The first study of mental illness using the CAT scan was published in 1976 by Eve Johnstone, a British psychiatrist, and it contained an astounding finding: the very first physical abnormality in the brain associated with one of the three flagship mental illnesses. Johnstone found that the brains of schizophrenic patients had enlarged lateral ventricles, a pair of chambers deep within the brain that contain the cerebrospinal fluid that nourishes and cleanses the brain. Psychiatrists were thunderstruck. Ventricular enlargement was already known to occur in neurodegenerative diseases like Alzheimer’s when the brain structures surrounding the ventricles began to atrophy, so psychiatrists naturally inferred that the ventricular enlargement in schizophrenic brains was due to atrophy from some unknown process. This landmark finding was promptly replicated by an American psychiatrist, Daniel Weinberger at the NIMH.
Before the shock waves from the first psychiatric CAT scans had begun to subside, another brain-imaging marvel arrived that was even better suited for studying mental disorders: magnetic resonance imaging (MRI). MRI used a revolutionary new technology that enveloped a person within a powerful magnet and measured the radio waves emitted by organic molecules of the body when they were excited by the magnetic field. MRI was used to image the brain for the first time in 1981. Whereas the CAT scan enabled psychiatric researchers to peek through a keyhole at brain abnormalities, MRI thrust the door wide open. MRI technology was able to produce vivid three-dimensional images of the brain in unprecedented clarity. The MRI could even be adjusted to show different types of tissue, including gray matter, white matter, and cerebral fluid; it could identify fat and water content; and it could even measure the flow of blood within the brain. Best of all, MRI was completely harmless—unlike CAT scans, which used ionizing radiation that could accumulate over time and potentially pose a health risk.
MRI in the axial view (looking down through the top of the head) of a patient with schizophrenia on reader’s right and a healthy volunteer on the left. The lateral ventricles are the dark butterfly-shaped structure in the middle of the brain. (Courtesy of Dr. Daniel R. Weinberger, MD, National Institute of Mental Health)
By the end of the 1980s, the MRI had replaced CAT scans as the primary instrument of psychiatric research. Other applications of MRI technology were also developed in the ’80s, including magnetic resonance spectroscopy (MRS, measuring the chemical composition of brain tissue), functional magnetic resonance imaging (fMRI, measuring brain activity rather than brain structure), and diffusion tensor imaging (DTI, measuring the long tracts that carry signals between neurons).
The brain imaging bonanza of the ’80s wasn’t limited to magnetic technologies. The decade also witnessed the refinement of positron emission tomography (PET), a technology that can measure the brain’s chemistry and metabolism. While PET provides only a hazy picture of brain structure—compared to the fine spatial resolution afforded by MRI—PET measures the brain’s chemical and metabolic activity in quantitative detail. Perhaps anticipating the use of PET scans by psychiatrists, James Robertson, the engineer who carried out the very first PET scans at the Brookhaven National Laboratory, nicknamed the PET scanner the “head-shrinker.”
Diffusion Tensor Image of the brain presented in the sagittal plane (looking sideways at the head with the front on the right side of picture and the back on the left side). The white matter fibers that connect neurons in the brain into circuits are depicted removed from the matrix of gray matter, cerebrospinal fluid, and blood vessels. (Shenton et al./Brain Imaging and Behavior, 2012; vol. 6, issue 2; image by Inga Koerte and Marc Muehlmann)
PET scan images (top row) and MRI images (bottom row) of patients presented in three planes of view. Left column is the axial plane (looking at brain through the top of the head), middle column is the coronal plane (looking at brain through the face), and the right column is the sagittal plane (looking at brain through the side of the head). The PET scan is of a radiotracer (biologic dye) that binds to dopamine receptors in the brain which are concentrated in the bright structures (basal ganglia) in the brain’s interior and more diffusely in the surrounding cerebral cortex. The MRI that shows the brain’s structure, highlighting the gray and white matter and the ventricles and sub-arachnoid space containing cerebrospinal fluid (black), is used in combination with PET scans to determine the anatomic locations where the radiotracer has bound. (Abi-Dargham A. et al./Journal of Cerebral Blood Flow & Metabolism, 2000; 20:225–43. Reproduced with permission.)
As a result of these magnificent new imaging technologies, by the end of the twentieth century psychiatrists could finally examine the brain of a living person in all its exquisite splendor: They could view brain structures to a spatial resolution of less than a millimeter, trace brain activity to a temporal resolution of less than a millisecond, and even identify the chemical composition of brain structures—all without any danger or discomfort to the patient.
The venerable dream of biological psychiatry is starting to be fulfilled: after studying hundreds of thousands of people with virtually every mental disorder in the DSM, researchers have begun identifying a variety of brain abnormalities associated with mental illness. In the brains of schizophrenic patients, structural MRI studies have revealed that the hippocampus is smaller than in healthy brains; functional MRI studies have shown decreased metabolism in frontal cortex circuits during problem-solving tasks; and MRI studies have found increased levels of the neurotransmitter glutamate in the hippocampus and frontal cortex. In addition, PET studies have shown that a neural circuit involved in focusing attention (the mesolimbic pathway) releases excessive amounts of dopamine in schizophrenic brains, distorting the patients’ perceptions of their environments. We’ve also learned that schizophrenic brains exhibit a progressive decline in the amount of gray matter in their cerebral cortex over the course of the illness, reflecting a reduction in the number of neural synapses. (Gray matter is brain tissue that contains the bodies of neurons and their synapses. White matter, on the other hand, consists of the axons, or wires, which connect neurons to one another.) In other words, if schizophrenics are not treated, their brains get smaller and smaller.
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 i
ndividual 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.
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