The Disordered Mind

by Eric R. Kandel

  After Leborgne died, Broca examined his brain, looking for clues to his affliction. He found a region in the forward part of the left hemisphere that appeared blighted by disease or injury. Broca eventually encountered eight additional patients with the same difficulty producing language and found that they all had damage in the same area on the left side of the brain, a region that became known as Broca’s area (fig. 1.1). These findings led him to conclude that our ability to speak resides in the left hemisphere of the brain, or as he put it, “We speak with the left hemisphere.”1

  In 1875 Wernicke observed the mirror image of Leborgne’s defect. He encountered a patient whose words flowed freely but who could not understand language. If Wernicke told him to “Put object A on top of object B,” the man would have no idea what he was being asked to do. Wernicke tracked this deficit in language comprehension to damage in the back of the left hemisphere, a region that became known as Wernicke’s area (fig. 1.1).

  Wernicke had the great insight to realize that complex mental functions like language do not reside in a single region of the brain but instead involve multiple, interconnected brain regions. These circuits form the neural “wiring” of our brain. Wernicke demonstrated not only that comprehension and expression are processed separately but that they are connected to each other by a pathway known as the arcuate fasciculus. The information we obtain from reading is transmitted from our eyes to the visual cortex, and the information from hearing is sent from our ears to the auditory cortex. Information from these two cortical areas then converges in Wernicke’s area, which translates it into a neural code for understanding language. Only then does the information proceed to Broca’s area, enabling us to express ourselves (fig. 1.1).

  Wernicke predicted that someday, someone would find a disorder of language that involves simply a disconnect between the two areas. This proved to be the case: people with damage to the arcuate pathway connecting the two areas can understand language and express language, but the two functions operate independently. This is a bit like a presidential press conference: information comes in, information goes out, but there is no logical connection between them.

  Scientists now think that other complex cognitive skills also require the participation of several quite distinct but interconnected regions of the brain.

  Figure 1.1. The anatomical pathway for language comprehension (Wernicke’s area) and expression (Broca’s area). The two areas are connected by the arcuate fasciculus.

  Although the circuitry for language has proved to be even more complex than Broca and Wernicke realized, their initial discoveries formed the basis of our modern view of the neurology of language and, by extension, our view of neurological disorders. Their emphasis on location, location, location resulted in major advances in the diagnosis and treatment of neurological disease. Moreover, the damage typically caused by neurological diseases is easily visible in the brain, making them far easier to identify than most psychiatric disorders, in which the damage is much subtler.

  The search for localization of function in the brain was enhanced dramatically in the 1930s and ’40s by Canada’s renowned neurosurgeon Wilder Penfield, who operated on people suffering from epilepsy caused by scar tissue that had formed in the brain after a head injury. Penfield was seeking to elicit an aura, the sensation many epileptic patients experience before a seizure. If successful, he would have a good idea of which tiny bit of the brain to remove in order to relieve his patients’ seizures without damaging other functions, such as language or the ability to move.

  Penfield’s patients were awake during the operation—the brain has no pain receptors—so they could tell him what they were experiencing when he stimulated various areas in their brain. Over the next several years, in the course of nearly four hundred operations, Penfield mapped the regions of our brain that are responsible for the sensations of touch, vision, and hearing and for the movements of specific parts of our body. His maps of sensory and motor function are still used today.

  What was truly amazing was Penfield’s discovery that when he stimulated the temporal lobe, the part of the brain that is just above the ear, his patient might suddenly say, “Something is coming back to me as if it is a memory. I hear sounds, songs, parts of symphonies.” Or, “I hear the lullaby my mother used to sing to me.” Penfield began to wonder if it were possible to locate a mental process as complex and mysterious as memory to specific regions in the physical brain. Eventually, he and others determined that it is.

  NEURONS: THE BUILDING BLOCKS OF THE BRAIN

  Broca’s and Wernicke’s discoveries revealed where in the brain certain mental functions are located, but they stopped short of explaining how the brain carries them out. They were unable to answer basic questions such as, What is the biological makeup of the brain? How does it function?

  Biologists had already established that the body is composed of discrete cells, but the brain appeared to be different. When scientists looked through their microscopes at brain tissue, they saw a tangled mess that seemed to have no beginning and no end. For this reason, many scientists thought the nervous system was a single, continuous web of interconnected tissue. They weren’t sure there was such a thing as a discrete nerve cell.

  Then, in 1873, an Italian physician named Camillo Golgi made a discovery that would revolutionize scientists’ understanding of the brain. He injected silver nitrate or potassium dichromate into brain tissue and observed that, for reasons we still don’t understand, a tiny fraction of the cells took up the stain and turned a distinctive black color. Out of an impenetrable block of neural tissue, the fine and elegant structure of individual neurons was suddenly thrown into high relief (fig. 1.2).

  Figure 1.2. Golgi stain

  The first scientist to take advantage of Golgi’s discovery was a young Spaniard named Santiago Ramón y Cajal. In the late 1800s Cajal applied Golgi’s stain to brain tissue from newborn animals. This was a wise move: early in development the brain has fewer neurons, and their shape is simpler, so they are easier to see and examine than neurons in a mature brain. Using Golgi’s stain in the immature brain, Cajal could identify isolated cells and study them one at a time.

  Cajal saw cells that resembled the sprawling canopies of ancient trees, others that ended in compact tufts, and still others that sent branches arcing into unseen regions of the brain—shapes that were completely different from the simple, well-defined shapes of other cells in the body. In spite of this startling diversity, Cajal determined that each neuron has the same four principal anatomical components (fig. 1.3): the cell body, the dendrites, the axon, and the presynaptic terminals, which end in what are now known as synapses. The main component of the neuron is the cell body, which contains the nucleus (the repository of the cell’s genes) and the majority of the cytoplasm. The multiple, thin extensions from the cell body, which look like the slender branches of a tree, are the dendrites. Dendrites receive information from other nerve cells. The single thick extension from the cell body is the axon, which can be several feet long. The axon transmits information to other cells. At the end of the axon are the presynaptic terminals. These specialized structures form synapses with the dendrites of target cells and transmit information to them across a small gap known as the synaptic cleft. Target cells may be neighboring cells, cells in another region of the brain, or muscle cells at the periphery of the body.

  Eventually, Cajal united these four principles in a theory now called the Neuron Doctrine (fig. 1.4). The first principle is that each neuron is a discrete element that serves as the fundamental building block and signaling unit of the brain. The second is that neurons interact with one another only at the synapses. In this way, neurons form the intricate networks, or neural circuits, that enable them to communicate information from one cell to another. The third principle is that neurons form connections only with particular target neurons at particular sites. This connection specificity accounts for the astonishingly precise circuitry that underlies the complex tasks o
f perception, action, and thought. The fourth principle, which derives from the first three, is that information flows in one direction only—from the dendrites to the cell body to the axon, then along the axon to the synapse. We now call this flow of information in the brain the principle of dynamic polarization.

  Figure 1.3. Structure of the neuron

  Figure 1.4. The four principles of Cajal’s Neuron Doctrine

  Cajal’s ability to look through a microscope at a fixed array of neurons and imagine how the nervous system works was an extraordinary feat of scientific intuition. In 1906 he and Golgi were awarded the Nobel Prize in Physiology or Medicine—Golgi for his stain and Cajal for using it to establish the structure and function of neurons. Amazingly, Cajal’s insights have held firm from 1900 to the present.

  THE SECRET LANGUAGE OF NEURONS

  For neurons to process information, and thus to instruct behavior, they need to communicate with other neurons and with the rest of the body. This is an absolute necessity for the brain to function properly. But how do neurons speak to one another? It wasn’t until years later that the answer to this question began to emerge.

  In 1928 Edgar Adrian, a pioneer in the electrophysiological study of the nervous system and recipient of the 1932 Nobel Prize in Physiology or Medicine, surgically exposed one of the many small nerves, or bundles of axons, in the neck of an anesthetized rabbit. He then removed all but two or three of the axons and placed an electrode on the remaining ones. Adrian observed a flurry of electrical activity every time the rabbit took a breath. He attached a loudspeaker to the electrode and immediately began to hear clicking noises, a fast rapping similar to Morse code. The clicking noise was an electrical signal, an action potential, the fundamental unit of neural communication. Adrian was listening in on the language of neurons.

  What produced the action potentials that Adrian heard? The inside of the membrane that surrounds a neuron and its axon has a slightly negative electric charge relative to the outside. This charge results from an unequal distribution of ions—electrically charged atoms—on either side of the cell membrane. Because of this unequal distribution of ions, each neuron is like a tiny battery, storing electricity that can be released at any moment.

  When something excites a neuron—whether it’s a photon of light, a sound wave, or the activity of other neurons—microscopic gates called ion channels open up all over its surface, allowing the charged ions to rush across the membrane in both directions. This free flow of ions reverses the electrical polarity of the cell membrane, switching the charge inside the neuron from negative to positive and releasing the neuron’s electrical energy.

  The rapid discharge of energy causes the neuron to generate an action potential. This electrical signal propagates rapidly along the neuron, from its cell body to the tip of its axon. When scientists say neurons in a particular region of the brain are active, they mean that the neurons are firing action potentials. Everything we see, touch, hear, and think begins with these little spikes of electricity racing from one end of a neuron to the other.

  Adrian next recorded electrical signals from individual axons in the optic nerve of a toad. He amplified the signals so that they could be displayed on an early version of the oscilloscope as a two-dimensional graph. In this way, he discovered that the action potentials in any given neuron maintain a fairly consistent size, shape, and duration. They are always the same little spike of voltage. He also found that a neuron’s response to a stimulus is all or none: the neuron either generates a full-blown action potential or it doesn’t fire one at all. Once initiated, an action potential travels without fail from the dendrites of the receiving cell to the cell body and along its axon to the synapse. This is quite a feat in, say, a giraffe, which has axons that begin in the spinal cord and extend several meters to the muscles at the end of its leg.

  The fact that action potentials are all-or-none events raises two interesting questions. First, how does a neuron that responds to sensory stimuli report differences in the intensity of a stimulus? How does it distinguish a light touch from a heavy blow, or a dim light from a bright one? And second, do neurons carrying information from different senses—sight, touch, taste, hearing, or smell—use different types of signals?

  Adrian found that a neuron signals intensity not by changing the strength or duration of its action potentials but by varying the frequency with which it fires them. A weak stimulus causes the cell to fire only a few action potentials, while a strong stimulus produces much more frequent firing. Moreover, he could gauge the duration of the stimulus by monitoring the duration of the firing of action potentials (fig. 1.5).

  Figure 1.5. The frequency and duration of action potentials determine the strength of the neuron’s downstream chemical signal.

  Adrian went on to record action potentials from neurons in the eyes, skin, tongue, and ears to see whether they were different. He found that the signals are similar, irrespective of where they come from or what kind of sensory information they convey. What distinguishes sight from touch and taste from hearing is the particular neuronal pathway carrying the signal and its destination. Each type of sensory information is carried along its own neural pathway to a corresponding region in the brain.

  How does an action potential in one neuron spark an action potential in the next neuron in the circuit? Two young British scientists, Henry Dale and William Feldberg, observed that when an action potential reaches the end of the axon in the sending, or presynaptic, cell, something astonishing happens: the cell releases a spurt of chemicals into the synaptic cleft. These chemicals, now known as neurotransmitters, cross the synaptic cleft and bind to receptors on the dendrites of the target, or postsynaptic, cell. Each neuron sends information by making thousands of synaptic connections with its target cells and in turn receives information through thousands of connections from other neurons. The receiving neuron then adds up all the signals it has received through these connections, and if they are strong enough, the neuron translates them into a new action potential, a new all-or-none electrical signal that is transmitted to all the target cells that the receiving neuron makes contact with. The process is then repeated. In this way neurons can relay information almost instantaneously to other neurons and to muscle cells, even over long distances.

  Alone, this simple computation might not seem very impressive, but when hundreds or thousands of neurons form circuits carrying signals from one part of the brain to another, the end result is perception, movement, thought, and emotion. The computational nature of the brain provides us with both a road map and a logic for analyzing disorders of the brain. That is, by analyzing glitches in neural circuits, we can begin to probe the mysteries of the brain—to figure out how electrical circuits generate perception, memory, and consciousness. As a corollary, brain disorders give us a way to see how the processes of the brain create mind and how most of our other experiences and behavior are rooted in this computational marvel.

  THE DIVIDE BETWEEN PSYCHIATRY AND NEUROLOGY

  Despite the many advances in brain science in the nineteenth century—advances that formed the foundation of modern neurology—psychiatrists and addiction researchers did not focus on the anatomy of the brain. Why didn’t they?

  For a very long time psychiatric and addictive disorders were viewed as fundamentally different from neurological disorders. When pathologists examined the brain of a patient at autopsy and found obvious damage, as they did in cases of stroke, head trauma, or syphilis and other infections of the brain, they classified the disorder as biological, or neurological. When they failed to detect clearly visible anatomical damage, they classified the disorder as functional, or psychiatric.

  Pathologists were struck by the fact that most psychiatric disorders—namely, schizophrenia, depression, bipolar disorder, and anxiety states—did not produce visibly dead cells or holes in the brain. Since they did not see any obvious damage, they assumed that these disorders were either extracorporeal (disorders of mind rather than the bod
y) or too subtle to detect.

  Because psychiatric and addictive disorders did not produce obvious damage in the brain, they were considered to be behavioral in nature and thus essentially under the individual’s control—the moralistic, non-medical view that Pinel deplored. This view led psychiatrists to conclude that the social and functional determinants of mental disorders act on a different “level of the mind” than do the biological determinants of neurological disorders. The same was held to be true, at that time, of any deviation from the accepted norms of heterosexual attraction, feeling, and behavior.

  Many psychiatrists considered the brain and mind to be separate entities, so psychiatrists and addiction researchers did not look for a connection between their patients’ emotional and behavioral difficulties and the dysfunction or variation of neural circuits in the brain. Thus, for decades psychiatrists had difficulty seeing how the study of electrical circuits could help them explain the complexity of human behavior and consciousness. In fact, it was customary as late as 1990 to classify psychiatric illnesses as either organic or functional, and some people still use this outdated terminology. Descartes’s mind-body dualism has proved hard to shake because it reflects the way we experience ourselves.

  MODERN APPROACHES TO BRAIN DISORDERS

  The new biology of mind that emerged in the late twentieth century is based on the assumption that all of our mental processes are mediated by the brain, from the unconscious processes that guide our movements as we hit a golf ball to the complex creative processes that underlie the composition of a piano concerto to social processes that allow us to interact with one another. As a result, psychiatrists now see our mind as a series of functions carried out by the brain, and they view all mental disorders, both psychiatric and addictive, as brain disorders.