ParisTech Review

With an average weight of 1500 grams, the brain allows us to move, feel, act, love, think, and reflect. With one hundred billion neurons each with 10 million billion synaptic connections between them, just one cubic millimeter of our brains contains half a billion connections housed primarily on the nearly two square meters (21 square feet) to which a spread cortex extends. Such is the scope of the universe to be explored, which opens a field of limitless discovery. If we add that the brain is not an electronic molecular machine in the modern sense of the term, that data transfer within a synapse is probably of an analogical nature while all the same dealing with a very large number of input stimuli, that its connectivity is selective, that only a fraction of the neurons function at a given time, allowing to limit the required “power consumption”, one can better understand than what we currently perceive about what in essence is the center of our interactions with the world is but a tiny fraction of what’s out there, or rather – in there.

How is it possible that such a monument should fit in the mere 1500 cubic centimeters (50 fl oz.) of a human skull? To investigate this infinitely complex architecture, researchers have long been forced to alternately examine either the tree (the single neuron) or the forest (the networks of neurons). With new tools like the biphotonic microscope (which slows the flow of neutrons), it is now possible examine both at once. In the past two decades, research on the brain has been revolutionized by technological advances in bioinformatics and imaging. Understanding the normal and altered (neurological and psychiatric diseases) functioning of the nervous system constitutes a fundamental challenge for knowledge and health in our society.

Spirit and matter
To describe the mysteries of this terra incognita in these few pages would be a long shot. The purpose of this paper is, for illustrative purposes, to review recent research in an array of major issues still under decryption that may shed some light on the complexity inherent to the field. First, one must realize that the seat of our intelligence and our consciousness is an integral part of our body, which has a hold on the brain that the brain cannot discard. And that our brain, deeply rooted in our body, is more in touch with the most basic functions of life than with our intellect.

The first mystery or shall we say the first surprise is the time that science has taken to understand the importance of the brain. It was not until the fourteenth century that the brain was put in its place, that is to say, at the source of all human expression. The heart has long been favored over the brain although some great physicians, such as Hippocrates and a few others have made it the central organ for sensations and consciousness. In particular this is where Hippocrates locates the seat of the “sacred disease” (i.e. epilepsy). Later Galen dissected the brains of cattle and pigs and described, between the human heart and the skull, an “admirable” network carrying some form of vital energy from the cardiac “boiler” to the lower base of the brain where it turned into spiritual principles. Shakespeare, himself, chose not to choose: “Tell me where is fancy bred, Or in the heart, or in the head?” asks the hero of The Merchant of Venice. In the early sixteenth century cerebral ventricles were cast in wax for the first time by Leonardo da Vinci, but the path to cerebro-centrism still had a long way to go. Even Descartes deemed that the brain’s role was purely mechanical. It was not until Galvani that we did away with animal spirits, thanks to the discovery of animal electricity linking the brain to the muscles. With the discovery of an energy specific to the nerves, the era of the great adventure of cerebral localization began – after thirty centuries of “cardiocentrist” rule.

Neuronal life
What was viewed until recently as a second mystery about the brain consisted in the belief that shortly after birth, neurons stopped renewing themselves, unlike other cells in the human body. Our brain plasticity only stemmed from changes in the synaptic connections between neurons. Just a few years ago, evidence has been provided that new neurons are born in the adult brain while integrating themselves into existing neural circuits, specifically in the olfactory bulb and in the hippocampus, a structure that plays a key role in memorization. This neurogenesis is currently at the heart of very active research. Indeed it is not known whether these new neurons have a function and whether one could direct them to perform the mission of curing certain medical conditions. But with the discovery of this “reconstruction kit”, a tenet taught to entire generations of medical students fell, and with it fell the myth of the inexorable decline of neuronal populations.

This quite naturally leads to the very recent unraveling of a third mystery about the brain. Contrary to what was imagined, normal aging is not associated with neuronal death. This overly pessimistic concept is now contradicted by recent studies in which a precise counting of specific nerve cells in several brain areas has been carried out. It is now estimated that nerve cells do not die over time – they do survive but lose part of their functional capabilities by giving up some of their connections. This has the consequence of limiting the information that circulates and the functions that depend on it. Aging is therefore more a case of losing synapses than one of neuronal death. The new approaches envisioned consist in identifying neurotrophic factors (the equivalent of “fertilizers”) responsible for regenerating neuronal activity. In short, as age sets in, a neuron knows how to defend itself and survives in an ongoing battle between decay and vitality.

Only very briefly will we discuss a fourth mystery: how the shape of the container commands the quality of its contents. Much has been written about the shape of the skull and its geometry since the days of anthropometric measurements. In fact, the cerebral tissue may find its place in a brain which size is sufficient, regardless of the salient features. The frontal lobe amounts to one third of the brain and it has multiple areas that at once house intelligence, abstract thinking, short-term memory, decision making, planning. However, it does not necessarily rest behind a so-called “intelligent” prominent forehead and, in the cases of Einstein or Diderot, its facade was not particularly flattering. Owing to its layered surface and convolutions, the brain is able to occupy but a discreet space.

A social organ
A fifth breakthrough came from the discovery of “mirror neurons” by an Italian team in the 1990s – a kind of effectors of a “social brain” built around mutual mimicking behaviors. Suppose that right under the eyes of an ape, a man should take a few olives in his hand. This will trigger a mirror “neuron” in the cortex of the animal. The ape then simulates the man’s action “in its head.” What applies to a primate also applies to young children and it is surmised that mirror neurons are triggered whenever they see their reflection in a mirror. A young child then understands that the one he is mimicking in the mirror is actually none other than himself.

But thanks to the fact that we encode our representations of others within our brain, we also get to understand each other. Thus experiences are shared and learned when they arise on a daily basis. To imply that this fundamental modality of knowledge is the source of compassion is one short step. What is self-evident, in any case, is that we build our personalities by mingling with others, and that loneliness leads to feelings of non-fulfillment. To infer that the brain is a social organ is therefore not unfounded. Social bonds quite probably help in keeping cognition active, and gerontologists even anticipate that a prolonged professional life may delay the onset of Alzheimer’s disease.

Evolutionary tinkering
The sixth mystery asks “Where does our brain come from?” From “evolutionary tinkering”, in the words of François Jacob. The latest data is consistent with the general theory of evolution. We tend to instinctively make choices that echo an edifice of acquired atavism within a gene pool that is specific to humans. But beyond the acquisition of such an envelope, reminiscent of the primacy of the body, of our kinship with other animal species and of the imprint of a lower origin, with the mark of the experience of generations past still lingering in our brain, our uniqueness lies in the very long period of learning that comes after birth. Because beyond our gene pool, the structural and functional plasticity of synaptic connections allow our environment and our social life to leave a real imprint of sensory experience. These connections are shaped by stimuli resulting from our activity and our interaction with others. Evolution probably started out by creating blind systems without any room for freedom. Complexity on the other hand allowed the emergence of individuals free to make choices.

The seventh mystery of the brain is precisely its plasticity. This plasticity allows for reorganization of neural connections, owing to the molecular and cellular foundations of the brain. Throughout life, this organ undergoes constant changes, but its ability to reorganize is much higher in children than in adults. And one thing the cortex hates is to lay fallow somewhere – an abandoned territory is promptly colonized by neighboring areas. Such phenomena of brain plasticity are the ones that make it possible to at least partially recover some functions for instance after a stroke (cerebrovascular accident or CVA), even though for some regions known as “eloquent” areas, losses are generally heavy and irreversible. Conversely, epidemiological studies show that the vast majority of patients that have undergone surgery for slow infiltrating tumors show no identifiable functional deficits and are able to perform professional duties normally. Similarly, it is widely accepted that neurodegenerative conditions have a long prodromal and asymptomatic phase, due to the fact that plasticity masks the degeneration that only expresses itself clinically when the number of destroyed neurons is of such magnitude that it cannot be “compensated” by the ones remaining, that is to say, presumably many decades after the onset of the disease. In short, the adaptive process is versatile and its dynamics require the implementation of multidisciplinary approaches.

How does it work?
Eighth mystery: human brain by no means functions like a computer. Memory, to take one example, is not stored the way it would be in a computer because we constantly reinvent our memories and are programmed to have a certain measure of freedom. But more importantly, our brain does not work in input/output modes. Man constantly anticipates, simulates future actions, and builds representations of the world constructed around expectations, calculations, desires and hopes. But the human brain is also part of the world. It shapes external reality by projecting its desires, intentions and perceptions into it. Our brain is therefore of a projective nature. It is also a comparator. It compares the state of the external world with its assumptions – this in turn triggers fear, regret, or joy.

Ninth mystery: the brain and chaos theory. It was epilepsy that gave us a new understanding of the way the brain functions. During an epileptic seizure, certain neural networks are hyperactive and synchronized and in a way that triggers an electric discharge that neutralizes all cerebral activity encountered along its course, causing the different forms to take on absence seizures. A young mathematician guessed that seizures came from the transition from disorder (micro-electrical currents flowing in all directions) to order (the synchronization of hundreds of millions of neurons leading to the buildup of an electric current of devastating intensity to the brain).

With the help of an “attractor” he was able to track down the moment where “the transition to order” triggers the attack, whereby he succeeded in predicting the occurrence of an attack of temporal lobe epilepsy several minutes in advance. One can imagine that a few years from now, patients suffering from this form of epilepsy will rid themselves of the triggering of absences, with the help of a recording device, a computer, and an antiepileptic drug-injecting pump, all duly miniaturized. Intelligent micro-stimulators that can detect both the neural switchover leading to an attack and block it are likely to appear in the foreseeable future. But this discovery may also have implications for the way brain signals are modeled mathematically.

Could our brain actually be a musician?
Tenth mystery: could our brain actually be a musician? Many studies support this idea, going as far as deeming probable that we exploited our brain’s capacities in activities of vocalization long before we started to use it for speech.

Aphasic people, dyslexic children and people with Alzheimer’s or Parkinson’s disease all seem to benefit from clinical effects directly rooted in music, whether it is listening to it or practicing it. Many studies suggest that music exerts an influence on our behavior that goes beyond its simple aesthetic or emotional components. The neural basis for the previous mystery’s curiosa mathematica is to be linked to the neural basis for music. The presence of neural circuits essential to musicality in the superior temporal regions and the proximity of music networks and networks of language probably constitute an answer to why “music therapies” are a viable option nowadays.

As the conclusion of this review of how our brain functions draws near, we shall refrain from addressing topics such as intelligence, emotions, and consciousness. Does consciousness arise from a compartment, from a department of the brain, or from a serial processing of information rather than from a parallel one? Although it is known to us that emotions and reason mingle within the frontal lobe, all that we have so far are hypotheses about which every researcher has an opinion.

Even more so, unlocking the secrets of the soul is just a dream. Does it embrace the entire brain rather than one of its regions? Could it be rooted in a broader body with which relations of some intensity have been established? Could it somehow be diluted among all those, present and future, in whom a trace of our passage will have been kept?

A research priority
What is certain is that many extraordinary enigmas remain to be unencrypted, all demanding total interdisciplinarity as well as the inclusion of cerebral dysfunctions that continually allow for new windows of insight to be opened upon that organ. This was how research on epilepsy led to locate several of laughter’s centers. Therefore neuroscientists, biologists, neurologists, neuropharmacologists, mathematicians, physicists, chemists, medical imaging specialists, but also psychiatrists (psychiatry having its roots both in hard sciences and the psyche), not to mention social sciences, must all combine their knowledge and insights. Understanding the brain requires a huge research effort drawing upon genetics, molecular biology and general cell biology, imaging and investigation of the physical and social environment; this will require the united efforts of the representatives of a number of disciplines. This is the task to which the Federation for Brain Research is dedicated.

Almost one quarter of Europe’s population suffers from one or more cerebral conditions, at a cost of 400 billion euros per year, far more than the costs incurred by cardiovascular diseases and cancer. At a time when the funds invested in brain research in Europe amount to just 4 to 5 billion euros, that is to say a mere 1% of the aforementioned costs. In the United States and Japan, the last two decades have been dedicated to the brain. Let us hope that France and Europe finally grant it the priority it so well deserves – that of a root cause.