Shrinks (29 page)

There have been similar neural revelations about other mental disorders. In 1997, Helen Mayberg, a neurologist at Emory University, used PET imaging to examine the brains of depressed patients and made a startling discovery: Their subgenual cingulate gyrus, a small structure deep in the front part of the brain, was hyperactive. And that wasn’t all—when these patients were treated with antidepressant medication, the excessive activity in their subgenual cingulate gyrus was reduced to that of healthy subjects. Mayberg’s finding led directly to a new type of therapy for individuals suffering from very severe depression who did not respond to medication:
deep brain stimulation
. During DBS, electrodes are directly implanted into a patient’s brain in the region of the subgenual cingulate gyrus to reduce the firing of neurons causing the hyperactivity.

Imaging studies have also unveiled some very interesting details regarding suicide. The vast majority of people who commit suicide suffer from a mental illness, with depression being the most common. Yet, not everyone who suffers from depression becomes suicidal. This prompted researchers to ask if there might be some difference in the brains of those depressed individuals who
do
decide to take their own lives. Subsequent studies have revealed that their brains have an increase in a particular kind of serotonin receptor (5-HT1A) located in a part of the brain stem known as the dorsal raphe. The increase in dorsal raphe serotonin receptors was first identified in the postmortem brains of individuals who had committed suicide, and then confirmed in living patients using PET imaging.

PET and fMRI studies have also demonstrated that patients with anxiety disorders have an overactive amygdala in their brains. The amygdala is a small almond-shaped structure on the inner surface of the temporal lobe that plays a critical role in our emotional reaction to events. Research has shown that when pictures that provoke emotional reactions are presented to an individual with an anxiety disorder, his amygdala tends to produce an exaggerated response compared to the brains of healthy patients. (We will learn more about the amygdala’s crucial role in mental illness in the next chapter.)

The brains of infants suffering from autism evince distinct structural signatures that appear during the first twenty-four months of life as the illness first takes hold. The white matter develops differently in autistic brains, an abnormality detectable as early as six months of age, which seems to mean that the connections between certain brain cells are not getting properly established in autistic children. In addition, the cerebral cortex of autistic infants expands excessively in the second year of life, possibly due to the failure of the mechanism by which the proliferation of synaptic connections is regulated.

But sometimes understanding the brain requires more than just gazing at pictures—it requires conducting actual experiments on the gritty, wet reality of neural circuits, cells, and molecules. From the 1900s to the 1970s, very few psychiatrists spent any effort at all trying to understand the physiological operations of the brain directly in humans or by using animals as was done in the other medical specialties. After all, most psychiatrists during this long era of stagnation believed that mental illness was ultimately a psychodynamic or social issue. But a lone American psychoanalyst decided that the path to understanding the mind ran straight through the fissures of the brain.

The Other Psychiatrist from Vienna

Eric Kandel was born in 1929 in Vienna, Austria, not far from the home of seventy-three-year-old Sigmund Freud. In 1939, because of the
Anschluss
, Kandel’s family fled to Brooklyn, New York, as Freud’s family fled to London. Kandel was profoundly affected by his childhood experience, watching a city of friendly neighbors turn into a mob of hateful racists. Consequently he entered Harvard with the intent to study European history and literature in order to understand the social forces that produced such a malevolent transformation in his countrymen.

While at Harvard, he began dating a young woman named Anna Kris. One day she introduced him to her parents, Ernst and Marianne Kris, eminent psychoanalysts who had been members of Freud’s inner circle in Vienna before immigrating to the United States. When Ernst asked the young Kandel about his academic goals, Kandel replied that he was studying history in order to make sense of anti-Semitism. Ernst shook his head and told Kandel that if he wanted to understand human nature, he should not study history—he should study psychoanalysis.

On the recommendation of his girlfriend’s father, Kandel read Freud for the first time. It was a revelation. While Kandel eventually lost touch with Anna, her father’s influence endured. Some forty years later, in his Nobel Prize address, Kandel recalled, “I was converted to the view that psychoanalysis offered a fascinating new approach—perhaps the only approach—to understanding the mind, including the irrational nature of motivation and unconscious and conscious memory.”

After graduating from Harvard in 1952, Kandel entered New York University Medical School intending to become a psychoanalyst. But in his senior year, he made a decision that set him apart from most would-be shrinks: He decided that if he truly wanted to understand Freudian theory, he needed to study the brain. Unfortunately, nobody on the faculty at NYU actually did that. So during a six-month elective period, when most medical students were doing rotations on clinical services, Kandel ventured uptown to the laboratory of Harry Grundfest, an accomplished neurobiologist at Columbia University.

Kandel asked Grundfest if he might assist on research in his lab. Grundfest inquired what Kandel was interested in studying. Kandel replied, “I want to find out where the ego, id, and superego are located.” At first, Grundfest could barely contain his laughter, but then he gave the ambitious young medical student some sober advice: “If you want to understand the brain, then you’re going to have to study it one nerve cell at a time.”

Kandel spent the next six months in Grundfest’s lab learning how to record the electrical activity of individual neurons. For an aspiring psychiatrist, this was a peculiar and questionable endeavor—akin to an economics student trying to understand economic theory by learning how the Bank of England printed banknotes. But as Kandel gradually mastered the use of microelectrodes and oscilloscopes, he came to believe that Grundfest was right: Studying nerve cells was the royal road to understanding human behavior.

By the time Kandel left the Columbia lab he had become convinced that the secrets of mental illness lay hidden within neural circuitry. Even so, he still maintained an abiding belief that psychoanalysis offered the best intellectual framework for understanding these secrets. In 1960, he began his psychiatric residency at the Freud-dominated Massachusetts Mental Health Center, where he underwent his own psychoanalysis. By 1965, Kandel had become a rare bird indeed: a fully accredited psychoanalytical psychiatrist who was also well trained in the techniques of neural research—simultaneously a psychodynamic psychiatrist and a biological psychiatrist. So what kind of a career would a young physician with such seemingly paradoxical interests pursue?

Kandel decided to study memory, since the neurotic conflicts so central to the Freudian theory of mental illness were predicated upon memories of emotionally charged experiences. If he could understand how memories worked, he felt he would understand the fundamental mechanism behind the formation of neurotic conflicts, which were the basis of mental illness. But rather than probe patients’ memories through word associations, dream analysis, and talk therapy, Kandel took as his professional project something no psychiatrist had ever attempted before: the elucidation of the biological basis of memory.

His prospects were far from encouraging. In the mid-1960s, virtually nothing was known about the cellular mechanisms involved with memory. The nascent field of neuroscience was hardly a guide, since it hadn’t yet coalesced into a coherent discipline. No medical schools boasted departments of neuroscience, and the Society for Neuroscience, the first professional organization representing this field, was not founded until 1969. If Kandel wanted to unravel the mysterious neural tapestry of memory, he would have to do it on his own.

Kandel guessed that the formation of memories must rely on modifications in the synaptic connections between neurons. But there was not yet any known way to study synaptic activity in humans. He considered investigating synapses in rodents, a common lab animal used in behavioral studies in the 1960s, but even the rat brain was too sophisticated to use as a starting point. Kandel realized he needed a much simpler organism—a creature whose brain was less complicated than a rat’s, but still large enough that he could analyze the cellular and molecular processes of its neurons. After a long search, he finally hit upon the perfect beast: the California sea slug,
Aplysia californica
.

This marine mollusk possesses an extremely simple nervous system consisting of just 20,000 neurons, compared to about 100 billion in the human brain. At the same time, the cell bodies of the sea slug’s neurons are easily visible and extremely large by anatomical standards: about 1 millimeter in diameter, compared to 0.1 millimeter in humans. While a sea slug’s memories are obviously much different from a human’s, Kandel hoped that by studying the small invertebrate he might discover the physiological mechanisms by which any animal’s memories were formed. His reasoning was based upon the evolutionary theory of conservation: Since memory was both biologically complex and essential for life, once the basic cellular mechanisms of memory evolved in a very ancient species, the same mechanisms were probably conserved in the neurons of all its varied descendents. In other words, Kandel speculated that the cellular processes for encoding memories were the same for sea slugs, lizards, rats—and humans.

Kandel toiled in his laboratory at New York University, painstakingly subjecting the sea slugs to a series of conditioned learning experiments of the same general sort that Ivan Pavlov once administered to salivating dogs. Kandel studied simple reflexes, such as the withdrawal of the sea slug’s gill when something touched its siphon, and discovered that these reflexes could be modified through experience. For example, after gently touching the slug’s siphon, he zapped the slug’s tail with an electrical jolt, which caused the slug to retract its gill much more powerfully. Eventually, the slug retracted its gill powerfully from the gentle touch alone, which showed the creature knew that the touch signaled an impending jolt—the slug
remembered
the previous jolts.

After the sea slug demonstrated a new memory, Kandel cut the slimy creature open and painstakingly examined its neurons for any structural or chemical changes that might make up the biological signature of the slug’s memory. This was quite likely the very first time that a psychiatrist used a nonhuman creature to study brain functions related to human mental activities, a method of experimental investigation that scientists refer to as an “animal model.” While animal models had long been common in other fields of medicine, most psychiatrists had assumed it was not possible to emulate the seemingly uniquely human mental states in an animal—especially not in a primitive invertebrate.

Most psychiatrists paid little attention to Kandel’s research, and those who did usually considered it interesting but irrelevant to clinical psychiatry. What could sea snails possibly have in common with an orally fixated person with a passive dependent personality or the superego rigidity of the obsessive-compulsive patient? How could identifying a snail’s memory of an air puff to its gill help psychiatrists resolve unconscious conflicts or better understand the patient’s transference to their therapist?

But Kandel persisted. After years of research on the giant neurons of the
Aplysia californica
, Kandel made a profound discovery. As Kandel explained to me, “I began to see what happens when you produce a short-term memory and, even more interesting, when you convert a short-term memory to a long-term one. Short-term memory involves transient changes in the activation of connections between nerve cells. There is no anatomical change. Long-term memory, on the other hand, involves enduring structural changes from the growth of new synaptic connections. I finally began to understand how the brain changes because of experience.” Kandel’s discovery of the divergent biological mechanisms of short-term and long-term memory remains one of the most important foundational principles of modern neuroscience.

In addition to his groundbreaking work on memory, Kandel also made an impressive series of discoveries that enhanced our understanding of anxiety disorders, schizophrenia, addiction, and aging. For example, Kandel’s lab isolated a gene called RbAp48 that produces a protein involved in memory formation in the hippocampus. Kandel discovered that this gene is expressed less and less as we age, suggesting that treatments that sustain or increase the gene’s activity could potentially reduce age-related memory loss. As our expected lifespan continues to increase, RbAp48 might just hold the key to preserving our memories in our ever-lengthening golden years.

Kandel’s greatest contribution to psychiatry, though, may not have been any single neurobiological discovery, but his cumulative influence over psychiatry’s direction. As a new generation of psychiatrists came of age in the 1970s and witnessed the therapeutic effects of psychopharmaceuticals and the new images of living brains, they began to believe there was more to mental illness than psychodynamics. The brain beckoned as an unopened treasure chest of insights and therapies—but how to unlock the mysteries of this mysterious organ? There was little psychiatric scholarship on the brain itself, and even less research on the cellular and molecular mechanisms of the brain. The few dedicated brain researchers tended to focus on relatively tractable functions like vision, sensation, and movement. Very few possessed the audacity (or foolishness) to tackle the higher mental functions underpinning human behavior… and Eric Kandel was the first of these few.