The Mind-Fixers

by Jon Franklin

© 1984 by The Evening Sun

This piece won the inaugural Pulitzer

for expository journalism in 1985

Since the days of Sigmund Freud the practice of psychiatry has been more art than science. Surrounded by an aura of witchcraft, proceeding on impression and hunch, often ineffective, it was the bumbling and sometimes humorous stepchild of modern science. But for a decade and more, research psychiatrists have been working quietly in laboratories, dissecting the brains of mice and men and teasing out the chemical formulas that unlock the secrets of the mind. Now, in the 1980s, their work is paying off.

They are rapidly identifying the interlocking molecules that produce human thought and emotion. They have devised new scanners that trace the flickering web of personality as it

dances through the brain. Armed with those scanners, they are mapping out the terrain of the human psyche.

As a result, psychiatry today stands on the threshold of becoming an exact science, as precise and quantifiable as molecular genetics. Ahead lies an era of psychic engineering, and the development of specialized drugs and therapies to heal sick minds.

But that's only the beginning: The potential of brain chemistry extends far beyond the confines of classic psychiatry.

Many molecular psychiatrists, for instance, believe they may soon have the ability to untangle the ancient enigma of violence and criminality.

Further, there is the promise that the current technology will lead to the development of drugs capable of expanding the workings of the normal mind -- enhancing memory, heightening creativity and perhaps, one day, even increasing intelligence.

Ultimately, interviews with more than 50 scientists indicate, the revolution may offer us the most important gift of all: a dramatically improved understanding of who we are, why we are that way, and what it means to be human.

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Molecular psychiatry, like the new genetics, is based on a chemical interpretation of events in and around the living cell. Human perception, feelings and behavior are seen to result from submicroscopic interactions -- the complex interplay of Tinker-Toy like molecules that make up natural substances resembling heroin, Valium and alcohol.

Like molecular genetics, molecular psychiatry possesses the inherent ability to be both precise and quantifiable and, again like genetics, it lends itself to the deliberate process

of altering nature, the process called "engineering."

But unlike molecular genetics, which concerns itself only with the physical makeup of the human animal, molecular psychiatry pushes the frontier of science to the eerie and

mythical boundary that divides the physical and the mental.

Many philosophers, in recent years, have begun to ask whether that barrier will be breached. But according to most of the scientists involved, the point is moot. The mind-brain barrier has been probed and found not to exist.

They say there is no distinction between mind and brain; the one is a direct, mechanistic outgrowth of the other. At least a few philosophers share this view.

"We're out-and-out materialists," says Dr. Daniel C. Dennett, professor of philosophy at Tufts, summing up a Johns Hopkins scientific conference on the issue.

Or, in the blunter words of one neuroanatomist, "The brain is an organ; it produces thoughts the same way the kidney produces urine."

If that attitude outrages some philosophers and priests, the scientists themselves are unperturbed.

A little philosophical discomfort, they say, is a small price to pay for a new science capable of curing the mental diseases that afflict perhaps 20 percent of the population and constitute a major drain on the gross national product.

And scientists like Dr. Candace Pert, a key figure in brain chemistry at the National Institute on Mental Health, say the mechanistic view is in fact the most humanitarian one.

She argues that thinking of the mind as something spooky and apart has historically led to judgmental attitudes toward the insane.

"It's sad, but even today, this far into the 20th century, mental illness is not even totally talked about. It's still considered something ugly, something to hide. People are ostracized.

"But people who act crazy are acting that way because they have too much or too little of some chemicals that are in their brains. It's just physical illness! The brain is a physical thing!"

As molecular psychiatry proceeds in the direction of curing and even improving the function of the brain, it has become a magnet for some of the brightest minds and biggest names in biology.

Francis Crick, the molecular geneticist who won the 1962 Nobel prize for his part in unraveling the secret of DNA, has switched his field of study to molecular psychiatry. Another convert is Gerald M. Edelman, who won the Nobel for studies of the molecular basis of immunity. They are joined by hundreds of top students from the nation's medical schools and graduate programs.

What is this new science? What are its principles? From what promises flow its optimism and appeal?

The flavor is conveyed most dramatically in the words of the scientists themselves as they strive to convey their view of the brain and their hopes for the future:

Dr. Michael Kuhar, a brain chemist at the Johns Hopkins Medical School: "The working unit of the brain is the [receptor]. You can think of the receptor as a button. Chemicals

come and push that button and make things happen.

"The brain is this complex array of buttons. You give certain drugs which hit certain receptors and certain things happen in the body. It might be an emotional experience, a

thought experience -- it might be a constriction of blood vessels, or a release of gastric acid. You know, stuff like that."

Dr. Marcus Raichle, neurologist and radiologist at Washington University in St. Louis: "This is very seductive stuff . . . for the first time we have the prospect of looking [inside the brains of] living patients with emotional disease, and looking at specific regional changes in their brains.

"I think we are going to find that there is a biological basis for many behavioral disorders."

Dr. Paul Mandel, at the Center for Neurochemistry in Strasbourg, France: "People don't realize that psychology is a result of chemical behavior. That's why alcohol changes behavior . . . it acts on the other molecules. A lot of behavior has relatively simple physical causes.

"Specifically, the purpose of my research is to produce drugs for aggression . . .

"Aggression is like any other disease. It's the lack of inhibitory mechanisms that can be produced by genetics and/or the environment, and there's no reason not to treat it if we can."

Dr. A. John Rush, a brain scanner expert at the University of Texas Health Science Center in Dallas: "I would think that within 10 years we'll have at least one or two biotechnologies that will tell us a great deal about the probabilities that someone will in fact develop a [psychiatric] illness. I think we're going to able to identify people with a reasonable degree of reliability . . . say seventy percent."

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The technology that underlies the attitude, and the hope for the future, is often traced to Baltimore. It is here, in 1973, that Dr. Solomon Snyder and Candace Pert, then a doctoral candidate in Snyder's laboratory at Johns Hopkins, succeeded in labeling and identifying the sub-microscopic chemical sensors that stud the membranes of brain cells -- the "buttons" that Dr. Kuhar describes.

That discovery opened up psychology as a quantifiable science.

The excitement spread rapidly through brain laboratories around the world as scientists confirmed the Snyder-Pert research and went on to identify, label and map the distribution of other behavior-affecting molecules in the brain.

The technology behind the Snyder-Pert breakthrough also led to an ability to readily create powerful new chemicals capable of literally changing the mind.

Most of the early work, which required dissection of the brain, was performed on animals. But before the 1970s were out, scientists had produced several types of powerful brain scanners capable of monitoring the living chemistry of thought in the human brain itself.

The scanners do for brain scientists what telescopes did for early astronomers. Though the scanner technology is still in its infancy, it has already allowed scientists to peer into the

brains of living, thinking human beings -- and has produced a variety of findings that tend to bear out the mechanistic view of the mind-brain.

For example:

o At the University of Texas Health Science Center in Dallas, scientists have discovered that normal people use their brains in very individualistic ways, producing scans so

characteristic that they can be likened to "fingerprints." In patients with multiple personalities, shifts in the patterns correlate with changes in persona.

o At the Washington University in St. Louis, where the first of the new generations of brain scanners was developed by a team led by Dr. Michel M. Ter-Pogossian, scientists have

produced the first solid proof linking a perceptual disease with a chemical abnormality. The disease involves panic attacks.

o At the Brookhaven National Laboratory in New York,

scientists with one of the most modern scanners available seem to be homing in on pinpointing a similar abnormality in the brains of schizophrenics.

o At Hopkins, in Baltimore, researchers led by Dr. Henry Wagner have for the first time labeled and mapped the distribution of receptors in the living human brain. In the

process they have uncovered evidence that may explain why males become calmer as they grow older.

The explosive pace of discovery, says Dr. Joseph Coyle at Hopkins, "bodes well for the future.

"It suggests that we're approaching a point when we'll be able to make some coherence out of this wealth of information. I'm optimistic . . . we've gone from ignorance to

almost a surfeit of knowledge in only 10 years."

Dr. Fred Goodwin, chief scientists at the National Institute of Mental Health and as such the government's top research psychiatrist, agrees.

"We're being flooded with data," he says. "If you project the rates of growth [of knowledge], you'd have to say it's still accelerating . . . expanding exponentially.

"As we become sophisticated about understanding the biology of behavior, the more potential we get for altering behavior biologically."

He says scientists now understand, for instance, the chemistry of anxiety. "We now know biologically what anxiety is. We can turn it on and turn it off."

The objective is nothing less than mind control . . . the therapeutic kind.

In addition to anxiety, the target diseases include the obvious ones: schizophrenia, depression, manic-depressive disease, obsessive-compulsive disease, Huntington's disease and

Alzheimer's disease.

But the list goes on to conditions that laymen tend to consider from a moralistic, not medical, point of view.

Many scientists, for instance, suspect that drug addiction may occur because of genetic or environmentally induced defects in the addict's psychological pain centers.

In this view the addict takes drugs in an attempt to alleviate a terrible agony; in his position, any one of us might do the same.

And then there's the subject of criminality.

Dr. Goodwin at NIMH sees the violence-prone criminal as often suffering from one of many physical brain ailments that makes him unable to control his actions.

If those ailments could be diagnosed and treated (and there is research to this end), society might be spared a large percentage of its violent crime. The rising costs of the penal

system might also be trimmed.

Such research quickly spills over into the political arena.

In France, Dr. Mandel's research on the chemistry of aggression has convinced him that the Ayatollah Khomeni is a sick man, suffering from a chemical imbalance in his brain

triggered by religious fanaticism.

In Dr. Mandel's theoretical framework, the Ayatollah and his followers could "benefit" from the administration of drugs being developed in Mandel's laboratory.

And still, penetrating further and further into forbidden territory, the possibilities unfold.

If the new science could alter the minds of psychotics, criminals and bigots, what might be done to enhance the functioning of the "normal" brain?

Plenty, in the view Dr. Goodwin at the NIMH. Already, he says, there is a drug that will improve the memory of normal subjects. And research seems to be pointing toward still another

drug, perhaps related to PCP, that will enhance creativity.

Dr. John Lion, an aggression expert at the University of Maryland Medical School, believes such findings puts molecular psychiatry at serious odds with the current social and legal

systems.

Where does that conflict lead?

According to Dr. Fritz Henn, chief psychiatrist at the

State University of New York at Stony Brook, most scientists shy away from thinking about that question. He doesn't think about it much himself.

"It's much more fun," he explains, "to talk about what the next [important neurochemical] is going to be, and how it may be a key to unraveling an illness you're interested in. This [question of dangers] is a much stickier and tougher question. And it's not really a scientific question. It's a political question."

But when the tape recorder is turned off, a few scientists admit that they do think about it -- and that they're very concerned.

"We're approaching an historic moment of truth," muses one scientist. "The knowledge that's being produced is rapidly becoming an irresistible force, and it challenges our basic perceptions about who we are . . . about religion, politics, criminality, right, wrong and free will.

"Historically, society doesn't react very well to challenges like this -- especially when they come without warning, out of the sun. And most people are blithely unaware of

what's happening. Philosophers, those who get involved at all, put most of their energy into denying the obvious. So there's no preparation, and it's all happening very rapidly.

"Under circumstances like that, society is pretty much an immovable object. It always has been. So there is going to be a collision, and it's going to be epochal proportions."

The Mind-Fixers: Part II

The Theory

Brain scientists have developed a revolutionary new theory of molecular psychology that is catapulting the study of human behavior into the realm of the exact sciences.

That theory, now broadly confirmed by laboratory experiment, reveals that the human mind is controlled by the chemical flux of molecules playing against the surface of brain

cells.

Don't be misled by the word "theory." In the world of science the development of a theory is a substantive event, a turning point that often leads rapidly to a technological

revolution with broad social impact.

So it was with the theory of relativity, which opened the way to fission and fusion bombs, atomic power, and nuclear medicine. In biology, the more recent development of a theory of

molecular genetics during the 1950s and '60s led, in the '70s and '80s, to genetic engineering.

The new body of knowledge about molecular psychology also appears to be leading to a new type of engineering -- psychic engineering.

This involves a precise alteration of the chemical activity in the brain in order to correct for, and therefore overcome, mental illness. Prominent researchers also believe

such engineering can also be used to enhance the function of the normal mind.

So it is that the new psychology may have medical, social and political consequences at least equal to those flowing out of the theories of relativity and molecular

genetics.

To understand why this is so we must focus our attention on the theory itself, and on the once-mystical organ of personality -- the human brain.

On the level of the naked eye, the brain is a gray, jelly-like mass that retains its shape only because it's encased in a tough membrane. It weighs an average of two and a half

pounds, and is so unimposing that, throughout most of the Christian era, anatomists assumed that its function was only marginally important.

It was only with the discovery of the microscope that the incredible complexity of the nondescript gray organ became apparent.

Under the light microscope, the functioning unit of the brain can be seen to be an individual gray cell called a "neuron." There are so many neurons that no one has ever

succeeded in counting them; estimates of their numbers in the average brain range from 10 billion to a trillion. Brain cells come in various sizes and shapes, but each

has a long tail called an "axon."

The tail stretches through the brain until, as it nears its destination, it splits up into smaller tails. The end of each tail-let lays against the surface of another brain cell.

In the 1800s it was discovered that one of the functions of the neuron was to generate electrical signals and "fire" them down their axons. More modern scientists with delicate probes

determined that the neuron idled at about one impulse per second, but could almost instantly increase its frequency to sixty impulses per second.

Though each charge is relatively weak, there are so many firings in any given instant that they average out to produce a measurable magnetic field; that's the source of the squiggly

lines on a neurologist's electroencephalograph, or EEG machine.

By early in this century scientists had begun to understand that the brain was a computer of some sort; the individual elements were apparently the brain cell, and their

axons comprised the electrical wiring.

The electrical "wiring diagram," though, had one very puzzling aspect. The axons that carried the charge didn't make actual physical contact with their "target" cells.

Instead, the axons terminated in club-like structures that looked like barnacles and were named "boutons." There were so many boutons that they literally covered the brain cells . .

. covered them, but didn't touch them.

That was a real enigma. How did the electrical message get from the bouton to the brain cell? Certainly the electrical charges couldn't jump the gap; there could be no sparks in the

wet goo of the brain.

This gap between bouton and brain cell, called the "synapse," came under intense scrutiny when electron microscopes became widely available in the 1950s and '60s.

Finally, from the laboratories of biochemists and electron microscopists, the answer began to emerge. It was a strange one, and it carried scientists of the mind into the

submicroscopic, Tinker-Toy world of the molecule.

The gray neuron, it turned out, had not one function but two. In addition to producing electrical charges it manufactured strange, hormone-like chemicals called "neurotransmitters."

What's more, the tail of the gray cell wasn't much like a wire at all: It was a hollow tube. While electrical charges flowed down the outside, neurotransmitters were pumped down the

inside and stored in the bouton at the end.

The bouton, as it turned out, was covered with tiny nozzles on its underside. Each time it was hit by an electrical charge, the nozzles opened and chemicals streamed out, spraying

onto the surface of the adjacent brain cell

. Somehow, these chemicals transmitted information from the bouton to the underlying cell.

The messages, scientists first surmised and later proved, were coded in the shape of the molecule -- as was the case with hormones.

Only one question remained to complete the story of brain cell communication: How did the receiving cell "hear" the messages that were spraying onto its surface?

Scientists guessed that the answer was tiny, shape-sensitive antenna molecules on the cell's surface. Those theoretical "receptor" molecules were likened to locks; the

transmitter molecules were keys that snapped into the locks and, by doing so, activated them.

This idea assumed that brain cells were studded with thousands of receptor molecules.

The receptors were probably long molecules that extended from the surface of the cell deep into its interior, where the "foot" of the receptor was hooked into the cell's metabolic

throttle.

The exposed end of the receptor functioned as an antenna, equipped to sense one specific class of neurotransmitter molecule.

Presumably, when a transmitter molecule struck the surface of the receptor, the receptor's shape changed. In the cell's interior the "foot" of the receptor moved against the

throttle and the cell's metabolic engine speed either increased or decreased by one notch.

How many times the receptor's tail twitched each second probably depended upon how many transmitters were bombarding its antenna. Since there were hundreds or thousands of receptors on

each cell, and they were all being bombarded by transmitter molecules, the firing rate of the cell depended on the averaged-out signals.

That made sense, but it was guesswork. The proposed receptors were speculation; until they could be found, labeled and isolated for study, this new theory of how the brain worked

on a molecular level would remain a subject of debate among specialists.

Then, in 1973, at the Johns Hopkins Medical School, it happened.

The scientists were Dr. Solomon Snyder and a doctoral candidate, Candace Pert. Working together, they devised sophisticated new technique that allowed them to locate and label brain receptors with radioactive chemicals.

Their discovery was published that summer in Science magazine -- and it was a bombshell.

The scientific community understood the implications immediately. Cell-to-cell communication was the basis of thought and emotions, and the Snyder-Pert paper provided the last

chemical link in that chain of communications.

In a matter of months, the receptors were isolated and analyzed, and the whole picture coalesced into sharp focus.

As the tide of transmitters rose and fell in the living brain, and the receptors reacted, the neurons selectively changed their firing rates. As those rates changed, feelings and

thoughts wafted through the mind.

In principle, at least, the chemistry of thought was now understood; being understood, it could be specifically manipulated with drugs.

The age of molecular psychology had dawned.

Snyder and Pert gained instant worldwide fame in the scientific community; their breakthrough paper became one of the most widely quoted in recent history.

Within a few years Snyder would receive the coveted Lasker Award, assume the leadership of a major new neurosciences department at the Hopkins, and become a favorite candidate for a

Nobel Prize. He would also become a founding member of a drug research company with stock so hot that he would become a millionaire -- at least on paper.

Pert, the junior member of the team, walked into a bright future that would propel her to the head of a major neurosciences laboratory at the National Institute of Mental

Health.

They and other scientists, in the meantime, worked feverishly to confirm and elaborate on the theory. As the 1970s grew to a close, the organ of personality emerged as a

gizmo -- as a computer, no more and no less.

But it is no less wondrous for its mechanistic nature; as an information-processor, the brain puts man-made supercomputers to shame.

The most sophisticated human computers function in classic "digital" fashion: at any instant, a circuit is either off or on. The brain does this too . . . any transmitter

represents an "on" or "off" command, depending on whether or not it is a "stimulant" or a "depressant."

But while the variables in a man-made computer are confined to that digital code, the digital nature of the human brain represents only its most superficial level.

In the brain, for instance, the cellular "clock" can vary from one cycle per second to sixty. Additionally, the efficiency with which the cell can manufacture and transport

neurotransmitters down its tail is subject to rapid change. Finally, the receptors on its surface can change from minute to minute, making the cell more or less sensitive to input.

The brain incorporates another neat trick of nature when it uses chemicals instead of electrical impulses as a medium of communication. Electrical impulses are all the same, more or

less, but chemicals can differ almost infinitely.

So far scientists have identified about 50 neurotransmitters; there may be thousands before the full story is known.

Each represents a different way of saying "yes" or "no," and insures against "crosstalk" -- a "yes" message directed at one set of cells can't get mixed up with a different "yes"

message directed at another set, because each receptor can "hear" only one molecular shape.

The brain, in other words, is no mere computer. It is hundreds, perhaps thousands of computers, each superior to anything yet conceived by human engineers.

Yet all those systems and sub-systems and sub-sub-systems are completely integrated, tying together mood with thought with instinct with observation and summing them all

up in something called "personality" and "behavior."

The full complexity of the brain will not be plumbed in this century, and perhaps not ever. But the general theory, as it emerges as a laboratory tool, has immediate applications with

direct, practical implications for human society.

The easiest example to understand goes back to that 1973 Snyder-Pert breakthrough.

At the time, their work was financed by the drug abuse arm of the Alcoholism, Drug Abuse and Mental Health Administration. Their specific objective was to discover the

chemical mechanism of heroin abuse and addiction.

So it was that the first receptor to be discovered was the one for opiates . . . the class of chemicals that include opium, morphine and heroin. In broad terms, at least, the

discovery explained the mechanism of addiction.

Today, eleven years later, the addiction process remains a favorite example for explaining how the physical function of the brain translates into human mood and consciousness -- and

how specific drugs can be engineered to affect thought and feeling.

The heroin molecule, it turned out, is addictive because it happens to mimic the shape of a neurotransmitter that was later to be named enkephalin.

Enkephalin is manufactured in the pain centers of the brain -- not just the physical pain centers, but the psychological pain centers as well. Both use the same

neurotransmitters because, in the course of evolution, the psychological pain centers evolved from the physical ones.

That fact lies behind the world's drug abuse problem, and some of its most serious behavioral problems as well.

In the areas of the brain where physical pain is

processed, enkephalin serves a straightforward function.

Pain impulses flow continuously upward from the body, and must be screened. Enkephalin, pumped constantly into those pain centers, suppresses and desensitizes the pain-recognition cells so that they respond only when the pain exceeds a certain level.

In the psychological pain centers, the same transmitter suppresses minute-to-minute psychological pain. But in addition, it serves as a "good-feeling" chemical that rewards us for

behaviors that have been programmed into our brain either by genetics or environment (both are apparently of equal importance).

Enkephalin, it appears, is what we feel when mother smiles at us. Later in life, it rewards us when we achieve something mother would have classified as "success."

If on the other hand we DON'T have a mother's love, or if we have too little success, we are deprived of enkephalin. The same effect would result, regardless of mother and her love,

from a genetically weak enkephalin system.

Either way, the result is supersensitivity to background psychological pain. That pain is called "depression" and is no less excruciating for its "imaginary" nature.

If we live in a ghetto, and suffer that pain, we may discover a substitute for love and success -- a substitute that can be administered by needle. As the heroin floods into our

brain, the psychological anguish eases.

It matters not one whit whether our psychological pain is due to socioeconomic deprivation or a genetic malfunction in our enkephalin producers or receptors. The "addictive

personality" may in fact be a result of a luckless combination of both.

A similar effect, mediated through different receptors, can be achieved with alcohol, barbiturates, marijuana, and other drugs.

The pain-relieving high can even be achieved naturally, by torturing ourselves physically and thus stimulating the natural production of enkephalins.

So it is that the bed of nails is in fact a road to peace, and the "runner's high" is so potent that addicts have been known to run on broken ankles.

More subtle versions of the same thing can be discovered in our individual behaviors. Habits are mediated, in part, by the internal pumping of enkephalin. Depression, both natural and

pathological, is profoundly influenced by our enkephalin levels. Love is addicting. Food is addicting. Belief is addicting.

The broad point made by the Snyder-Pert experiments and those that followed was that natural drugs are the basis of human nature and behavior.

It followed, then, that malfunctions in personality such as schizophrenia or violent behavior might be caused by chemical disruptions in the brain.

That being the case, might the new theory of molecular psychology enable scientists to isolate the chemical defect involved?

And might the theory, coupled with the new technology used by scientists like Snyder and Pert, be harnessed to produce new drugs to combat behavioral diseases of the brain?

As for the question of powerful new drugs, the answer seemed to be an emphatic YES!

In one set of experiments a junior researcher at the Hopkins, working alone, was in two years able to produce a caffeine-like drug that was 500,000 times more powerful than the

original.

The race was on.

The object: Find the chemical basis of mental disease, and devise ways to correct it.

Whether cast in terms of economics or of human suffering, the stakes were astronomical.

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Mental disease, which in the nomenclature of molecular psychology also includes addiction, directly affects perhaps 20 percent of the population. It has a profound impact, both psychologically and economically, on all of us.

The cost of mental disease and addiction, for instance, was 106 billion in 1977, the latest year for which figures are available. This is more than half the projected federal deficit -- and those numbers are considered by most experts to be very conservative.

They do not reflect, for instance, the mind-shattering affect on the children of alcoholics, schizophrenics and depressives.

They do not include the cost of "accidents" that have a suicidal component. They do not include the cost, both to society and to the victim, of criminal behavior. And they do not

include the billions of dollars a year that flow out of the country as a result of illegal drug trafficking.

The human agony of the addictive disorders is reflected in the raw numbers produced by federal experts on drug and alcohol abuse.

There are at least 5.75 million alcoholics in America, for instance, and another 18 million "problem drinkers". About 60 million Americans have been addicted to other drugs, and 37.4

million are believed to have abused drugs within the last 12 months.

In the new psychology, addiction is viewed as a series of secondary changes in brain chemistry caused when a victim of a painful mental illness, such as depression, "self-treats"

himself with pain-killing drugs.

Experts on the traditional mental illnesses keep their numbers in a different form, but they are just as grimly impressive.

At least 10 percent of all children under 18, 15 percent of all adults, and 10 percent of adults over 65 suffer from classic mental diseases.

In the adult group, the most common forms of mental illness are the "affective disorders," which includes clinical depression and manic-depression disease.

These conditions afflict perhaps 8 percent of the adult population. They are characterized by disabling mood changes -- changes that brain scientists now believe can be

attributed to chemical alterations in the victim's brain.

A vulnerability to the affective disorders can be inherited, but the diseases are believed to manifest themselves as a result of environmental pressures.

The next most common category includes the phobias, anxieties and other neurosis, which affect about 7 percent of adults.

Once thought to be of purely "psychological" origin, at least one of these diseases (a type of panic reaction) has recently been traced directly to a physical impairment in a

specific section of the emotional brain.

Finally, there is schizophrenia -- a profound, inherited perceptual disorder that causes the patient to hear voices and see things that aren't there.

Though schizophrenia only afflicts about one percent of the population, it is a chronic and disabling disease that makes it economically comparable to the affective disorders and the

neurosis. It has been shown to involve chemical changes in the "dopamine" chemical system at the base of the brain.

Additionally, certain diseases have a preference for specific age groups. Autism is a disease of childhood, for instance, and senile dementia is generally found in older

people.

A number of these ailments, including Huntington's disease (an inherited physical defect that manifests itself as insanity in later middle age) and Alzheimer's disease (a form of

senility) are already known to be of strictly physical origin.

The Mind-Fixers: Part III

Depression

Perhaps 18 million Americans are victims of clinical depression. They are the "walking wounded" of the high pressure modern world, and the blue misery that dogs them affects the

rest of us as well; depression puts a steady drain on national productivity and is a major spoiler of family life and social tranquility.

But now scientists are making rapid progress in understanding the disease, and have already managed to trace it to a malfunction in two of the brain's chemical subsystems.

That and a cascade of other findings about the nation's most common mental illness has emerged from the new science of molecular psychology during the last few years.

"There have been incredible breakthroughs in the understanding of depression," says Dr. Candace Pert, one of the founders of the new science. "The prospects for the future have never been so bright."

Dr. Pert's enthusiasm echoes that of many neurochemists. And most believe the explosion of knowledge will translate directly into the creation of effective new drugs to combat depression.

Though no reputable scientist is willing to make specific predictions, most insiders interviewed by The Evening Sun say they would be surprised, even shocked, if such drugs didn't begin to appear within a decade.

More effective drugs for depression would have a dramatic social and economic impact, not just on the victims and their families but on the nation at large.

The various identifiable types of "clinical depression," as distinguished from the day-to-day depression experienced by normal people in the face of real setbacks, is thought to affect about 8 percent of Americans.

The diagnostic symptom is an overwhelming feeling of helplessness and a conviction that nothing the victim does will make any difference.

Other symptoms include loss of interest in the outside world, malaise, feelings of self-hatred and a delusional expectation of punishment or impending tragedy.

But in the complexity of the human mind, those symptoms may be masked by other responses (see box).

What's more, the symptoms can jump from the mental to the overtly physical as the disease runs its course and the patient, full of self-hatred, fails to practice good hygiene.

Whatever the manifestations, depression is among the most relentlessly painful of all known illnesses. Patients with overt depression who have also suffered a notably painful physical condition, such as kidney colic, report that the psychic pain is far worse than the physical.

Untreated victims of depression often end their agony with suicide, while others choose a slower form of self-destruction: drugs and alcohol.

Experts believe that much addiction can be attributed to depression; the victim becomes addicted in a desperate quest to numb the psychic pain of an underlying depression.

If this is so, and there is substantial evidence to suggest it is, then the "pure" depressive patient represents only the tip of the iceberg and the disease really affects up to 20 percent of the population.

This leads to an almost desperate need for antidepressants, but the search for those compounds has been severely limited.

For one thing, no one knew the cause of depression. For another, depressive disease was known to exist only in humans, so potentially useful drugs couldn't be screened in animals.

As a result, most of the currently-available antidepressant drugs were discovered by accident. Since they can't be readily improved through animal tests they are often

ineffective and retain serious, unpredictable and sometimes deadly side effects.

Today the single most effective therapy for severe depression remains electric shock treatment -- an alternative that many consider unacceptable.

Consequently millions of citizens with untreated depressive disease continue to function at home and work, but their performance in both arenas is often marginal.

Their listlessness and lack of motivation, coupled with their use of alcohol and drugs, is thought to be a major cause of absenteeism and work accidents, and to constitute a steady drain on productivity.

In addition, by contributing to the deterioration of family structures, depression entails an incalculable social cost.

"As we get new drugs for these things, it's going to have a tremendous economic impact," says Dr. Michael Kuhar, a neurochemist at Johns Hopkins University. "It's fantastic!"

Such effusive optimism from what is traditionally the most conservative quarter of biological science stems from the rapidly-accelerating pace of discovery in the field.

Depression, most molecular psychiatrists are now convinced, involves two specific subsystems in the brain.

One of those systems consists of brain cells that communicate with one another via the chemical transmitter "norepinephrine." The other uses "serotonin" to carry its signals.

Both are centrally involved in the limbic system, where mood and emotion are processed.

One of the clues that convinces scientists they're on the right track involves the recent discovery of how the antidepressant drug imipramine works.

Imipramine, despite its side effects and the fact that it is not universally effective, is one of the best antidepressants currently in use. But like other psychotropic

drugs, it was discovered by accident and no one knew why it worked.

Now molecular psychiatrists have found that it exerts its influence by snapping into a into a previously-unknown receptor in the emotional part of the brain.

Because of its shape, the imipramine molecule activates that natural receptor very much the same way the shape of a morphine molecule activates the receptor for enkephalin.

Morphine, of course, directly interferes with a major neurotransmitter system, the normal function of which is to establish a pain threshold. As that threshold rises, the morphine user gets a "high."

Imipramine exerts a much more subtle and specific modulating effect. The receptor it activates apparently controls fine-tuning in the serotonin system, which is responsible in part for the maintenance of mood equilibrium.

The imipramine triggers a metabolic chain reaction that results in the brain becoming more sensitive to its own serotonin. As it does so, the patient becomes less depressed.

Another recent piece of evidence involves the discovery that imipramine receptors are also present on the surfaces of some blood cells . . . but there are abnormally fewer of them on

the blood cells of depressed patients.

"In conjunction with this," adds Dr. Pert, "there are studies that show that there's reduced serotonin in the brain and cerebral spinal fluid of people who die by suicide. So it's

all wonderfully consistent. There's obviously something chemical going on."

Scientists are certain that that "something chemical" is, at least in part, genetic.

Studies of identical twins reared in the same household, for instance, have shown that if one twin becomes clinically depressed, the other has more than a 50-50 chance becoming

depressed as well.

But if the twins are fraternal, sharing parents, environment and birthdays but without identical genes, the statistics are dramatically different. If one such twin becomes clinically depressed, the risk to the second is elevated only slightly above normal.

Significantly, alcoholism tends to run in the same families as depression.

None of this is to say environment does not play a strong role. In fact, most experts believe that depression usually strikes people with a genetic vulnerability and who are also subjected to an environmental stress -- the "double hit" theory.

Even so, it has recently been shown that, if the stress is intense enough, the environment alone is enough to induce depressive disease.

In fact, environmental stress has been used to produce, for the first time, an animal model that can be used in laboratory experiments on depression.

One of the experts in induced depression in animals is Dr. Fritz Henn, Chief of Psychiatry at the State University of New York at Stony Brook.

Based on experimental work done at the University of Pennsylvania and elsewhere, he says, severe depression can now be triggered in any animal, "from rats to goldfish to humans."

The method is simple, and involves what psychologists euphemistically term "exposure to adverse stimuli."

A rat, for instance, might be put in a cage with a metal floor and exposed to occasional, unpredictable electrical shocks to its feet.

But it's not the shocks that induce depression. If there is a ledge the rat can jump onto when the jolts begin, the animal can endure the shock cage for extended periods of time while remaining psychologically normal.

But if the shelf or other escape route is removed, and the rat is totally helpless, the effect is dramatically different.

"When they can't predict when [the shocks] are going to come, and there's nothing they can do to stop them or escape from them . . . when they're waiting all the time to get hit . . . after a while . . . it looks as if [their minds] just shut down.

"They stop even trying to get away. They stop trying to do much of anything."

Like depressed humans, the rats exhibit eating disorders land lose interest in sex. They have trouble sleeping, and it's more difficult for them to learn.

Depressed humans say they feel helpless, without any ability to influence what happens to them. The rats act, at least, as though they feel the same way.

And, once depressed, they don't get over it.

If they are put back in the shock cage, but are now provided with an escape route, they don't use it. They don't even seem to have the will to try; instead, they hunker down and accept the shocks almost as though they deserve them.

"But when you treat them with a drug that's effective clinically [in humans]," Dr. Henn says, "something changes. Then they'll use the escape route."

By killing the rats at various stages, dissecting their brains and recording the chemical changes, Dr. Henn's group made a remarkable discovery.

As the rats become depressed, predictable alterations occur in their brain receptors. Those changes occur at the same time the behavioral changes are taking place, and affect the brain in exactly those places where anatomists would expect it to.

"We see these changes in certain receptor fields in the

[emotional] system. The receptors become more or less dense . . . "

The principal alterations, he says, involve a subtype of norepinephrine receptors in one area and serotonin receptors in another.

"And so both receptors seem to play a role," says Dr. Henn, "but they do it at different places. And they change as a result of experience . . . and they stay changed.

In itself, the development of an animal model for depression represents a significant breakthrough. As a result, drugs can be engineered specifically to activate or suppress the affected parts of the brain, and can then be tested and improved on live animals.

"I'm very excited about this," says Dr. Henn. "[With the rat model] we can really take apart the neurochemical systems and see what's changing, and what's changing in conjunction with the behavioral changes.

"And we can then treat the animal with medications and we can reverse the behaviors. We can look and see what's changing."

The result, he believes, will be to dramatically accelerate the development of new drugs to alleviate the agony and reduce the cost of human depression.

According to Dr. Fred Goodwin, chief scientist at the National Institute of Mental Health, it would be difficult to overestimate the importance of the exponential growth in our

knowledge of depression and other mental diseases.

He says a small foretaste of things to come can be found in the success story of lithium treatment for manic-depressive disease.

Manic-depressive disease is a subtype of depression that strikes about two percent of the population. It is characterized by dramatic mood swings from profound depression to manic hyperactivity.

During the 1960s it became a target disease for the development of the first rationally-engineered "psychotropic" drug. Though that work predated the revolution in molecular psychology, the scientists were nonetheless successful.

Lithium was introduced in Europe during the late 1960s, and proved dramatically effective in smoothing out the mood swings and restoring manic-depressive patients to good mental health. By 1974 it was in wide use in this country.

By 1982 the federal government had computed that the introduction of lithium had saved the taxpayer what Dr. Goodwin calls "a very conservative $18 billion dollars."

That figure, Dr. Goodwin emphasizes, does not take into consideration the indirect social costs of the disease, which includes diminished work productivity. Also, it did not consider

the impact on the families and children of manic-depressive patients.

As molecular psychology becomes an increasingly exact science, Dr. Goodwin says, he expects to see the development of new, more specific drugs with fewer side effects to replace currently-available antidepressants.

He also expects to see new drugs that will be effective for the 15 percent of manic-depressive patients who do not respond to lithium, and in the larger group of patients who don't respond at all to current antidepressant therapy.

Such drugs could dwarf the social and economic savings attributed to lithium.

If the theories that link depression to drug addiction are correct, and new antidepressant therapy can be translated into better drug treatment, the revolution in molecular

psychology will directly affect perhaps 20 percent of the population.

"There's no question," says Dr. Henn of Stony Brook, "that addiction is far and away the most serious and most costly mental health problem in the country.

"A study that was just completed at NIH documents that.

Just walking away, alcoholism is the single most serious mental

health problem we have.

"If we can find out what that is, and do something about it, the impact in terms of savings to the country would just be enormous. Absolutely enormous."

Not since the public health revolution in the 1800s, and the eradication of filth-borne diseases have the stakes been higher.

And depression research represents but one battlefront in the molecular psychology revolution.

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Sidebar

The Fortunate Ones

Feel the Pain

Depressive illness is one of the most painful conditions known to medical science. Yet, because of the strange ability of the mind to damp out and transfer pain, many victims aren't even aware that anything's wrong.

"The vast majority of people who are depressed do not know they're depressed," says Dr. Joe Coyle, a molecular psychiatrist at Johns Hopkins Medical School.

He says that the victims who can feel the psychic pain directly are in some respects the lucky ones. Their pain may compel them to go to a psychiatrist and get treatment.

But the majority of victims, unable to face the situation squarely, are not so fortunate.

Unable to accept the psychic pain for what it is, their brains translate the agony into a more readily understandable form of pain -- the physical kind. Or they wall it off and treat it with psychic painkillers like alcohol or heroin.

That presents a real problem, Dr. Coyle says, both for psychiatrists and for family doctors whose waiting rooms are filled with people whose pain, quite literally, is all in their heads.

The Hopkins neurochemist tells a classic story of a team of scientists who were searching for volunteers to help test a new antidepressant drug.

The researchers advertised in the paper, offering free treatment for depression in return for participation in the drug trials. They got a few takers, but not many.

Then one of the scientists had a brainstorm.

The next ad didn't ask outright for depressed volunteers. Instead it included a simple checklist of symptoms: Have you lost interest in sex? Do you feel hopeless? Do you have trouble with insomnia? Do you often feel that you are a bad person? The scientists' telephone started ringing as soon as the newspaper hit the streets, and didn't stop for days.

"Many people," said Dr. Coyle, "got very upset when they found out they were calling a psychiatric clinic. They didn't perceive that they had a psychiatric problem.

"There's a very high tendency for persons with psychic pain to complain of physical pain . . . many of these people go to their local physician with inscrutable disorders, and with pain that doesn't seem to have any physical basis."

Pain clinics, including the one at Johns Hopkins, have documented that many people with intractable back pain are in fact suffering from depression and similar disorders.

The traditional psychiatric explanation is that the mental pain gets subconsciously channeled into the physical pain processors in the brain.

A molecular psychiatric explanation, says Dr. Coyle, is that in depression the pain threshold is lowered throughout the brain. As a result, otherwise minor pain is translated into unbearable agony.

"The mind plays tricks. Different people do different things. A lot of people don't think psychologically . . . they don't put all these symptoms together and say, 'Well, I must be depressed.'

"What you're talking about is this oppressive feeling of hopelessness and lack of energy . . . I can't sleep . . . my appetite's lousy . . . you know, it requires a certain amount of sophistication to tie those things together and see it as a problem with mood.

"We're talking about a rather serious disturbance in brain function that has pervasive affects on the brain and in the body as a whole.

"We call it 'depression' but in fact the prominent symptoms can involve all the fundamental bodily functions. Individuals often ascribe the mood change, the depression, to the fact that they're physically sick . . . rather than the other way around."

But if mentally ill patients often end up in treatment for physical ailments, the opposite is also true.

Many patients who seek psychiatric treatment for depression turn out not to have primary depression at all. Instead, the depression is being inadvertently caused by a drug prescribed by their family doctor -- many drugs, including compounds commonly prescribed for heart disease and high blood pressure, can induce depression as a side effect.

But when a patient is in fact clinically depressed, and when that patient gets to a psychiatrist, the treatment can be straightforward.

If the depressed patient is one of those for whom drugs like imipramine are effective, the course of therapy can be relatively brief. The physical symptoms go away first, and are followed by the psychological ones.

"It usually takes somewhere between two and six weeks to respond to treatment with antidepressants," says Dr. Coyle. "Then they feel better. They're able to go back and live their lives."

Often the patient is surprised, even disbelieving, as the symptoms vanish.

"The ones who are psychotically depressed frequently have great difficulty making sense out of what happened," says the Hopkins scientist. Some patients never do quite comprehend that they were the helpless victims of changes in their brain chemistry.

Many deny that the doctor did anything at all.

"You just tell them, 'Okay,'" sighs Dr. Coyle. "You tell them, 'Well, if these things return . . . come back and see us and we'll make you feel better again."

The Mind-Fixers: Part IV

Schizophrenia

Schizophrenia, the most expensive and devastating of all the common mental illnesses, has been revealed as a physical ailment involving a malfunction in the dopamine system at the base of the brain.

Since 1973, when it became possible to study the brain's chemical communications network in detail, the story of schizophrenia has unfolded so rapidly that scientists are having trouble just keeping track of new discoveries.

Most senior researchers are confident that those discoveries, as they coalesce into new theories of the disease, will eventually result in the creation of specific drugs that will allow victims of the disease to live more normal lives.

Such drugs, which may begin appearing within the next ten years, would have a dramatic economic and social impact.

Schizophrenia, which strikes about one percent of the population and tends to run in families, is the classic example of mental illness.

Its victims hear voices, have visual hallucinations, and often become profoundly and even dangerously paranoid. As the disease progresses, patients frequently withdraw and become

suicidal.

Schizophrenia is particularly tragic because it generally strikes in the teens and early 20s. The disease is chronic, progressive and incurable, sentencing 80 percent of its

victims to lifelong dependency on mental health and social welfare agencies.

According to Dr. Fred Goodwin, chief scientist at the National Institute of Mental Health, these factors combine to make schizophrenia a disproportionately expensive diseases.

In 1976 alone, he says, schizophrenia cost the nation a conservative $20 billion dollars.

That does not include indirect social and economic costs to the families, nor does it include the expense of crime attributable to schizophrenia.

Though only a tiny minority of schizophrenics commit crimes, those who do are usually responding to paranoiac impulses -- they are in effect trying desperately to protect themselves from dangers that only they perceive.

As a result the violent schizophrenic is very unpredictable, and the crimes he commits can be bloody and spectacular.

Until the second half of the 20th century schizophrenics were warehoused in the back wards of mental hospitals. Most psychiatrists considered the disease to be a psychological one, resulting from a poor family environment.

However, Freudian-based methods were notably unsuccessful in alleviating the symptoms of the disease. The only useful treatments were prefrontal lobotomy and

electroconvulsive shock therapy, which sometimes served to make them slightly more manageable.

Then in 1957 an accidental discovery led to the introduction of the drug thorazine and foreshadowed the development, a decade and a half later, of the new molecular psychology.

As was common in those days, scientists were using mental patients to test a new drug -- in this case an antihistamine designed for the control of allergy symptoms.

The compound, as it turned out, didn't do much for the schizophrenics' runny noses. But, remarkably, the schizophrenics' minds seemed to improve; their hallucinations subsided, and they began making contact with reality.

Though termed a "tranquilizer" by a misunderstanding public, thorazine had very specific effects on the perceptual function of the mind. History's first truly antipsychotic drug had been discovered.

A whole new generation of scientists, studying the effects of thorazine, became convinced that schizophrenia must be a physical disease of the brain. That implied that other serious mental illnesses might also have a physical basis.

It was a revolutionary perception. If true, then there was hope to be had from science. If only researchers could develop a chemical theory of the brain, they might design other

drugs that would help a wide variety of patients with other "mental" diseases as well.

This proved to be a powerful dream. After a decade of work by visionary scientists, it led directly to the development of the new field of molecular psychology in the '70s and '80s.

Thanks to thorazine, and to better versions of the same thing that came afterwards, the lot of the schizophrenic improved.

The strait jacket and isolation cell faded into memory; shock treatment and prefrontal lobotomy fell into relative disuse. Increasingly, schizophrenics on drug treatment were released from mental institutions.

Despite early claims, however, the patients were by no means cured. Thorazine relieved the hallucinations but the "negative" symptoms, including withdrawal and emotional isolation, continued unabated as the disease ran its course.

Most schizophrenics, while no longer confined, remained unable to live normal lives; the vast majority remained social and economic wards of the state. Many listlessly wandered the streets.

To make things worse, the drugs produced serious side effects. Early in the course of treatment the patient often developed a Parkinson-like slowing of bodily movements and awkward posturing. Sometimes the eyes rolled up into the head.

These early effects could be treated with anti-Parkinsonian drugs and, if all else failed, they subsided if the thorazine was withdrawn. But a longer-term set of side effects, termed "tardive dyskinesia," were permanent.

Tardive dyskinesia was horribly disfiguring. The victim's limbs moved restlessly; his face jerked, his mouth made involuntary chewing movements, and his tongue writhed and darted in and out, snakelike.

Tardive dyskinesia occurred in as many as 40 percent of the cases. It made the schizophrenic repulsive to others, and thus contributed further to his isolation.

On the one hand, the antipsychotic drugs relieved the hallucinations and delusions of schizophrenia; on the other, the side effects were a powerful incentive for the schizophrenic to avoid taking the stuff.

In the years following the 1957 discovery of thorazine, the victims of other mental illnesses -- most notably manic-depressive disease -- benefited dramatically from the discovery that chemical compounds could be used to treat thought disorders.

But schizophrenia, the most profound psychosis of all, remained resistant. While doctors learned to treat the early side effects, and could often stave off tardive dyskinesia by a more conservative use of drugs, the "negative" effects of the disease remained untreatable.

The key to better treatment would be found, scientists believed, once the chemical nature of the mind was better understood.

And so it was that in 1973 the discovery of the first brain receptor at Johns Hopkins Medical School by Dr. Solomon Snyder and Candace Pert triggered an explosion of schizophrenia research.

Within a year the search had narrowed to a structure in the base of the brain corpus striatum. The striatum was composed of brain cells that communicated with one another via a chemical transmitter called "dopamine."

Significantly, the striatum had two projections, or nerve trunklines, that reached up into the higher brain. One of those projections went to the limbic system, where emotion is

processed; the other led to the frontal lobes of the cortex, the seat of consciousness and personality.

These projections were the conduit through which the striatum pumped dopamine into the higher structures. Presumably, the dopamine was the means by which the striatum regulated thought and emotions.

According to Dr. Solomon Snyder, whose laboratory isolated the dopamine receptor in 1974, it is now known that all drugs effective in schizophrenia work by blocking the action of dopamine.

By blocking dopamine communication, the thorazine and related compounds reduce the amount of dopamine pumped into the upper brain.

Now that they knew how the antipsychotic drugs worked, scientists had a whole new appreciation of what schizophrenia was and why the drugs had such terrible side effects.

The most obvious conclusion was that whatever schizophrenia was, it involved the dopamine system. Either there was too much dopamine produced, or the victim's brain cells were for some reason supersensitive to it.

Other, more subtle pieces of the puzzle fell into place as well.

During the 1960s, as the drug culture developed, scientists had observed that abusers of amphetamines (or "speed") often developed hallucinations that emergency room physicians found indistinguishable from schizophrenia. Also, they found, schizophrenics who took amphetamines got a lot worse.

This was explained by the discovery in the mid '70s that amphetamines increase dopamine production.

As the chemistry of schizophrenia was worked out, scientists also came to understand why prefrontal lobotomy had worked: The surgery severed the trunk lines through which the dopamine system pumped the chemical into the upper brain.

Since lobotomy was also effective in treating severe obsessive-compulsive disorders, the schizophrenia research may have fall-out in terms of that disease as well.

But perhaps most important, the new knowledge explained why thorazine and the other antipsychotic drugs had such profound side effects.

The corpus striatum, it turned out, wasn't the only place in the brain that dopamine was used. It wasn't even the main one -- most dopamine production took place in the motor control centers of the brain, where muscle movement was controlled.

By blocking dopamine, the antipsychotic drugs suppressed the hallucination-producing striatum, but it also reduced the brain's ability to process movement; eventually, the motor system was permanently damaged.

Once they knew why thorazine produced its side effects, researchers were in a position to begin the development of side-effect free drugs.

According to Dr. Joseph Coyle, an expert on schizophrenia at the Hopkins, the first major effort was to look for differences that might exist between the dopamine receptors in the motor system and in the striatum.

Subtle variations are known to exist in other chemical communications systems which are used in more than one part of the brain . . . presumably they help the brain to avoid "cross-talk" between different brain centers that use the same transmitter.

If such differences could be found between the two dopamine systems, psychochemists might develop a drug that would block the receptors in the striatum without affecting those in the motor system.

Despite intensive efforts, such differences have not yet been found. But the search has recently revealed another difference that may be exploited instead.

The dopamine system associated with schizophrenia, Dr. Coyle says, has been found to use a co-transmitter; it speaks, in a sense, with two chemical tongues. The motor system

apparently does not use the co-transmitter.

Scientists are now searching for chemical compounds that will suppress the combination without affecting dopamine alone. Such a drug, in theory at least, should knock out the

schizophrenic hallucinations and delusions without the devastating side-effects on the motor system.

Other scientific teams, in the meantime, are pursuing other ideas. At the State University of New York at Stony Brook, for instance, a group led by Dr. Fritz Henn is proceeding on the

assumption that the imbalance in the dopamine system is caused by more specific defects in other systems which, in turn, trigger the abnormal dopamine reactions.

While it is too early to predict yet which tactic will prove most fruitful, scientists involved in the work are generally confident that breakthroughs are coming.

"The pace of discovery bodes well for the future," says Dr. Coyle.

"It suggests that we're approaching a point when we'll be able to make some coherence out of this wealth of information. I'm optimistic . . . we've gone from ignorance to almost a surfeit of knowledge in only 10 years."

As discoveries in the field heighten interest and draw increased funding, Dr. Coyle adds, scientists are also beginning to get some clues regarding schizophrenia's puzzling "negative" symptoms of withdrawal and emotional detachment.

Scientists in England and at the National Institute of Mental Health have recently used CATscanners, for instance, to document widespread shrinkage of the cortex in schizophrenics. The cortex is where the more "human-like" functions of the brain are processed.

"These changes in the cortex," says Dr. Coyle, "appear to correlate with the negative symptoms of schizophrenia."

The structural changes are also reminiscent of alterations found in other illnesses long recognized to be physical in nature, such as Alzheimer's disease, or senile dementia.

"Some people feel that the negative symptoms of schizophrenia do have a dementia-like quality to them," says Dr. Coyle. "That is, a dilapidation of higher cortical functions and a crudening of the social skills that one sees in other type of dementias, like Alzheimer's.

"There is this growing appreciation of the relatedness of these disorders, and it's become difficult to sort them out in terms of research. The more we understand about the cortex,

through research on Alzheimer’s, the more we're going to understand about schizophrenia . . . and vice versa."

According to Dr. Snyder, recent discoveries have led to increasing optimism that the negative effects of schizophrenia will, like the positive ones, prove amenable to drug treatment.

He says one drug, being used now in Europe, seems to improve the negative symptoms as well as the positive ones. That drug, in addition to blocking dopamine, interferes with calcium

metabolism in the brain cells.

In the meantime, a powerful new type of brain scanners are being developed to augment the chemical techniques that have been used since the '70s to map the distribution and density of

receptors in the brain.

Those chemical techniques limited the scientists to working with dead brains that could be sliced and examined.

The new scanners, however, are allowing scientists to monitor the chemical reactions of thought and emotion as they take place in the living, thinking, feeling -- and

hallucinating -- human brain.

Dr. Marcus Raichle, a scanner scientist at Washington University in St. Louis, where one of the most powerful devices was invented, predicts that the scanner technology is certain to dramatically increase the pace of discovery involving schizophrenia.

He says the scanners should allow scientists to discover even more precisely what goes wrong with the brain as the disease takes hold, and to watch the disease process as it runs its course.

In a year or so, he predicts, scientists studying schizophrenia with the new scanners will present the world with "studies that are going to mean something.

"It's coming," he says, reflecting the enthusiasm of schizophrenia experts. "I don't doubt that."

But the development of the chemically-based brain scanners, in combination with the biochemical tools, has implications that go far beyond the study of schizophrenia . . . or even of other diseases.

They are going to lead, scientists agree almost unanimously, to a much broader understanding of the normal brain. They may have the ability to reveal dramatic new truths about who we are, what we're about, and what it means to be human.

The Mind-Fixers: Part V

The Mind-Scanners

Brain scientists have developed a new family of high-tech scanners that illuminate the chemistry of thought as it flashes through the living, thinking, feeling human brain.

The devices represent a fundamental breakthrough; they promise to do for human psychology what the telescope did for astronomy and the microscope did for biology.

While the scanners bear a superficial resemblance to the CATscanners presently used in many of the nation's hospitals, the differences in what they can see is dramatic.

CATscanners reveal only the structure of the brain. They can detect swelling and pinpoint tumors, but the chemical machinery of thought is beyond their capabilities.

The new brain-mind scanners, however, reveal those chemical reactions. They trace the mental processes of the subject as he moves, sees, hears, listens to music, meditates or experiences emotions.

The instruments are primitive yet, limited both by their resolution and by the scientists' abilities to interpret the results. But both the machines and the humans that use them are steadily becoming more sophisticated.

Increasingly, the scanner laboratories are producing a cascade of discoveries that illuminate the physical basis of thought and emotion.

At UCLA, for instance, scientists have photographed epileptic seizures as they explode in the living brain.

At Washington University in St. Louis, doctors have used a scanner to show that patients who suffer a common type of uncontrollable panic attack do so because they have a metabolic abnormality that "unbalances" their emotional brains.

At the University of Texas Health Science Center in Dallas, psychiatrists have established that each individual has a characteristic brain pattern -- and that those patterns shift dramatically as patients with multiple personality switch from persona to persona.

In Baltimore, scientists at Johns Hopkins Medical School have labeled and visualized the dopamine receptor fields believed to lie at the root of schizophrenia -- and discovered that fundamental changes occur as the brain matures.

The list goes on, and on, and on, each new discovery reconfirming the theory of molecular psychology and offering new insights into what sort of creatures we really are.

Currently, the most popular of the new devices being used to probe the brain is the PETscanner, developed during the late 1970s by Dr. Michel Ter-Pogossian and associates at Washington University in St. Louis.

Like the CATscanner, PET uses a donut-shaped array of sensors into which the subject's head is inserted. In both cases the sensors consist of radiation detectors that collect the impulses and relay them to a bank of computers. The computers record the collected data and use it to reconstruct three-dimensional images of the brain.

The big difference between CAT and PET has to do with where the radiation comes from.

CATscanners use X-rays directed at the brain from the outside, and thus produce "shadow" pictures of the shape of the brain.

The PETscanner works quite differently, and produce a dramatically more revealing image not only of shape, but of chemical process as well.

First, before the scan begins, the PETscan team manufactures a radioactive version of some chemical normally used in the thought process.

Then, the subject's head in the donut, the chemical is injected or inhaled. The scanner then watches, and records, what happens as the chemical is metabolized during the thought process.

Most scanner experiments are quite complex, and difficult to understand without a thorough grounding in the theory of psychochemistry. But the principle can be illustrated with the relatively simple glucose studies.

Glucose is the fuel of the living cell, and the harder the cell works the more it needs. As a result, scientists can use radioactive glucose tracers to reveal which parts of the brain "turn on" during a specific mental task.

A radioactive glucose experiment, for instance, can "light up" the visual centers in the brain as the subject examines a picture or a test pattern. Radioactive glucose tracers can also show which parts of the brain are involved in such tasks as emotional memory, movement coordination, or even meditation.

The trickiest part of a PETscan experiment is not the scan itself, but the design and creation of the radioactive neurochemical that the scientists hope to trace through the subject's brain.

This preparatory phase of the experiment can take months, and involves the effort of a team of brain and chemical specialists.

And, because the radiation must be very short lived in order to be safe for the human subject, the tracer chemical must be created on the spot. This means that a PETscan facility must include a cyclotron, and the team must include specialists in cyclotron technology.

"It takes a lot of people," explains Dr. Candace Pert, a neurochemist at the National Institute of Mental Health. "It's a team effort . . . it's ten people sitting around the table. It's organizational, high-tech, lot of steps, hard to do . . . like putting a man on the moon."

As a result, a PETscan facility approaches the cost of a small astronomical observatory. Hopkins scientists, for instance, estimate they've got two million dollars invested in their PETscan facility -- and that doesn't include the operating budget for the team of specialists required to operate it.

The current generation of scanners is also limited by resolution. The chemical workings of the mind take place on a microscopic level, and require only milliseconds to occur. The scanners take from one to twenty minutes to record a "picture," and presently have resolutions of about a half inch.

As a result, the scans they produce are little more than blurs. But those blurs, revealing as they do the chemical dynamics of thought, are of unparalleled value.

So, despite the substantial expense involved in building and operating a PETscan facility, they are rapidly proliferating. To date there are about 15 PETscan facilities in

the United States, and at least an equal number are in operation, or soon will be, in Europe and Japan.

As more scientific teams gain access to PETscanners, the techniques are being refined to answer ever more specialized questions.

At Hopkins, for instance, the PETscan facility is dedicated to mapping the all-important neurotransmitter receptor fields.

Receptors are the sub-microscopic, chemical "antenna" molecules on the surface of brain cells. It's these receptors that make the mind respond to natural transmitters, like dopamine, and unnatural ones, like heroin and nicotine.

Discovering exactly where the different types of receptors are located, and how they proliferate or die off in illnesses like drug addiction or schizophrenia, is a central issue in neurochemistry.

Dr. Michael Kuhar, a Hopkins pioneer in that effort, explains that his early receptor-mapping work required that the brains be sliced, exposed to radioactive chemicals that locked

onto the receptors, and then laid on photographic film for several weeks. During that time the radioactive chemicals burned their image into the film and revealed the location of the receptors.

The technique, though considered revolutionary when Dr. Kuhar started using it in the 1970s, had severe limitations. The most obvious was that he could only use dead brains, and thus couldn't observe how the receptors changed over days and weeks and how, in the process, the patient's personality was altered.

The Hopkins PETscanner, the first to successfully map a receptor field in the living brain, changed all that.

"Man, that thing's incredible," Dr. Kuhar says. "It used to take us weeks to produce a study. Now a guy lays down on the table, you inject him [with radioactive tracers], you turn on

the scanner . . . and there's his receptor map! And he gets up off the table and walks away!

"And you can do him again if he gets well, or gets sick, or whatever, and you can compare the two studies. To go that distance in ten years absolutely blows my mind, just blows my mind! I just can't tell you! It's amazing!"

The specific ambition, at Hopkins and elsewhere, is to record the dynamic process of mental disease and thereby discover the nature of that disease. At Hopkins, for instance, PETscan scientists have a particular interest in the changes that occur in schizophrenia and drug addiction.

But first the scientists must scan normal brains under a variety of circumstances. Until the meaning of "normal" is understood, scientists can't probe the biochemical definitions of words like "insane."

Those normal studies, as preliminary as they may be, are anything but dull. The chemical dynamics of the human personality is the darkest of all scientific mysteries, and the exploration is yielding an endless supply of eyebrow-raising results . . . and generating new questions about who we are and how we work.

At the University of Texas Health Science Center in Dallas, for instance, scientists using a scanner similar to PET have discovered that each normal person has a characteristic way of using his brain. This is reflected in very individualistic scanner patterns.

"We call it a 'fingerprint,'" says Dr. A. John Rush, a research psychiatrist at the Dallas facility.

"What we've found is that there's a great range of normal people. They have no brain disease, no psychiatric disease, but they all have a distinctive [scanner] pattern."

"If you ask the same different, normal person to come back three times . . . say separated by a week . . . they have basically the same [scan] pattern. But that pattern could be quite different from that of other very normal people."

Though there is yet no proof, presumably the patterns found by the Dallas scientists reflect individual personalities. Presumably they change over time as the person experiences new situations, learns new things, and matures.

In Baltimore, Hopkins scientists led by Dr. Henry Wagner, chief of nuclear medicine, have discovered a more puzzling peculiarity of the normal brain, this one involving the all-important dopamine receptor fields.

Dopamine receptors in primitive structures at the base of the brain serve in part to modulate alertness; changes in the density of those fields is suspected of playing a key role in the development of schizophrenia.

But in examining dopamine receptor densities in normal brains, a surprising observation emerged. In females, dopamine receptor fields remain stable for life, but in males the fields become less dense with age.

Do these changes correlate with the increasing calmness observed in the maturing male? Might they have to do with the observed tendency in male drug addicts to "mature out" of their addiction in their 30s? Might they reveal something about differences in male and female behavior?

No one knows. And, at PETscan facilities all over the world, such surprising findings abound.

"This whole field is incredibly exciting," one PETscan scientist enthused. "It's like pointing a telescope at the heavens for the first time. Everywhere we look, we see something new and unexpected. It almost doesn't matter what we do.

"And every time we see something, even if that something is normal, we've discovered two more diseases. In principle, for every normal reaction you can bet there's someone, somewhere, who has an under-reaction . . . and someone else who has an over-reaction. The trick is going to be linking what we're seeing to known mental diseases."

That such linkages could be made was, until recently, a matter of faith among neurochemists. But this year scientists at the University of Washington, where the PETscanner was developed, used the instrument forge just such a cause-and-effect connection.

Dr. Marcus Raichle, a neurologist and a senior PETscan scientist at Washington University, said the disease in question is Decosta's syndrome.

It affects between one and two percent of the population. The chief symptom is periodic panic attacks that strike without warning or provocation.

Because such patients also have an exercise intolerance, and because panic is characterized by changes in heart function, Decosta's syndrome victims were for many years thought to be suffering from heart disease. Frequently they end up in emergency rooms with what appears to be heart attacks.

But in recent years the panic attacks were found to be triggered by elevations in blood lactate levels, which are normally produced by exercise.

This deepened the mystery: normal people have elevated blood lactate levels when they exercise, too, but the lactate doesn't trigger panic attacks. Presumably the high lactate levels triggered some otherwise benign defect in the brain.

The primary defect was discovered when Dr. Raichle and his group examined Decosta's syndrome patients in a PETscanner. It quickly became apparent that emotional centers in the left mesial temporal lobe, a part of the emotional brain, were not "kicking in" when they should. The companion centers on the opposite side of the brain were functioning normally.

"These people are DIFFERENT," Dr. Raichle explained. "The brain, if you will, is kind of unbalanced."

One of the most striking results of the experiment is that there were no exceptions; every Decosta's syndrome patient had precisely the same abnormality.

"This is the cleanest piece of data we've generated in a long time. To our knowledge this is the first study to identify a discrete brain abnormality in patients with a primary psychiatric disorder."

A similar linkage between scanner images and specific diseases appears to be developing at the University of Texas Health Science Center in Dallas, where personality "fingerprint" scans are being studied.

According to the Dallas team's Dr. Rush, the group recently put a patient with multiple personalities on the scanner . . . and were able to observe a personality switch.

The results were spectacular. As the patient's personality changed, so did his scanner "fingerprint."

Similar preliminary work at other centers has scientists hopeful that scanners will soon produce characteristic patterns for schizophrenia and depression. There are indications that receptor field changes may also play a role in addiction.

As mental illnesses become identifiable by means of chemical scanner patterns, those patterns should tell neuropharmacologists what sort of drug they need to design to treat each illness.

The scanners should also play a major role in the development and testing of those new drugs. With the scanners, the affects of experimental compounds can be observed directly. This should eliminate the decades of experimental fumbling that now characterizes the development of psychoactive drugs.

Though scanner scientists share a confidence that the new machines will lead to breakthroughs in the understanding of mental disease, and in the development of drug treatment, there is debate over whether the devices will ever play a direct role in clinical psychiatry.

At the Hopkins, for instance, Dr. Joseph Coyle suspects that the high cost of PETscanners, coupled with the need for teams of experts to tend the machinery, will forever bar the routine scanning of mental patients. A majority of scientists interviewed by The Evening Sun expressed similar views.

But at least some experts take an opposite tack. They predict that the cost of routine scans may be offset by dramatically improved therapy.

Misdiagnosis and ineffective treatment, they point out, can also be very costly -- both in terms of money and human suffering.

At the University of Texas Health Science Center in Dallas, Dr. Rush is one of the hopeful ones.

The most obvious application, he says, would be in diagnosis. For one thing, diagnostic scans might tell doctors not only what disease they were dealing with, but what type of treatment might be most useful as well.

Scanners could also be used to monitor a patient in treatment to determine whether or not the drugs are improving his condition, and to determine when he's cured.

Documentation of cure could be especially valuable when patient's illness is characterized by violence, or when the treatment is court-ordered.

The type of information produced by scans might also prove to be of great value to classical psychiatrists, who use interpersonal therapy instead of, or in addition to, drugs. Such psychiatrists have historically been forced to infer brain function from what the patient says and does . . . a notoriously tricky and imprecise process.

"We have this tendency to think that the only way to change a patient's mind is with drugs," says one brain scientist. "But in the normal course of events, experience changes the mind too. And that includes the therapeutic experience of visiting a psychiatrist.

"A person who has gone through psychotherapy is in many important respects different than he was before the treatment began. We can't quantify this difference yet, but it must exist. If it didn't, people wouldn't go to therapists.

"We need to see if we can pinpoint these differences, and provide meaningful feedback to the psychotherapist."

But to Dr. Rush the most exciting possibility – if perhaps the most speculative -- is that the scanners might be used for the early diagnosis of mental illness.

Today, mental illness is rarely diagnosed until it's progressed to full-scale insanity.

"But we know that depression, schizophrenia and a variety of other disorders run in families. They appear to be genetic, at least in part. And it's intriguing to think that [scanners] could tell us who might develop one of these diseases.

"That would allow us to intervene with some sort of preventive strategy before the patient actually develops the illness."

If that could be done, he says, presently incurable mental illnesses might be prevented, the same way the treatment of high blood pressure is now used to prevent strokes.

The Mind-Fixers: Part VI

Violence

Is much or even most violent criminal behavior caused by imbalances in brain chemistry? Could such imbalances be treated with drugs, reducing the general level of violence in society while at the same time substantially alleviating overcrowding in our prisons?

Increasing numbers of molecular psychologists think the answer to both questions may be yes.

If they are correct, isolating those imbalances and developing drug treatments could prevent crimes, restore criminals to productive lives, and save billions of dollars a year that are now spent to warehouse convicts.

But even within the ranks of molecular psychiatrists there are doubts about whether such an achievement would be legally, ethically and emotionally acceptable to the American

people.

One of the most visible proponents of psychiatric treatment for violent criminals is Dr. Fred Goodwin, chief scientist at the National Institute of Mental Health.

"As we become sophisticated about understanding the biology of behavior," he says, "the more potential we get for altering behavior biologically.

"The question is, how much of the enormous cost of violent crime in this country is based on aberrant brain behavior? What percentage of people who episodically kill, or assault, or rape, have a brain disorder?

"Pilot studies indicate quite a high percentage. A majority."

In one study, he said, prisoners who were repeatedly sent to solitary confinement as a result of violent episodes were treated with lithium, a mood stabilizer generally used for manic-depressive patients.

"There was a very substantial reduction in episodic violence, a very substantial reduction."

"We might have a very revolutionary impact. And I use the word 'revolution' advisedly.

But is the world ready for such a revolution? Would society allow it? On these questions, many molecular psychiatrists have their doubts.

"I can's share [Dr. Goodwin's] optimism at all," says Dr. John Lion, formerly a specialist in violence at the University of Maryland in Baltimore and now in private practice.

"My skepticism has to do with the politics. Treating prisoners . . . we're talking about treating criminals! That's something that's not possible in current American penology."

Dr. Lion believes that at least some violent behavior can be traced to epileptic-like "storms" in the emotional brain. Like many of his colleagues, he successfully treats many such patients with anti-convulsants.

But, he says, scientific knowledge of the biochemistry of violence lags far behind research on the more classical mental illnesses, such as depression or schizophrenia.

The reason, he says, is that American society is profoundly ambivalent about violence, and isn't at all sure it wants science to tamper with it.

For example, Dr. Lion says a section of the emotional brain called the amygdala is known to be involved both in the expression and control of violence -- but attempts to do human studies on the criminal population in the '60s and '70s were quickly squelched.

"To make a long story short," says Dr. Lion, "the ACLU and patient's rights groups vehemently objected to the study of aggression in man.

"What I'm trying to point out is that the idea of tampering with man's aggressive drive is very hazardous and controversial in this society.

"It's okay to tamper with depression . . . that's bad. We all know it's bad to be depressed. Anything that fixes up depression is good. And we know that schizophrenia is tragic. Do what you want . . . however you can help a schizophrenic is good.

"I can treat a depressed patient and make that patient lethargic, even induce cardiovascular toxicity, or a parkinsonianism . . . such side effects are acceptable in a psychotic patient or in a depressed patient as a price to be paid for liberating him from the psychosis or depression.

"But If I have a drug that will control aggression, but makes people lethargic or has some other side effect . . . that may NOT be so acceptable to society."

Dr. Goodwin believes that rising concerns about the costs of violence, and of prisons, coupled with an increasing ability to diagnose criminals with organic brain malfunctions, will eventually lead to a more sympathetic public attitude. But Dr. Lion isn't so sure.

"Sometimes I wonder." he says. "I think violence is a very highly valued trait in Western societies. I think we give lip service to a lot of these concerns.

"You know . . . it's like we can send a man to the moon but we can't seem to stop drunken drivers. The largest, most easily identifiable subgroup of violent people in the United States is recidivist drunken drivers, but nothing is done about it. There's an astonishing tolerance for that.

"The whole issue of violence is politically laden, it has many social policy implications, particularly in America. You can't do research on prisoners in America, right?

"Isn't that strange? How can we study those who commit violence if the government does not allow it? See? You can't get informed consent, so you can't study them. The only studies you can do on a prison population are demographic studies.

"I think it's political. I think it's like gun control."

But if research into the biochemistry of violence is being retarded in this country the same is less true in Europe, where psychological treatment and even procedures such as surgical castration for rapists have long been a traditional part of penology.

There, one of the leading researchers is Dr. Paul Mandel, a biochemist with the Center for Neurochemistry in Strasbourg, France. Working with rats, mice and other animals he and his group has focused in on two major neurochemical systems.

The systems, he says, involve brain cells that communicate with serotonin and GABA. Both are chemical inhibitors that serve to damp down the function of the emotional brain.

Using different strains of rats, some of which are inherently violent and some of which are not, he has been able to show that the violent tendencies are characterized by uncommonly low levels of the inhibitor transmitters in the brain.

Further, he has been able to manipulate those behaviors. Aggressive rats become markedly less so when they are given substances that raise serotonin and GABA levels; passive rats can be made aggressive by administering chemicals that lower those levels.

In his original series of experiments, the aggressive and passive rats were produced by breeding -- evidence that genetic predisposition can play a role in serotonin and GABA levels and, thereby, in aggression.

But Dr. Mandel says levels of GABA and serotonin can also be changed, and behavior altered, by environmental manipulation.

One classic experiment involves isolation, which is known to produce aggressive behavior in both animals and humans. Studying several groups of rats, the Mandel group found that isolation lowered GABA and serotonin levels for all the animals.

But those who had a genetic disposition to violence, as measured with low GABA and serotonin levels, became much more violent than the others -- and tended to do so with less isolation stress.

When subjected to overcrowding, the opposite effect occurred. GABA and serotonin levels went up, and the animals became passive and lethargic. But the violence-prone animals, apparently protected by their already low levels of GABA and serotonin, suffered the least.

In another, highly suggestive set of experiments, Mandel demonstrated that rats became more violent, and that their brain inhibitor levels dropped, by merely SEEING other animals being aggressive.

Mandel, less cautious than many of his colleagues about extrapolating to the human condition, says those experiments indicated that human children do become more violent when they watch violence on television. Likewise, publicizing crimes -- and capital punishment -- presumably begets still more violence.

Extrapolating further, Mandel believes that emotional self-stimulation can also change serotonin levels and trigger changes in the tendency to solve problems by violent means. Religious fanaticism, he predicts, will one day prove to be linked to lowered serotonin levels.

"The Ayatollah Kohmeni, for instance," says Dr. Mandel. "He's suppressed his GABA and serotonin levels through religious excitation . . . and now there's no inhibition."

Dr. Mandel believes that violence is a result of a psychochemical disease process, and should be viewed, and treated, in that fashion.

"Aggression is like any other disease," he says. "It's the lack of inhibitory mechanisms that can be produced by genetics and/or the environment, and there's no reason not to treat it if we can."

The French group's purpose is the development of drugs that can produce changes in human patterns of aggression. He has already produced one such drug, Valproic acid, which has been at least partially effective in reducing violence in some patients with emotional-system disease.

But Mandel does not claim that drug treatment, alone, can convert violent criminals into model citizens.

Rather he sees drugs as an adjunct to other treatment -- including psychotherapy and environmental changes, such as improved living conditions and better education, that would work together to raise serotonin and GABA levels.

At NIMH, Dr. Goodwin believes that such combination treatment schemes will eventually prove so effective, both medically and economically, that they will achieve acceptance even in the United States.

"I grant you," he says, "that there are dangers in that. Everyone gets concerned, perhaps overly concerned, about the specter of mind control -- particularly when you're talking about criminal justice.

"Criminal justice is extremely sensitive to any efforts to intervene medically with any individuals whose misbehavior may be a function of a brain disorder. And the system is geared, maximally, to protect people from such intervention . . . on what I think is a rather old fashioned notion that there are greater risks than there are benefits.

"I acknowledge that there are risks, but I think society is sufficiently alert to those risks that it's rather far-fetched to think that properly monitored treatment programs, with properly-selected individuals, wouldn't in fact be much more beneficial to the individuals -- not to mention society."

Dr. John Rush, a research psychiatrist at the University of Texas Health Science Center in Dallas, Texas, agrees that molecular psychiatry, coupled with the new scanners and other technology for diagnosing mental disease, is on a collision course with the legal system.

"I think we all assume that we can by will power control virtually everything we do. But a lot of psychiatric technology and information is revealing the fact that the brain, which is the basis for all we do, is an organ like any other organ in the body and it will not always obey our commands. That's a scary concept. It puts sort of a limit around free will."

"To the layman, it sounds very scary -- your brain can go bad, and you do not know that it's going bad, and you can't control it. It's a mixed blessing."

Dr. Rush, who has used scanners to watch shifts in the brain processes of patients with multiple personalities, believes that the new technology will inevitably alter how we think about right, wrong, and criminality.

"I think if you look at Hinkley, for example, at one level he knows he's absolutely crazy. And at another level he knows he can't control it. And he has, as far as I can tell -- and I'm relying on the public media -- it would appear that he has some variant of schizophrenia.

"And while he knows that it's crazy, he also realizes over time that he really cannot control it. If you asked him if he really wanted to do what he did, at one level he'd say yes . . . and on another level he'd say, 'absolutely not. It's crazy!'

"All of us are vulnerable to that kind of thing, where we find ourselves doing things that we don't want to do, that we cannot control.

"At one level the biological approach to psychiatry is reassuring. It indicates that yes, there are diseases of the brain, the effects of which you cannot control.

"On the other hand they're very frightening to average people, like most of us, who thinks they can control most of the things that they do. But there are great limits to will power, motivation, decision or a sense of reality. I think this is frightening."

As the science of molecular psychology evolves, Dr. Rush says, the legal system must evolve with it.

"I think, for instance, that it will require some very substantial revisions in the insanity defense. What they are . . . I wouldn't care to speculate. But I think they will evolve over the next 20 or 30 years as our ability to diagnose gets better and better."

But skeptics like Dr. Lion believe that evolution, if indeed it occurs at all, will be slow and painful.

"At the moment," he says, "There's not even any official rehabilitation program in the American penal system.

"I think that in order for a biochemist to exert an effect on a criminalogic system there would have to be massive dialogue and profound policy changes. And I don't see any evidence of that."

It's true, he concedes, that there is an increasing willingness to use drugs like depo-Provera to chemically castrate rapists, as an alternative to prison. But he points out that those programs, and the drugs used in them, are