Homo : small steps in the enlargement of the Australopithecus brain would have
been of selective advantage mainly by increasing the time and distance that the
possessor would be able to pursue his mobile food supply . Considering the
young , injured and aged as well as normal adults of all species of potential food
available to our ancestors , there was a continuous gradation in pursuit times nec -
essary to bring down game . At first , Australopithecus could run down only those
animals most quickly exhausted , and must have been in keen competition with
many other carnivores . As the reward in food for successful pursuit of game
tended , on the average , to go to those individuals with the greater mental time
spans , selective pressure would favor larger brains with better memories . (Krantz
1968 : 451 )
The Brain Is the Body 239
Eckhardt (1987) has criticized Fialkowski 's idea that the reliability of a
complex systemsuch as a computer could be enhancedby increasing the
number of elementsand the interactions among them. He maintains that
increasingthe number of processingelements(chips or neurons) doesnot
increasethe reliability of the system; rather, it has just the opposite effect.
In fact, he maintains that " the existing solution to this problem in com-
puter scienceis not merely to add more chips, but to integrate an error-
correcting code. This strategy which enablesthe memory to function even
after hundreds of errors (typically accumulated over many years) is per-
haps more analogousto neural reorganization than to memory expansion
via mere repetitive subunit addition " (1987: 194). If the brain increased
TheBrainIs theBody 241
the number of neurons under heat stress to cope more effectively with a
hot environment , one would expect this increase to occur in the part of
the brain responsible for vital functions - more specifically , the areas in -
over the last 2- 4 million years are the association areas of the cortex ,
been mainly oriented toward the vital ones " ( 1986 : 290 ).
admitted that some relationship can exist between heat stress and an in -
crease in brain size among early hominids . In fact , he suggests that the re -
lationship between heat stress and increasing hominid brain size was not
Thus , once again , memory comes into play . Recall Krantz ' s hypothesis
that memory was probably one of the more powerful selective pressures
situations where early hominids had to survive in the hot , dry savanna ,
memory of water holes in areas where they hunted could have had sur -
vival value . Present - day Bushmen hunt an area as large as 10 , 000 km2
and from memory know the location of every water hole : " no other
Therefore , heat and memory may be two of several factors that con -
verged on the force that increased selective pressures toward the acquisi -
tion of a bigger brain . If this were the case , then we would be forced to
admit that toolmaking , new social modes of life , and so on would have
been consequences rather than causes of the initial increase in brain size
phrase his conclusion , the increase in size and complexity of the hominid
brain was largely a side effect of a quite different adaptation that had lit -
Is the mind (mental processes ) a " side effect " function of a brain devel -
oped through evolution just for survival purposes under selective, al-
though multifactorial , environmental pressures? This is one of the most
intriguing and crucial questions in philosophical anthropology.
Evolutionary biology is providing piecesof a complicated puzzle that we
hope will lead to a better understanding of the human brain. What seems
more and more evident from different scientific approachesto the study
of humans , and in a more consistent way , is that " Human brains evolved
from the brains of preceding animals, sharing much with them struc-
turally and functionally as well as cognitively . However remarkable the
human brain is, it is a product of Darwinian evolution , with all the con -
straints that such a history implies " (Llinas and Churchland 1996 : ix ).
Given this perspective , environmental temperature was probably one of
the multiple factors that contributed to the development of humans
through evolution .
This suggests that body , brain , and mind are a continuum under a uni -
tary construction of humans through time . (Mora , 1995 , 1999 ) In this
process , there could have been circumstances or needs that led to the de -
with the brain and the appearance of mind processes . If we assume for a
minute that Fialkowski 's hypothesis is correct , the enlargement of the
brain initially evolved to cope with environmental heat stress until more
effective heat -dissipating systems evolved . When the loss of fur was com -
plete and eccrine sweat glands evolved over the general body surface to
increase evaporative cooling dramatically , more of the brain became
available for cognitive functions . In turn , these cognitive functions
proved to have survival value and have been used to preserve the integrity
of humans through a constant flow of information from the environment
to the body -brain -mind and from them to the environment in a more and
more efficient manner.
Body-brain-mind-environment representsa flow of functional informa -
tion . Modern biology is clearly showing that there is a continuum be-
TheBrainIs theBody 243
Atkins , E., and P. Bodel . (1972 ). " Fever." N . Eng . J. Med . 286 (1): 27 - 34 .
Austin , M . G ., and J. W. Berry . (1956 ). Observations on one hundred cases of
heatstroke . JAMA 161 : 1525 - 1529 .
Bach , V., F. Telliez , et al . (1996 ). Body temperature regulation in the newborn in -
fant : Interactions with sleep and clinical implications . Neurophysiol . Cline 26 :
379 - 402 .
246 References
University Press .
1148 - 1152 .
Brinnel , H ., M . Cabanac , et ale ( 1987 ) . Critical upper levels of the body tempera -
ture , tissue thermo sensitivity and selective brain cooling in hyperthermia . In Heat
gic systems in the brain : Does the substantia nigra playa role ? Brain Res . 234 :
275 - 286 .
Biochemistr ) ~ E . Schonbaum and P . Lomax ( eds .), 255 - 307 . New York :
Cabanac , M . ( 1993 ) . Selective brain cooling in humans : " Fancy " or fact ? FASEB
J . 7 : 1143 - 1147 .
395 - 433 .
391 - 402 .
248 References
Dahlstrom , A ., and F. Fuxe (1964 ). Evidence for the existence of monoamine con -
taining neurons in the central nervous system . I . Demonstration of monoamines
in the cell bodies of brain stem neurons. Acta Physiol. Scand. 62(Suppl. 232):
1- 55 .
Damasia , A . R . (1994 ). Descartes ' Error : Emotion , Reason and the Human
Brain . New Yark : Putnam .
Dart , R . A . (1964 ). The ecology of the South African man -apes. In Ecological
Studies in Southern Africa , D .H . S. Davies (ed.), 49 - 66 . The Hague : H . W . Junk .
Darwin , C. (1871). The Decent of Man . London: Murray .
De Vries , A . L ., and Y. Lin . (1977 ). The role of glycoprotein anti -freezes in the sur -
vival of Antarctic fishes. In Adaptations Within Antarctic Ecosystems , G . A .
Llano (ed.), 439- 458. Washington, D. c .: Gulf Publishing.
Dean , J. B., and J. A . Boulant . (1989 ). Effects of synaptic blockade on thermosen -
sitive neurons in rat diencephalon in vitro . Am . J. Physiol. 257: R65-R73.
Donald, D . E., D . J. Rowlands, et al. (1970). Similarity of blood flow in the nor-
mal and the sympathectomized dog hind limb during graded exercise . Circe Res.
26 : 185 - 199 .
DuBois , E. F. (1949 ). Why are fever temperatures over 106 F rare ? Am . J. Med .
Sci . 217 : 361 - 368 .
Gehring, W. J., and R. Wehner. (1995). Heat shock protein systhesisand thermo-
tolerance in Cataglyphis, an ant from the Saharadesert. Proc. Natl . Acad. Sci. 92:
2994 - 2998 .
Gisolfi , C . V. (1973 ). Work -heat tolerance derived from interval training . J. Appl .
Physiol. 35: 349- 354.
Gisolfi, C. V., R. D . Matthes, et al. (1991). Splanchnic sympathetic nerve activity
and circulating catecholaminesin the hyperthermic rat. J. Appl . Physiol. 70(4):
1821 - 1826 .
Hong , S. K ., and H . Rahn . (1967 ). The diving women of Korea and japan . Sci.
Am . 216 (5 ): 34- 43 .
Hong , S. K ., D . W . Rennie , et ale (1987 ). Humans can acclimatize to cold : A les-
son from Korean women divers . NIPS 2 : 79 - 82 .
Horne, J. (1988). Why We Sleep: The Function of Sleep in Human and Other
Mammals . New York : Oxford University Press.
Horowitz , M ., A . Maloyan , and J. Shlaier. (1997). HSP 70 kDa dynamics in ani-
mals undergoing heat stresssuperimposedon heat acclimation. Ann. N ."}-: Acad.
Sci . 813 : 617 - 619 .
Perinatal . 12 : 61 - 71 .
Yark : Elsevier .
stroke - induced cerebral ischemia and cell death in rats . J . Appl . Physiol . 80 :
680 - 684 .
171 - 178 .
Press .
93 - 127 .
Knochel , J . P . ( 1989 ) . Heat stroke and related heat stress disorders . Disease - a -
Krantz , G . S . ( 1968 ) . Brain size and hunting ability in earliest man . Curro Anthro .
9 : 450 - 451 .
References 255
agents during passive heating in the rat . J . Appl . Physiol . 68 ( 3 ) : 1220 - 1227 .
Proc . 20 : 214 .
Kuhnen , G . , and C . Jessen . ( 1991 ) . Threshold and slope of selective brain cooling .
589 - 598 .
Philadelphia : Davis .
mal . Sensori - motor , visual , and auditory fields in the Echidna . J . Neurophysiol .
27 : 37 - 48 .
Lewis , T . ( 1941 ) . Observations on some normal and injurious effects of cold upon
the skin and underlying tissues . III . Frostbite . Brit . Med . J . 2 : 869 - 871 .
thermotolerant Chinese hamster fibroblasts and in their stable heat resistant vari -
Mora , F. (1977). The Neural Basis of Feeding, Drinking and Reward. Doctoral
thesis , Oxford University .
Mora , F. (1995). El problema Cerebromente. Madrid : Alianza Editorial .
Mora , F. (ed.) (1996 ). EI Cerebra Intimo . Ariel : Barcelona .
Mora , F. (Ed .). (1999 ). La Razon Emocional del Cerebra . Madrid : Arbor .
Mora , F. (1999). The brain and the mind . In The New Oxford Textbook of
Psychiatry , M . G . Gelder , J. J. Lopez -Ibor , and N . Andreasen (eds.). Oxford :
Oxford University Press.
Mora , F., and M . Cobo. (1990). The neurobiological basis of prefrontal cortex
self-stimulation : A review and an integrative hypothesis. frog . Brain Res. 85:
419 - 431 .
Morrison , P. R., and F. A . Ryser. (1952). Weight and body temperaturesin mam-
mals . Science 116 : 231 - 232 .
Olsson , Y., H . S. Sharma , et ale (1995 ). The opioid receptor antagonist naloxone
influences the pathophysiology of spinal cord injury. In Neuropeptides in the
Spinal Cord, F. Nyberg, H . S. Sharma, and Z . Wiesenfeld (eds.), 381- 399.
Amsterdam : Elsevier .
Paladino, F. V., and J. R. Spotila. (1994). Does the physiology of large living rep-
tiles provide insights into the evolution of endothermy and paleophysiology of ex-
tinct dinosaurs ? DING FEST . 261 - 273 .
Pantin , C . F. A . (1956 ). The origin of the nervous system . Pub . Staz. Zool . Napoli
28 : 171 - 181 .
Papez
, J. W. A. (1937). A proposed mechanism of emotion . Arch . Neurol .
Psychiat
. 38: 725- 743.
Parker, G. H . (1919). The Elementary Nervous System. Philadelphia: Lippincott .
Parmegiani, P. L. (1980). Temperature regulation during sleep: A study in home-
ostasis. In Physiology in Sleep, J. Onens and C. D . Barnes (eds.), 97- 143. New
York : Academic Press.
References 259
306 - 313 .
thalamus in the cobra , Naja naja . Cell Tissue Res . 217 : 505 - 529 .
the pigeon to changes of the brain and spinal cord temperatures . Pflugers Arch .
338 : 31 - 42 .
Renbourn , E . T . ( 1960 ) . Body temperature and pulse rate in boys and young men
149 - 175 .
Nature 259 : 41 - 42 .
54 - 61 .
Roberts , M . F . , C . B . Wenger , et ale ( 1977 ) . Skin blood flow and sweating changes
following exercise training and heat acclimation . J . Appl . Physiol . 43 : 133 - 137 .
702 .
Simon, E., F. K . Pierau, and D . C. M . Taylor. (1986). Central and peripheral ther-
mal control of effectors in homeothermic temperature regulation. Physiol. Rev.
66 : 235 - 300 .
Strydom, N . B. (1980). Heat intolerance: Its detection and elimination in the min-
ing industry. S. Afr. J. Sci 76: 154- 156.
Sweatman , P., and R . M . Jell . (1977 ). Dopamine and histamine sensitivity of ros -
tral hypothalamic neurons in the cat: Possibleinvolvement in thermoregulation.
Brain Res . 127 : 173 - 178 .
van der Zee, J., G. C. van Rhoon, et al. (1990). Clinical hyperthermic practice:
Whole-body hyperthermia. In An Introduction to the Practical Aspectsof Clinical
Hyperthermia, S. B. Field and J. W. Hand (eds.), 185- 212. London: Taylor &
Francis .
Van Holde , K . E. (1980 ). The Origins of Life and Evolution . New York : Alan R .
Liss .
References 263
von Neumann , J . ( 1963 ) . Probabilistic logic and the synthesis of reliable organ -
isms for unreliable components . In his Collected Works , vol . 5 , 329 - 378 .
R213 - R221 .
sponsive neuron in slice preparation of rat brain stem . Am . J . Physiol . 250 : R553 -
R559 .
1338 - 1344 .
Wenger , C . B . ( 1987 ) . More comments on " Keeping a cool head . " NIPS 2 :
150 - 151 .
579 - 593 ( American Physilogical Society ) . New York : Oxford University Press .
ated with infection in burn patients . Arch . Surge 123 : 1313 - 1319 .
This excerpt from
endothermy , 43 Bruck , K . , 71
Black bile , 191 Burton , A . C . , 115 - 116
Blatteis , C . M . , 70 , 203
Bligh , J., 51 , 64 Cabanac , M ., 149
Blood , 191 Cancer , 221 , 226
Blood -brain barrier , 163 , 202 - 203 Cardiac output , 179 - 184
Blood temperature , 144 Carotid rete , 143 , 144 , 149
Blubber , 109 , 111 Cavernous sinus , 148 - 149 , 151
thermometers of the cell , 175 Hypothalamus, 47, 49- 50, 51, 54- 58,
Heatstroke , 104 , 153 , 157 - 159 , 61 , 63 - 64 , 70 - 73 , 77 , 79 , 100 , 157 ,
161 - 162 , 165 - 166 , 168 , 185 , 217 201
Index 269
Insensible perspiration , 98
Insensitive neurons , 102 Macrophages , 199
Intestinal permeability , 160 , 168 , 177 Mean body temperature , 131 - 133
Melanoma , 96
Kluger, M . J., 192- 193, 196, 206, 208 Muscle blood flow , 180 - 182
Krantz , G . S ., 238
Kregel, K . C., 157 Naloxone , 166
Neurotransmitters , 49 , 66 , 69 , 70 62 - 63
32 , 39 - 41 Sleep, 85- 89
Roth , J., 134 NREM , 86 - 88 , 120
Rowell , L . B ., 180 REM , 85 - 86 , 89
R yanodine , 218 Sleepdeprivation 88
Slow-wave sleep(SWS), 85
Saltin , B . , 186 Spinal cord, 50, 52- 54, 63- 64, 86,
Satinoff , E ., 50 - 51 , 73 , 81 - 83 205