Prolonged insomnia, prolonged physical exertion, infections, injections of
toxins and of strychnin, rage and fear, physical injury under anesthesia,
in fact, all the adequate stimuli which affected the brain and
the adrenals, produced constant and identical histologic changes
in the liver--the cells stained poorly, the cytoplasm was vacuolated,
the nuclei were crenated, the cell membranes were irregular, the most
marked changes occurring in the cells of the periphery of the lobules
(Figs. 69 and 70). In prolonged insomnia the striking changes
in the liver were repaired by one seance of sleep.
Are the histologic changes in the liver cells due to metabolism or toxic
products, or are they "work" changes incident to the conversion of latent
into kinetic energy? Are the brain, adrenals, and liver interdependent?
The following facts establish the answers to these queries:
(1) The duration of life after excision of the liver is about
the same as after adrenalectomy--approximately eighteen hours.
(2) The amount of glycogen in the liver was diminished in all the
experiments showing brain-adrenal activity; and when the histologic
changes were repaired, the normal amount of glycogen was again found.
(3) In crossed circulation experiments changes were found in the liver
of the animal whose brain received the stimulus.
From these premises we must consider that the brain, the adrenals,
and the liver are mutually dependent on one another for the conversion
of latent into kinetic energy. Each is a vital organ, each equally vital.
It may be said that excision of the brain may apparently cause death
in less time than excision of the liver or adrenals, but this statement
must be modified by our definition of death. If all the brain
of an animal be removed by decapitation, its body may live on for at
least eleven hours if its circulation be maintained by transfusion.
An animal may live for weeks or months after excision of the cerebral
hemispheres and the cerebellum, while an overtransfused animal may
live many hours, days even, after the destruction of the medulla.
It is possible even that the brain actually is a less vital organ
than either the adrenals or the liver.
In our research to discover whether any other organs should be
included with the brain, the adrenals, and the liver in this mutually
interdependent relation, we hit upon an experiment which throws
light upon this problem.
Groups of rabbits were gently kept awake for one hundred hours
by relays of students, an experiment which steadily withdrew
energy but caused not the slightest physical or emotional injury
to any of them; no drug, toxin, or other agent was given to them;
they were given sufficient food and drink. In brief, the internal
and external environments of these animals were kept otherwise normal
excepting for the gentle stimuli which insured continued wakefulness.
This protracted insomnia gradually exhausted the animals completely,
some to the point of death even. Some of the survivors were killed
immediately after the expiration of one hundred hours of wakefulness,
others after varying intervals.
Histologic studies were made of every tissue and organ in the body.
Three organs, the brain, the adrenals, and the liver, and these three only,
showed histologic changes. In these three organs the histologic changes
were marked, and were almost wholly repaired by one seance of sleep.
In each instance these histologic changes were identical with
those seen after physical exertion, emotions, toxins, etc.[*] It
would appear, then, that these three organs take the stress of life--
the brain is the "battery," the adrenals the "oxydizer," and the liver
the "gasoline tank." This clear-cut insomnia experiment corresponds
precisely with our other brain-adrenal observations.
[*] Further studies have given evidence that the elimination of the acids
resulting from energy-transformation as well as the conversion
of energy stored in the kinetic organs causes histologic changes
in the liver, the adrenals, and possibly in the brain.
With these three kinetic organs we may surely associate also the
"furnace," the muscles, in which the energy provided by the brain,
adrenals, and liver, plus oxygen, is fabricated into heat and motion.
Benedict, in his monumental work on metabolism, has demonstrated
that in the normal state, at least, variations in the heart-beat
parallel variations in metabolism. He and others have shown also that
all the energy of the body, whether evidenced by heat or by motion,
is produced in the muscles. In the muscles, then, we find the fourth
vital link in the kinetic chain. The muscles move the body,
circulate the blood, effect respiration, and govern the body temperature.
They are the passive servants of the brain-adrenal-liver syndrome.
Neither the brain, the adrenals, the liver, nor the muscles, however,
nor all of these together, have the power to change the rate of
the expenditure of energy; to make possible the increased expenditure
in adolescence, in pregnancy, in courting, and mating, in infections.
No one of these organs, nor all of them together, can act as a
pace-maker or sensitizer. The brain acts immediately in response
to the stimuli of the moment; the adrenals respond instantly
to the fickle brain and the effects of their actions are fleeting;
the liver contains fuel only and cannot activate, and the muscles
in turn act as the great furnace in which the final transformation
into available energy is made. The Thyroid
Another organ--the thyroid--has the special power of governing
the RATE OF DISCHARGE of energy; in other words, the thyroid is the
pace-maker. Unfortunately, the thyroid cannot be studied to advantage
either functionally or histologically, for there is as yet no available
test for thyroid secretion in the blood as there is for adrenalin,
and thyroid activity is not attended by striking histologic changes.
Therefore the only laboratory studies which have been satisfactory
thus far are those by which the iodin content of the thyroid
has been established. Iodin is stored in the colloid lacunae
of the thyroid and, in combination with certain proteins,
is the active agent of the thyroid.
Beebe has shown that electric stimulation of the nerve supply of
the thyroid diminishes the amount of iodin which it contains, and it
is known that in the hyperactive thyroid in Graves' disease the iodin
content is diminished. The meagerness of laboratory studies, however,
is amply compensated by the observations which the surgeon has been
able to make on a vast scale--observations which are as definite
as are the results of laboratory experiments.
The brain-cells and the adrenals are securely, concealed from
the eye of the clinician, hence the changes produced in them
by different causes escape his notice, but the thyroid has always
been closely scrutinized by him. The clinician knows that every
one of the above-mentioned causes of increased brain-cell, adrenal,
liver and muscle activity may cause an increase in the activity
of both the normal or the enlarged thyroid; and lie knows only too
well that in a given case of exophthalmic goiter the same stimuli
which excite the brain, the adrenals, the liver, and the muscles
to increased activity will also aggravate this disease.
The function of the thyroid in the kinetic chain is best evidenced,
however, by its role in the production of fever. Fever results
from the administration of thyroid extract alone in large doses.
In the hyperactivity of the thyroid in exophthalmic goiter one sees
a marked tendency to fever, in severe cases there is daily fever.
In fact, in Graves' disease we find displayed to an extraordinary
degree an exaggeration of the whole action of the kinetic mechanism.
We have stated that in acute Graves' disease there is a tendency
to the production of spontaneous fever, and that there is a magnified
diurnal variation in temperature which is due to an increased output
of energy in even the normal reaction producing consciousness. In Graves'
disease there is, therefore, a state of intensified consciousness, which is
associated with low brain thresholds to all stimuli--both to stimuli
that cause muscular action and to stimuli that cause fever. The intensity
of the kinetic discharge is seen in the constant fine tremor.
It is evident that the thresholds of the brain have been sensitized.
In this hypersensitization we find the following strong evidence as to
the identity of the various mechanisms for the production of fever.
In the state of superlative sensitization which is seen in Graves'
disease we find that the stimuli that produce muscular movement,
the stimuli that produce emotional phenomena, and the stimuli that
produce fever are as nearly as can be ascertained equally effective.
Clinical evidence regarding this point is abundant, for in
patients with Graves' disease we find that the three types
of conversion of energy resulting from emotional stimulation,
from infection stimulation, and from nociceptor stimulation
(pain), are, as nearly as can be judged, equally exaggerated.
In the acute cases of Graves' disease the explosive conversion
of latent energy into heat and motion is unexcelled by any other
known normal or pathologic phenomenon. Excessive thyroid secretion,
as in thyrotoxicosis from functioning adenomata, and excessive
thyroid feeding, cause all the phenomena of Graves' disease except
the exophthalmos and the emotional facies (Figs. 15 and 23).
The ligation of arteries, the division of its nerve supply,
or the excision of part of the gland, may reverse the foregoing picture
and restore the normal condition. The patient notes the effect
on the second day and often within a week is relatively quiescent.
On the contrary, if there is thyroid deficiency there results
the opposite state, a reptilian sluggishness.
At will, then, through diminished, normal, or excessive administration
of thyroid secretion, we may produce an adynamic, a normal,
or an excessively dynamic state. By the thyroid influence,
the brain thresholds are lowered and life becomes exquisite;
without its influence the brain becomes a globe of relatively
inert substance. Excessive doses of iodin alone cause
most of the symptoms of Graves' disease. As we have stated,
the active constituent of the thyroid is iodin in a special
protein combination which is stored in the colloidal spaces.
Hence one would not expect to find changes in the cells of the thyroid
gland as a result of increased activity unless it be prolonged.
We have thus far considered the normal roles played by the brain,
the adrenals the liver, the muscles, and the thyroid in transforming
latent into kinetic energy in the form of heat and motion as an
adaptive response to environmental stimuli.
The argument may be strengthened, however, by the discussion of
the effect of the impairment of any of these links in the kinetic
chain upon the conversion of latent into kinetic energy.
Effect Upon the Output of Energy of Impaired or Lost Function
of Each of the Several Links in the Kinetic Chain
(1) _The Brain_.--In cerebral softening we may find all the organs
of the body comparatively healthy excepting the brain.
As the brain is physically impaired it cannot normally stimulate
other organs to the conversion of latent energy into heat or
into motion, but, on the contrary, in these cases we find feeble
muscular and intellectual power. I believe also that in patients
with cerebral softening, infections such as pneumonia show a lower
temperature range than in patients whose brains are normal.
(2) _The Adrenals_.--In such destructive lesions of the adrenals
as Addison's disease one of the cardinal symptoms is a subnormal
temperature and impaired muscular power. Animals upon whom double
adrenalectomy has been performed show a striking fall in temperature,
muscular weakness,--after adrenalectomy the animal may not be able
to stand even,--and progressive chromatolysis.
(3) _The Liver_.--When the function of the liver is impaired
by tumors, cirrhosis, or degeneration of the liver itself,
then the entire energy of the body is correspondingly diminished.
This diminution of energy is evidenced by muscular and mental weakness,
by diminished response and by gradual loss of efficiency which finally
reaches the state of asthenia.
(4) _The Muscles_.--It has been observed clinically that if the muscles
are impaired by long disuse, or by a disease such as myasthenia gravis,
then the range of production of both heat and motion is below normal.
This is in agreement with the experimental findings that anesthetics,
curare, or any break in the muscle-brain connection causes diminished
muscular and heat production.
(5) _The Thyroid_.--In myxedema one of the cardinal symptoms
is a persistently subnormal temperature and, though prone
to infection, subjects of myxedema show but feeble febrile response
and readily succumb. This clinical observation is strikingly
confirmed by laboratory observations; normal rabbits subjected
to fear showed a rise in temperature of from one to three degrees,
while two rabbits whose thyroids had been previously removed and who
had then been subjected to fright showed much less febrile response.
Myxedema subjects show a loss of physical and mental energy
which is proportional to the lack of thyroid. Deficiency in any
of the organs of the kinetic chain causes alike loss of heat,
loss of muscular and emotional action, of mental power, and of the power
of combating infections--the negative evidence thus strongly supports
the positive. By accumulating all the evidence we believe we
are justified in associating the brain, the adrenals, the thyroid,
the muscles, and the liver as vital links in the kinetic chain.
Other organs play a role undoubtedly, though a minor one.