OCTUBER 02nd, 2013

October, 2nd 2013
We begin today the publication of an article that saw the light in 2001 in Medical Hypothesis: it contains the summary of our Master Degree in Medicine, Mysticism and epilepsy, defended in 1998 in the Faculty of Medicine of University of Murcia (Spain).

In it we expressly stand up glutamatergic transmission as pathogenic mechanism of many psychiatric symptoms, such us déjà vu, panic attacks, crises of depersoanalization, abrupt depressive or manic phases, sudden and unexpected episodes of hallucinations and/or delusional ideas, etc.

A lot of investigations appeared in the last two decades about gulatamate hypotheses of schizophrenia confirm and reinforce the validity of statements that we pose more than fifteen years ago.


This work stems from our previous study entitled Mística y depresión: San Juan de la Cruz (= “Mysticism and Depression: Saint John of the Cross”), in which we studied the relationships between the stages of a mystic process, known in Spiritual Theology as phases of passive purification, and those which in Psychiatry are denominated phases of endogenous depression. Indeed, most Christian mystics passively experience moments of intense psychic suffering imposed on their lives in stages which are in every way equivalent to the phases of endogenous depression.

However, while that research was in progress, another psychopathological phenomenon —different from depression— was becoming more and more persistently apparent in the lives of many interesting Christian religious people, and we realized that numerous Christian mystics, regardless of whether they suffered from endogenous depressions, have presented such varied and polymorphous psychic manifestations throughout their lives, that there is only one illness which might offering an explanation for this combination of symptoms occurring in a single person: epilepsy.

In fact, mystics such as Saint Paul, Saint Augustine, Saint Hildegard of Bingen, the Blessed Angela of Foligno, John Tauler, the Blessed Henry Suso, and especially the Spaniards Saint Ignatius of Loyola, Saint Teresa of Jesus, and Saint John of the Cross, presented such precise, well-defined, and varied psychic symptoms, that only partial epileptic seizures and their multiple psychic manifestations offer any explanation for the diverse psychopathological phenomena found together in given individuals.

We repeatedly find, in all of them, one surprising phenomenon: the same person, at different times of his or her life, exhibits such widely differing symptoms as acute crises of depersonalization, sudden experiences of derealization of the surrounding world, unexpected panic attacks and abrupt visual or auditory hallucinatory phenomena, which are accompanied by pronounced hyperæsthesia and forced thinking suddenly interrupting their consciousness, experiences of autoscopy (mind-body dissociation), uncontrolled blasphemy, suicidal tendencies, etc. 

These psychic experiences always show the characteristic phenomena of partial epileptic seizures and their psychic manifestations, such as a paroxysmal nature with a sudden start and finish, a narrowing and intensification of consciousness, and a consequently diminished contact with reality for the few moments that the process lasts. There is also a great intensification of inner experiences and finally, passivity to and automatism of whatever goes through the mind, whence the typical air of bewilderment.

Moreover, along with these simple psychic symptoms, it is very frequent to find more complex mental states such as an expression of these epileptic seizures, with a quick succession of depressive phases alternating with manic phases in the individual´s mind without apparent cause. The patient suddenly and automatically goes from a state of intense happiness to one of utter sadness, or vice versa.

The mental vicissitudes of epileptics during fits, similar in same respects to the clinical manifestations of manic depression or bipolar disorder, led Henri Ey to comment thus on the great difficulty of arriving at a differential diagnosis: 

“Among the psychopathological manifestations of epileptics, the manic-depressive episodes can replace the epileptic crises. That is to say, the cerebral affection manifests itself just as readily through paroxysms that are somewhat deep and quick, as through diverse alterations of the consciousness that constitute manic depressive states” [my italics].

At first sight, therefore, the evidence suggests that these extraordinary mystic phenomena —the bizarre psychic experiences that the mystics underwent throughout their spiritual processes— were partial epileptic seizures, for the experiences are alike, with similar manifestations, which leads us to conclude that both stem from the same underlying neurobiological process.

My first hypothesis would therefore be that epilepsy formed the basis of mystic phenomena. If, however, this hypothesis were to suffice alone, we would have to attribute the most outstanding religious and artistic achievements of humanity to pathology pure and simple. Indeed, everything we have said about mystics is equally applicable to a great many artists and thinkers who also show psychic symptoms characteristic of partial epileptic seizures throughout their lives. Such experiences served as a basis for many of the creations of, for example, William Blake, Vincent Van Gogh, Fiodor Dostoyevsky, Juan Ramón Jiménez, Emile Michel Cioran, etc.

It would therefore seem that many of man’s major creations in the arts, religion, or sciences, originated in these pathological experiences. This clearly seems quite illogical, so a more satisfactory interpretation must be found.

When we was thus obliged to search for a solution to this apparent paradox, an answer occurred to us: why should we continue to interpret these extraordinary experiences, which have their origin in a neuronal hypersynchronism, as something pathological? Why should we not consider them to be physiological? If they are the starting point for the mystics, the artists, and the philosophers for accomplishing their brilliant creations, why should we continue to classify them as morbid? Would it not be preferable to hypothesize that we are dealing with normal cerebral productions, derived from the physiological capacity of neurons in certain parts of the brain to work hypersynchronously?


The most surprising aspect of this study is that from the moment we began to work on this hypothesis, trying to prove its validity, we discovered a body of information on epileptogenesis which clearly supports our position. Many clinical and laboratory data exist about epilepsy that are difficult to integrate but which could easily be understood as a whole by applying our hypothesis, whereby the hypersynchronism of epilepsy —at least the first stage of it— is conceived as a physiological activity. From these apparently contradictory (or insufficiently clarified) data, three important questions arise, which may be summarized as follows: 

Every time an attempt has been made to discover the root cause of an epileptic seizure, the same surprising fact has without fail been met with: the onset of an epileptic fit is due to the entry in operation of certain neuronal groups that are naturally designed for hypersynchronous activation, as if it were their normal physiological function. 

Another conspicuous set of information is as yet unexplained: epileptologists have gradually been separating two epileptiform activities that are not only different, but also seem to be mediated by different receptors. They are known as interictal activity and ictal activity, and both are generally included under epileptic activity although a weight of evidence shows them to be mutually exclusive in time. How can we explain this contradiction? 

Finally, how do we explain the close relationship between the epileptiform functioning of the brain and the learning process? As shown below, kindling and long-term potentiation are two models of epileptogenic activity of the brain that are intimately related with the processes of acquisition and storage of data. In fact, in reference to this illogical association, Michel Baudry literally suggested “the possibility that epilepsy may represent a dangerous side-effect of an efficacious learning mechanism”.

These inconsistencies would be comprehensible with the aid of our second hypothesis, whereby all of what currently goes under the heading of epileptic attack should be divided into at least two different parts corresponding to two equally different activities. In the first phase the hypersynchronous discharge takes place in a group of neurons and is propagated through certain specially designed circuits, to be translated into a psychic experience of extraordinary intensity, and of a paroxysmal and entirely automatic character. The psychic nature and the content of that experience would depend on areas of the cerebral cortex in which the discharge occurred. This first stage would be completely physiological. The second stage would correspond to the starting up of another form of neuronal hypersynchronism —epileptic activity as such— which is different from the first stage and is probably effected by different receptors. Its mission is probably to bring an end to a hyperia that has become excessive.

This concept of hyperic and epileptic activities, as not only different but opposed functions, would explain all the problems —clinical and pharmacological— mentioned above and which are still unsolved. Indeed, all the evidence points to the idea that hyperia and epilepsy are functions that are mutually exclusive. 


Let us begin by analysing the first of the three major paradoxes summarized above. We have stated that all the research carried out in search of a supposed pathological cause of epilepsy is fraught with surprise, for it all leads us to think that the neuronal activity facilitating the onset of an epileptic fit is actually of a physiological nature. In fact, there are certain regions in the mammalian brain abounding in neurons designed to work spontaneously in a hypersynchronous and epileptiform way.

This surprising and, at the same time, important fact, has been mentioned by a great many specialists interested in the presence of this apparently physiological origin of the convulsiveness of the brain. John Hughlings Jackson called attention to this point, going so far as to consider certain types of epileptic attacks as not only normal, but even healthy: “A sneeze is a sort of healthy epilepsy”.

Many of his colleagues have also manifested their surprise at an activity with an apparently endogenous and physiological onset. Philip Schwartzkroin, for instance, states that “The activity that we call epilepsy, then, may reflect a basic underlying propensity of the central nervous system”. He then goes on to suggest again the idea that epilepsy is a normal and natural function; even more forthrightly: 

“Given the presence of these bursting cells, and the occurrence of excitatory interactions among the normal tissue, it may actually seem somewhat surprising that epileptiform discharge is not a ‘normal’ characteristic of such cell populations."

Massimo Avoli also describes an activity with an apparently physiological origin: “The patterns of activity generated by neurons in human epileptogenic cortex appear in most instances to be remarkably normal”. For his part, Philip C. Jobe exclaims: 

“Epilepsy appears to result from a broader array of interacting components. This interactional concept is not in disharmony with the well-documented findings that epileptic discharges can occur under the correct experimental conditions in isolated tissue slices obtained from normal brain.”

Peter Fenwick also conceives epilepsy as a consequence of a high neuronal excitability of an absolutely physiological nature which may happen in the absence of any cerebral damage: 

“This idea also suggests that there may be some cases in which the level of cortical excitability is so high that, even in the absence of brain damage, generalized seizures may occur. This group of patients would have true idiopathic epilepsy as their seizures would depend on an inbuilt genetically determined increase of brain excitability rather than on an interaction of brain damage and seizure threshold.”

We have found then, different epilepsy specialists showing their recognition of a hypersynchronous activity of the brain, in which a group of neurons – seemingly in an entirely physiological way – are simultaneously activated by means of sustained potential. Actually, in mammals, certain regions of the brain are strongly epileptogenic, especially region CA3 of the hippocampus and layers 4 and 5 of the motor or visual neocortex. In these regions of the brain, we find neurons that are clearly capable of being activated synchronousally with adjacent ones, either spontaneously, or in response to certain circumstances. They are called intrinsically bursting neurons, or IBNs, and act as starters for epileptic activity.

These bursting neurons respond to certain stimuli, especially to repetitive physical stimuli (electric, luminous, acoustic, etc.) by becoming activated synchronously, giving rise to a giant excitatory post-synaptic potential (EPSP), which recruits multiple adjacent neurons, to respond in unison with barrages of paroxysms and sustained action potentials, called epileptiform bursts (EBs).

These initial EBs are the crux of the matter and never fail to arouse questions in experts: Should we consider this initial epileptic activity, thanks to which bursting neurons give rise to giant action potentials, physiological or pathological? What characteristics must the neurons triggering these potentials possess? Do these pacemaker neurons suffer from some biochemical disturbance that could constitute the pathological root of epilepsy? If so, why do we never find anything? Why does the essence of these biochemical disturbances always elude us? Why is it that every time we extirpate an epileptogenic focus and examine its neurons, we always find them completely normal? Regarding this enigma, Schwartzkroin exclaims:

“A striking feature of epileptic tissue in many experimental models is how ‘ordinary’ it may appear (Schwartzkroin & Price, 1978). As seen electrophysiologically, cellular activities in tissue slices of neocortex and hippocampus from human epileptic patients are generally quite normal. In some sense, this observation parallels the older data obtained from acute animal models, in which the electrophysiological properties (intrinsic and synaptic) of cells in an epileptic focus were found to be indistinguishable from control cells except during the period of burst discharge or seizures (Schwartzkroin & Wyler, 1980). Given the relatively normal appearance of cells in slices from epileptic brain, we might conclude that we have somehow missed the critical site, the epileptic focus."

It is as if on the way from the operating theatre to the pathology laboratory, we kept losing the peculiar features that would characterize the epileptic focus cells as pathological, for we never find anything, however painstaking our research may be.

So far, we have described an epileptiform activity that begins at a certain point, and spreads almost instantaneously along given cerebral paths that would be naturally adapted for this hypersynchronous function. There is convincing evidence leading us to think that this variety of hypersynchronous activity – genesis and spreading through specific cerebral networks – should be considered a normal physiological function, for which we propose the name hyperia.

After this first phase, the spreading of hyperic activity, a second moment may occur, brought about by an excessive spreading of this activity, which goes beyond the neuronal circuits designed to carry it. We may assume that this initial hyperic activity would undergo a kind of “derailment” and would spread inappropriately through other cerebral structures not designed for this type of hypersynchronous functioning, whereupon a generalized convulsivogenic activity would arise to put an end to the whole process. We believe the term epilepsy and its derivatives should be reserved for this second part of the process, and that only this second stage should be considered pathological.


Such is our hypothesis. Be that as it may, during our review of the physiopathology of neuronal hypersynchronism, while trying to verify our hypothesis, we observed that most epileptologists do speak of two distinct moments that are clearly differentiated in the process, firstly the genesis of the epileptiform activity, a phase which, as we have just seen, they balk at qualifying as pathological in laboratory tests, for everything leads them to consider it to be of physiological origin; and a second phase when the convulsive activity spreads and becomes general throughout the brain. They do not, however, divide hypersynchronous cerebral activity into the same two phases as we do: a physiological one followed by a pathological one. These two different phases of hypersynchronous activity are usually given the names interictal epileptic activity, and ictal epileptic activity, and they correspond to the phases that we propose to call, respectively, hyperic hypersynchronism and epileptic hypersynchronism.

There are numerous indications that these two phases are in fact two different functions controlled by different neuronal synapses or, at least, by different receptors and neurotransmitters. Thus, for Karen Gale, and in line with our views, these two moments of onset and generalization of epileptogenic activity are not only different but occur in equally different areas of the brain, for the capacity of one area of the brain to emit a local hypersynchronous discharge has absolutely nothing to do with its capacity to spread the discharge: 

“The ability to evoke local seizure discharge within a structure is unrelated to ability to provoke a propagated seizure. Focal drug stimulation in certain areas (e. g., the dorsal hippocampus) can evoke local electrographic seizure discharge without evoking a propagated seizure, whereas in other regions (e. g., the area tempestas) focal drug stimulation can evoke propagated seizures without first evoking local seizure discharges”.

Wilson and Bragdon are even more severe in their approach to this puzzling dichotomy between interictal and ictal activity, for their in vitro studies actually underline the existence of two different and mutually exclusive epileptiform activities, in line with our hypothesis for hyperia and epilepsy as antagonistic activities: 

“We were fascinated to find that the epileptiform bursts (EBs) and the electrographic seizures (EEGs) had different sites of initiation […]. These data suggest a possible new principle for the relationship between EBs and EEGs, namely, that EBs and EEGs can arise in separate, mutually interactive, locations. Moreover, although EBs can trigger EEGs, their main effect may be to suppress seizures arising in their target areas. Thus, interictal spikes in humans may have a suppressive effect on seizure discharges”.

Interictal hypersynchronous activity —hyperic activity for us— appears here not only as  different from ictal hypersynchronous activity —epileptic activity in our view—, but as antagonistic to it, even inhibiting it. It is not surprising, then, that these authors conclude their work with a question: 

“Is interictal activity pro- or anti-epileptic? It seems to depend on the state of the network. Apparently, if the interictal activity is very strong and if the underlying pacemakers for it are hard to inhibit, then persistent bursting can suppress EEGs. How they do it is not at all clear. On the other hand, if the EEGs are easy to trigger, if the bursting is strong, and if the pacemaker for it is inhibited for a while after the EGS, then the EBs can apparently build up and develop into a full EGS”.

There is, then, sufficient evidence to suggest that epileptic activity, different from hyperic activity and even antagonistic to it, may be thought of as a tool used by the brain to arrest hypersynchronous hyperia, which has spread and become excessively persistent, to the point where it is undesirable and has to be brought to an end.

To be continued...