A NEUROSCIENCE SAMPLING
I list here four major accomplishments in neuroscience in the past year that have inspired me. I begin by saying that in a field as broad and as deep as neuroscience, it is difficult to select simply four contributions. I therefore consider this a sampling of the contributions that drive my optimism rather than a true selection of the top four. Moreover, I have simplified the task by dividing the field into four areas: Molecular Neuroscience, Systems Neuroscience, Cognitive Neuroscience, and Neuroscience of Psychiatric Disease.
Molecular Neuroscience. The discovery of the double helix by Watson and Crick in 1952 gave rise to a central dogma in molecular biology, according to which genes (encoded in DNA) give rise to messenger RNAs which encodeproteins, the workhorses of the cell. The discovery a few years ago of microRNAs, a class of small non-coding genetic elements that control the translation of target messenger RNAs, highlighted a new layer of gene regulation downstream from DNA. MicroRNAs have been described in numerous species across the evolutionary spectrum, and there are thought to be about 500 different microRNAs encoded in the human genome. Although microRNAs are very short (only 21 nucleotides long), each is thought to bind to a number of different messenger RNA targets. Thus they may have a very profound effect on gene action in both the human brain and in simpler experimental animals. The existence of microRNAs has been known for several years but only recently has it become recognized that they are particularly important in the nervous system where they serve, among other functions, to regulate synaptic strength—the effectiveness with which one neuron communicates with another.
In the year 2006, two important papers emerged in this area. The first one by Ashraf and Kunes revealed that a microRNA regulates the synthesis of proteins locally at synapses in the Drosophila brain following learning and that microNRAs are essential regulatory components at the synapse of memory storage. A second example is from Michael Greenberg’s laboratory, where it was discovered that a brain-specific microRNA is important for the development of dendritic spines in hippocampal neurons. They demonstrated that a particular microRNA inhibits development and maturation of the spine, which is a preferential site of contact between neurons that form a synapse together. In both cases these microRNAs have turned out to be very important for the formation of synapses and for synaptic plasticity. Thus, these discoveries open up a new molecular treasure chest, a new level of regulation that had not been appreciated.
Systems Neuroscience. In the late 1960s and 1970s, David Hubel and Torsten Wiesel gave us the initial insight as to how the early input stages of the cerebral cortex process and transform the incoming visual messages. This gave us our first insight of how an image—say, an image of a face or a landscape—is first deconstructed and then reconstructed in the brain. In all living creatures, from simple animals to people, knowledge of space is central to behavior. We live in space, we move through it, we explore it, and we defend it. Space is not only important but it is fascinating because unlike other sense modalities, it is not analyzed by special sensory organs like the eye for seeing or the ear for hearing. This has raised the question, How is space represented in the brain? Immanuel Kant, the great German idealist philosopher argued that the ability to represent space is built into the mind. He argued that people are born with principles of ordering space and time. These are part of what he called the categorical imperatives. When other sensations are elicited such as visual sensations of objects, or auditory sensations of melodies, or touch experiences, they are interwoven automatically in specific ways with space and time. We remember people and events in a spatial context. Because we do not have a special organ dedicated to space, the representation of space is the cognitive sensibility par excellence. It is the binding problem write large. The brain must combine inputs from several different sensory modalities and then generate a complete internal representation that does not depend exclusively on one input. The brain commonly represents information about space in many areas in many different ways and the properties of each representation vary according to purpose.
John O’Keefe, working in England, first discovered in 1971 that the hippocampus of the rat contains a multisensory representation of space. O’Keefe found that when an animal walks around in an enclosure, some cells in the hippocampus fire action potentials, and they do so only when the animal moves in a particular location. Other cells fire when the animal moves in another point in spoace. In this way the brain breaks down its surroundings into small overlapping areas, similar to a mosaic, each represented by activity in specific cells in the hippocampus. The internal map of space develops within minutes of the rat’s entrance into a new environment.
But in many higher order areas, we know little about the nature of the transformations. The perception of space is a particularly vexing example because it is mediated by the combination of several sense modalities. During the past year we have learned from the work of May-Britt Moser and Edvard Moser of Norway how spatial information is transformed by the hippocampus. In experimental animals, particularly the mouse, one of the most important sensory representations in the hippocampus—a structure important for memory storage—is the representation of external space within which the animal is placed. It is now clear that the initial representation of space occurs not in the hippocampus proper but in an association cortex—the entorhinal cortex—that serves as the input stage to the hippocampus. The Mosers have found that the entorhinal cortex already has a unique form of spatial representation encoded by grid cells. These grid cells convey to the hippocampus, via the convergence of several grid cells onto the hippocampal place cell, information about position, direction, and distance that is essential for navigation.
Cognitive Neuroscience. When you and I talk to one another, we not only know the contents of our own mind but we also have a sense of the content of what the other person is thinking and how they are reacting. We have, so to speak, a sense of the social expectations of the situation and the kinds of ideas that the conversation brings forth in the colleague with whom we are communicating. During the past year several important studies have localized aspects of this function in the cerebral cortex. First, Rebecca Saxe has found that there is a specific area in the brain at the junction between the temporal and parietal lobes that encodes aspects of the theory of mind. It becomes active when a person entertains ideas about another person’s possible responses to our actions. This new finding extends a series of important findings from Rizzolatti’s group in Italy which first showed that there are certain cells in the premotor areas of parietal cortex of the monkey that respond not only when a monkey picks up a peanut but also when the monkey sees another monkey or a human being pick up a peanut. These cells are called mirror cells because they respond not only to personal action but in an imitative way to the action of others. In addition to showing a cellular basis for a theory of mind, these cells also illustrate that the motor systems have cognitive function. Imaging experiments by Ramachandran have shown that this area is present in people, and that it appears to be disturbed in patients with autism.
In a larger sense, social cognition is an extreme example of a broader issue in biology of mind, and that is social interaction in general. Even here we are beginning to make some rather remarkable progress. Cori Bargmann, a geneticist at the Rockefeller University, has studied two variants of a worm called C elegans, that differ in their feeding pattern. One variant is solitary and seeks its food alone; the other is social and forages in groups. The only difference between the two is one amino acid in an otherwise shared receptor protein. If you move the receptor from a social worm to a solitary worm, it makes the solitary worm social. This is one of several examples in which changing a single gene alters the social behavior of an animal. Another example is male courtship behavior in Drosophila, which is an instinctive behavior that requires a critical protein called fruitless. Fruitless is expressed in slightly different forms, one in male flies and the other in female flies. Ebru Demir and Barry Dickson have made the remarkable discovery that when the male form of the protein is expressed in females, the females will mount and direct the courtship toward other females or toward males that have been engineered to produce a characteristic female odor. Dixon went on to show that the gene for fruitless is required during development for hardwiring the neural circuitry for courtship behavior and sexual preference.
Neuroscience of Psychiatric Disease. A major source of optimism is the emergence of an empirical, evidence-based psychotherapy. There are now a number of excellent studies that show that mild to moderately severe depression, as well as fear-based anxiety disorders and obsessive-compulsive disorders, respond to different versions of psychotherapy that are designed to focus not on deep underlying conflict but on the management of specific symptoms. The best established of these is cognitive behavioral therapy, first introduced in the 1970s by Aaron Beck at the University of Pennsylvania.
In the late 1950s, when Beck began his investigations, depressive illness was commonly viewed as a form of introjected anger. Freud had argued that depressed patients feel hostile and angry toward someone they love. Because patients cannot deal with negative feelings about someone who is important, needed, and valued, they handle those feelings by repressing them and unconsciously directing them against themselves. It is this self-directed anger and hatred that leads to low self-esteem and feelings of worthlessness.
Beck tested Freud’s idea by comparing the dreams of depressed patients with those of patients who were not depressed. He found that depressed patients exhibited not more, but less hostility than other patients. In the course of carrying out this study and listening carefully to his patients, Beck found that rather than expressing hostility, depressed people express a systematic negative bias in the way they think about life. They almost invariably have unrealistically high expectations of themselves, overreact dramatically to any disappointment, put themselves down whenever possible, and are pessimistic about their future. This distorted pattern of thinking, Beck realized, is not simply a symptom, a reflection of a conflict lying deep within the psyche, but a key agent in the actual development and continuation of the depressive disorder. Beck made the radical suggestion that by identifying and addressing the negative beliefs, thought processes, and behaviors, one might be able to help patients replace them with healthy, positive beliefs. Moreover, one could do so independent of personality factors and the unconscious conflicts that may underlie them.
To test this idea clinically, Beck presented patients with evidence from their own experiences, actions, and accomplishments that countered, challenged, and corrected their negative views. He found that they often improved with remarkable speed, feeling and functioning better after a very few sessions. This positive result led Beck to develop a systematic, short-term psychological treatment for depression that focuses not on a patient’s unconscious conflict, but on his or her conscious cognitive style and distorted way of thinking.
To evaluate systematically the effectiveness of this mode of therapy, Beck and his associates initiated controlled clinical trials comparing cognitive behavioral therapy with placebo and with antidepressant medication. They found that cognitive behavioral therapy is as effective as antidepressant medication in treating people with mild and moderate depression; in some studies, it appeared superior at preventing relapses. In later controlled clinical trials, cognitive behavioral therapy was successfully extended to anxiety disorders, especially panic attacks, post-traumatic stress disorders, social phobias, eating disorders, and obsessive-compulsive disorders.
What was next needed is a biological approach to psychotherapy. Until quite recently, there have been few biologically compelling ways to test psychodynamic ideas or to evaluate the efficacy of one therapeutic approach over another. A combination of effective short-term psychotherapy and brain imaging may now give us just that—a way of revealing both mental dynamics and the workings of the living brain. In fact, if psychotherapeutic changes are maintained over time, it is reasonable to conclude that different forms of psychotherapy lead to different structural changes in the brain, just as other forms of learning do.
The idea of using brain imaging to evaluate the outcome of different forms of psychotherapy is not an impossible dream, as studies of depression and obsessive-compulsive disorder have shown. Helen Mayberg had earlier found that Area 25 in the cerebral cortex is overactive in depressed patients. She then went on to find that this overactivity is reversed by cognitive behavioral therapy if, and only if, the therapy is successful. Obsessive-compulsive disorder has long been thought to reflect a disturbance of the basal ganglia, a group of structures that lies deep in the brain and plays a key role in modulating behavior. One of the structures of the basal ganglia, the caudate nucleus, is the primary recipient of information coming from the cerebral cortex and other regions of the brain. Brain imaging has found that obsessive-compulsive disorder is associated with increased metabolism in the caudate nucleus. Lewis R. Baxter, Jr. and his colleagues at the University of California, Los Angeles have found that obsessive-compulsive disorder can be reversed by cognitive behavioral psychotherapy. It can also be reversed pharmacologically by inhibiting the reuptake of serotonin. Both the drugs and psychotherapy reverse the increased metabolism of the caudate nucleus.
Short-term psychotherapy now comes in different forms and brain imaging may provide a scientific means of distinguishing among them. If so, it may reveal that all effective psychotherapies work through the same anatomical and molecular mechanisms. Alternatively and more likely, imaging may show that psychotherapies achieve their goals through distinctly different mechanisms in the brain. Psychotherapies are also likely to have adverse side effects, as drugs do. Empirical testing of psychotherapies could help us maximize the safety and effectiveness of these important treatments, much as it does for drugs. It could also help predict the outcome of particular types of psychotherapy and would direct patients to the ones most appropriate for them.
