The Disordered Mind: What Unusual Brains Tell Us About Ourselves

by Eric R. Kandel

Alzheimer’s disease is characterized by deficits in recent memory. It results from the loss of synapses, the point of contact where neurons communicate. The brain can regrow synapses in the early stages of the disease, but in the later stages, neurons actually die.

Alzheimer performed an autopsy on Auguste D. and found three specific alterations in the cerebral cortex that have since proven to be characteristic of the disease. First, her brain was shrunken and atrophied. Second, the outside of the nerve cells contained deposits of a dense material that formed what we now call amyloid plaques. Third, inside the neurons was an accumulation of tangled protein fibers that we now call neurofibrillary tangles.

Scientists have learned that the amyloid-beta peptide is responsible for forming amyloid plaques. This peptide is part of a much larger protein called the amyloid precursor protein (APP), which is thought to be lodged in the cell membrane of dendrites, the short, branching extensions of neurons (fig. 5.7). Two separate enzymes cut through the precursor protein, each in a different place, releasing the amyloid-beta peptide (fig. 5.7). Once released from the cell membrane, the peptide floats in the space outside the neuron.

Another protein involved in Alzheimer’s disease is called tau, and it is located inside the neuron. To function, a protein must have a three-dimensional shape. It assumes this shape by means of folding, a process in which the amino acids that make up the protein twist themselves into a very specific conformation. Think of it as exquisitely complicated origami. When a molecular defect causes the tau protein to misfold, it forms toxic clumps (fig. 5.8) that create neurofibrillary tangles.

The most significant risk factor found to date is the apolipoprotein E (APOE) gene. This gene codes for a protein that combines with fats (lipids) to form a class of molecules called lipoproteins. Lipoproteins package cholesterol and other fats and carry them through the bloodstream. Normal amounts of cholesterol in the blood are essential for good health, but abnormal amounts can clog the arteries and give rise to strokes and heart attacks. One allele, or variation, of this gene is APOE4. The APOE4 allele is rare in the general population, but it puts people at risk of developing late-onset Alzheimer’s disease. In fact, about half of the people with late-onset Alzheimer’s have this allele.

A number of studies have shown that type 2 diabetes is a risk factor for Alzheimer’s disease.

Frontotemporal dementia begins in very small areas of the frontal lobe of the brain that are involved with social intelligence, particularly our ability to inhibit impulses (fig. 5.10). The disorder was once considered impossible to distinguish from Alzheimer’s disease in a living person, but today that is no longer true. Frontotemporal dementia commonly results in profoundly disordered social behavior and moral reasoning. People may commit uncharacteristic antisocial acts, such as shoplifting.

The first scientist to describe a protein-folding disorder was Stanley Prusiner, who observed misfolding in the 1980s in Creutzfeldt-Jakob disease, a rare disorder. Other scientists, as we have seen, went on to show that protein misfolding contributes to Alzheimer’s disease and frontotemporal dementia. At first glance, these dementias might seem to have little, if anything, in common with movement disorders. But a closer look reveals that Parkinson’s disease and Huntington’s disease also result from protein misfolding. We will turn to those brain disorders in chapter 7.

How does impulse relate to creativity? Limb and Braun found that before the pianists began to improvise, their brain showed a “deactivation” of the dorsolateral prefrontal cortex. However, when they were playing the memorized tune, this region remained active. In other words, while they were improvising, their brain was damping down their inhibitions normally mediated by the dorsolateral prefrontal cortex. They were able to create new music in part because they were uninhibited and not self-conscious about being creative.

Freud had documented the importance of unconscious thought, which is not rational and is not governed by a sense of time, space, or logic. Moreover, he pointed to dreams as the royal road to the unconscious. The Surrealists attempted to eliminate logic from their work and to draw on dreams and myths for inspiration, thus unlocking the power of the imagination.

The first and most important process was automatic drawing.

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.”

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.

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.

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.

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.

Just as DeLong was working on the subthalamic nucleus, a new drug, billed by dealers as “synthetic heroin,” showed up on the street. This drug was contaminated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a substance that causes the slowness of movement, tremor, and muscular rigidity typical of Parkinson’s disease. After some young people who had taken the drug died, autopsies revealed that MPTP had destroyed the subthalamic nucleus, and with it the brain cells that produce dopamine. Such damage could not be reversed in survivors, but they did respond positively to L-dopa.

DeLong’s discovery led Alim-Louis Benabid, a neurosurgeon at the Joseph Fourier University in Grenoble, France, to start thinking about using deep-brain stimulation to treat people with Parkinson’s. Deep-brain stimulation, as we have seen, involves implanting electrodes in the brain and a battery-operated device elsewhere in the body. The device sends high-frequency electrical impulses into a neural circuit, in this case the subthalamic nucleus. The impulses essentially inactivate the circuit, much as the damage to the monkey’s subthalamic nucleus did, thus preventing the abnormal activity from interfering with controlled movement (fig. 7.3). The treatment is adjustable and reversible.

Approximately thirty thousand people in the United States have Huntington’s disease, a disorder that affects both sexes equally. The age at which the disease first appears varies widely, but the average age of onset is forty. The disorder was first described in 1872 by George Huntington, a Columbia University–trained physician who noted the hereditary nature, involuntary movements, and changes in personality and cognitive functioning that characterize the disorder. His description was so clear and so accurate that other physicians could readily diagnose the disorder, and they named it after him. Unlike Parkinson’s disease, which is fairly localized at first, Huntington’s disease can become more widespread quite early and can lead to cognitive as well as motor defects, including sleep disorders and dementia. It primarily affects the basal ganglia, but it also affects the cerebral cortex, the hippocampus, the hypothalamus, the thalamus, and occasionally the cerebellum (fig. 7.4).

Ten years later, an international collaborative group called the Gene Hunters, organized by the Hereditary Disease Foundation, finally isolated and sequenced the mutant huntingtin gene.11 Once the gene was isolated, it could be inserted into a worm, a fly, or a mouse to see how the disease would progress. The Gene Hunters noticed that one portion of the huntingtin gene is larger than normal. This portion is called a CAG expansion, and it is what causes the disease.

Learning how prions form opened up new possibilities for research directed toward preventing or reversing protein misfolding. Currently, there are no drugs that slow brain degeneration, but prion formation presents three points at which such an intervention might be possible: (1) the point at which a normal precursor protein folds into a prion form, (2) the point at which the prion form aggregates into fibers, and (3) the point at which plaques, tangles, and bodies form (fig. 7.9). Prusiner’s astonishing observations about prions—that they can reproduce and infect other cells, yet contain no DNA—were initially met with considerable resistance in many scientific quarters.

By adding helper proteins, the dopamine-producing neurons were no longer compromised. Chaperone proteins have also been found to protect against movement disorders: flies with a mutant SNCA gene are poor climbers, but when flies with the same mutation overexpress chaperone proteins they are able to climb normally. This technique also works in fruit fly models of other neurodegenerative diseases—of which there are many now—as well as in mouse models of some neurodegenerative diseases, illustrating once again the utility of animal models for the study of human disease.

Many structures in the brain are involved in emotion, but four of them are particularly important: the hypothalamus, which is the executor of emotion; the amygdala, which orchestrates emotion; the striatum, which comes into play when we form habits, including addictions; and the prefrontal cortex, which evaluates whether a particular emotional response is appropriate to the situation at hand (fig. 8.4). The prefrontal cortex interacts with, and in part controls, the amygdala and striatum.

Joshua Greene, an experimental psychologist, neuroscientist, and philosopher at Harvard, has made use of a fascinating puzzle known as the “trolley problem” to study how emotion affects our moral decision making.12 The trolley problem has numerous variations, but the simplest poses two dilemmas (fig. 8.8). The switch dilemma goes like this:

All of our positive emotions, our feelings of pleasure, can be traced to the neurotransmitter dopamine. Although our brain contains relatively few dopamine-producing neurons, they play an outsized role in the regulation of behavior, largely because of their intimate involvement with the production of pleasure. First discovered in the 1950s by the Swedish pharmacologist Arvid Carlsson, dopamine is released primarily by neurons in two regions of the brain: the ventral tegmental area and the substantia nigra (fig. 9.1). Neurons in the ventral tegmental region extend their axons to the hippocampus, which is involved in the memory of people, places, and things, and to the three most important brain structures for regulating emotion: the amygdala, which orchestrates emotion; the nucleus accumbens, a region of the striatum that mediates the impact of emotion; and the prefrontal cortex, which imposes will and control on the amygdala. This communications network, known as the mesolimbic pathway, is the major network in the brain’s reward system. It puts dopamine-producing neurons in a position to broadcast information widely, including to regions throughout the cerebral cortex.

Wolfram Schultz, a neuroscientist at the University of Cambridge, has studied the role of rewards in learning.2 Schultz’s experiments with monkeys drew on Pavlov’s early experiments with conditioned learning in dogs. Schultz would play a loud tone to monkeys, wait for a few seconds, and then squirt some drops of apple juice into their mouths. While the experiment was unfolding, Schultz monitored the electrical activity inside individual dopamine-producing neurons in the animals’ brains. At first, the neurons didn’t fire until the juice was delivered. However, once the animals learned that the tone predicted the arrival of juice, the same neurons began firing at the sound of the tone—that is, at the prediction of reward instead of the reward itself. To Schultz, the interesting feature about this dopamine learning system was that it is all about expectation.

The expectation of reward helps us form habits. A good habit, one that is adaptive, helps us survive by enabling us to perform many important behaviors automatically, without thinking about them. Adaptive habits are promoted by the release of dopamine into the prefrontal cortex and the striatum, the areas of the brain involved with control and with reward and motivation. The release of dopamine not only creates a feeling of pleasure, it also conditions us. Conditioning, as we know, creates a long-term memory that enables us to recognize a stimulus the next time we see it and to respond accordingly. If the stimulus is positive, as in the case of adaptive habits, conditioning motivates us to pursue it. For example, if you eat a banana and find it delicious, the next time you see a banana you will feel motivated to eat it. Addictive drugs, whether legal or illegal—our body doesn’t make a distinction—also stimulate dopamine-producing neurons in the brain’s reward system. In this case, however, the result is greatly increased dopamine concentrations in the prefrontal cortex and the striatum. The excess dopamine generates intense pleasure and creates a conditioned response to the environmental cues that predict pleasure. Such cues—say, the smell of cigarette smoke or the sight of a needle—elicit an intense craving for the drug, which, in turn, elicits drug-seeking behavior.

Freud divided our mind into conscious and unconscious components. The conscious mind, the ego, is in direct contact with the outside world through our sensory systems for vision, hearing, touch, taste, and smell. The ego is guided by reality, what Freud called the reality principle,

The unconscious mind, the id, is not governed by logic or reality but by the pleasure principle—that is, by seeking pleasure and avoiding pain.

While Freud held that an infinite number of such instincts exist, he reduced them to a basic few, which he divided into two broad groups. Eros, the life instinct, covers all self-preservation and erotic instincts; Thanatos, the death instinct, covers all aggressive, self-destructive, and cruel instincts. Thus it is incorrect to think of Freud as asserting that all human actions spring from sexual motivation. Those that spring from Thanatos are not sexually motivated; moreover, as we shall see, the life and death instincts can be fused.

He added a second component, the superego. The superego is the ethical component of mind that forms our conscience.

Freud completed his structural model of the mind by adding a third component, the preconscious unconscious, which is now called the adaptive unconscious. This third unconscious component is part of the ego; it processes the information necessary for consciousness without our being aware of it (fig. 11.1).

Much of Freud’s work was devoted to the id, our unconscious storehouse of socially unacceptable desires, traumatic memories, and painful emotions, and to the study of repression, the defensive mechanism that keeps these emotions from entering our conscious thought.

After designing and conducting a series of experiments that used brain imaging to study visual perception, Baars introduced the theory of the global workspace in 1988.2 According to this theory, consciousness involves the widespread dissemination, or broadcasting, of previously unconscious (preconscious) information throughout the cortex. Baars suggested that the global workspace comprises a system of neural circuits that extends from the brain stem to the thalamus and from there to the cerebral cortex.

Put simply, when you are conscious of a particular word, that word becomes available in the global workspace, a process that takes place separately from your visual recognition of the word. Although the word is flashed in front of your eyes for only a very brief moment, you can keep that word in mind with your working memory. You can then broadcast it to all of the areas that need it.

This astonishing result might suggest that we are at the mercy of our unconscious instincts and desires. In fact, however, the activity in our brain precedes the decision to move, not the movement itself. As Libet explains, the process of initiating a voluntary action occurs rapidly in an unconscious part of the brain; however, just before the action is begun, consciousness, which comes into play more slowly, approves or vetoes the action. Thus, in the 150 milliseconds before you lift your finger, your consciousness determines whether or not you will actually move it. What Libet showed is that activity in the brain precedes awareness, just as it precedes any action we take. We therefore have to refine our thinking about the nature of brain activity as it pertains to consciousness. In the 1970s Daniel Kahneman and Amos Tversky began to entertain the idea that intuitive thinking functions as an intermediate step between perception and reasoning. They explored how people make decisions and, in time, realized that unconscious errors of reasoning greatly distort our judgment and influence our behavior.11 Their work became part of the framework for the new field of behavioral economics. Kahneman and Tversky identified certain mental shortcuts that, while allowing for speedy action, can result in less-than-optimal judgments. For example, decision making is influenced by the way choices are described, or framed. In framing a choice, we weigh losses far more heavily than equivalent...

Kahneman went on to describe two general systems of thought.12 System 1 is largely unconscious, fast, automatic, and intuitive—like the adaptive unconscious, or what Walter Mischel, a leading cognitive psychologist, calls “hot” thinking. In general, System 1 uses association and metaphor to produce a quick rough draft of an answer to a problem or situation. Kahneman argues that some of our most highly skilled activities require large doses of intuition: playing chess at a master level or appreciating social situations. But intuition is prone to biases and errors. System 2, in contrast, is consciousness-based, slow, deliberate, and analytical, like Mischel’s “cool” thinking. System 2 evaluates a situation using explicit beliefs and a reasoned evaluation of alternatives. Kahneman argues that we identify with System 2, the conscious, reasoning self that makes choices and decides what to think about and what to do, whereas actually our lives are guided by System 1.

Third, with some notable exceptions, psychoanalysts have not embraced the last fifty years’ worth of knowledge about the biology of the brain and its control of behavior.

We have learned more about the brain and its disorders in the past century than we have during all of the previous years of human history combined. Decoding the human genome has shown us how genes dictate the organization of the brain and how changes in genes influence disorders. We have new insights into the molecular pathways that underlie specific brain functions, such as memory, as well as the defective genes that contribute to disorders of those functions, such as Alzheimer’s disease. We also know more about the powerful interaction of genes and the environment in causing brain disorders, such as the role of stress in mood disorders and PTSD. Equally remarkable are recent breakthroughs in brain-scanning technology. Scientists can now track particular mental processes and mental disorders to specific regions and combinations of regions in the brain while a person is alert, with active nerve cells lighting up to create brightly colored maps of brain function. Finally, animal models of disorders have pointed us toward new avenues of research in human patients.

Several disorders of movement and of memory, such as Parkinson’s disease and Alzheimer’s disease, result from misfolded proteins. The symptoms of these disorders vary widely because the particular proteins affected and the functions for which they are responsible differ. Similarly, both autism and schizophrenia involve synaptic pruning, the removal of excess dendrites on neurons. In autism, not enough dendrites are pruned, whereas in schizophrenia too many are. In another example, three different disorders—autism, schizophrenia, and bipolar disorder—share genetic variants. That is, some of the same genes that create a risk for schizophrenia also create a risk for bipolar disorder, and some of the same genes that create a risk for schizophrenia also create a risk for autism spectrum disorders. The interplay of unconscious and conscious mental processes is critical to how we function in the world. We see this particularly clearly in creativity and decision making. Our innate creativity—in any field—hinges on loosening the bonds of consciousness and gaining access to our unconscious. This is easier for some people than for others.