The Disordered Mind

by Eric R. Kandel

  This modern view derives from three scientific advances. The first was the emergence of a genetics of psychiatric and addictive disorders pioneered by Franz Kallmann, a German-born psychiatrist who immigrated to the United States in 1936 and worked at Columbia University. Kallmann documented the role of heredity in psychiatric disorders such as schizophrenia and bipolar disorder, thereby showing that they are indeed biological in nature.

  The second advance was brain imaging, which has begun to show that the various psychiatric disorders involve distinct systems in the brain. It is now possible, for example, to detect some of the areas of the brain that function abnormally in people with depression. In addition, imaging has allowed researchers to watch the action of drugs on the brain and even to see the changes that result from treating patients with drugs or with psychotherapy.

  The third advance was the development of animal models of disease. Scientists create animal models by manipulating the animals’ genes and then observing the effects. Animal models have proven invaluable in studies of psychiatric disorders, providing insights into how genes, the environment, and the interaction of the two can disrupt brain development, learning, and behavior. Animal models, such as mice, are particularly useful for studying learned fear or anxiety because these states occur naturally in animals. But mice can also be used to study depression or schizophrenia by inserting into their brain altered genes that have been shown to contribute to depression or schizophrenia in people.

  Let us first consider the genetics of mental disorders, then the imaging of brain functions, and finally animal models.

  GENETICS

  For all its wonders, the brain is an organ of the body—and like all biological structures, it is built and regulated by genes. Genes are distinct stretches of DNA that have two remarkable qualities: they provide cells with instructions for how to start an organism anew, and they are handed down from one generation to the next, thereby transferring those instructions to the organism’s offspring. Each of our genes provides a copy of itself to almost every cell in our body, as well as to generations that succeed us.

  We all have about twenty-one thousand genes, and roughly half of them are expressed in the brain. When we say a gene is “expressed,” we mean that it is turned on, that it is busy directing the synthesis of proteins. Each gene encodes—that is, issues the instructions for making—a particular protein. Proteins determine the structure, function, and other biological characteristics of every cell in our body.

  Genes generally replicate reliably, but when one doesn’t, a mutation results. This alteration in a gene can occasionally prove beneficial to an organism, but it can also result in the overproduction, loss, or malfunction of the protein that the particular gene encodes, thus compromising cell structure and function and possibly leading to disorders.

  Each of us has two copies of each gene, one from our mother and one from our father. The pairs of genes are arranged in precise order along twenty-three pairs of chromosomes. As a result, scientists can identify each gene by its location, or locus, on a specific chromosome.

  The maternal and paternal copies of each gene are referred to as alleles. The two alleles of a particular gene usually differ slightly: that is, each one consists of a particular sequence of nucleotides, the four molecules that make up the code of DNA. Thus, the sequence of nucleotides in the genes you inherit from your mother is not exactly the same as the sequence of nucleotides in the genes you inherit from your father. Moreover, the nucleotide sequences you inherit are not exact copies of your parents’ sequences; they contain some differences that occurred by chance when the gene was copied from your parent to you. These differences lead to variations in appearance and behavior.

  In spite of the many variations that give us our sense of individuality, the genetic makeup, or genome, of any two people is more than 99 percent identical. The difference between them results from these chance variations in one or more of the genes they inherited from their parents (although there are rare exceptions, which we will touch on in chapter 2).

  If almost every cell in our body contains the instructions for every other cell, then how is it that one cell becomes a kidney cell, while another becomes part of the heart? Or, in the brain, how does one cell become a hippocampal neuron, involved in memory, and another a spinal motor neuron, involved in the control of movement? In each instance, a distinct set of genes in the progenitor cell was activated, setting in motion the machinery that gave that cell its particular identity. Which particular set of genes is activated depends upon the interaction of molecules inside the cell and the interaction of the cell with both its neighboring cells and with the organism’s external environment. We have a finite number of genes, but the turning on and off of different genes at different times gives rise to an almost infinite complexity.

  To fully understand a brain disorder, scientists try to pinpoint the underlying genes and then understand how variations in those genes, interacting with the environment, bring about the disorder. With a basic knowledge of what has gone wrong, we can begin to figure out ways of intervening to prevent or ameliorate the disorder.

  Genetic studies of families, beginning with those done by Kallmann in the 1940s, show just how pervasive genetic influences are in psychiatric disorders (table 1). We refer to genetic “influences” because the inheritance of psychiatric disorders is complex: there is no single gene that causes schizophrenia or bipolar disorder. What Kallmann found is that a person with schizophrenia is much more likely than a person without schizophrenia to have a parent or a sibling with the disorder. Even more compelling, he found that an identical twin of a person with schizophrenia or bipolar disorder is much more likely than a fraternal twin to have the same disorder. Because identical twins share all the same genes and fraternal twins share only half their genes, this finding clearly implicated the identical twins’ genes, rather than their shared environment, in the higher incidence of these mental disorders.

  Studies of twins show that autism also has a powerful genetic component: when one identical twin has autism, the other identical twin has a 90 percent chance of developing the disorder. A different sibling in that same family, including a fraternal twin, is considerably less likely to develop autism, while an individual in the general population has only a scant chance of developing the disorder (table 1).

  We have learned a great deal about the role that genes play in medical disorders by looking at family histories. Based on those histories, it is possible to divide genetic illnesses into two groups: simple and complex (figs. 1.6a and 1.6b).

  A simple genetic illness, like Huntington’s disease, is caused by a mutation in a single gene. A person who has that mutation will have the disease, and if one identical twin has the disease, they both will. In contrast, vulnerability to a complex genetic disease like bipolar disorder or depression is dependent upon the interaction of several genes with one another and with the environment. We can tell that bipolar disorder is complex because we know that if one identical twin develops the disorder, the other may not. This means that environmental factors must play a key role. When both genes and environment are involved, it is usually easier to find candidate genes first, by carrying out large-scale studies to determine which genes correlate with depression and which correlate with mania, and then try to sort out the environmental contribution.

  Figure 1.6. A simple genetic illness can involve the mutation of a single gene (A), whereas a complex genetic illness may involve several genes as well as environmental factors (B).

  BRAIN IMAGING

  Until the 1970s, clinicians had limited tools to examine the living brain: X-rays, which reveal the bony structure of the skull but nothing of the brain itself; angiography, which reveals the blood supply in the brain; and pneumoencephalography, which reveals the ventricles of the brain (the hollow spaces filled with cerebrospinal fluid). Using these crude radiological methods in addition to autopsy, brain scientists for years examined depressed and schizophrenic people b
ut could detect no damage to the brain. In the 1970s, however, two categories of imaging that would dramatically change our understanding of the brain began to emerge: structural imaging and functional imaging.

  Structural imaging looks at the anatomy of the brain. Computed tomography (CT) combines a series of X-ray images taken from different angles into a cross-sectional picture. These scans are used to contrast the density of different parts of the brain, such as the bundles of axons that make up the white matter and the cell bodies and dendrites of neurons that make up the cerebral cortex, or gray matter.

  Magnetic resonance imaging (MRI) makes use of a very different technique: it contrasts the response of various tissues to applied magnetic fields. The resulting picture provides more-detailed information than computed tomography. For example, MRI has revealed that in people with schizophrenia, the lateral ventricles of the brain are enlarged, the cerebral cortex is thinner, and the hippocampus is smaller.

  Functional imaging goes one step further, introducing the dimension of time. Functional imaging enables scientists to observe activity in the brain of a person who is carrying out a cognitive task, such as looking at a work of art, hearing, thinking, or remembering. Functional magnetic resonance imaging (fMRI) works by detecting changes in the concentration of oxygen in red blood cells. When an area of the brain becomes more active, it consumes more oxygen; to meet the demand for more oxygen, blood flow to the area increases. Thus, scientists can use fMRI to create maps showing which parts of the brain are active during a variety of mental tasks.

  Functional imaging evolved from studies pioneered by Seymour Kety and his colleagues, who in 1945 developed the first effective way to measure blood flow in the living brain. In a series of classic studies, they measured blood flow in the brains of people who were awake and people who were asleep, thereby establishing the basis for subsequent studies using functional imaging. Marcus Raichle, a pioneer of brain imaging, has noted that the impact of Kety’s studies on our understanding of the circulation and metabolism of the human brain cannot be overestimated.

  Kety then proceeded to study normal and disordered brain function. He found that overall blood flow in the brain is not altered in a surprising range of conditions, from being deeply asleep to being fully awake, from doing mental arithmetic to being mentally disorganized as a result of schizophrenia. This led him to suspect that measuring blood flow in the entire brain doesn’t capture important changes that might be taking place in specific regions of the brain. He therefore decided to search for ways of measuring regional blood flow.

  In 1955, together with Louis Sokoloff, Lewis Rowland, Walter Freygang, and William Landau, Kety devised a method of visualizing local blood flow in twenty-eight different regions of the cat brain.2 The group made the remarkable discovery that visual stimulation increases blood flow only to the components of the visual system, including the visual cortex, the region of the cerebral cortex that is dedicated to processing visual information. This was the first evidence that changes in blood flow are directly related to brain activity and, presumably, to brain metabolism. In 1977 Sokoloff developed a technique for measuring regional metabolic activity and used that technique to chart where specific functions are located in the brain, thereby providing an independent way for researchers to localize function in the brain.3

  Sokoloff’s discovery laid the foundation for positron emission tomography (PET) and single-photon emission computed tomography (SPECT), the imaging methods that made it possible to visualize brain function in thinking human beings. PET advanced scientists’ understanding of the chemistry of brain processes by enabling them to label specific neurotransmitters used by different classes of nerve cells as well as the receptors on target cells that those transmitters act upon.

  Structural and functional imaging techniques have given scientists a new way to look at the brain. They can now see which regions of the brain—and sometimes even which neural circuits within those regions—are not working properly.

  This information is essential, because the modern view of psychiatric disorders is that they also are disorders of neural circuits.

  ANIMAL MODELS

  An animal model of a disorder can be engineered in two ways. One, as we have seen, is by identifying the genes in an animal that are equivalent to the human genes thought to contribute to a disorder, altering those animal genes, and then observing the effects on the animal. The second is by inserting a human gene into an animal’s genome to see whether it produces the same effects in the animal as in people.

  Animal models such as worms, flies, and mice are critical to our understanding of brain disorders. These models have given us insights into the neural circuit of fear that underlies stress, a major contributor to several psychiatric disorders. Animal models of autism have enabled scientists to observe how the expression of human genes that contribute to the disorder alter the animals’ social behavior in various contexts.

  Mice are the preeminent animal species for modeling brain disorders. Mouse models have given scientists important insights into how rare structural mutations in genes lead to abnormal brain activity in autism and schizophrenia. Moreover, genetically modified mice are proving to be extremely valuable for studying the cognitive deficits of schizophrenia. They can even be used to model environmental risk factors: scientists can expose mice in utero to risks such as maternal stress or activation of their mother’s immune system (as might occur when a mother contracts an infection) to determine how such factors affect brain development and function. Animal models make possible controlled experiments that reveal connections between genes, the brain, the environment, and behavior.

  NARROWING THE DIVIDE BETWEEN PSYCHIATRIC AND NEUROLOGICAL DISORDERS

  Understanding the biological underpinnings of neurological disorders has greatly enriched our understanding of normal brain function—of how the brain gives rise to the mind. We have learned about language from Broca’s and Wernicke’s aphasias, about memory from Alzheimer’s disease, about creativity from frontotemporal dementia, about movement from Parkinson’s disease, and about the link between thought and action from spinal cord injuries.

  Studies are beginning to show that some diseases that produce different symptoms come about in the same way; that is, they share a common molecular mechanism. For example, Alzheimer’s disease, which primarily affects memory; Parkinson’s disease, which primarily affects movement; and Huntington’s disease, which affects movement, mood, and cognition, are all thought to involve faulty protein folding, as we shall see in later chapters. The three disorders produce strikingly different symptoms because the abnormal folding affects different proteins and different regions of the brain. We will undoubtedly discover common mechanisms in other diseases as well.

  Presumably, every psychiatric illness arises when some parts of the brain’s neural circuitry—some neurons and the circuits to which they belong—are hyperactive, inactive, or unable to communicate effectively. We don’t know whether those dysfunctions stem from microscopic injuries that we can’t see when we look at the brain, from critical changes in synaptic connections, or from faulty wiring of the brain during development. But we do know that all psychiatric disturbances result from specific changes in how neurons and synapses function, and we also know that insofar as psychotherapy works, it works by acting on brain functions, creating physical changes in the brain.

  Thus, we now know that psychiatric illnesses, like neurological disorders, arise from abnormalities in the brain.

  How are psychiatric and neurological disorders different? At the moment, the most obvious difference is the symptoms that patients experience. Neurological disorders tend to produce unusual behavior, or fragmentation of behavior into component parts, such as unusual movements of a person’s head or arms, or loss of motor control. By contrast, the major psychiatric disorders are often characterized by exaggerations of everyday behavior. We all feel despondent occasionally, but this feeling is dramatically amplified in depression. We all
experience euphoria when things go well, but that feeling goes into overdrive in the manic phase of bipolar disorder. Normal fear and pleasure seeking can spiral into severe anxiety states and addiction. Even certain hallucinations and delusions from schizophrenia bear some resemblance to events that occur in our dreams.

  Both neurological and psychiatric disorders may involve reduced function. For example, as there is a loss of control over movement in Parkinson’s disease, so there is a loss of memory in Alzheimer’s disease, a loss of the ability to process social cues in autism, and reduced cognitive skills in schizophrenia.

  A second apparent difference is in how readily we can see actual physical damage to the brain. Damage resulting from neurological disorders, as we have learned, is often clearly visible at autopsy or in structural imaging. Damage resulting from psychiatric disorders is often less obvious, but as imaging techniques improve in resolution, we are beginning to detect changes resulting from these disorders. For example, as mentioned previously, we can now identify three structural changes in the brains of people with schizophrenia: enlarged ventricles, thinner cortex, and a smaller hippocampus. Thanks to improvements in functional brain imaging, we can now observe certain changes in brain activity that are characteristic of depression and other psychiatric disorders. Finally, as techniques for detecting even subtler damage to nerve cells become available, we should be able to find such damage in the brains of all people with psychiatric disorders.

  The third apparent difference is location. Because of neurology’s traditional emphasis on anatomy, we know a great deal more about the neural circuitry of neurological disorders than of psychiatric disorders. In addition, the underlying neural circuitry of psychiatric disorders is more complex than that of neurological disorders. Scientists have only recently begun to explore the brain regions involved in thought, planning, and motivation, the mental processes that are disordered in schizophrenia and in mood and emotional states such as depression.