Current evaluation of the concepts of centrecephalic and cortico-reticular seizures

Electroencephalography and clinical Neurophysiology, 1991, 78:2-11 Elsevier Scientific Publishers Ireland, Ltd.

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EEG 00782

Guest Editorial Current evaluation of the concepts of centrencephalic and cortico-reticular seizures Herbert H. Jasper

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4501 Sherbrooke W. No. 1F, Westmount, PQ H3Z 1E7 (Canada)

The eentrencephalic integrating system and centrencephalic seizures The concept of a centrencephalic integrating system involved in the 'highest level' of neuronal integration, selecting and coordinating neuronal activities of the two hemispheres, mediating conscious mental experience and initiating, directing and coordinating goal directed motor behavior was proposed as a working hypothesis by Wilder Penfield at an A.R.N.M.D. meeting in New York in 1950 after consultation with Stanley Cobb and Herbert Jasper (Penfield 1952). He defined the centrencephalic system in this original publication as follows: "that central system within the brain stem which has been or may be in the future, demonstrated as responsible for the integration of the function of the two hemispheres." He did not consider it to be limited to the reticular activating system of Magoun and Moruzzi, although probably included as part of it. It included 2-way interconnections between all areas of cerebral cortex and an extensive network of neurones in diencephalon and brain stem. It was a working hypothesis, deliberately lacking precise anatomical identity, to be worked out in the future. We then used the term centrencephalic seizures for those generalized epileptic seizures consisting of almost exclusively or initially a loss of consciousness, as in classical petit real or absence attacks, or for generalized seizures beginning with a loss of consciousness described in our book on Epilepsy and the Functional Anatomy of the H u m a n Brain (Penfield and Jasper 1954). Centrencephalic seizures could only be diagnosed, in

1 This review is dedicated to Prof. Henri Gastaut and to his late wife, Mme. Yvette Gastaut for their outstanding contributions to etectroencephalography and to the study of the epilepsies over the years. Correspondence to: Dr. Herbert H. Jasper, OC, MDCM, 4501 Sherbrooke W. No. IF, Westmount, PQ H3Z 1E7 (Canada).

0013-4649/91/$03.50 © 1991 Elsevier Scientific Publishers Ireland, Ltd.

some cases, following exhaustive studies to rule out the possible presence of a deep seated cortical epileptogenic lesion. We proposed that there were several forms of centrencephalic seizure, all with a bilaterally synchronous onset, but with a different form of clinical attack, generalized from the onset. The form of the E E G was also different in the various forms of centrencephalic seizure. This included the classical petit mal absence, the petit mal automatism, akinetic or 'drop' attacks, bilateral theta ( 4 - 6 h) seizures and the bilateral multiple spike seizures of myoclonic and generalized convulsions (grand mal). In all of these cases there were paroxysmal dysrhythmias associated with the clinical seizures, but relative normal E E G patterns between attacks, and no evidence of diffused brain disease or encephalopathy. This would imply that there were several different centrencephalic systems with bilateral projections, interconnected in some cases as when the seizure would begin with an absence attack and proceed into a major generalized convulsion (petit and grand mal). We were well aware of the many organic brain diseases and encephalopathies which could mimic some aspects of the E E G in centrencephalic seizures, as originally pointed out by Lennox and called the 'petit mal variant.' This has been confirmed by Andermann (1967). But the E E G in these cases was characterized by diffusely abnormal tracings between attacks and the patients showed signs of progressive mental retardation. Our classification was based mainly upon the original comprehensive E E G and clinico-pathological studies, combined with electrocorticograms taken from the exposed surface of the cortex during operations by Dr. Penfield for the relief of focal areas of epileptogenic tissue. Our findings were analyzed with John Kershman in our paper on electroencephalographic classification of the epilepsies (Jasper and Kershman 1941). It was in this publication that we first suggested that the bilaterally synchronous spike and wave patterns, arising suddenly out of a normal background EEG, must be due to a subcortical pacemaker which was able to control the electrical activity of homologous areas of the two hemispheres.

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Secondary bilateral synehrony In our publication with Penfield in 1954 we also described a number of patients with generalized seizures resembling a form of centrencephalic seizure both in the E E G and in the pattern of the clinical attack, but were found to have deep seated epileptogenic lesions in the cerebral cortex of one hemisphere even though the surface EEG was characterized by bilaterally rhythmic slow waves and atypical spike and wave variants simulating quite closely the EEG pattern of some patients with classical petit mal attacks. Recording with implanted electrodes inserted in deep parasagittal and orbital surfaces of the frontal lobes, or deep in the temporal region, with some even in parasagittal parietal regions, we were able to discover areas of focal spiking typical of a cortical focus. The local cortical spikes in these areas seemed to trigger the bilaterally synchronous rhythmic waves recorded in the surface EEG. In some cases the seizures were also similar to the 'absence' attacks of petit mal. Many such cases have since been described by Bancaud and colleagues in Paris from their extensive studies with stereoencephalography (Bancaud et al. 1965). It would seem that certain cortical areas, not accessible to the usual surface EEG, were capable of triggering a centrencephalic-like seizure, though usually with atypical or asymmetrical spike and wave forms and persistent abnormalities in background activity (see also Walker and Morello 1967).

The evolution of Penfield's views on centrencephalic integrating systems Penfield's primary interest in the centrencephalic hypothesis was an effort to understand the age-old brainmind problem. He had concluded in 1936 in his Harvey Lecture (Penfield 1938) that it was in the brain-stem, including the diencephalon, not in the cerebral cortex, that one should search for the 'essential substratum' of consciousness. In his Harvey lecture in 1936, he stated that: "There is evidence for a level of integration within the nervous system that is higher than that found in the cerebral cortex . . . . a' regional localization of the neuronal mechanisms involved most intimately with the initiation of voluntary movement and with the sensory summation prerequisite to it . . . . All regions of the brain m a y well be involved in normal conscious processes, but the indisputable substrat u m of consciousness lies outside the cortex, not in the new brain b u t in the old . . . . probably in the brain-stem and diencephalon."

This conclusion was derived from Penfield's neurosurgical experience with large removals of cerebral cortex in alert conscious epileptic patients without an impairment of consciousness, while pressure applied to the

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wall of the third ventricle or brain-stem caused an immediate and reversible loss of consciousness. It seemed reasonable to assume that epileptic seizures which consisted almost exclusively of a brief loss of consciousness, or began in this manner before developing into a generalized convulsion, might well involve similar subcortical mechanisms. He did not mean that the cortex was not involved in highest level functions, but that there were specialized networks of neurones in diencephalon and brain-stem which served to integrate the activity of the two hemispheres and to control states of consciousness and behaviour by their interaction with various areas of cerebral cortex. In reaction to much criticism Penfield stated: " I t would be absurd to suppose that central integration could take place without implication and employment of cortical areas selected appropriately to the needs of the organization that faces the brain mechanism. To suppose that centrencephalic integration is possible without utilization of the cortex would be to return to the thinking of Descartes and to enthrone again a spiritual homunculus in some area such as the nearby pineal gland. It would be equally absurd to consider that the reticular formation is functionally separable from the cortex."

In discussing this subject at the Vatican 'Semaines d'Etudes sur le Cerveau et Exprrience Consciente' (Jasper 1966) I added that: "Penfield states the problem well when he emphasizes functional interaction rather than localization, and selection of only certain cortical processes by some as yet u n k n o w n process to be dominantly involved in perceptual awareness at a given time in the stream of consciousness. He might have added that it would be equally absurd to assume that all of the multitudinous activities of the brain as a whole can be simultaneously involved in the perceptual awareness of a given moment."

Penfield was not the first to propose that the reticular core of the brain-stem and diencephalon might play a leading role in central integrative functions of the brain. Ram6n y Cajal and Judson Herrick, for example, came to this conclusion from their detailed anatomical studies of a reticular network of neurones in the central core of the brain-stem and diencephalon separate from the principle sensory and motor pathways. Other conceptions of the importance of the reticular core of the brain-stem for central integration and generalized seizures have been reviewed by O'Leary and Cohen (1958) and O'Leary and Goldring (1976). Neurosurgeons would generally agree with some form of centrencephalic hypothesis involving the higher brain-stem and diencephalon, though the precise nature of the anatomical substrate of a 'centrencephalic system' as defined by Penfield was uncertain (see Kristiansen 1964; Perria 1964). It is generally agreed, however, that the brain-stem is involved in the control of states of sleep and coma.

4 I n his M a u d s l e y lecture o n the centrencephalic system Penfield (1958b) wrote: "the circuits of this system run out into the various functional areas of cortex and back again. In a very real sense there is no 'higher' and no 'lower' in this system. The place of understanding is not wailed up in a cell or center of grey matter. It is to be sought in the perfect functioning of all these converging circuits." ... Centrencephalic integration must be the outcome of synchronous central and cortical activity, activity in the brain-stem and in those areas of cortex of either hemisphere whose function is suited to the changing requirements of the moment."

I n his later years, Penfield was more impressed b y the work of Walle N a u t a o n the integrative properties of transcortical circuits b e t w e e n frontal a n d parietal cortex a n d the limbic system as well as the i m p o r t a n c e of transcortical circuits a n d the limbic system i n auditory a n d visual perception as described b y Mishkin. H e was also very m u c h impressed b y the work of Sperry who showed the i m p o r t a n c e of the corpus callosum in dividing the states of consciousness i n the split-brain p r e p a r a t i o n (Sperry 1966). The work of Sperry a n d m a n y other critical studies were presented at a n o t h e r i m p o r t a n t i n t e r n a t i o n a l study week organized b y J o h n Eccles u n d e r the title of Brain and Conscious Experience 10 years after the L a u r e n t i a n Conference (Eccles 1966). It was held u n d e r the auspices of the Pontifical A c a d e m y of Science in R o m e i n 1964. Penfield's c o n t r i b u t i o n to this m e m o r a b l e s t u d y week was entitled Speech Perception and the Uncommitted Cortex in which he s u m m a r i z e d his classical studies o n the exposed cerebral cortex o n a b o u t 1000 u n a n a e s t h e tized epileptic patients. I n the discussion at the end of his p r e s e n t a t i o n of observations o n cortical localization of various functions he returns to a c o n s i d e r a t i o n of the centrencephalic system as follows: "Consciousness continues regardless of what area of cerebral cortex is removed. On the other hand, consciousnessis inevitably lost when the function of the higher brain stem (diencephalon) is interrupted by injury, pressure, disease, or local epileptic discharge. The detailed anatomy of the diencephalon (which includes the thalamus) is still obscure. Nevertheless, it is clear that within the diencephalon there is a system of nerve fibres and gray matter that communicates directly with the functional units of the two hemispheres. It is on the action of this system that the existence of consciousnessdepends.... I began to call this hypothetical communication the centrencephalic system. It served to call attention to the fact that the so-called cortical association tracts could not account for integration of function in the brain ... and that the centrencephalic system is only a means of communication, coordination, and integration and that it unites the diencephaIon with the prosencephalon above and the mesencephalon below in functional unity." (Penfield, 1966, pp. 234-235.) I n his c o n t r i b u t i o n to the first s y m p o s i u m o n Basic Mechanisms of the Epilepsies, after further c o n s i d e r a t i o n a n d study of his epileptic patients, Penfield c o n c l u d e d

H.H. JASPER that there are p r o b a b l y two centrencephalic systems, one which has to do with the p r o g r a m m i n g of m o t o r b e h a v i o u r a n d the other related to consciousness (Penfield 1969). H e also p o i n t e d out in this p u b l i c a t i o n that c e n t r e n c e p h a l i c seizures might be triggered or paralyzed by deep seated focal cortical epileptic discharge: "the same mechanisms may be paralyzed secondarily by bombardment from an epileptogenic focus in frontal or temporal cortical areas. The beginning is different, the eventual automatism much the same." Finally, in a p u b l i c a t i o n which appeared only a few weeks before his death in 1976 at 85 years of age, entitled The Mystery of the Mind, Penfield a d m i t t e d that he h a d failed i n his search for that mysterious link b e t w e e n the b r a i n a n d the m i n d . I quote from his final o p i n i o n recorded i n the last chapter entitled After

Thoughts: "working as a scientist all through my life, I have proceeded on the one element hypothesis, that activities of the highest centers and mental activity are one and the same thing, or are different sides of one thing'.... In the end I conclude there is no good evidence, in spite of new methods, the study of conscious patients, and the analysis of epileptic attacks, that the brain alone can carry out the work that the mind does. I conclude that it is easier to rationalize man's being on the basis of two elements rather than on the basis of one. But one should not pretend to draw a final conclusion, until the nature of the energy responsible for mind-action is discovered as, in my own opinion, it will be." It is a pity that Penfield died before he could appreciate the r e v o l u t i o n a r y advances m a d e d u r i n g recent years o n the molecular n e u r o c h e m i c a l a n a t o m y of the brain, which shed a completely new light o n the concept of the c e n t r e n c e p h a l i c system a n d its relation to states of consciousness, l e a r n i n g a n d m e m o r y , perceptual awareness, m e n t a l activities a n d the p r o g r a m m i n g a n d control of m o t o r behaviour. I have q u o t e d Penfield i n considerable detail to try to get a n accurate a n d clear idea of his view of the c e n t r e n c e p h a l i c system before describing m a n y experim e n t a l studies aimed at refuting the hypothesis of c e n t r e n c e p h a l i c seizures w i t h o u t c o n s i d e r a t i o n of the evolution of Penfield's views over the years.

Experimental evidence pro and con T h e c o n c e p t of a centrencephalic integrating system has b e e n the subject of m u c h controversy over the past 40 years, a n d likewise for the concept of centrencephalic seizures. It has s t i m u l a t e d m u c h interesting a n d exciting research with which the readers of this j o u r n a l are p r o b a b l y quite familiar. It has been the subject of a n u m b e r of good reviews which make it possible for me

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to cite only a few extracts from some of them for the purposes of this discussion. In the beginning there was considerable experimental support for the centrencephalic hypothesis. Morison and Dempsey had shown that there was a diffuse thalamo-cortical projection system arising in the intralaminar regions of the thalamus, which they called the 'recruiting system.' Electrical stimulation of the intralaminar thalamus in cats was capable of controlling the rhythmic electrical activity of large areas of cerebral cortex, particularly prominent in frontal and parietal regions (Morison and Dempsey 1942). In collaboration with the Dutch neuroanatomist Jan Droogleever-Fortuyn who came to join us in Montreal as a Rockefeller post-doctoral fellow immediately following the war in 1945, we were able to reproduce the bilaterally synchronous spike and wave pattern in lightly anaesthetized cats similar to the classical pattern of the E E G in petit mal epilepsy. This was reported at the A.R.N.M.D. meeting in New York in 1946 (Jasper and Droogleever-Fortuyn 1947). This was the same meeting as was presented the paper on 'Highest level seizures' with Wilder Penfield (Penfield and Jasper 1947). Morison was present at the meeting and was amazed to see that stimulating the intralaminar thalamus at 3/sec could reproduce so closely the bilateral spike and wave pattern of petit real epilepsy as well as the 'recruiting response.' There was, in fact, a diffuse projection system distinct from the specific thalamo-cortical projections from the principle specific thalamic nuclei which could be involved in generating the petit mal attack as would be predicted from the centrencephalic hypothesis. Later we were able to reproduce an 'absence'-like seizure in waking animals (cats and monkeys) by electrical stimulation of the intralaminar thalamus. We called this the 'arrest reaction' and it was characterized by staring with unresponsiveness, arrest of ongoing behaviour, and even with myoclonic twitches about the face as often occurs in patients during a typical absence attack (Hunter and Jasper 1949). A few years later there appeared the classical paper of Moruzzi and Magoun on the ascending reticular activating system which was also a diffuse projection system arising in the mesial portion of the midbrain, separate from lemniscal sensory systems and from the principle cortical efferent projection systems. It was shown to control states of sleep and waking with the accompanying characteristic changes in the EEG, consistent with the centrencephalic hypothesis (Moruzzi and Magoun 1949). This and other work stimulated the organization of the international symposium on Brain Mechanisms and Consciousness held in the Laurentian mountains near Montreal in 1953. There were many distinguished participants including Adrian, Brazier, Bremer, Fessard, Gastaut, Grey Walter, Hebb, Hess, Jasper, Jung, Kubie,

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Lashley, Magoun, Rioch, Morison, Moruzzi, Nauta, Olzewski, Penfield, Whitlock, and some fellows who aided in the proceedings (Adrian, Bremer, Jasper and Delasfresnaye 1954). Evidence for and against the concept of a centrencephalic integrating system in relation to the brain-stem reticular system was given full consideration with much support and critical skepticism by some who favoured transcortical and callosal high level integrating systems as well, and hesitated to give such important mechanisms of consciousness to the more primitive systems of the brain-stem. In the meantime there have been many other experimental studies which have cast doubt upon the hypothesis of centrencephalic seizures and many others giving it strong support. Space does not permit me to give a full account of these many interesting and important studies. Fortunately there have been several good reviews to which I can refer, with a few quotations and comments for purposes of this discussion. The first comprehensive review was organized by Henri Gastaut and Robert Naquet in Marseilles in 1966 under the auspices of the Summer Courses of NATO and with the cooperation of the World Federation of Neurology and the International League against Epilepsy. Gastaut wrote the Preface and first chapter entitled 'Introduction to the study of functional generalized epilepsies' with his colleagues, Rohmer, Cossette and Kurtz. The proceedings and discussion were then edited by Gastaut, Jasper, Bancaud and Waltregney and published in 1969. Most important for the present discussion was the review by Gastaut who proposed the term 'holencephalic' for many cases of generalized seizures caused by diffuse organic brain diseases, various forms of encephalopathy or neurochemical causes such as convulsant drugs, enzyme deficiencies or poisons, etc. He felt that there was still a place for the concept of centrencephalic seizures in the classical 'petit mal absence.' The centrencephalic hypothesis was considered in further detail in this symposium in comprehensive reviews by Ajmone Marsan (1969), Gloor (1969) with conclusions in Part V of the Symposium by Jasper (1969). In my conclusions I emphasized the importance of recent evidence for various ascending widely distributed systems of neurones originating in the brain-stem which control the release of neurochemical substances capable of controlling the excitability of cerebral cortex. The first of these was acetylcholine which was described by Shute and Lewis as' the ascending cholinergic reticular system' (1967). ACh was shown in experiments with Gastone Celesia and others to be liberated in cerebral cortex in increased amounts during waking as opposed to sleep and increased by electrical stimulation of the ascending reticular system of the brain-stem associated with an arousal response of the EEG. Focal

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spiking and the onset of a seizure discharge was also elicited in a local area of cortex which had been pretreated by eserine (Celesia and Jasper 1966). It was also shown that neuro-active excitatory and inhibitory amino acids, glutamic and aspartic acids, and GABA, in cerebral cortex could be increased many-fold by electrical stimulation of the mid-brain reticular system (Jasper et al. 1965; Jasper 1969a, b; Jasper and Koyama 1969; Jasper and Krjnevic 1969). These studies gave a new dimension to the concept of centrencephalic systems controlling the excitatory state of cerebral cortex, a view that was never considered by Penfield because of his retirement from active research by this time. This concept has been elaborated much more during recent years, with many more neurochemical substances involved in this new view of centrencephalic systems. New neurochemical anatomical techniques have shown many chemically specific ascending and diffusely projecting afferent systems to cerebral cortex from the diencephalon and brain-stem, independent but interacting with the principle sensory and motor pathways. They have overlapping projections to all of the specific areas of the cerebral cortex. We now have a plethora of 'centrencephalic' neuronal systems interconnecting the brain-stem and diencephalon with the cerebral cortex which might be included in a centrencephalic integrating system. A description of the monoamine innervation of the cerebral cortex was treated in some detail in an international symposium held at the University of Montreal on 'Monoamine Innervation of Cerebral Cortex' organized and edited by Decarries, Reader and Jasper (1984). Tom Reader and I presented our micro-iontophoretic studies of 'Interactions between monoamines and other transmitters in cerebral cortex' (Reader and Jasper 1984) showing specially important interactions with acetylcholine and GABA. Sensory stimulation produced a surprising reduction in the liberation of noradrenaline and dopamine, probably due in part to the interaction with acetylcholine acting presynaptically on monoamine terminals in cortex. There were also important interactions shown between serotonin and dopamine and noradrenaline, some of a long lasting nature suggesting second messenger mediation. They were all controlled by specific diffuse projection systems arising in the brain-stem and diencephalon reaching the cortex directly, without relay in the thalamus, and widely distributed throughout all areas of cerebral cortex, though not equally in all areas. Susan Iversen contributed a particularly interesting and important chapter to this volume, entitled 'Cortical monoamines and behavior' (Chapter 17, pp. 321-349) in which she describes the anatomy of the monoamine and acetylcholine pathways in the 'isodendritic core' of the brain-stem and basal forebrain and a fascinating

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account of their significance in sensory perception, plasticity, learning and behaviour. There were many other contributions to this book from leading workers throughout the world covering morphology, receptors, and functional significance of these ascending monoamine systems and their interactions with other system in cerebral cortex. These neurochemical systems are obvious candidates for the new view of a centrencephalic integrating system of importance to some of highest level integrating systems in the brain. Neurotransmitters in cerebral cortex have been treated more completely in a recent symposium entitled 'Neurotransmitters and Cortical Function: from Molecules to M i n d ' organized and edited by Avoli, Reader, Dykes

and Gloor (1988) as a celebration of my 80th birthday. In this recent symposium there was a very extensive coverage of the neuro-active amino acids, especially the excitatory amino acids, the N M D A receptors, and GABA, and their importance for epilepsy as well as for learning and normal function of hippocampus and cerebral cortex. Acetylcholine and the monoamines were also treated in considerable detail, with the addition of important chapters on the neuropeptides (Renaud, Ch. 32; Chretien et al., Ch. 33; Gainer, Ch. 34; Beaudet et al., Ch. 35; and a particularly pertinent Ch. 36 on 'Neuropeptide receptors in the brain, possible relevance to function' by Remi Quirion in which he discussed substance P and the tachykinins, atrial natriuretic factors, angiotensin and neuropeptide Y). Other chapters deal with the enkephalins, somatostatin, vasoactive intestinal polypeptide and others of possible importance in certain aspects of cortical function, especially as modulators of the action of the more traditional neurotransmitter substances. In the final chapter (Ch. 38) we wrote an overview entitled 'Molecular controls and communication in cerebral cortex' in which we list 60 peptides and neurohormones known to have various transmitter or modulator actions on cerebral cortical cells and synapses. We emphasized communication as well as molecular controls, and the importance of state-dependent reactions of the brain controlled by many specific neurochemical substances of subcortical origin. This is a greatly expanded view of multiple centrencephalic integrating systems of bewildering complexity.

The role of the brain-stem and reticular core in generalized epileptic seizures

There have been many recent studies of the importance of subcortical structures in the initiation or elaboration of generalized seizures. Of particular importance is the review of Faingold (1987) and the book edited by Fromm, Faingold, Browning and Burnham

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(1987) entitled "Epilepsy and the Reticular Formation," the Role of the Reticular Core in Convulsive Seizures' with a foreword by Henri Gastaut. These reviews provide evidence that subcortical structures are involved in almost all epileptic seizures, local as well as generalized. Certain subcortical nuclei, such as the inferior colliculus, the substantia nigra, a particular forebrain nucleus called the area tempestus by K. Gale, and their studies of the action of GABA and various anticonvulsant drugs upon these structures are particularly interesting and important (Maggio and Gale 1989). The foreword by Henri Gastaut is also of particular interest to me in view of his visit to the Montreal Neurological Institute with his charming wife Yvette in 1949 as a visiting scientist of the Rockefeller Foundation. Yvette was also a distinguished electroencephalographer, Henri's most important collaborator and companion throughout his life 2. They became very much interested in our view of centrencephalic seizures, and the experimental work on thalamo-cortical relationships which gave it much support. This was the beginning of a life-long friendship and close association on many occcasions, at scientific meetings throughout the world, from Moscow, Paris, Marseilles, London, Detroit to Montreal. Our association included sailing on the Mediterranean and skiing in the Alps. Gastaut's own book on the epilepsies was published in 1954. It was translated by Mary Brazier with a Preface by Wilder Penfield to whom the book was dedicated.

The penicillin model and the concept of cortico-reticular epilepsy The penicillin model of centrencephalic epilepsy was introduced by Prince and Farrell (1969; Fisher 1977). It was adopted by Gloor and his colleagues for an extensive series of studies of the mechanisms of action during bilaterally synchronous simulated spike and wave patterns elicited in the electrical activity of homologous areas of cerebral cortex which seemed to produce an electrical and behavioural replication of some of the features of petit mal epilepsy, as well as generalized grand mal attacks. There was, of course, continuous abnormality in the background activity unlike true centrencephalic seizures. Gloor's studies of cortico-thalamic and cortico-reticular relationships led him to suggest that we should abandon the centrencephalic theory and substitute a cortico-reticular concept of generalized spike-wave epilepsy (Gloor 1968, 1969, 1979; Avoli et al. 1983). Gloor thought that the cerebral cortex was primarily involved 2 See tribute by Antoine R6mond, Yvette Gastaut 1918-1989. Neurophysiol. Clin., 1991, 20: 79-81.

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in the penicillin model, with only secondary involvement of the thalamus. He was able, however, to confirm the importance of the thalamic reticular system (recruiting system of Morison and Dempsey 1942) as was shown by Jasper and Droogleever-Fortuyn (1947) who were able to reproduce very closely the 3/sec spike and wave pattern, synchronous in homologous cortical areas in cats under light barbiturate anaesthesia, or in 'encrphale isolr' preparations, by stimulation of the mesial intralaminar nuclei of the thalamus at 3/sec. If the animals were too alert, the recruiting response of Morison and Dempsey was observed and no spike and wave forms appeared. Alerting the animals, the stimulation of the ascending reticular activating system with desynchronization of the EEG prevented the spike-wave response, similar to the blocking of a petit real attack produced in patients with an arousing or alerting stimulus. Gloor also found that reticular stimulation blocked the spike and wave discharge induced by penicillin. In the elegant microelectrode studies of Avoli et al. (1983), thalamic units were found to be synchronized with the cortical units, and even preceded them at times, suggesting a thalamic pacemaker. Certainly an interaction between intralaminar thalamic units and cortical units was found in all of these studies, but Gloor felt that the cortex led the thalamus during the development of the organized spike and wave discharge. There is some question as to how closely the penicillin model really reproduces the pattern of centrencephalic epilepsy, except perhaps in the petit mal variant forms associated with diffuse encephalopathy or systemic disease affecting the brain as a whole. It was comparable to the effect of parenteral or intramuscular administration of convulsant drugs. Direct application of penicillin to the surface of both left and right homologous cortical areas also produced a bilaterally synchronous rhythmic response on the electrocorticogram, occasionally resembling somewhat the spike and wave of petit mal epilepsy though at a higher frequency. This was similar to the earlier findings of Marcus and Watson (1966) produced by the bilateral cortical application of cobalt or conjugated oestrogens which produced bilaterally synchronous spike and wave EEG patterns shown to be dependent upon the corpus callosum rather than upon the thalamus for its bilateral synchrony. The behavioural as well as the electrical pattern of 'absence' attacks was also reproduced in unanaesthetized monkeys following bilateral frontal cortical applications of convulsant drugs (Marcus et al. 1968). Subconvulsive doses of convulsant drugs administered systemically also are known to produce similar EEG patterns. It has long been known that enzyme poisons, such as fluoroacetate (Ward 1947), may also cause bilaterally synchronous EEG discharge resembling roughly some forms of centrencephalic seizure.

8 Furthermore, as Penfield has pointed out, a centrencephalic seizure can be triggered by a focal cortical discharge. Gloor and colleagues have given clear evidence that the recruiting system of the thalamus is involved in his model, but that the reticular system of the brain-stem seemed to arrest rather than participate in the spike and wave pattern of feline generalized penicillin epilepsy (FGPE). At any rate, focal as well as generalized seizures of cortical origin project to the reticular system. This leaves little rationale for the suggestion that centrencephalic seizures should be called cortico-reticular seizures. In some animal models of genetic generalized seizures, the thalamus has been found to be involved primarily in the onset of the attacks (Avoli et al. 1990). Gloor has stated that the spike and wave formation, produced by stimulation of the recruiting system of the thalamus, is caused by an increase in the excitability of the cortex so that it no longer can produce the usual recruiting waves. This is doubtful since the increased excitation caused by alerting stimuli m a y block the spike and wave of patients during a petit real attack. Also the experimental spike and wave is more readily obtained with the animal under light barbiturate anaesthesia, hardly a condition which increases the excitability of the cortex (Pollen et al. 1963). It was found by Perot that the cortical reactivity to intralaminar thalamic stimulation could be changed from recruiting waves to the spike and wave complex by a train of conditioning stimuli delivered to the midbrain tegmentum. The spike and wave reactivity of the cortex outlasted the tegmental stimulation by several seconds, suggesting that the liberation of some neurochemical substance might be involved. Whatever is responsible for the change in cortical reactivity with tegmental stimulation, it is more likely inhibitory than excitatory. The wave of the wave and spike is a prolonged hyperpolarizing IPSP when recorded with intracellular electrodes as shown by Pollen (1964). Weir has shown that this experimental model corresponds very closely in all details of wave form with that seen in the E E G of patients during an absence attack (Weir 1964), and that there is a profound inhibition with arrest of firing in many cortical neurones as recorded with extracellular microelectrodes (Weir and Sie 1966).

H.H. JASPER Montreal Neurological Institute in June of 1988 and published in 1990 (Avoli et al. 1990). There were m a n y important chapters in this review bringing the subject of generalized seizures up to date from the clinical and experimental points of view, using m a n y modern electrophysiological, neurochemical and neuroimmunological techniques, in addition to non-invasive neuroimaging techniques for the study of local brain metabolism and blood flow. I was particularly interested in the work of Coulter Huguenard and Prince on 'Cellular actions of petit mal anticonvulsants: implication of thalamic low-threshold calcium current in generation of spike-wave discharge' (Coulter, Huguenard and Prince, Ch. 30, pp. 425-435). It was found that ethosuximide reduces low-threshold calcium currents in thalamic neurones in vitro. This may lead to a better understanding of some of the ionic processes involved in thalamic mechanisms generating the spike-wave discharge. Steriade gave an interesting account of his studies of thalamic rhythmicity in relation to the genesis of spindles and epileptic spike-wave activity (Ch. 12). There were many other interesting and important contributions to this symposium. In my chapter on the Historical Introduction I reviewed the various concepts, E E G and experimental studies of generalized epilepsy over the years, beginning with Hippocrates, Hughlings Jackson and William Gowers. The views of Lennox and Gibbs on generalized cerebral dysrhythmia and the centrencephalic system of Penfield and Jasper were briefly described as well as the work of Marcus and Watson which cast doubt on the concept of centrencephalic seizures. There was also a description of the photosensitive seizure-prone baboon (Papio papio) of Bobby Naquet and the Killams whose seizures seem to arise in frontal regions without important involvement of subcortical structures (Killam et al. 1967). The work of Gloor and his colleagues was also cited as described above, together with other critics of the conception of centrencephalic seizures.

Conclusions I will quote from the conclusions reached from this historical survey as follows:

Generalized epilepsy, neurobiological approaches (1990) This brings us to the most recent and final review I would like to cite in this brief presentation of my own conclusion regarding the terms 'centrencephalic' or cortico-reticular epilepsy. It is based upon a very interesting and successful international symposium organized by Avoli, Gloor, Kostopoulos, and Naquet, held at the

"There are many models of generalized seizures, and each one demonstrates some aspects of the form or mechanisms that may be of importance in some forms of generalized epilepsy. Patients with diffuse bilateral epileptogenic lesions may well correspond to the model of Marcus and Watson, whereas patients whose seizures are due to extracerebral causes, in the form of convulsant drugs or critical enzyme poisons, may also have their counterparts in patients with metabolic dysfunction or systemicor diffuse neuronal disease (Andermann 1967). In these cases, the term holencephalic, as suggested by

CENTRENCEPHALIC SEIZURES Gastaut, may well apply. There are patients with generalized seizures, however, who do not fit these models, since no such cause can be demonstrated. Animal models of genetic epilepsy are particularly relevant to certain forms of generalized seizures in patients with a strong hereditary predisposition. But here again we have different genetic forms as well as different genetic animal models. The genetic rat model of petit mal seizures, as reported by Vergnes et al. in this book, is of particular interest, since these non-convulsive behavioural seizures occur spontaneously and resemble an absence attack with the spike-wave pattern in the EEG, beginning, usually, in the thalamus. The original proposal of Lennox and Gibbs that the form of the EEG dysrhythmia determines the form of the clinical attack has considerable merit even today, though the localization of the involved cerebral tissue, which is both cortical and subcortical and specialized in function, must be taken into account, together with the nature of its involvement as reflected in the form of the dysrhythmia in the EEG. The pattern of the EEG dysrhythmia may well be determined by the neurochemical selectivity of the primary neuronal elements involved. Topographical holencephalic may not be neuronal holencephalic. Centrencephalic seizures and the centrencephalic integrating system of Penfield, revised in the light of recent anatomical, histochemical, and neurophysiological studies, is still a useful working hypothesis in studies of the highest level of neuronal integration underlying conscious cognitive mental life and brain mechanisms involved in primary generalized epileptic attacks with an initial loss of consciousness, and particularly 'petit mal' or absence seizures. The attempt to prove mutually exclusive cortical or subcortical mechanisms in primary generalized seizures should be abandoned for a more dynamic view of the interdependence between cortical and subcortical neuronal systems. The bilaterally synchronous spike and wave of petit mal absence is an enlarged thalamo-cortical surface-negative recruiting wave associated with excitatory postsynaptic potentials (EPSPs) in many cortical cells, followed by a prolonged surface-negative deep positive wave associated with hyperpolarizing inhibitory postsynaptic potentials (IPSPs) in many cortical cells, which inhibits the development of a generalized convulsive seizure. Initially, the pacemaker may be either cortical or subcortical, but oscillating reverberating hypersynchronous discharges of alternating excitatory and inhibitory synaptic potentials are always involved in a spike-wave absence seizure. The arrest of ongoing behaviour and conscious awareness seems to be due largely to a widespread inhibitory blockade of integrative function, which is particularly important in the bilateral frontal and parietal association cortex. Sufficient inhibition of the cortico-spinal motor system may also cause a transient plantar extension (Babinski) reflex during some spike-wave seizures. Specialized systems of widely distributed cortical and subcortical neuronal circuits, with different specific neurochemical identities, are probably involved in generalized absence attacks as well as in the regulation of states of consciousness. This is the modern view of a centrencephalic integrating system."

Reflecting upon these conclusions while writing this review for my old friend and student, Gastone Celesia, I am not ,sure that we should continue using the concept of "centrencephalic seizures' but I am sure that there is no good reason to exchange it for cortico-reticular

seizures. There are many centrencephalic systems involved in 'highest level' integrations underlying conscious mental life and the control of coordinated goal-directed behaviour. Many widely distributed cell assemblies and

9

neurochemical mechanisms in cortical and subcortical structures are involved in centrencephalic integration as proposed by Penfield. It is perhaps better to describe the attacks objectively, such as ' p r i m a r y generalized' rather than to use terms with anatomical connotations which are as yet unknown or uncertain. We owe largely to Henri Gastaut the International Classification based upon clinico-pathological and electroencephalic correlations which has become a standard nomenclature uncomplicated by hypothetical mechanisms such as centrencephalic or cortico-reticular.

Addendum I am not yet prepared to agree with Penfield that there may be no solution to the brain-mind problem, even though I do agree that we have not yet found that illusive link between the special brain mechanism involved in conscious awareness and mental activity. I do believe that there is some neuronal organization specialized for this purpose widely distributed throughout the brain and varying with the mental or behavioural activities of each moment, many centrencephalic systems if you will, but too vague to be used to describe forms of epileptic attack in the present state of our knowledge. However, the search is becoming more and more exciting and worth the effort in spite of its bewildering complexity.

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