TOWARDS PHARMACOLOGY INTEGRATIVE ACTIVITY OF THE MIND

I. — INTRODUCTION

The term “integrative activity” was proposed at the beginning of the century by Sherrington, to define the central nervous processes that make starting from the basic reflexes one elaborates a voluntary movement. The integrative concept had been anticipated even before, by Hughlings Jackson who had written: “the simplest spinal reflex ‘thinks’ so to speak in movement and not in muscles “(after Sherrington, 1931). These reflexes elementary are “integrated” through a central mechanism.

Although initially considered at the spinal level, the notion of activity integrative was quickly used by the Sherringtonian school itself, in the physiological interpretation of the higher nervous levels.

Since then, research on brain function has taken place in two different ways, although complementary:

a) An analytical direction that uses histological methods and electrophysiological studies and seeks to establish the structural and functional details neurons and their interrelationships.

b) A synthetic direction that preferably uses methods behavioral and studies the brain as an organ of control of all the activity of the individual and the interaction with his environment. This is the direction initiated, also at the beginning of the century, by Pavlov and his school.

It does not seem possible at the present time to carry out a comprehensive study of of the brain, which would take into account all the knowledge lytic, anatomo-physiological available. Nevertheless, it is in this
direction that the neurological sciences are progressing, that is, toward a analytico-synthetic entanglement. This is how we see more and more research using the most advanced neurophysiological methods refined in awake subjects and even in free behavior. It will be recalled that the pioneers of this trend were Durup and Fessard (1935), Gastaut (1957), Livanov (1945), Delgado (1954), Roy John (1960) and Fessard (1960).

In what follows, we will introduce – based mostly on our own work – a new pharmacological approach to the problem of the integrative activity of the brain.

Not pretending to have a general view of the problem, but in order to situate it in the current context, we will first consider some neurophysiological and neuropharmacological pemisses.

II — NEUROPHYSIOLOGICAL PREMISSES AND NEUROPHARMACOLOGY

NEUROPHYSIOLOGY

The integrative activity of the brain and in particular that of telencephalon is of extreme complexity. However, we could define it as the set of operations by which the brain performs its function essential: to allow us to acquire new experiences, to relive previous experiences and thus act on our past and our future. We generally accept the idea that in space and cerebral time, There is, thanks to sensory afferent systems, a representation of a “Ghost” of the real world. This representation, synthesis of experiences past, is in continual interaction with other processes, of a nature still insufficiently known which, starting from the sensory inputs generate a proper activity of the brain, activity for which Gantt (1957) had proposed the term autokinesis. All this leads to the psychic fact or mental, such as perception, consciousness, and other characteristics of the inner life of a human being.
Thus, as Bergson (1900) had written: “my senses and my conscience give me reality only a practical simplification “. From this view which accepts the total entanglement between the integrative activity of the brain and sensory messages, the notion of neuropsychic identity that philosophically opposes brain-thought or nervous-psychic dualism. The highest aspects-integration of brain activity, including the introspection of man, are just complex aspects of a neuronal activity that is more familiar at the elementary levels.
This over-general view of the integrative activity of the brain could be better used if we accept that it is characterized by two aspects fundamental: mental unity and state of consciousness. The mental unit is realized by all the processes that take place in both cerebral hemispheres and of which depend in all its nuances, the ability to learn and remember. As examples of Such processes can be described as perceptual integrations, connections transcortical and commissural, filtration and codification of informatiomations, the formation of engrams etc.

The state of consciousness can go from wakefulness to sleep deep and coma. It is the expression of a certain cortical tone (Bremer, 1936) moderated by sensory, reticular, rhinencephalic afferences etc., which in turn modulates the periphery.
The mental unit and the state of consciousness are two facets of the same telencephalic activity. For example: the consolidation is function within certain limits of the level of reticular excitability (Barondes, 1970; Bloch, 1966). Similarly some sensory receptors can be alert by expectation or conditioned anxiety (Granit, 1966; Boissier, 1969).
Recall again that all the processes that ensure unity mental and consciousness are nerve activities called plastic. Indeed, it is accepted that the central nervous system of higher animals is endowed with two fundamental properties: reactivity and plasticity (Konorski, 1967).
The reactivity of the system is its ability to be active by stimulation receiving structures.
Plasticity is the ability of the central nervous system to change its reactive properties following successive activities. Learn and get remember, integrate each piece of information in the baggage In order to take the necessary decision, all the special aspects plastics of C.N.S.

ROLE OF TELENCEPHALON IN THE INTEGRATIVE ACTIVITY OF C.N.S.

If the integrative activity, as an overall aspect of the property of plasticity exists in various forms at all levels of the C.N.S. However, from this point of view, it is important to specify the primordial importance of telencephalon in higher mammals.
It is not at the cellular level that we will find the functional characteristics of our corticalite. Indeed, with the exception of
functional particularities still under study (Eccles, 1966a), the neurophysiology tells us that the cerebral cortex is composed of nerve cells that essentially resemble nerve cells lower floors of the nevraxe. The same goes for glial cells whose specific role in the integrative activities of the brain is postulated for a long time (Galambos, 1961). What differentiates the cerebral cortex other levels of the brain is its extreme complexity in the neuronal organization.
Nowhere else does the number of synapses per neuron reach the figure of 50-60,000, as in the cerebral cortex (Eccles, 1966b). The dendritic pimples, the “gemmules” already described by Ramon-y-Cajal (1934) as a criterion for the maturation of cortical neurons, appear to be present only at the neo-cortical and hippocampal level and not at the lower levels of the brain (Hamlyn, 1963).
From the functional point of view, there is at the cortical level a huge convergence of sensory information. Indeed, many experiments have led to the conclusion that most cortical neurons are “polyvalent” because they respond by activation to the stimulation of several sensory modalities (Eccles 1966 b).
The synthesis that the cerebral cortex makes from perceptions is well demonstrated in the experiments of Teuber (1966). Indeed, the monkey to whom we put prismatic glasses that moves the field of vision, can adapt, compensate for this visual distortion after 6 to 8 hours.
There is no adaptation in the animal with bi-frontal lobectomy, while the removal of the same amount of occipital, parietal or temporal cortex does not prevent the compensation. Done not only, it is the cortex that realizes the adaptation to the deformed visual field, but even more specifically, the pre-frontal cortex.
Moreover, everyone can make a very simple experience of themselves to realize the synthetic nature of the world of perceptions. In fact, what we are looking at remains stable when the retinal images are changed by the normal movements of the body, head, or eyes, but changes when the eye is moved by manual pressure.
In the field of reflex activity conditions in mammals, the historical dispute between Lashley and Pavlov seems to be resolved, in the sense that for certain tasks, such as learning a course of a labyrinth, there is while for others, such as discriminative conditioning, performance depends on the availability of certain well-defined areas of the brain. The general review of this problem was made by Chow (1967), to whom we refer the interested reader.
Moreover, it seems well proved that for a given conditioned reflex, the more complex the task, the more it depends on the functional integrity of the cerebral cortex.
Neff (1961) ablated the temporo-insular area described as a crossroads of broad multi-sensory convergence (Woolsey 1960, Desmedt 1960).
Like Babkin (1914) who had made a wider temporal ablation, Neff found that the ablation he had, he practiced, abolished the capacity for fine discrimination (a melody) but not that of gross discrimination.
Finally, there are many evolutionist arguments that support the concept of the integrative role of telencephalon, of which we will cite only one.
We know that the human brain is noticeable among those of mammals not only because of the very large volume of the cerebral cortex, but also, as Penfield (1966) notes, in the figure we reproduce  here, in a simplified form, by the fact that most of the human cortex is neither motor nor sensory, but associative (“interpretative” or “not engaged” in Penfield terminology).

Evolution of the brain of mammals; relative importance of areas (Penfield 1966)
Associative areas (the “un-committed” cortex) are not directly related to sensory perception or motor control. It is these areas (in white) that gain more and more importance in the evolution of the brain from the rat to man.

This corresponds, moreover, to the physiological conclusion of Moruzzi (1966) that the percentage of cerebral activity which is directly related to perception is extremely small.

We thus return to Sherrington’s admirable intuition, which had said that “the essential character of the neuronal mechanism of the brain lies in its integrative power” (quoted from Eccles, 1966).

 

NEUROPHARMACOLOGY

From a neuropharmacological point of view, numerous investigations have shown the effect of chemical substances on learning and natural storage (McGauch and Petrinovitch, 1965).

It is not the purpose of this work to review them. We can only attempt a generalization that includes many exceptions, admitting that most of these drugs indirectly influence the integrative activities of the brain, by interventions on the processes of attention, perception or motivation. Thus, anticholinergics, barbiturates and depressives in general reduce the efficiency of learning and retention. On the contrary, anticholinesterases, stimulants or convulsants at subconvulsive doses, facilitate these same processes.

It should also be noted, with Roy John (1967) that substances such as strychnine, picrotoxin, nicotine, pentylene tetrazol, physostigmine, caffeine, amphetamine, and others that facilitate learning, are all CNS stimulants, but possess mechanisms of action well differentiated.

For example, it has been demonstrated that some stimulants accelerate the synthesis of RNAs in the brain (strychnine, tricyanoaminopropene, pemoline, diphenylhydantoine and procaine amide), while others, such as amphetamine, do not have this effect (Carlini). and Carlini 1965, Essman 1966, Glasky and Simon 1966, Gordon et al., 1968, Lima et al., 1966, Weissman 1967).

Thus, in the aggregate, products that facilitate memory and learning phenomena could do so by indirectly influencing – stimulation or sedation – two fundamental mechanisms:
     a) Neuronal reverberation activity, by modulating the number of neurons who could participate;
     b) the speed of the chemical processes involved in the mechanical consolidation.
We have seen – with evolutionist, structural, and functional arguments – the particular role telencephalon plays in higher mammals in the integrative activity of the brain. It is therefore conceivable that one could act pharmacologically in a direct, specific manner on the integrative activity of telencephalon.

With the help of an example, we will try to demonstrate that this possibility has become a reality which opens, it seems to us, a new field of pharmacological news. This is the pharmacology of Piracetam, of which we will present here mainly the aspects related to the integrative activity of the brain.

Most of these aspects have already been the subject of specialized publications (to which we refer the reader every time), but not that of an interpretative synthesis whose present work is its first attempt.

 

III. – PIRACETAM AND THE TELENCEPHALIC HYPOTHESIS

THE “UNUSUAL” NEUROPHARMACOLOGY OF PIRACETAM

Piracetam is an original substance, chemically apparent in Gaba (see Fig. 2)

1 ° Inhibitory effect on central and vestibular nystagmus

Without being able to dwell here on the history of pharmacological research on Piracetam, which began in the years 1964-1965, it should be remembered that this product has been tried by us, for theoretical reasons explained elsewhere (Giurgea et al. , 1965), in the so-called “central” nystagmus test, that is to say obtained by electrical stimulation – the Rabbit – of the lateral knee body (Bergmann et al., 1959).

Piracetam administered intravenously or orally in a wide range of doses has been shown to be highly active, starting at 2 mg / kg, by inhibiting central nystagmus (Giurgea et al., 1967).

On a peripheral vestibular nystagmus, Piracetam has a similar effect in rabbits and in! Man (Giurgea and collaborators, 1967).

This effect of Piracetam was in itself a curiosity, because in these tests, only antihistamines and anticholinergics are active, but Piracetam is neither antihistamine nor anticholinergic, even if doses much higher than those which inhibit the excitability of the nystagmogenic structures.

2 ° Absence of behavioral, electroencephalographic or autonomic effects

Piracetam not only has no antihistaminic or anticholinergic properties, but is inactive in most routine pharmacological tests (Giurgea et al., 1967).

Up to doses of a few g / kg intravenously or per os, in the mouse, rat, cat, dog and monkey, single or repeated administration, Piracetam is devoid of toxicity (in dogs, for example). for example, it has been possible to administer for one year the product by increasing the dose up to 10 g / kg / day) and does not produce behavioral, electroencephalographic or autonomic changes in the animal species studied.

The main tests in which Piracetam has been shown to be inactive in a wide range of doses are listed in Tables I, II and III.

In the case of focal epilepsy, by application to the sensorimotor cortex of Rabbit, strychnine or penicillin, Piracetam has a particular effect; it limits to the focus the paroxysmal discharges, prevents their cortical propagation. In the same sense, it partially protects rats against audiogenic epilepsy (Giurgea et al., 1969).

3 ° Protection on electroencephalographic pattern against hypoxia

The inhibitory effect of Piracetam on the central nystagmus as well as the absence of any foreseeable side effect, led us to propose clinical trials in the field of vertigo and in particular in those of central origin as in the case of cranial traumatises.

Given the encouraging results in this area (see page 147) and Taking into account the role of cerebral anoxia in the pathophysiology of cerebral trauma (Ingvar and Lassen, 1964) we hypothesized that Piracetam would protect against anoxic anoxia.

Therefore, we studied the effect of Piracetam on the evolution of electroencephalogram of rabbits subjected to deep anoxia by inhalation of nitrogen. It is known that under nitrogen, it produces a gradual deterioration of the electroencephalogram until “electrical silence” and that, if the animal is rapidly returned to the atmosphere, it recovers a normal electroencephalographic trace (Gastaut and Meyer, 1961, Pternitis and Passouant, 1961).

Under these conditions, we have found – comparing animals treated with saline solution to those treated with Piracetam – that Piracetam significantly increases the “resistance” cerebral (the time of appearance of electrical silence after the start of infusion of nitrogen in its cabin) but especially facilitates the “recuperation” cerebral (the time taken for the restoration of a normal electroencephalogram after readmission of the air). These experiments have been published elsewhere (Giurgea et al., 1970) and on this occasion we have shown that several analeptics such as benzedrine, methylphenidate, caffeine, theophylline and pentylenetetrazol not only do not exert a protective effect. but show rather toxic effects in this experimental procedure.

For illustration, we give a figure (Figure 3) showing the positive effect of Piracetam on cerebral recovery.We will see later that Piracetam has protection against hypoxia in other experimental situations as well.

 

4 ° Facilitation of memory and learning in normal animals or in a deficit state

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IV. – ATTEMPTING NOOTROPIC CONCEPT IN THE PHARMACOLOGY OF INTEGRATIVE BRAIN ACTIVITY