Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat
Biographies de neurologues
Nouvelle Iconographie de La Salpêtrière
 L'histoire des neurosciences à La Pitié et à La Salpêtrière J Poirier
The history of neurosciences at La Pitié and La Salpêtrière J Poirier
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 Encephalitis lethargica.
Its sequelae and treatment
von Economo C
Translated by KO Newman
London: Oxford University Press
Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases
McCall S, Henry JM, Reid AH, Taubenberger JK
J Neuropathol Exp Neurol.
2001; 60; 11; 1121-2
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20 janvier 2005
The Journal of Nervous and Mental Disease
march 1930, 71, 3
Baron Constantin von Economo1876 - 1931
Paper read before the College of Physicians and Surgeons
Columbia University New York, Dec. 3, 1929
Cinquante ans de sommeil O Sacks


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The search for a so-called sleep center may at first sight appear a paradoxical idea. In the same manner as the waking state, so also does sleep appear as such a complex biological condition that the problem makes us at first sit up and take notice. Indeed, our entire life takes place in the alternating change of two biological conditions, the waking and sleeping state and in this way the problem might appear primarily of the same category as the problem of the center of life itself. The problem of a center of life in the nervous system has often been discussed in past centuries. But it has been put away as life is a much too complex condition as to be localized. So is sleep, too. But the change of sleep and waking state might, anyhow, have something to do with some special centers of the nervous system and that question has always been discussed over again. If we do not give to the word "center" a too narrow definition but if we agree that the expression "nervous center" signifies only such an accumulation of nervous grey matter the action of which is of direct primary importance for the production of a definite function, we might nowadays again discuss the possibility of locating sleep, regulation in some definite part of the nervous system since we know that even so complicated a biological function as the temperature of our body has got a very definite and localized regulating center in the diencephalon.
Most of the scientists, physiologists as well as pathologists, were thoroughly contented with these explanations of sleep. The former attempts to locate sleep function were looked at as obvious. Though some curious pathologic facts were known, for instance, the occurrence of sleep as a frequent symptom in cases of tumor of the infundibulum and were especially mentioned by Claude and Lherniitte, this Lhermitte himself stated in 1910, during the discussion of narcolepsy, "We absolutely object to the thought of the existence of a nerve center attributed to the function of sleep." Veronese expressed his doubt in the sentence, "The conception of a center for sleep is erroneous, as it disavows the most simple principles of physiology." And Dejerine said in 1914: "Sleep cannot be localized."
So stood the facts when two years later the appearance of lethargic encephalitis, which I first described in 1916 -17, refuted all these statements however well founded they appeared. The lethargic epidemic encephalitis shows in its most ordinary somnolent-ophthalmoplegic form, outside of disturbances of the eye muscles, as the most striking symptom, a sopor of different degree varying from simple somnolence to the deepest sopor in which the patients may sleep for weeks and months but from which in the majority of cases, it is possible to arouse them. The disease is produced by an inflammation of the central grey matter localized in the main in the cap of the interbrain at its junction with the thalamus. The inflammation may spread frontally and caudally to other parts of the nervous system and produce other symptoms. So it could be shown later that those cases of encephalitis which began with choreatic unrest presented at the beginning a striking and tormenting insomnia. The combinations chorea and insomnia on the one hand, eye muscle disturbances and sleep on the other hand, and our knowledge that many choreiform diseases originate in the region of the stem ganglia, leads to the assumption that the inflammation in cases associated with insomnia, is localized anteriorly in the lateral wall of the third ventricle, near the corpus striatum while it is localized in cases showing disturbances of ocular muscles with sopor in the posterior wall of the third ventricle near the nuclei of the oculomotorius in the cap of the interbrain.
The lethargic encephalitis produces, furthermore, outside of insomnia and sopor, a number of other disturbances of sleep, for instance, the inversion of sleep, i.e., the reversal of the periodicity of sleeping and waking, patients sleeping in the day time and being awake at night. Another very frequent sleep disturbance in encephalitis it what I call the dissociation of cerebral and body sleep and observed in a series of akinetic cases, patients being in day time mentally wideawake while their bodies were akinetic and drowsy as in sleep; at night these patients are again mentally asleep while their bodies are restless, which circumstance produces states of somnambulism. It was supposed by many investigators that it might be the toxic effect of lethargic encephalitis being an infectious disease, that was the reason for the sleep symptoms. But I called attention to the fact that quite a number of other diseases affecting the same region of the nervous system, as lethargic encephalitis does, namely, Wernicke's disease, Gayet's disease, then tumors of the infundibular region present outside of disturbances of the eye muscles, also sopor. Some recent findings in cases of softening (in hemorrhages) of this region have shown the sanie syniptomatology. The consideration that diseases of such different nature can always be productive of sleep if they occur in this region of the nervous system, proves the correctness of the statement that not the individuality of the disease as such, but its localization at this very definite area of the nervous system is decisive for the occurrence of sleep. Inasmuch as furthermore in lethargic encephalitis sleep is disturbed in such various ways as sopor, insomnia, inversion of sleep, dissociation of sleep, etc., we have additional proof that we must consider this region of grey matter as the site from which sleep can be primarily and directly influenced. This area is therefore selective for the function of sleep and as in more than 85 per cent of the cases of encephalitis there occur some troubles of the sleep function, we must suppose that the virus of encephalitis has a special affinity to these accumulations of grey matter which are of special importance for the sleep and which I designate as the "center for regulation of sleep."
We must insist on the anatomical fact that the center for regulation of sleep is in the immediate vicinity of the other important vegetative centers located in the infundibular region and we can suppose that it forms with them a larger physiological entity but that it is, anyhow, to be distinctly separated from the other vegetative centers by its localization as well as by its chemical affinity as its affinity to the virus of encephalitis proves, because in the acute stage of that disease we generally do not find other disturbances of the vegetative nervous system.
The action of that sleep-regulating center probably consists in a coordination of the different changes which occur in sleep in our vegetative animal and psychic system. As to the psychic system, the center for regulation of sleep has the rôle of initiating the cerebral sleep which, as we know, is characterized by partial extinction of consciousness and by the difficulty of conduction in the brain. How does this mechanism act physiologically? I think that Pawlow's experiments give us a precious hint to answer this question. We know by these experiments on conditional reflexes that a repeated interruption of these reflexes have a local inhibitory action on the cerebral cortex which can with a certain experimental arrangement, spread over the entire cerebral cortex. If that inhibition spreads over the whole cortex, it suddenly produces sleep. This experimental fact suggests that normal cerebral sleep might be considered as an inhibitory action brought about by the center of sleep regulation upon the cerebrum and thalamus. We are acquainted with different similar inhibitory processes in the nervous system in other conditions, for instance the inhibition of antagonists during stimulation of motor centers or the inhibitory fibers of the heart, etc. This way of acting by a nervous inhibition explains also the possibility of being aroused from sleep and many other particularities of normal sleep much better than the theories of anemia or the chemical theories can do because in chemical and vasomotor states we can't admit such sudden changes.
Outside of the effects of cerebral functions, the center of sleep regulation certainly exerts a regulating influence as previously mentioned, on the other vegetative and animal components of sleep which we might call "body sleep" for instance the change of respiration, perspiration, metabolism, etc. That influence is effected directly on the neighboring vegetative centers as for instance the centers of temperature, for sugar and calcium content of the blood, for regulation of the water metabolism, etc., which all change during sleep and the centers of which are located in the subthalamic region and in the wall of the third ventricle.
To fall asleep is therefore to be regarded as a very complex function. Its coordination and release is effected by the center of sleep regulation although the character of sleep and its periodicity is as previously mentioned, much more deeply and more generally anchored in the vegetative organism, somewhat similar to the hormonal explanation.
Now we must put forward the question "what sets the regulation center into action?" It seems most plausible to admit that this center is ordinarily and normally set into action by fatigue substances while circulating in the blood in an amount yet insufficient to bring about intoxication but acting already in small quantities specifically on that center of sleep. The latter then inhibits by an active nervous inhibition, the action of brain and thalamus which produce cerebral sleep and directs, in the meantime, the coordination of the different subthalamic centers concerned with body sleep. In this sense, the statemerit of Claparède that we sleep not because we are intoxicated by hypnotoxins but in order not to get intoxicated by them, is probably quite correct. This also differentiates the normal sleep from other abnormal sleep-like states. We might say the normal sleep is an active nervous inhibition, whilé syncope, narcosis, and other similar states are conditions which differ from it by their being passive intoxicatory and mechanical interruptions of nervous function. In consequence the latter are not immediately reversible as normal sleep is, which ends in the very moment the nervous inhibition by the sleep regulating center is set off.
Schema of the median section of the interbrain; the dotted line is the boundary of the field, in which the center for brain regulation is lying. We may, then, assume that the localized mechanism we postulate. for the supervision of sleep is really existing and we must look out how best we can localize it. Our experience with cases of lethargic encephalitis and other infundibular processes shows that sopor may occur in these diseases as an isolated symptom but that it appears principally associated with paralysis of eye muscles, especially with ptosis. That corresponds to the most frontal part of the nucleus oculomotorius, so we must place the posterior border of the center for sleep regulation immediately in front of the nuclei of the eye muscles in the grey junction of interbrain and thalamus where the aqueduct of Sylvius opens into the third ventricle.
The anterior part of that center may be located further frontally in the grey walls of the third ventricle near the caput of the corpus caudatum, as we find the symptom of insomnia combined with choreatic disturbances. Pathological-anatomical examination of encephalitis material has not resulted in a more exact localization but I am under the impression that we have to do not so much with a narrowly circumscribed grey nucleus but with a mass of grey substance spreading over the posterior and lateral walls of the third ventricle and reaching laterally also into the hypothalamus. The different parts of that grey matter act in a sort of balancing way. I arrive at this conclusion on account of the multiplicity of sleep disturbances observed in the course of encephalitis.
To return then once again to the previously discussed definition of the words "nervous center," the center of sleep regulation cannot be classified within a narrow definition of this term. It is not considered a narrowly circumscribed seat of sleep function but as a center in a wider sense, i.e., as an accumulation of grey matter the function of which is of primary importance for the normal course of sleep.
The problem of more exact localization could only be solved in a conclusive way by physiological experiments. Different attempts in this direction have been made by Spiegel, Inaba, Demole, Marinesco. But all these attempts are surpassed by the very recent experiments of Hess in Zurich. He succeeded in making cats fall asleep normally with all symptoms of fatigue, of yawning and position of rest, by electrical stimulations with very fine electrodes introduced into the brain and by very weak currents which acted upon the anterior region of the aqueduct and the posterior wall of the third ventricle. If these results are verified in the future, irrefutable proof is furnished for the correctness of our conception of a center for the supervision of sleep situated at the junction of the thalamus and the interbrain from which sleep is actively initiated. It is therefore manifest by all these recent studies, that there is an apparatus which controls the general periodic alternation of sleeping and the constellation of our organism similar to high and low tide and similar to other vegetative function centers of the central nervous system.
As we have seen not only lethargic encephalitis but also other diseases of that region in the diencephalon may produce sleep disturbances. It is very probable though not yet proved, that the narcolepsy of Gélineau, Westphal and Redlich has its primary cause in a yet unknown disease of that region.
Now you may think the statement of the existence of such a regulating center for sleep is a very interesting physiological fact but you will ask for the practical consequence of such a statement. I will first point out to you that all knowledge of localization has a practical effect inasmuch as it helps us to localize different diseases, for instance, tumors, and helps us to get at them practically in a curative way. On the other hand, you know we are ardently seeking to find methods to excite externally either by electricity or rays or diathermy through the skull,4he centers of our nervous system in the intention of producing a therapeutic effect. Some initial results have already been obtained in that direction by diathermy. Imagine we once had an effective method of influencing deep lying centers, in this case the exact knowledge of the localization of the center for sleep regulation which I have attempted to give you, would make it possible to treat insomnia and other sleep disturbances in a better and more active way than by drugs or by the roundabout way of hydrotherapy and psychotherapy. Let us express the hope that we shall soon be able to have such results.
Baron Constantin von Economo1876 - 1931

Sleep as a problem of localisation von Economo 1930 - pdf