The Disordered Mind

by Eric R. Kandel

  This outburst of artistic creativity supports John Hughlings Jackson’s contention that the left brain and right brain have different functions and that they inhibit each other. Although this distinction oversimplifies the nature of complicated processes such as creativity, which most certainly have multiple origins, we now have enough evidence from imaging studies to conclude that some aspects of artistic and musical creativity do come from the right hemisphere of the brain.

  Like Alzheimer’s disease, frontotemporal dementia may result in dramatic changes in an artist’s style of painting, as well as his or her behavior. In “The Mysterious Metamorphosis of Chuck Close,” the writer Wil S. Hylton observes that at age seventy-six the noted painter had radically upended his distinctive style of portraiture—in fact, his entire life. Hylton writes:

  Over the past year, I have been stopping off to see Close in various homes and apartments up and down the Eastern Seaboard, trying to get a handle on the changes in his life and their connection to his work. On my most recent visit to his beach house … he looked tan and rested … and had been working all morning in the studio behind us on a large self-portrait that I knew he was excited about.… [I]t was a radical departure from the last 20 years of his art. Gone were all the swoops and swirls that he typically paints into each square of the grid. In their place, he had filled each cell with just one or two predominant colors, creating a clunky digital effect like the graphics of a Commodore 64. The colors themselves were harsh and glaring, blinding pink and gleaming blue, while the face in the portrait—his face—was cleaved right down the middle, with one side of the canvas painted in different shades from the other.36

  When Close entered the room and started chatting with Hylton about the painting, he often lost his train of thought. After about a dozen times, Hylton suggested that they take a break, and they agreed to meet again the next day. In thinking about his encounter with Close and his new painting style, Hylton reflected on what the nineteenth-century critic William Hazlitt wrote about the old age of artists: “One feels that they are not quite mortal, that they have one imperishable part about them,” what Theodor Adorno called the “late style.”37

  While talking to Hylton the next day, Close mentioned to him that he had received a mistaken diagnosis of Alzheimer’s disease the previous year. After spending weeks in a panic, he learned that the diagnosis was wrong and that he had instead another diagnosis.38 He has since mentioned to others that he has frontotemporal dementia, which would explain both his changed behavior and his brilliant new style.

  CREATIVITY AS AN INHERENT PART OF HUMAN NATURE

  The idea that creativity is correlated with mental illness is a Romantic fallacy. Creativity does not stem from mental illness; it is an inherent part of human nature. As Rudolf Arnheim points out, “Present psychiatric opinion holds that psychosis does not generate artistic genius but at best liberates powers of the imagination that under normal conditions might remain locked up by the inhibitions of social and educational convention.”39

  Andreasen takes a somewhat different approach to the question of creativity and mental illness. In her essay “Secrets of the Creative Brain,” she asks, “Why are so many of the world’s most creative minds among the most afflicted?”40

  To begin with, Andreasen’s studies and those of many others support the notion that creativity is not related to IQ. Many people with high IQs are not creative and vice versa. Most creative people are smart, but as Andreasen puts it, they don’t have to be “that smart.”

  What Andreasen did find is that many of the creative writers she studied had suffered from a mood disturbance at some point in their lives, compared to only 30 percent of the controls in her study, who were not as creative as the writers but who had comparable IQ scores. Similarly, Jamison and the psychiatrist Joseph Schildkraut have found that 40 to 50 percent of the creative writers and artists they studied suffered from a mood disorder, whether depression or bipolar disorder.41

  Andreasen also found that exceptionally creative people were more likely than controls to have one or more first-degree relatives with schizophrenia. This finding suggested to her that some particularly creative people owe their gifts to a subclinical variant of schizophrenia that “loosens their associative links sufficiently to enhance their creativity, but not enough to make them mentally ill.”42

  Andreasen ends her essay on creativity with a quotation from A Beautiful Mind, Sylvia Nasar’s biography of John Nash, a mathematician who won the Nobel Prize in Economics and who had schizophrenia:

  Nasar describes a visit Nash received from a fellow mathematician while institutionalized at McLean Hospital. “How could you, a mathematician, a man devoted to reason and logical truth,” the colleague asked, “believe that extraterrestrials are sending you messages? How could you believe that you are being recruited by aliens from outer space to save the world?” To which Nash replied: “Because the ideas I had about supernatural beings came to me the same way that my mathematical ideas did. So I took them seriously.”43

  In a large study published recently in Nature Neuroscience, Robert Power, a scientist affiliated with deCODE Genetics in Iceland, and his colleagues found that genetic factors which raise the risk of bipolar disorder and schizophrenia are more prevalent in people who are in creative professions.44 Painters, musicians, writers, and dancers were, on average, 25 percent more likely to carry these gene variants than people who work in professions judged to be less creative: farmers, manual laborers, and salespeople. Kári Stefánsson, founder and CEO of deCODE and a coauthor of the study, said: “To be creative, you have to think differently. And when we are different, we have a tendency to be labeled strange, crazy and even insane.”45

  By viewing psychotic states as totally foreign to normal behavior, we fail to recognize that such states are often dramatic representations of character types or temperaments found in the general population—and often found to a greater degree in the minds of creative thinkers, scientists, and artists. That said, people with a brain disorder may very well have readier access to certain aspects of their unconscious than people who are not mentally ill. That difference is particularly critical in terms of creativity. Equally important, the ready accessibility of a mentally ill person to the creativity of his or her unconscious world can be emulated, as Surrealist artists have attempted to show.

  LOOKING AHEAD

  After setting aside the notion that creativity is inspired by the muses or by madness, and embracing the fact that it is based in the brain, we are nonetheless left with questions.

  Creativity feels out of the ordinary to us. We all have an imagination, and we all make creative use of it to solve problems and come up with new ideas. Yet there is something undeniably different about people who are capable of creating remarkable new things. Inner drive and hard work, while essential, don’t seem sufficient to explain why some people are extraordinarily creative.

  Psychiatric disorders such as schizophrenia and bipolar disorder have illustrated the central role of unconscious mental processes in creativity. Studies of people with autism cast new light on the nature of talent and creative problem solving. Alzheimer’s disease and frontotemporal dementia reveal the plasticity of our brain. These disorders may damage the left side of the brain, freeing up the more creative, right side of the brain and resulting in newfound, or radically different, creativity.

  What we have learned from biology so far is that creativity results in part from a loosening of inhibitions and the unconscious creation of new associations in the brain. The result is new ways of seeing the world that, Andreasen has found, often occasion strong feelings of joy and excitement.46 We call on our unconscious in any kind of creative endeavor, whether solving a problem, seeing a slightly new relationship between two scientific findings, painting a portrait, or viewing a portrait.

  The unconscious! We call on it in every action, perception, thought, memory, emotion, and decision we make, in sickness and in health. Consciousness is no diff
erent. Consciousness is the last great mystery of the human brain, and it, too, as we shall see in chapter 11, entails unconscious processes.

  7

  MOVEMENT: PARKINSON’S AND HUNTINGTON’S DISEASES

  Because movement feels so intuitive to most of us, we may not realize how complicated it is. Before we can act, our brain must issue commands to our body, ordering muscles to flex or relax. Those commands are controlled by the motor system, an elaborate set of neural circuits and pathways that begin in the cortex, extend down the spinal cord, and radiate out to every inch of our body.

  When something goes wrong with the motor system, it shows up in unusual behavior or movements, or in loss of control over movement. It also shows up clearly in the brain, which is why neurologists have focused so keenly on anatomy, on tracing neurological disorders to the specific neural circuits in the brain that are responsible for them.

  Those studies of neurological disorders contributed greatly to our understanding of normal brain function. In fact, until the 1950s, clinical neurology was known humorously as the medical discipline that could diagnose everything but treat practically nothing. Since then, however, new insights into the molecular underpinnings of neurological disorders have revolutionized treatments for people with Parkinson’s disease, stroke, and even severed spinal cords.

  Many of the new insights in neurology come from studies of protein folding. Proteins normally fold into specific, three-dimensional shapes. If they misfold or otherwise malfunction, they can clump together in the brain and lead to the death of nerve cells. As we have seen, Alzheimer’s disease and frontotemporal dementia are disorders of protein folding. We have now learned that Huntington’s, Parkinson’s, and other diseases also seem to involve defective protein folding.

  In this chapter we begin by examining the workings of the motor system. We then look at what we know about Parkinson’s and Huntington’s diseases. Finally, we explore the common features of protein-folding disorders, the self-propagation of bizarre proteins known as prions, and genetic studies of protein misfolding.

  THE EXTRAORDINARY SKILLS OF THE MOTOR SYSTEM

  The motor system controls more than 650 muscles, giving rise to an immense repertoire of possible actions, from the reflexive scratching of an itch to the pirouettes of a ballet dancer, from sneezing to walking a tightrope. Some of these actions are inborn, meaning that our ability to carry them out is built into our brain and spinal cord. Thus, for example, we are programmed to walk upright. But many actions are learned, requiring thousands of hours of practice.

  Coordinating all of those muscles is a tremendous challenge, yet the motor system carries out most movements without any conscious instruction. We don’t think about how to run or jump or reach for an object, we just do it. How does the brain initiate and coordinate a complex series of actions?

  About one hundred years ago the English physiologist Charles Sherrington realized that while our senses provide many ways for information to enter the brain, there is only one way out—movement. The brain takes in a constant barrage of sensory information and ultimately converts it into coordinated movement. If we could understand movement, he reasoned, we would be a giant step closer to understanding the brain.

  Sherrington discovered that each of the motor neurons in our spinal cord sends signals to one or more of the body’s 650 muscles. Moreover, he realized that in addition to initiating movements and carrying them out, the brain needs feedback about the body’s performance. Did the muscle make the intended movement? How quickly? How accurately?

  The brain has a special class of neurons that report back on the movement of each muscle. They are known as sensory feedback neurons, but they are not the same as the sensory neurons that relay information about the outside world from our sense organs to our brain. The feedback neurons are part of the motor system, and the brain uses information from them to create our internal sense of our own body and the relative position of our limbs in space, a sense known as proprioception. Without proprioception, we would be unable to point to an area of our body with our eyes closed or take a step without looking at our feet.

  To study the coordinated action of the motor system, Sherrington turned to the simplest motor circuit of all, the reflex. Reflex movements are controlled by a pathway that connects feedback neurons in the muscle directly to motor neurons in the spinal cord—without involving the brain. That’s why you can’t exert much control over a reflex, even if you try.

  By experimenting with reflexes in cats, Sherrington discovered that motor neurons receive and respond selectively to one of two very different signals: excitatory signals and inhibitory signals. Excitatory signals trigger the action of the motor neurons that initiate extension of a limb, for example, while inhibitory signals tell the motor neurons that control flexion, the opposing movement, to relax. Thus, even a simple knee-jerk reflex requires two simultaneous and opposite commands: the muscles that extend the knee must be excited, while the opposing muscles that flex the knee must be inhibited.

  This surprising discovery led Sherrington to formulate a principle that can be applied not just to reflexes but also to the organizational logic of the brain as a whole. In the broadest sense, the task of every circuit in the nervous system is to add up the total excitatory and inhibitory information it receives and determine whether to pass that information along. Sherrington called this principle “the integrative action of the nervous system.”1

  Sherrington demonstrated, for the first time, that we can understand complex neural circuits by studying simpler ones, a principle now widely used in neuroscience. In this sense, he both laid out the challenges that we face today and established a way to overcome them. In 1932 he and Edgar Adrian, whom we met in chapter 1, shared the Nobel Prize in Physiology or Medicine for their discoveries about how neurons orchestrate activity.

  PARKINSON’S DISEASE

  About 1 million people in the United States have Parkinson’s disease. Every year, sixty thousand new cases are detected and a significant number of additional cases evade detection. Worldwide, 7 to 10 million people suffer from this disorder, which usually begins around the age of sixty.

  Parkinson’s disease was first described in 1817 by the British physician James Parkinson in “An Essay on the Shaking Palsy.”2 Parkinson described six patients, each of whom had three characteristics: tremor at rest, abnormal posture, and slowness and paucity of movement (bradykinesia). In time, the patients’ symptoms became worse.

  It was another century before anything more was published about the disease. In 1912 Frederick Lewy described inclusions, or clumps of proteins, inside certain neurons in the brains of people who had died of Parkinson’s disease. Then in 1919 Konstantin Tretiakoff, a Russian medical student in Paris, described the substantia nigra, a part of the brain that he thought was involved in Parkinson’s disease (fig. 7.1).

  The substantia nigra, or black substance, appears as a dark band on each side of the midbrain. It gets its color from a compound called neuromelanin, which we now know is derived from dopamine. What Tretiakoff found during an autopsy on the brain of a person with Parkinson’s was decreased pigment, indicating cell loss. Not only that, he saw the inclusions that Lewy had described. Tretiakoff called them Lewy bodies, and they are a hallmark of the disease.

  Another forty years went by before Arvid Carlsson discovered dopamine—specifically, low concentrations of dopamine—in the brains of people with Parkinson’s disease. Carlsson was interested in three neurotransmitters: noradrenaline, serotonin, and dopamine. He particularly wanted to know which of these was involved in drug-induced Parkinson’s. Reserpine, a drug that was used to treat high blood pressure, had been found to cause symptoms of Parkinson’s in people and in animals. No one knew how reserpine worked, but early investigators found that it causes a decrease in serotonin.

  Carlsson wondered if reserpine also decreased dopamine. He injected the drug into rabbits and found that it makes them listless; their ears droop and they can’t
move. In an attempt to counteract these effects, he injected the chemical precursor of serotonin into the rabbits. Nothing happened. He then injected the precursor of dopamine, L-dopa, and behold, the animals woke up. Carlsson recognized the importance of his finding, and in 1958 he proposed that dopamine is somehow involved in Parkinson’s disease.3

  Figure 7.1. Regions of the brain affected by Parkinson’s disease. Dopamine produced in the substantia nigra is transmitted along the nigrostriatal pathway to the basal ganglia.

  Subsequent studies by Carlsson showed that dopamine is essential to the regulation of muscle movement.4 As we learned in chapter 4, antipsychotic drugs used to treat people with schizophrenia can reduce dopamine in the brain, resulting in the abnormal muscle movements typical of Parkinson’s disease. Carlsson went on to find that the early symptoms of Parkinson’s disease result from the death of dopamine-producing neurons in the substantia nigra, although he didn’t know then what caused the cell death.5 Today, we know that those neurons die from a protein-folding disorder: the Lewy bodies inside dopamine-producing neurons are clumps of misfolded proteins that are thought to kill the cells. As the disease worsens, other areas of the brain besides the substantia nigra become involved.

  Figure 7.2. People with Parkinson’s disease lose dopamine-producing cells (seen as dark patches) in the substantia nigra.

  Oleh Hornykiewicz of Austria found at autopsy that dopamine is depleted in the brain of people with Parkinson’s (fig. 7.2).6 In 1967 George Cotzias, of the Brookhaven National Laboratory in New York, gave patients L-dopa to replace the depleted dopamine.7 Initially, L-dopa was viewed as a cure, but after a honeymoon of several years, it fell out of favor because it was only effective as long as there were dopamine-producing cells in the substantia nigra. It turned out that as more dopamine-producing cells died, the drug’s beneficial effects wore off abruptly, leaving patients with involuntary movements, called dyskinesias. Clearly, an alternative treatment was needed.