SCIENCE; THE LAST GRE; AT FRONTIER

The brain is the ultimate enigma. Now, after centuries of study by philosophers and scientists, some of its deepest secrets are being unveiled. In the first of a three- part series, we look at the technological advances that have led to these discoveries

THE HUMAN BRAIN is the most complicated structure in the known universe. All the great voyages of discovery, from the secrets of the atom to the mysteries of deep space, would come to nothing without that lump of grey matter sitting between our ears. Despite its pivotal role in elucidating the natural world, the brain remains an enigma. Now the last great frontier of human know-ledge - the seat of knowledge itself - is being explored in a way unimaginable a few decades ago. Scientists even feel they may soon understand life's ultimate mystery: our conscious inner selves. Over the last 20 years there has been a revolution in brain research. For much of the previous century, such studies centred on the dead or diseased. A living, pulsating brain in a healthy human being could only be imagined from the dead tissue on a pathologist's slab or the abnormal behaviour of a disordered mind. In recent years, however, the increasingly sophisticated technology of brain scanners has brought together researchers from traditionally unrelated disciplines. The minds of psychologists and molecular biologists are beginning to cross-fertilise in their search for a better understanding of evolution's greatest achievement.

NO SUPERLATIVE, it seems, is too grand to explain what is happening to brain research, precisely midway through the international ''Decade of the Brain''. Gerald Fischbach, professor of neurobiology at Harvard, believes philosophers enquiring into the human condition can no longer ignore the brain experiments that are "among the most urgent, challenging and exciting" in all of science. "Our survival and probably the survival of this planet depend on a more complete understanding of the human mind," he says.

Paul Churchland, professor of philosophy at the University of California, San Diego, is equally enthusiastic about the new research. "We are now in a position to explain how our vivid sensory experience arises in the sensory cortex of our brains: how the smell of baking bread, the sound of an oboe, the taste of a peach, and the colour of a sunrise are all embodied in a vast chorus of neural activity."

SO WHERE can any meaningful discussion of this most complex structure begin? The brain's vital statistics may not at first seem grand. It weighs between one and two kilograms, depen-ding on a person's build, although brain size itself bears no relation to intellectual ability. It may account for only about 2 per cent of total body weight, but it consumes 20 per cent of the energy needed by an adult. Not only does it eat up oxygen and glucose like no other organ, it needs energy continually day and night and cannot tolerate more than a few minutes without it.

The reason for this prodigious and unremiting demand is the enormous amount of effort the brain expends on continually generating electrical voltage. Each nerve cell transmits signals in the form of a change in this voltage between the inside and outside of the cell. Electrical waves lasting just a few thousandths of a second pass down the nerve cell to the point where one nerve meets another. It is at this minute gap - the synapse - that the really clever processing of nerve impulses takes place.

This is where the electrical signal gives way to a chemical transmitter that travels almost instantaneously across the synapse to act upon another nerve. Scientists have identified something approaching 50 different neurotransmitters, each capable of acting in a unique way, sometimes stimulating, other times inhibiting, the firing of further electrical impulses in a second neuron.

The best known example is acetylcholine, the first neurotransmitter to be discovered, nearly 70 years ago. Like other neurotransmitters it works by binding to a specific receptor on the membrane of a nerve cell, much like a key fitting a lock. Change the lock or the key and you block the neurotransmitter. Curare, the toxin used by South American hunters to paralyse their quarry, binds to acetycholine's receptors, thereby preventing the union of key with lock.

It is the sheer number of cells and their connections that really makes the brain special. There are 100 billion nerve cells - neurons - in everyone's head and each cell can connect with up to 10,000 others. There are about as many nerve cells in each person's head as there are stars in the Milky Way, but that alone cannot account for the brain's complexity. As Gerald Fischbach says: "The liver probably contains 100 million cells, but 1,000 livers do not add up to a rich inner life."

The real secret of the brain's uniqueness rests in its nerve connections, which occur in unimaginable profusion. Susan Greenfield, lecturer in pharmacology at Oxford University, who gave last year's Royal Institution Christmas Lec-tures, cites the startling fact that if you were to start counting all the connections in just the cortex of the brain - its outer layer - at the rate of one a second, it would take you 32 million years to count them all. And to think that each connection is like a sophisticated dimmer switch.

Paul Churchland has another analogy to explain the brain's enormous potential. Take a typical televison screen, which is composed of about 200,000 picture dots, or pixels. Each pixel is capable of varying its brightness to make a composite, moving image. Professor Church-land says that each neuron in the brain can be likened to one of these pixels, but because there are so many more of them it means that "the brain's representational capacity" is about half a million times greater than that of a televison screen. "To get a TV display large enough to compete with the representational power of a single human brain, we would have to tile the entire outside surface of one of the twin towers of the World Trade Centre in New York City - all 500,000 square feet of it - with fully one-half million 17- inch TV screens, all glued cheek to cheek and facing outwards."

SO MUCH for the sheer profusion of brain cells, but what exactly are they? The first person to see a nerve cell was Camillo Golgi, an Italian scientist who allegedly accidentally knocked a piece of brain tissue into a solution of silver nitrate where it remained for several weeks before he found it again. The silver nitrate had leached into the neurons, making them stand out against the background of other cells when Golgi viewed the tissue under a microscope.

What he saw was that each neuron has a squat cell body between two-hundreths and one-tenth of a millimetre long, out of which sprout long tentacle- like filaments. These are the transmission cables that pass the nerve impulse from one end of the cell to another. The length of the tentacles and the amount of branching varies from cell to cell and from person to person.

A newborn baby has a brain about two-thirds the size of an adult; although we do not acquire new brain cells after birth, these cells grow out to make more connections with other cells as a child matures and develops. Scientists believe this is how we learn, memorise and acquire knowledge. In people with senile dementia there is a noticeable decline in the amount of branching and the number of connections. This shows that Shakespeare was right when he described the last of his seven ages of man as ''a second childishness and mere oblivion''.

Richard Frackowiak, director of the Wellcome Department of Cognitive Neurology at the Institute of Neurology in London, explains the importance of nerve connections being made, and indeed broken. "We know that the brain can modify its patterns of connectivity even though it is quite true that when a nerve cell dies it doesn't seem to regenerate. But nerve cells can alter the way they talk to other nerve cells very considerably. They can alter the number of nerve connections and the strength of connections. The change in connectivity is, in fact, probably the basis of our learning, the wisdom we gain from experience, and for everything we acquire in adult life."

THE BRAIN itself is nothing much to look at, bearing a passing resemblance to a dried-up walnut. To the cartographers of the human mind, however, each fold and crenulation is pregnant with possibilities. The two halves of the brain, the right and left hemisphere, may look the same but it has been clear for many years that they serve different functions.

The left hemisphere controls movements of the right side of the body, and vice versa, which is why for 90 per cent of the population (who are right-handed) the left side of the brain is said to be dominant. The left side of the brain is good at analysing information in a logical way, which is probably why the language centres are positioned there. The right side is important for perceiving emotions in other people and understanding visual patterns and music.

At this point it would be easy to gain the impression that the brain is a bit like the Numb-skulls cartoon strip, with each homunculus sitting in his own brain cell carrying out a designated task. Indeed, there are general conclusions that can be made about given areas of the brain being responsible for certain functions, but as brain-scanning has become more exact, it is clear that no single area of the brain acts in isolation. In fact, different parts of a single human activity, language for instance, appear to be processed by different regions of the cerebral map. Brain- scanning has shown, for example, that different areas of the brain are involved in the different language tasks of hearing words, seeing words, speaking words and generating verbs.

There are several types of scanning technology. The first, developed 20 years ago, is computed tomography or CT scans, where X-rays are fired into the brain to build up a three-dimensional pictures. Although this brought the first really useful images of the living brain, including tumours and disease, it has one substantial limitation, namely that it cannot show short-term changes in brain activity.

Much clearer and more detailed images came about with the development of magnetic resonance imaging or MRI. This relies on the fact that molecules act like tiny magnets and will line up in a stronger magnetic field. Stimulating the molecules with beams of radio waves makes them emit radio signals when they spin back into position, allowing the scanner to construct very detailed images of the brain based on the position of these molecules.

A further enhancement to the technique is known as "functional" MRI, where the aim of the scan is to relate activity within a brain region to a certain designated task. Blood flow, oxygen and glucose are the key markers used to monitor brain activity. "Whenever nerve cells fire in the brain they consume energy,'' says Professor Frackowiak. ''So whenever they fire, blood flow increases locally in the brain. By mapping local changes in blood flow, you can map where nerve cells are firing." This means that the scanner can pinpoint to within a few millimetres those regions of the brain working hardest on a particular task (reading a book for instance).

A similar technique is adopted by a further type of scan, called positron emission tomography or PET scan. This involves monitoring the movements of radioactive substances in the brain. If a patient is injected with radioactive glucose, for instance, a PET scan can monitor varying concentrations within the brain, again to identify areas that are working hardest on a particular task, which use up more glucose.

Volunteers may, for example, be asked to remember words on a screen while they are in a PET scanner in order to localise the areas of the brain involved in memory and language. Similarly, psychiatric patients may undergo PET scans in order to identify how their brain activity differs from that of healthy subjects.

Professor Frackowiak says that it takes at least 30 seconds to take a PET scan picture of the brain, which is no good for measuring the millisecond changes that occur within a brain. The race is on to improve on this and one of the most promising techniques involves placing electrodes around the head to monitor the minute changes in electrical and magnetic fields of firing neurons as and when they occur. "This technology is the least developed but it does give you millisecond upon millisecond resolution," he says.

Brain-scanning technology has already provided enormous insights into the human brain, from determining the differences between how men and women think to how differently musicians and non-musicians perceive sounds when listening to music. Some psychologists are even finding intriguing differences in the brain scans of murderers and non-violent criminals.

More importantly, scanning is starting to reveal the possible underlying causes of psychiatric illness and senile dementia, which affects one in 10 people and soaks up about half of the national health budget. "The understanding of what goes wrong in those brains is going to rely critically on our understanding of the function of the brain," Professor Frackowiak says. Studies of how the diseased or damaged brain can repair itself also promises to become of immense importance to the treatment of the mentally ill, he says.

"Curiously enough, a very common experience of people who suffer a stroke is that after the stroke there is over the longer term, say three to six months, a considerable recovery. Sometimes it can be so considerable as to be almost complete. This phenomenon has no explanation at the moment, but clearly if we could understand it in terms of functioning of the brain perhaps we could modify it to help patients in a way that's not been tried before."

Brain scans are only just beginning to open windows into the human mind. One day they may provide that most elusive of medical breakthroughs: a cure for mental illness. !

BRAINBOX

The brain weighs about the same as a bag of sugar - about 2 per cent of body weight - but accounts for up 20 per cent of the body's energy needs.

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A 100 billion nerve cells are packed into every human head. There are as many stars in the Milky Way galaxy as there are cells between your ears.

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Each nerve cell can be connected with up to 10,000 others. Counting each nerve connection in the human brain cortex - the outer layer - at the rate of one a second would take 32 million years.

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As each connection involves at least 50 different chemical transmitters, the human brain is the most complex structure known to the human mind.

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