Wednesday, 19.06.2019

Joseph Knoll: Enhancer Sensitive Brain Regulations and Synthetic Enhancers (Selegiline, BPAP) Which Counteract the Regressive Effects of Brain Aging
Chapter1: Joseph Knoll: Acquired drives ˗ the mechanism of the manipulability of mammalian behavior

After preliminary experiments, I began research in the early 1950s with two students, Karoly Kelemen and Berta Knoll, which aimed to investigate the exact reason in cortical mechanisms explaining why rats (in striking contrast to mice!as I soon realized) are capable offixing acquired drives.

We formulated a useful model, the “glass-cylinder-seeking” behavior, to study the development and the final, irreversible fixation of an acquired drive in rat brains and then tried, using the same device adjusted to mice, to measure exactly the basic difference in the behavior between these two closely related species.

Innatedrives divide into two subgroups and are responsible for a limited number of indispensable (life important) goals: drives that ensure the survival of the individual˗the urge to maintain internal stability (homeostasis); the urge to avoid anything that is endangering or unpleasing; and the urge to obtain water and food;and drives that ensure the survival of the species˗ the instinct to copulate and nurture offspring.

Acquired, unnatural drives are responsible for an unlimited number of dispensable goals. The capability to acquire an insuppressible urge for a goal, which is unnecessary for individual or species’ survival, represents the most sophisticated function of the telencephalon. Humans are the only beings on earth whose life is predominantly based on acquired drives. To a certain extent, a minority of the mammalian species (monkey, dog, horse, dolphin, rat, etc.) possess this endowment which remains, under natural conditions, unexploited. Nevertheless, humans obviously discovered thousands of years ago, probably through a kind of serendipity, that the behavior of such animals can be modified by proper training, and thus beganthe progressivedomestication of various species.

The development of an acquired drive always originates in some way in an innate drive.Though this relation becomes later unrecognizable, it is obvious that nothing exists in the human brain without a rational origin.

            The course of evolution is progressing towards the perfectibility of various species. For example, rats are one of the most teachable mammals readily capable of acquiringan unnatural drive, but indocile mice are devoid of this ability. The successful demonstration in the significant differences in the EEG arousal reaction in rats with extinguishable (ECR) and inextinguishable (ICR) conditioned reflexes, and many more unexpected data (Knoll et al. 1955a; Knoll et al. 1955b; Knoll et al. 1955c; Knoll 1956, 1957; Knoll et al. 1956; Kelemen et al. 1961; Knoll B 1961; Knoll 1968), inspired my realization that the development of mammalian brains capableto fix unnatural drives created the manipulability in behavior which rendered community life possible.

An acquired drive is fixable only on the basis of an innate drive, so our “glass-cylinder-seeking” drive was built on an unconditioned avoidance reflex (escape from a hot plate). The sound of a high-pitched bell served as a high-priority conditioned stimulus (CS). Rats were trained to vigorously search for a 30-cm-high glasscylinder and jump to the rim of it. The cylinder was open at bottom and top with diameters of 16 cm and 12 cm, respectively, and with a side opening through which a rat (up to 350-400 g body weight) could move inside the cylinder.

In the training procedure, rats (male or female) were pushed through the side opening of the glasscylinder which resulted in them standing on a metal plate heated to 60°C.The jumping reflex was then elicited for weeks, three times daily, for 10-50 repetitions at 10second intervals with bell and heat stimulation until a chain of ICRs developed and the rat indefatigably displayed the jumping reflex without heat stimulation, even after 100 times in succession (Knoll et al. 1955a; Knoll et al. 1955b; Knoll et al. 1955c). This was a transient stage leading to the manifestation of the “glass-cylinder-seeking” drive (Knoll 1969).

The rats that performed best in this study acquired the “glass-cylinder-seeking” drive in a stable manner and, thereafter, maintained this unnatural urge for life. The rats showed the same high-grade adaptability and readiness in overcoming different obstacles during goal-attainment as those influenced by innate drives, such as hunger or sexual desire (Knoll 1956, 1957; Knoll et al. 1956). In the most efficiently trained, best performing rats, the acquired drive was so powerful that it prevailed over life important innate drives. When said rat hadbeen deprived of food for 48 hours and then food was offered within the usual setup that contained the glasscylinder, the rat looked for the glasscylinder and left the food untouched. Similarly, when a receptive female was offered to a fully sexually active “glass-cylinder-seeking” rat in the usual setup, the male looked for the glasscylinder and neglected the receptive female.

The mouse, a rodent closely related to the rat, trained under the same experimental conditions as the rat, was unable to acquire the “glass-cylinder-seeking” drive, clearly demonstrating that the development of mammals with a brain capable to fix acquired drives possess a qualitatively higher developed brain than the mammals devoid of this ability (Kelemen et al. 1961; Knoll B 1961, 1968).

Berta Knoll worked for seven years carefully analyzing the physiologically important differences in the unconditioned and conditioned stimuli-induced excitation processes between the mouse (males or females) and the rat. She used, with dimensions adjusted to mice, essentially the same device as applied to fix the “glass-cylinder-seeking” drive in rats.The unconditioned stimulus (US) was capable of inducingan intensive dominant state of excitation in mice and a jumping reflex could be elicited, within 1 second latency, with the CS (bell sound) alone. Thus, the mouse behaved as if it possessed a conditioned reflex (CR) highly resistant to inhibition, but within a couple of hours, no sign of the behavioral change was detectable. A stable CR could not be established in mice, even when the number of associations was increased from 4 to 100 times daily and carried out over periods varying from oneweek to full lifetime.In 1959, the highly interesting details regarding the nature of this phenomenon, termed by Berta Knoll a “pseudo-conditioned reflex,”were published (Knoll 1959; Knoll 1969).

It is obvious that rats possess a qualitatively higher developed brain than mice; clearly demonstrating that the development of mammals capable to fix acquired drives, thus being in possession of behavioral manipulability, was the last qualitative change in development of the mammalian brain.

Vertebrates can be divided into three groups according to their brains’ mode of operation: (a) those that operate with only innate drives (the majority); (b) those with an ability to acquire drives (a minority); and (c) the “group of one” that operates almost exclusively with acquired drives (Homo sapiens sapiens) (Knoll 2005).

With the evolution of brains capable of acquiring drives, species developed whose members could manipulate each other’s behavior and act in concert. This was the condition sine qua non for the evolution of social living, a form of life that enabled species to qualitatively surpass the performance of any given individual. It goes without saying that training members in the skills needed to act in concert improved the quality of life. The learned behavior, for example, of five to six famished female lions act to collectively separate an animal chosen from its herd to consume, significantly increasedthe chances of capturing the prey. It was the evolution of the brain with the ability to acquire drives that made the appearance of life on earth so immensely variable.

With the development of the human brain, a functional network with more than
100 billion interrelated nerve cells and 1011 bit capacity arose. With this system, whose operation is inseparably connected to conscious perception, life on earth reached its most sophisticated form. Furthermore, the human being, who is primarily a social creature, is a building block in the creation of a gigantic network: human society.

The function and capacity of society obviously exceeds the sum in activity of its members. With the practically inexhaustible capacity of the human brain to acquire drives, human society represents a qualitatively new, higher form of life. For example, a country, presently the most sophisticated form of a human community, consists of millions or even more thana billion humans and operates de facto as a huge living complex interacting with other similar entities, more than200 at present.

The birth and development of human society, an insignificant moment and fleeting in the endless history of the universe, necessarily means everything to us. It can be taken for granted that during the birth of human society, probably somewhere in South-Africa,very small groups formed a micro-community, working together. Due to learning, practice and experience, their community life became more and more efficient, and the accumulation of basic knowledge opened the way for a more rapid development, truly reflected in population growth.

In the last phase of the Stone Age, about 8,000-9,000 years before our age, marked by the domestication of animals, development of agriculture, and the manufacture of pottery and textile, the human population on earth approached the one-million level. Thereafter, however, the population increased exponentially. By the beginning of the Common Era, it had reached 300 million, grew to 1.6 billion by 1900 and is today around 7.5 billion. The world population is still growing, but this tendency is already in decline. For example, the forecast for the yearly increase in 2020 is 1.09 % and in 2050 only 0.57 %, which is promising for the future.

After numerous experiments with rats and mice, I concluded that in the mammalian brain capable to acquire drives, untrained cortical neurons (Group 1) possess the potentiality to change their functional state in response to practice, training, or experience in either of three consecutive stages: (i) in an extinguishable conditioned reflex (ECR) (Group 2); or (ii) in an inextinguishable conditioned reflex (ICR) (Group 3); or (iii) in an acquired drive (Group 4).

It was crucial to find an exact measurable test to demonstrate the functional difference between the ECR and ICR. An EEG study, performed in Daniel Bovet’s department in Rome by Károly Kelemen in Vincenzo Longo’s laboratory, presented the expected experimental evidence to better understand the unique changes in the rat’s brain when it’s behavior is fully under the control of the “glass-cylinder-seeking” acquired drive (Kelemen et al. 1961; Knoll 1969).

The EEG experiments were performed by implanting two pairs of screw-electrodes into the rat’s scull in locations corresponding to the sensorimotor and association surfaces of the cortex. The electrodes were fixed to the bone with dental cement. During the EEG experiments the rats were kept in sound-proof chambers in shielded boxes measuring 60x80x100 cm that differed from the environment used for CR trials and rendered the performance of the learned reflex activity impossible. The bell was fixed above the box inside the chamber with the switch and the EEG apparatus outside. For EEG recording, the electrodes were connected with the device by flexible long-cables which did not interfere with the animal’s movements. After 1-3-hour adaptation, during which the rats grew accustomed to the box, a control record was made and compared with the activities recorded during continuous or intermittent bell ringing. Under these conditions, freely moving rats habituated for 1-3 hours displayed predominantly synchronized activity on the EEG record. Prior to the application of a specific stimulus, there was no difference between the EEG records of controls and rats with ECRs or ICRs. Under the influence of various indifferent stimuli, slow potentials with high amplitudes were suddenly replaced by 20-25 c/s and low-voltage waves predominating sometimes for seconds after the cessation of the stimulus. Simultaneously, the animals displayed a typical orientatory-searching behavior. After applying the specific (conditioned) stimulus, however, the individual experimental groups displayed differences in behavior.

            The effect of 20 min continuous bell ringing on the EEG arousal reaction was examined under the conditions described above. The controls responded to the bell sound in the usual way. When the sound began – a new stimulus! – desynchronization, i.e. excitation of the non-specific activation systems, began. This state lasted for a short period; after habituation to the stimulus, synchronized cortical activity was restored (Kelemen et al. 1961; Knoll 1969).

The effect of continuous bell stimulus on EEG arousal in traditionally conditioned animals (ECR) hardly differed from the controls’ effects. Although in this case the bell-stimulus was not indifferent, yet its desynchronizing effect on the activation system was only transitory. Habituation after EEG arousal set in at practically the same rate as in the controls. Thus, the conditioned reflex’s typical functional property, the appearance of extinction, paralleled with the extinction in EEG arousal, as expected on the basis of literary data (Kelemen et al. 1961; Knoll 1969).

In addition, an entirely different behavior was observed in rats whose ICR had been established during the procedure when the “glass-cylinder-seeking” acquired drive was fixed. Throughout the 20-min bell ringing, they displayed desynchronization, i.e., cortical activation. Thus, there was a parallelism between the absence of reflex extinction and the absence of habituation in the EEG arousal. Accordingly, the bell stimulus had a lasting capacity to cause excitation in the non-specific activation system or, in other words, to influence the centrencephalic system (Knoll 1969).

We also soon realized and described unknown basic differences between the ECRs and ICRs in their sensitivity toward psychopharmacological agents. While the ECRs were readily inhibited by sedatives/hypnotics and major tranquilizers, the ICRs were conspicuously resistant to sedatives/hypnotics, displaying only selective sensitivity to major tranquillizers (Knoll et al. 1961; Knoll J and Knoll B 1964, Knoll et al. 1961).

It is reasonable to conclude that the ability to acquire an irrepressible urge for a goal that is unnecessary for survival was the last step in the development of the mammalian brain. This is the most sophisticated function of the telencephalon.

By the end of 1953, experiments with the “glass-cylinder-seeking” rats led me to shape the working hypothesis that the appearance of the mammalian brain with the ability to acquire drives produced a species fit for domestic life, i.e.,to live in intimate association with and to the advantage of humans. This ability of the mammalian brain ensured the interaction of the individual and the group and finally led to the evolution of the most sophisticated form of organized life: human society.

To develop the full possibilities of this approach, I thereafter clarified during a 36-year research period those key important brain mechanisms, which determine the life of mammalian species whose members, being capable to fix acquired drives, possess a brain with a higher level of manipulability than mammalian species whose cortex is missing this potential. I finally summarized my theory,“The Brain and Its Self. A Neurochemical Concept of the Innate and Acquired Drives,” in a second monograph (Knoll 2005).

The physiology of acquired drives furnishes knowledge about the most important brain mechanism:the manipulability of mammalian behavior. As discussed, an acquired drive is always built on one of the innate drives that ensure the survival of the individual or the species. However, after the acquired drive has been ultimately fixed, its origin, the innate drive, cannot be recognized anymore either in humans or in domesticated animals. A “glass-cylinder-seeking” rat will never acquire this drive under natural conditions. The experimenter consciously manipulated the rat’s brain, making use of the innate potential to change a group of cortical neurons via proper training in a way that the rat is fixing an acquired drive. Finally, the “glass-cylinder-seeking” rat behaves as one possessing a “fanatical” desire for the glasscylinder. Essentially the same mechanism works in all mammals capable to acquire drives, including humans, who possess the most manipulable brain among all living creatures on earth.

The brain of a suicide killer is furtively manipulated. The properly acquired drive develops as a result of long-lasting training. The subject always acts under coercion, under severe mental pressure. Nevertheless, it is the nature of acquired drives that if manipulation is fully successful, then the individual ultimately behaves as one possessing a fanatical desire to reach the acquired-drive-motivated goal. Thus, current expert opinion that the global war on terror is a 7th-century ideology clashing with 21th-century weapons is certainly correct.

To terminate the still existing myth-based era of human society and arrive atthe rationally-directed phase of human history is obviously a most imperative necessity. To reach this era is not only a most desirable necessity;its establishment and stabilization, which fully depends on scientific development, is unstoppable.

The main message of my theory is that human society is still in the trial-and-error phase of its development. It already seeks to bring to an end the myths-directed era, the first part of its history, and reach its final goal: the rationally directed human society in which behavioral modification induced by the family/school/society triad will be based, from birth until death, on the total knowledge of how the human brain works. In this way, communities will understand how the human cortex created with its chaos function the myths of supernatural forces. This was the ideology which enabled the creation of human society prior to the sine qua nonknowledge of the creative and controlling forces in the universe needed to establish and maintain a rationally directed homogenous human society.

It is evident that the power of thinking in orderly rational ways, i.e., the capacity to understand the natural world (science), is that physiological reality which determines the conscious fight of the individual to find and fix acquired drives that optimally fit their natural endowments. Homo sapienssapiens appeared around 150,000 years ago; reached full behavioral modernity around 50,000 years ago; and slowly accumulated proper knowledge regarding natural forces. Science’s development finally brought to fruition the era of enlightenment, the spiritual revolution which dramatically changed the continued fate of the myths-directed human society. Separation of Church, by its nature the main creator and guardian force of the myths-directed era of human society, and State, interested by its nature in increasing support over time to rationally directed human activities, was more than 200 years ago the decisive step which enhanced with a previously unimaginable rapidity, the development of science and technology. Let me demonstrate the enlightenment-induced acceleration in science and technology with a convincing example described inone of my former monographs (Knoll 2016).

George Stephenson created the first steam engine in 1814. (His passenger train completed in 1825 its first 39 kilometers at24 kilometer/hour.)Only 62 years later, in 1876 Nikolaus Otto discovered the four-stroke combustion engine. Benz and Daimler created the automobile and Benz designed in 1885 the first usable automobile. Only 18 years later, in 1903, the Wright brothers developed the first airplane: 274 kg in weight, flying at48 kilometer/hour. The rocket technique soon developed with dramatic speed. The era of space research started. Gagarin, the first astronaut, left Earth on April 2, 1961, only 58 years after the first efficient airplane was created.

Mankind used the horse for thousands of years and after the spiritual revolution of enlightenment, science and technology accelerated within 147 years (!) from the first steam engine to the era of space research. Science, the continuously developing human brain product, would benefit even more with the termination of the regrettable but inescapable myths-directed phase of human society’s history.However, the dense ignorance of the overwhelming majority of the world population explains that despite the breath-taking acceleration of science and technology, more time, perhaps a few hundred years,isstill necessary to firmly establish and stabilize the ratio-directed human society.

We all seek a brain, which acquires drives with an utmost ease through a permanently active state. The acquisition of proper acquired drives in the most sensitive developmental period of life was always and remains forever in any individual’s life determinant. However, since we still live in the myths-directed era of human history, only a small segment of the world’s population, primarily the most creative artists and scientists, are lucky enough to possess the drive to work day and night enthusiastically and indefatigably in full harmony with their natural endowments. The majority, as a matter of fact, assume, most often, coerced professional drives that will ensure their place in society. Conformity of innate faculties and acquired professional drives are keenly important for lifelong equilibrium.

However, not only is the permanently active brain an ambition, but also there are times when a drive might need to be altered or replaced. While even the most satisfying professional drive becomes redundant after its permanent, continuous use, there is yet the undoubted desire to maintain the brain in a satisfyingly active state. Inexhaustible forms of supplementary activities serve this aim. Absolute dominance of a fully satisfying professional drive and the acquisition of beneficial-supplementary drives is the formula for a harmonious, well-balanced life. Lack of full satisfaction in the acquired professional and supplementary drives generates an urge to flee from frustration and seek salvation in “Ersatz” activities: smoking, alcohol, drugs, etc.

Metaphorically, every human being is born tabula rasa with a telencephalon that resembles a book with more than100 billion empty pages (untrained, naive cortical neurons, Group 1), and with the capacity to inscribe as much as possible in this book throughout life. In reality, cortical enhancer regulationthe modification of the presently still unknown chemistry of the cortical neurons throughlearning, aiming to establish cooperation between cortical neurons previously unacquainted with one another – is the essence of human life.

Whenever a drive is acquired, chains of ICRs are fixed in the brain and neurons responsible for emotions are coupled to the integral whole. Thus, cognitive/volitional consciousness is necessarily inseparable from an affective state of consciousness. The mechanism that binds emotions, appurtenances to any chain of ICRs, is crucially important to interpersonal communication.Cortical neurons belonging to Group 3 or 4 continuously synthesize their specific enhancer substance within their capacity. This means that even in the vigilant resting state (leisure), in the absence of a dominant drive, as well as in the non-vigilant resting state (sleeping), the cortical neurons representing the totality of the already fixed chains of ICRs and acquired drives are permanently under the influence of their specific enhancer substance.

Although the level of this permanent, undulating activation remains low, it is unpredictable as to when any group of cortical neurons will be influenced by enhancer substances on the level already inseparable from conscious perception. Thus, it is always unforeseeable what will suddenly come to our mind. As the totality of the cortical neurons belonging to Group 3 or 4 works continuously on an unconscious level, there is a steadily operating, chaotic background noise in the human telencephalon which can never cease to exist, but it never endangers the function of the dominant innate or acquired drives. Because of this phenomenon, rational brain activityis always amalgamated with irrational brain activity and we are in every moment of our life in readiness for experiencing the coexistence of order and chaos in our brain.

Thus, (a) whenever a chain of ICRs is fixed in the human brain, the proper cortical neurons remain, on an unconscious level, constantly active for life, and (b) if the proper method is used, even a chain of ICRs that had never been recalled after fixation can be activated to the level needed for conscious perception at any later date. The recalling of any chain of ICRs is necessarily inseparable from an affective state of consciousness, due to the emotions coupled as appurtenances to the cortical neurons when they synchronize with each other.

In summary,

(i)                 past experiences are irreversibly fixed in neurons belonging to Groups 3 and 4 that learned to cooperate with each other and constitute an integral whole;

(ii)               proper stimulation of the cooperating neurons as an integral whole allows the fixed information to be later recalled. This is inseparable from conscious perception and thus, past experiences are vividly re-lived in a cognitive and affective manner; and

(iii)             during the operation of a dominant drive the activity of the individual is primarily focused on reaching the goal represented by this drive (rational activity), but the ability to simultaneously, consciously revive past experiences that are outside the limits of the operating dominant drive (irrational activity) is a natural endowment of our brain.

Because of the theoretically immense variability of cortical enhancer regulation, any trial to develop a compound that will reasonably stimulate learning seems to be, from a physiological point of view, a hopeless undertaking. The natural method of behavioral modification – by means of experience, training, or practice – will likely remain not only the most effective, but also the only viable way to change the performance of the cortical neurons in species capable of acquiring drives, presumably forever. Therefore, everything depends and will in all probability always depend on teaching, learning and education.

As the background noise in the brain is never interrupted and can even become more accentuated during sleep than in the vigilant resting state, the dream world, the classic example of a human-created universe, has always given inspiration to art. Its ultimate explanation awaits the resolution of scientific problems: the chemistry of cortical enhancer regulation and the natural law that determines the operation of “The Brain and Its Self” and is responsible for the immense variability of human activities.

Human society – the sustainability of which has always required the proper manipulation of the brain of its members – still finds itself in a state of development. It seeks its final equilibrium: namely, that state in which behavioral modification induced by the family/school/society triad will be based, from birth until death, on the exact knowledge of the neurobiological mechanisms that determine human behavior.

In this way, members of the community will understand that the simultaneity of order and chaos in their brain is the physiological reality thatdetermines human activity and they will consciously seek to find the acquired drivesthat optimally fit their natural endowments.

For the time being, those lucky enough to acquire the best fitting drives in due time, in the early uphill period of life, have had fair chances for success and happiness. In contrast, those who for any reason have missed this opportunity will remain frustrated and look for “Ersatz.” It seems reasonable to conclude that order and chaos are of equal importance in our brain.

Without the ability to adapt ourselves to the concrete (science),we would not be able to survive; without the ability which allows detachmentfrom the concrete and explorations in the infinite (art), life would not be worthliving.

The existence of a variety of animal species with extremely restricted abilities to fix ICRs and acquire drives marks Nature’s long road of experimentation with the brain. The end result of this process, the human brain, has been the most perfect variety.

The limitless capacity of the human cortex to fix ICRs and acquire drives allowed, in conjunction with the development of language, an unmatched interpersonal communication. This unique facility made the cognitive/volitional and affective states of consciousness of the human brain, and as a consequence of it, human social life, unparalleled. Because animals lack similar developments, there is no way to obtain direct evidence regarding the nature of their psychic experiences. Nevertheless, the observation of the goal-seeking behavior of trained monkeys, dogs, horses, dolphins and so forth furnishes convincing indirect evidence that the operation of ICRs and acquired drives is inseparable, even in animals, from an archetype of consciousness.

The historic billions who remained untouched by wartime mass killings of their innocent peers and were ready to die in the name of “God,”“Fatherland,”“King” and so on, illustrates the consequences of the practically unlimited capacity of the human brain to fix acquired drives. Even in the dark history of humanity, the Holocaust – the extermination of millions within a few years with unprecedented success, due to a systematically planned and executed evil mass manipulation of a whole nation (in the 20th century!)– was a unique event.

It is worth considering that after the extinction of Pithecanthropus erectus, Sinanthropuspekinensis, Roanthropusdawsoni, Homo heidelbergiensis, Homo sapiens fossilis, etc., Homo sapiens is the unique, surviving member of the human family.Humanity is born with a brain without any knowledge as to how the real world, the human body and the mind function. In contrast, we all are born with a brain capable of creating a “non-existing world.”Thus, Homo sapiens created the still operating myths-directed society. However, in order to survive, it was compelled to discover how the real world functions. By the end of the 18th century, general knowledge progressed to a critical level, and since the age of enlightenment, science and technology developed from strength to strength. Due to the undreamed speed ofsciences’ development, humanity rapidly approaches the final state: the rationally organized human society, grounded fully on scientific knowledge, first of all in understanding how the human brain, the creator of science, works. There is little doubt that the agony of the myths-directed phase of human-society’s history offers daily convincing proof that termination of this era,where one hand destroys what the other hand has created,is overdue.

Since “All the forces in the world are not so powerful as an idea whose time has come” (Victor Hugo: “Precious stones. Small anthology from Victor Hugo’s thoughts”; Drágakövek. Kis antológia, Hugo Victor gondolataiból (in Hungarian), Gutenberg, Budapest. 1930), I firmly believe that the development of science will finally terminate the myths-directed, short, first phase of human society and stabilize the ratio-directed, hopefully longer, and happier phase of human history on earth.



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June 7, 2018