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 Research & Giving News Article  15 Presentations on New Research in Basic Science, Mood Disorders and Schizophrenia Below are edited summaries of the presentations. Following each of the synopses is abridged commentary given by experts invited by NARSAD to put the research into perspective. The commentators for the Basic Science, Mood Disorders and Schizophrenia sessions were, respectively, Peter W. Kalivas, Ph.D., professor and chair of neurosciences at the Medical University of South Carolina; J. John Mann, M.D., Ph.D., professor of psychiatry and translational neuroscience, Columbia University College of Physicians & Surgeons and chief of neuroscience at the New York State Psychiatric Institute; and Jeffrey A. Lieberman, M.D., chair of psychiatry at Columbia University College of Physicians & Surgeons and director of the New York State Psychiatric Institute. Basic science refers to laboratory studies aimed at increasing knowledge about cells or genes involved in disease processes. Findings from such research may later be applied to patients. Mood disorders research addresses depression, anxiety, bipolar disorder and other conditions associated with mood. The session about schizophrenia concentrated on research aimed at better understanding and treatment of the condition. Herbert Pardes, M.D., president and CEO of NewYork-Presbyterian Hospital, and president of NARSAD’s Scientific Council, moderated the symposium. Robert M. A. Hirschfeld, M.D., Titus H. Chair and professor of the Department of Psychiatry and Behavioral Sciences at the University of Texas Medical Branch in Galveston and member of the NARSAD Scientific Council, selected the 15 researchers who reported at the symposium from a pool of 197 2005 NARSAD Young Investigators because of the outstanding nature of their research. Basic Science Mark Ansorge, Ph.D., Postdoctoral Fellow Laboratories of Jay Gingrich, M.D., Ph.D., and Rene Hen, Ph.D., Columbia University The Role of Serotonin in Modulating Depressive-Like Behavior Serotonin, a neurotransmitter found throughout the brain, is strongly involved in the regulation of emotion. Serotonin works by getting released from a presynaptic neuron into the synapse, an extracellular space between nerve cells. The chemical then binds to a postsynaptic neuron receptor, which stimulates a cascade of changes in that cell and others, all of which contribute to a perception of sadness or happiness. At some point, though, serotonin’s action has to stop. One mechanism to shut down serotonin activity is called reuptake. The process involves the absorption of the neurotransmitter by the serotonin transporter, which is located in the presynaptic neuron. Impeding the activity of the serotonin transporter has behavioral consequences. Drugs called selective serotonin reuptake inhibitors (SSRIs) — commonly known as Paxil or Prozac — act as antidepressants and antianxiety agents. Blocking the serotonin transporter increases the amount of serotonin available in the synapse causing more of it to bind to the postsynaptic neuron to exert the neurotransmitter’s effect. Interestingly, a genetic change found in humans in the gene for the serotonin transporter leads to a de-creased expression of the protein, yet has the opposite effect from what would be expected from the drugs’ action. The genetic alteration increases the likelihood that carriers will become depressed, even though more serotonin seems to be available in the synapses of these people. How can pharmacological blockage of the transporter help ameliorate the symptoms of depression and anxiety, while the genetic change in the gene is a risk factor for depression? To try to answer this question, Dr. Ansorge used a rodent model. Rodents are important for psychiatric research because they share many genes and brain-structure similarities with humans. Also, scientists have performed sophisticated behavioral tests with rodents to obtain insights about the impact of genetics on behavior. One such test involves putting a mouse that has been deprived of food into a new environment with an aversive center and a nearby food pellet. Initially, the mouse will stay in the corner, where it feels safe. After a while, though, the hungry animal will approach the center and start to eat. When the mouse is given antidepressants, which increase the level of serotonin in its brain, it will move faster to get the food. Animals without the gene for the serotonin transporter, however, will take more time to seek the food, even though they apparently have more serotonin available in their brains. Dr. Ansorge believes that the antidepressant and the absence of the gene lead to different results because the excess serotonin is working in the first case in an adult animal and in the second case during the development of the animal’s brain. He bases his hypothesis on recent results from a study in which he and his colleagues blocked the activity of the serotonin transporter between the fourth and 21st days after the animal was born. (That period is equivalent to the third trimester and the first couple of years of life in humans.) In the research, the animals were placed in different situations. In one, the mouse was shuttered in a box that had two sides. Put in one side and mildly shocked, a wild-type mouse will escape to the other side while a depressed or anxious mouse will not escape. Using this behavioral test, Dr. Ansorge found that mice missing the transporter gene during the developmental period take longer to escape, meaning they were in a more highly depressed state. When these mice were given Prozac, it had no effect because the target for the drug was absent. When healthy mice that had two copies of the serotonin transporter were given Prozac at this point in development, they also took longer to escape, as did mice that had only one copy of the transporter. In other studies with these mice, using drugs that block the transporter for the neurotransmitter norepinephrine, the researchers found the mice moved quickly to avoid the shock, indicating the drug was acting on a different pathway. Besides seeing the effect of excess serotonin during development, Dr. Ansorge and his colleagues studied what might help the animals when they became adults (and the gene for the serotonin transporter was active again). He found that providing the animals with an enriched environment, such as running wheels and tunnels, made the animals “feel” better in that they performed like healthy animals in the behavioral tests. The SSRIs did not help. Dr. Ansorge said he now has a system, using animal models lacking the transporter gene, to understand the biology of the genetic polymorphism in humans and it being a risk factor for depression. Moreover, people with the polymorphism do not respond well to SSRIs. In time, he said, it might be possible to predict among people with depression who might benefit from SSRIs and what might be the risk to pregnant mothers or children in taking SSRIs. Commentary from Dr. Kalivas: Dr. Ansorge did a nice job highlighting how SSRIs might impact brain development. We all are very familiar with the use of SSRIs in adults for depression. But he brought up the issue that use of the drugs in pregnant women who are depressed may have a negative outcome for the child. Although Dr. Ansorge did not address the subject in his talk, what is also important is the impact of SSRIs during adolescence. These drugs are being given to teens more frequently and their brains, too, are still developing. A completely formed brain doesn’t usually occur until someone is between 22 and 25 years old. It would be very interesting to see what kind of impact SSRIs have during adolescence. The other important thing Dr. Ansorge mentioned is that an enriched environment could help against depression. Such a finding highlights the limitations of our knowledge about depression. SSRIs are great drugs, and they work in a lot of cases. However, they could not reverse depression in the animal model Dr. Ansorge had created, but an enriched environment did, implying that there is a lot more than the serotonin reuptake system involved in depression and in regulating mood. Evaluating those additional factors will be very important in future research. Selena Bartlett, Ph.D., Director, Medications Development Group, Ernest Gallo Clinic and Research Center, University of California, San Francisco How Dopamine Receptor Trafficking and Signaling May Be Involved in Schizophrenia “All of us have been touched in some way by mental illness,” Dr. Bartlett said as she began her talk. “Many families don’t like to talk about it. But many of us know the devastating impact schizophrenia has on a family, on society, and on the person who has the condition.” For Dr. Bartlett, her sister’s experience with schizophrenia allowed her to bear witness to what people with schizophrenia suffer. Her sister’s first five to 10 years were relatively normal. When she was diagnosed, at 21, she was treated with antipsychotics. Over time, her life became a revolving door, in and out of hospitals, with medications ultimately not working. At the age of 38, she took her life. Today, Dr. Bartlett’s life commitment is to find new drugs to help people like her sister. She focuses on dopamine receptors and how they move inside neurons. Dopamine receptors bind the neurotransmitter dopamine to exert their action on neurons. Aberrant dopaminergic signaling is one of the determinants of schizophrenia and some allied disorders. At least five different subtypes of dopamine receptors exist, explained Dr. Bartlett. They are classified into two families. After binding dopamine, members of the D1 receptor family couple with a protein called GS and increase the level of the signaling molecule cAMP (cyclic AMP) inside the cell. The D2 receptor family acts differently from the D1 receptors. After binding dopamine, D2 receptors bind to the Gi receptor protein and decrease cAMP in the cell. Any imbalance in the activity of these receptors may lead to one type being more dominant than the other and different biological consequences. Although the receptors bind to dopamine on the surface of the cell, they also move around the inside, and the movement of these receptors inside and outside of cells plays an important role in how they exert action, Dr. Bartlett explained. She and her colleagues have been able to track the motion of the receptors by tagging them with dyes and watching them move under the microscope. The D1 receptor, which is called a recycling receptor, gets internalized by the binding of dopamine. The receptor then comes back out again onto the cell surface. The D2 receptor, however, does not get recycled. After the receptor and dopamine complex enters the cell, it gets degraded. As a result, the cell has to manufacture more D2 receptor to return to the cell surface and respond to new dopamine. Understanding why the D1 receptor gets recycled and D2 does not could provide clues to how this process might go awry in a disease state. To that end, Dr. Bartlett has identified a protein, called GASP, the G-protein coupled receptor associated sorting protein, that binds to the D2 receptor, but not the D1 receptor. In a series of experiments, Dr. Bartlett and colleagues have shown what happens when they prevent the binding of the GASP protein and the D2 receptor: the D2 receptor does not seem to be degraded by the cell, but instead becomes available again to react with dopamine. In the experiments, the researchers used an antibody to the GASP protein to impede its binding to the D2 receptor. Dr. Bartlett is now trying to find other ways to prevent the down-regulation of the D2 receptor and maintain its signaling by inhibiting GASP-D2 receptor binding. Findings may lead to new drugs for schizophrenia since dysregulation of the dopamine systems is a hallmark of the condition. Commentary by Dr. Kalivas: Dr. Bartlett de-scribed the technologies that molecular biologists are currently using to try to find new types of drugs that will be useful in treating psychiatric disorders such as schizophrenia. What she described is the outcome, in part, of about a decade of effort by scientists to try to understand the basic biology of receptor signaling. It goes far beyond simply binding a drug to the surface receptor. The trafficking of these receptors has turned out to be an incredibly dynamic event. These receptors get brought inside, they get shunted off to be broken down, or they get brought back to the surface. Different drugs could someday produce different effects on this cycling. Jean-Claude Beique, Ph.D., Postdoctoral Fellow Laboratory of Richard Huganir, Ph.D., Department of Neuroscience, Johns Hopkins University The Relationship Between Brain Scaffold Proteins and Schizophrenia The brain is composed of billions of neurons that dynamically communicate. Individual neurons fire an action potential, or an electrical impulse, to communicate. The impulse travels down a long projection of a presynaptic neuron called an axon and causes the release of a neurotransmitter into the extracellular space, or the synapse. The neurotransmitter crosses the cleft and activates receptors on the postsynaptic neuron. The receptors generate a current that will propagate through the secondary neuron into structures called dendrites. If enough currents occur, the secondary neuron will then fire an action potential, allowing it to communicate with other neurons. A typical neuron has about 30,000 synapses, giving the brain its computational power. Although the synapse is only a few microns wide, it has been the focus of intense study for years because of its importance in neuronal communication. There are two synapse types: excitatory and inhibitory. Dr. Beique focuses on the excitatory glutamatergic synapses, which release the amino acid glutamate, one of the most important and prevalent types of neurotransmitter. Virtually every neuron has a glutamatergic synapse. When an action potential comes to such neurons, glutamate is released and activates either the AMPA receptor or the NMDA receptor on the postsynaptic neuron. AMPA receptors mediate the bulk of fast neurotransmission, Dr. Beique explained. At any given moment, neurons are bombarded by synaptic activity that activates AMPA receptors. NMDA receptors are more modulatory, controlling the number of AMPA receptors at the surface of the postsynaptic neuron. If there are many AMPA receptors at the synapse, that synapse will be strong. If there are few AMPA receptors, then the synapse will be less strong. The trafficking of receptors at the surface of the neuron is believed to be related to learning and memory. Dr. Beique and other scientists study synapses because aberrancies in their structure may play a role in schizophrenia. Research has shown that some neurons in brains of people with schizophrenia have fewer glutamatergic synapses than do those of healthy people. The finding suggests that during the development of the brain, the synapses in these neurons were not formed correctly. During development, synapses are actively formed, pruned and stabilized. Other evidence implicating the glutamate system in schizophrenia comes from research about angel dust, or PCP, which leads to acute psychotic symptoms similar to those in schizophrenia. PCP is an NMDA antagonist that does not allow glutamate to bind to the receptor. Mice that express only 5 percent of the normal number of NMDA receptors exhibit behavioral abnormalities that are reminiscent of schizophrenia. For the past decade, scientists have identified hundreds of proteins involved in the structure, or scaffold, of the synapse and particularly in glutamate receptor trafficking. But which one might be a dominant protein or be involved in schizophrenia remains an open question. Dr. Beique said he believes he has found a coordinating protein: PSD-95, which, he said, binds many of the proteins already identified, including the NMDA receptor. Evidence suggests PSD-95 may help bring NMDA receptors to the cell surface and help control its levels of expression. PSD-95 levels are reduced in the brains of people with schizophrenia. To clarify PSD-95’s role in the synapse, Dr. Beique performed a series of experiments to show what happens when the protein is both over- and under-expressed in the neuron. Overexpressing PSD-95 is not trivial, Dr. Beique explained, because neurons do not like to be transfected with DNA. Transfection is the process in which a cell is given the DNA that codes for the protein that scientists want to put into it. In this case, Dr. Beique gave neurons DNA both for PSD-95 and for a green fluorescent protein so that the scientists could shine UV light on the cells and watch the PSD-95 movement inside and outside. What Dr. Beique found was opposite to what he had expected. Excess PSD-95 increased AMPA receptor function more than NMDA receptor function. He had expected increased PSD-95 to act on the NMDA receptor more. Results from mice with reduced PSD-95 expression reveal increased NMDA and decreased AMPA receptor activity. Putting the findings together, Dr. Beique has concluded that PSD-95 acts preferentially on AMPA and not NMDA receptors. Additional studies clarified how glutamate acts on the receptors, and how PSD-95 preferentially acts on AMPA receptors. By having a better understanding of how these proteins work in the synapse, Dr. Beique said, he and others might be able to develop drugs that act more specifically in schizophrenia. Commentary by Dr. Kalivas:> Dr. Beique’s study highlights the fact that Mother Nature does not release her secrets easily. A huge amount of work has gone into characterizing PSD-95 and these other proteins, and there is still more to do to understand how they work. It is estimated that there are approximately 500 proteins that make up that receptive zone in a single synapse. Each of those proteins has its own biology, and the biology of each one of those proteins changes, depending on whether that synapse is active or not. Another point about Dr. Beique’s talk is the importance of the glutamate system in how the brain works. Drugs are being developed for the treatment of addiction, depression and anxiety that act on the metabotropic glutamate receptor by going through the protein scaffold to affect the transmission at these synapses. This work and Dr. Beique’s reveal how important manipulating the scaffolding will be in developing new treatments for psychiatric disease. Stephanie L. Borgland, Ph.D., Associate Research Scientist, Ernest Gallo Clinic and Research Center, University of California, San Francisco The Role of Orexin/Hypocretin Signaling on Excitatory Synaptic Transmission of Midbrain Dopamine Neurons in Addiction Addictive behavior, like any other behavior, depends on changes in electrical activity in particular brain regions. Dr. Borgland studies the ventral tegmental area (VTA), located in the mid brain, which is rich in dopamine-producing neurons and important in addictive behaviors. Dopamine is produced in the VTA and released into the synaptic cleft where it interacts with receptors. Similar to the other systems discussed above, the dopamine system is highly regulated. Dopamine can be cleared from the synapse by dopamine transporters. In fact, these transporters are one of the targets of cocaine. The drug blocks transporter activity, causing extra dopamine to interact with the receptors and produce the high people experience on the drug. In the VTA, the brain cells engage in what is called spontaneous, tonic or pacemaker firing during which the neurons fire very regularly spaced action potentials, Dr. Borgland explained. In certain situations, this can change into burst-like firing activity, which can increase dopamine delivery to an adjacent neuron and alter an animal’s behavior. NMDA receptors can activate burst firing, and may increase dopamine release and, as discussed before, synaptic strength between neurons. Dr. Borgland studies what factors might influence VTA neurons to change their synaptic strength. One such agent is orexin, originally identified in 1998. There are two types of orexin (A and B), also known as hypocretin. They are produced in the lateral hypothalamus, a brain region involved in homeostatic regulation. Hypothalamic neurons project widely throughout the brain, including to the VTA. Studies have shown that when scientists place a stimulating electrode in the lateral hypothalamus of the rat brain, it will induce rats to press a lever in order to continue receiving the stimulation. Such findings imply that the lateral hypothalamus plays a role in reward behavior in rats and that orexin, produced by these neurons, may be involved in the process. Other research has revealed that low levels of orexin lead to narcolepsy, the circuitry of which may be tied to addiction. For example, when people with narcolepsy are treated with amphetamines they do not get addicted to them as do healthy people. Dr. Borland performed a series of studies to try to understand how orexin may modulate synaptic transmission in the VTA and to understand its behavioral consequences. She took slices of the midbrain, and used electrophysiology to record NMDA currents. When she applied orexin for five minutes, she found it potentiated the size of the NMDA currents. The effect was concentration dependent: As she increased the concentration of orexin, she increased the level of potentiation of NMDA currents. Additional experiments clarified how orexin could alter synaptic transmission in the VTA. First, orexin, when released from lateral hypothalamic neurons, interacts with orexin receptors in the VTA. The orexin binding then acts via intracellular signaling to translocate NMDA receptors either from inside the cell or from locations outside the synapse to the synapse to increase these NMDA currents. Dr. Borgland also studied the behavioral relevance of orexin in the VTA. She used a paradigm called cocaine sensitization, or locomotor sensitization. This behavior involves a progressive increase in the distance a laboratory animal will move in response to cocaine, and has been demonstrated to be dependent on NMDA receptor activation in the VTA. Since orexin potentiates NMDA receptors, Dr. Borgland decided to block the orexin receptor signaling to see the effect on locomotor sensitization behavior. She gave both cocaine and an orexin-1 receptor antagonist to an animal and found the antagonist reduced the development of sensitization. In other words, the orexin antagonist was blocking the behavior associated with the plasticity of these NMDA receptors. In summary, Dr. Borgland said she has found in her recent studies that orexin potentiates NMDA cur-rents in the VTA in a process that enhances synaptic transmission and may increase dopamine levels. She also has found that orexin receptor activation is essential for the development of behavioral sensitization, which is a behavior that’s been associated with cocaine craving and psychosis. She suggested that an orexin antagonist may provide an important therapeutic strategy for the treatment of addictions and other disorders, such as schizophrenia, that involve high levels of dopamine. Commentary by Dr. Kalivas: Every once in a while, something comes along that seems to be involved in almost everything. For the last decade, people have been studying orexin, mostly not at a molecular level, but with whole animals, injecting it and seeing what it does. Dr. Borgland mentioned the role in narcolepsy and addiction. It also has roles in obesity. Dr. Borgland has taken some of the knowledge of how synapses work and discovered what is probably the basic mechanism by which orexin is influencing all of these behaviors. Essentially, orexin affects how these glutamate (or the NMDA) synapses learn. Affecting that pathway has a broad influence on a number of disorders. Colleen McClung, Ph.D., Assistant Professor of Psychiatry, University of Texas Southwestern Medical Center at Dallas The Genes in Circadian Rhythms and Their Role in Mood Disorders Circadian rhythms are the cycles that humans experience during a 24-hour period. They include the patterns of sleeping and waking and the daily rhythm of hormones, temperature, mood, motivation, appetite and even drug response. For example, some people may be more attentive in the morning versus the evening, or may be in a better mood in the morning. Also, some drugs taken in the morning can have a different effect than if they were taken in the evening. Seasonal rhythms also affect the circadian rhythms. Scientists know a significant amount about the biological components of the circadian clock. Essentially, the rhythms are controlled by a set of proteins in an area of the brain known as the suprachiasmatic nucleus, located at the base of the hypothalamus. These proteins create a feedback loop that acts during the course of a day. Two proteins, CLOCK and BMAL1, are central activators of this complex. They act by changing the expression of other genes, which then inhibit the activity of CLOCK and BMAL1. This feedback loop occurs every day, during a 24-hour period, and regulates all the rhythms of daily rhythms described above. As most people are aware, disruptions to the circadian clock, such as overseas travel or staying up late, can cause sleep problems or jet lag. The research Dr. McClung is pursuing concerns the role the circadian clock plays in mood disorders. Although scientists have speculated for many years that the clock is involved in mood disorders, how it gets dysregulated remains unknown. It is known, though, that people have preferences for certain times of the day; so-called night owls enjoy the evening while “larks” are happier or more excited in the morning. Owls, it seems, are more susceptible to depression than larks. These preferences seem to run in families, and researchers have identified the genes associated with larks and owls. Another piece of evidence linking circadian rhythm to mood problems is the disruption in sleep and activity cycles people with depression and bipolar disorder experience. Some depressed individuals sleep all the time, while others may not sleep at all. People with bipolar disorder who are in a manic state might not sleep for days, but while in the depression state may sleep for a week. Depressed people also usually have their worst symptoms in the morning rather than the evening. These behaviors imply that these diseases are associated with disruptions in the sleep-wake cycle. Moreover, depression can be seasonal. Winter may cause some people to feel more lethargic than they do in summer, and in those areas of the world where darkness persists for long periods of time, such as Alaska and Scandinavia, depression is more prevalent. Also, some successful treatments for depression and bipolar disorder rely on resetting the circadian clock. For example, people who have seasonal affective disorder can be treated by bright light therapy, which works through resetting that internal biological clock. For some people, sleep deprivation can even be a short-term, acute treatment for depression. Unfortunately, when the person goes back to sleep, the effect wears off. Dr. McClung’s laboratory has used mice as a model system to study circadian rhythms and mood. What she and colleagues have done is mutate, or knock out, various members of the circadian clock individually or in combination and observed the effect on behavior in the animals. The behavior is assessed by a series of tests, such as the forced swim test or the learned helplessness test, that rely on scientists putting the animal in a situation in which it feels helpless and measuring the time the animal takes to struggle. Animals on antidepressants will struggle longer than “depressed” animals. The open field test and others measure anxiety. In these, the mouse is put into a situation in which it feels anxious or threatened, such as an open field, and scientists measure the time it takes the animal to move to a safer place. Rewards, such as food or drugs, are also used because “depressed” animals will not seek out such treats. Using the genetically engineered mice and these behavioral tests, Dr. McClung has found that the genes involved in circadian rhythms are in areas of the brain associated with mood and motivation and are affected by stress and antidepressant treatment. The studies have particularly revealed the relationship between behavior and the CLOCK gene, which has been linked to bipolar disorder along with its binding partner, BMAL1. Mice missing the CLOCK gene act similarly to patients with bipolar disorder when they are in their manic phase. They also find everything more rewarding. Dr. McClung said she believes these mice missing the CLOCK gene may represent the first animal model of mania. To better understand these animals, Dr. McClung gave them lithium, a mood stabilizer given to bipolar patients. She found that the genetically engineered mice given lithium returned to normal behavior. She also did a gene therapy experiment. She injected the CLOCK gene into the ventral tegmental area (VTA) of the brains of the genetically engineered mice and was able to restore their behavior to normal. She targeted that region because these altered mice are hyperdopaminergic and have increased cell firing and bursting in the VTA. Now, she and her colleagues are further studying the role CLOCK plays in the VTA. This new animal model gives them a new ability to see how CLOCK regulates dopamine transmission and manic behavior. Commentary by Dr. Kalivas: Marcel Proust said, “The real voyage of discovery is not in seeking new landscapes, but in having new eyes.” All the speakers at the symposia are the “new eyes.” They have new perspectives. And they are going to be bringing the world the next generation of drugs, and, hopefully, the potential to actually cure psychiatric disorders. Without cultivating these new eyes, we really can’t go anywhere. Mood Disorders Session Robert Berman, M.D., Ph.D., Postdoctoral Clinical Research Fellow in Affective, Anxiety and Related Disorders, New York State Psychiatric Institute, Assistant Attending Physician, Department of Psychiatry, NewYork-Presbyterian Hospital New Brain Stimulation Methods to Treat Resistant Depression, and Their Mechanisms of Action Electroconvulsive therapy, or ECT, is considered the gold standard of treatment for depression. It gets more people better than any other treatment, especially for acute depression. But it doesn’t help everyone. Approximately 60 percent to 80 percent respond, depending on who is doing the treatment, where it is being done and the different parameters of the care. The response rate is worse for antidepressant medications. Moreover, currently available treatments are widespread in their action and have side effects, limiting their continuing usefulness. Antidepressants, for example, affect the entire brain and parts of the body, such as the intestines. Likewise, ECT affects the entire brain, which is why some recipients experience memory loss. To overcome the problems of treatment-resistant depression, Dr. Berman is developing a new brain stimulation technique that targets specific areas of the brain to minimize side effects and to reach the area needing treatment. For the past several years, clinicians and researchers such as Dr. Berman have been learning more about the anatomy and circuitry in the brain of both normal mood regulation and the dysregulation observed in mood disorders. Imaging methods allow investigators to see those regions of the brain being affected in those patients who respond to ECT, antidepressants and transcranial magnetic stimulation, another modality. By comparing brain images from the three treatments, researchers have identified those regions that are common to all of them and, therefore, should be targeted to obtain an antidepressant effect in a particular individual. Today, approximately 15 different types of brain stimulation methods are under investigation. Some of the techniques rely on the induction of seizures. Some, such as vagus nerve stimulation or deep brain stimulation, require an electrode to be implanted in the body, opening up the possibility of infection and complications. Some use magnetic stimulation; others employ electrical stimulation. Recently, Dr. Harold Sackeim, a leader in modern ECT research at Columbia University Medical Center who has had a profound impact on the way ECT is practiced in this country and in reducing the side effects, came up with the idea for a new form of targeted ECT called FEAST, which stands for focal electrically administered seizure therapy. Dr. Berman works with Dr. Sackeim at Columbia. Instead of affecting the entire brain like ECT, FEAST aims to target that part of the brain relevant for the antidepressant response and to avoid those regions that might be responsible for the cognitive side effects. FEAST also uses a different kind of electrical pulse from ECT; its electrode is a different size and shape and is placed in a different area. The effect is more localized than ECT, stimulating seizures that initiate in the frontal part of the brain. To begin to explore how FEAST might work, Dr. Berman studied it in monkeys. He and his colleagues implanted three electrodes into the monkeys’ brains. Each of the electrodes had 10 sites that allowed the investigators to record the voltage induced by the treatments. The 30 contact sites would allow them to generate a map of what’s happening in the brain when they are stimulated with different forms of treatment and doses. With standard bilateral ECT, a voltage is induced in the brain that is constant from front to back. It is not focal and does not allow specificity for any region. FEAST, however, created a voltage that is very high in the front of the brain and very low toward the back, suggesting that this form of stimulation can be very much localized. FEAST also induced a low voltage in the front part of the temporal lobe, which is the area that clinicians hope to avoid because of side effects. The researchers initially did not use doses to induce seizure, but then increased dosages to induce seizures, which also were localized. Some of the seizures were on one side of the body. In other cases, they saw seizure activity in the brain, but no motor convulsion in the animal. A finding of a seizure without a convulsion is very significant, Dr. Berman said, because when patients are currently treated with ECT, clinicians usually have to anesthetize them and give them a muscle blocker so that they don’t hurt themselves when they have the therapeutic seizure. If FEAST were to work for depression at a dose that would not cause the motor component of the convulsions, clinicians might be able to stop using muscle blockers. The results of the monkey experiments have recently allowed Dr. Sackeim to develop a clinical protocol for the use of FEAST in10 patients. To date, seven have undergone the procedure. They had come in for ECT treatment and agreed to try the new method. The investigators found in these patients that FEAST was safe and that they obtained seizures. The seven patients responded at the same rate as to regular ECT. The researchers also administered a battery of neuropsychological tests to these patients to see if they experienced cognitive side effects. So far, the results are promising: FEAST may lead to fewer cognitive side effects than ECT, Dr. Berman said. Dr. Berman and colleagues are continuing their study of FEAST in animal models of depression and anxiety to maximize its clinical efficacy and minimize cognitive side effects. They also want to obtain a better understanding of how FEAST works in the brain compared to other stimulation methods. They are studying what neurotransmitters get released and where, and whether new neurons are generated (as occurs with ECT). Commentary from Dr. Mann: For the past five to 10 years investigators have been able to map in more detail than ever before the parts of the brain affected by depression. They have actually been able to localize to different brain regions specific components of the disease. As anybody who has been a patient, a relative of a patient or taken care of a patient knows, depression comes in many types, sometimes with certain symptoms predominating and at other times with others being more prevalent. The variation in symptoms has a biological basis that can be observed using scanning techniques. Investigators can actually distinguish patients who have more insomnia from those who are more agitated by distinct patterns in different parts of the brain. Such findings are important because they provide clues to the kind of circuitry that’s involved in depression, and it motivates the efforts that Drs. Berman and his colleagues have been pursuing; that is, to try to target the parts of the brain most critical in terms of causing the depression and correcting it while avoiding parts of the brain that, perhaps, are responsible for side effects. One of the critical questions that has always existed with ECT is: Can you get the patient better and yet avoid the most troublesome side effects, such as memory problems? It has become increasingly clear that the answer to that question is yes. The parts of the brain that are involved in the memory deficits related to ECT are not essential in the targeting of the treatment, and, therefore, clinicians should be able to get people better without producing the side effects. Traditional ECT applies a significant charge to the brain, and the skull diffuses it in directions that clinicians cannot control. Dr. Berman’s strategy with FEAST is to more focally apply the current and concentrate on that part of brain most important in getting patients better. With more data, the investigators will then be able to determine if this new approach is actually providing an antidepressant effect similar to ECT, which in some patients is the only treatment that works and allows them to be highly functional rather than severely disabled. Moreover, additional research should determine if the treatment can be given without creating seizures. Besides FEAST, other investigators are researching different localized methods of brain stimulation to treat depression, such as rapid transcranial magnetic stimulation (rTMS). rTMS is also highly targeted and has the same kind of potential for only activating or delivering the therapeutic magnetic effect that produces the therapeutic current in the part of the brain that’s critical for getting people better. Deep brain stimulation is another method in which clinicians place electrodes in a very specific, tiny area of the brain and get patients better by doing so. But if clinicians can avoid putting wires in people’s brains, that would be desirable. FEAST and rTMS are two noninvasive methods for this localized treatment of the brain, which many psychiatrists think is going to be the future of these sorts of brain stimulation therapies for depression. Amanda Guyer, Ph.D., Assistant Professor of Clinical Psychiatry, Columbia University and New York State Psychiatric Institute Temperament and Family History in Identifying Children at Risk for Bipolar Disorder Bipolar disorder in children is one of the most severe and debilitating of all of the childhood psychiatric illnesses. Like adults with the disorder, children have both manic and depressive episodes and are impaired even between the ups and downs. Approximately 97 percent of children with bipolar disorder are treated with some type of psychotropic medication; 66 percent have been hospitalized; 77 percent have thought about suicide; and 35 percent have even tried to take their own lives. Recently, there has been an increase in the diagnosis of bipolar disorder in children, including preschoolers. Although ADHD and severe irritability can be relatively common in preschoolers, people are debating whether bipolar disorder can really start as early as the preschool years. If so, what does bipolar disorder look like in a preschooler? This is a particularly important question because the use of psychotropic medication in preschoolers has been increasing. Between 1991 and 1995, the use of stimulants in 4-year-olds increased from 7 percent to 21 percent. Dr. Guyer’s research is focused on understanding the brain mechanisms that underlie bipolar disorder in children and adolescents. She and colleagues use techniques that allow them to take pictures of the brain of children and adolescents while they look at different stimuli. The goal is to understand how activities in the brain are related to the thoughts and behaviors of children who have bipolar disorder. Another aspect of Dr. Guyer’s research is to apply what is learned about children who have a bipolar diagnosis to children who are at increased risk for developing the disorder because they have either a parent or a sibling with the disorder. Studying at-risk children is important for several reasons. First, as with many psychiatric illnesses, bipolar disorder runs in families, meaning that at-risk children have a genetic susceptibility to the condition. Children at risk are 10 times more likely to develop bipolar disorder than children without any such family history of the disorder. Second, at-risk children often have very high rates of other kinds of psychiatric disorders. More than 20 percent of at-risk children have been reported to have ADHD, and approximately 33 percent have anxiety disorders. In addition, studying at-risk children may allow clinicians to identify what are called endophenotypes or heritable characteristics associated with an illness that are not direct symptoms of the illness. These endophenotypes could be biological or behavioral. By identifying these endophenotypes, Dr. Guyer hopes to improve the diagnosis of bipolar disorder in children. Once these traits are identified, they can help scientists isolate specific genes for the disorder and provide a better way of clarifying those children who face the greatest risk for developing bipolar disorder. Ultimately, Dr. Guyer said, the diagnosis of bipolar disorder should be based on both the child’s symptoms and the brain dysfunction causing those symptoms. By assessing behavioral traits, genes and brain dysfunction, clinicians should one day be able to facilitate more age-appropriate diagnoses for kids, treatments and, possibly, even prevention of the disorder. For the last two years, Dr. Guyer has been studying children at risk for bipolar disorder, including children from age 3 to 17. These children have a parent or a sibling with the diagnosis of bipolar disorder. To serve as a comparison group, she also includes children in the study who are not at risk. She decided to include preschool-aged children to learn whether such children are at increased risk and to recognize very early signs of bipolar disorder if, indeed, they are out there, as people have been debating. The results also could lead to the design of early interventions. In the study, Dr. Guyer and colleagues assess the children with a psychiatric interview. They test their IQ, language ability and skill in labeling emotions shown in pictures of people’s faces. They also measure how the children respond to a variety of different stimuli and how well they remember things. For children 9 and older, they use neuroimaging to study their brain structure, including how large or small specific brain regions were. They also study brain function, meaning how the brain responds when the child is looking at something, such as a picture of a face with an emotion on it. While the tests may seem cruel, Dr. Guyer said, they actually represent a typical situation a preschooler might encounter. By pairing the observations the investigators make of the children in these situations with the information from their parents, a full picture of the child’s functioning is established. With neuroimaging, the children go into a standard MRI scanner. Most do very well. But for some, such as those with ADHD, data cannot be obtained. In general, though, the children find it a “neat” experience. They get to walk away with a picture of their brain they can bring to school. Preschoolers cannot be scanned because they move too much. Instead, the investigators conduct a standardized interview with parents about their behavior. Additionally, the investigators observe the children while they’re playing and while they’re interacting with others. This helps them to characterize their behavior in a systematic way. They have a set-up in the laboratory where the children come in and investigators ask them to do different things while being videotaped. For example, the preschoolers may be asked to put together a puzzle missing a piece, which can be frustrating for them. The investigators watch and assess their responses. One of the emotional tests administered to children with bipolar disorder and those at risk asks them to label emotions. The children will see a picture and are asked to respond with what emotion they think is on the face. Is it happy, sad, angry or fearful? Past work by Dr. Guyer has shown that children who already have a bipolar diagnosis have difficulty identifying emotions on faces. Bipolar children make more mistakes on this task than healthy children do and more than children with other kinds of psychiatric disorders, such as depression, anxiety or ADHD. The inability to recognize emotions on a face seems to be specific to children with bipolar disorder. Dr. Guyer now has preliminary data indicating at-risk children also have the same difficulty in labeling emotions and faces as children with bipolar disorder. The ability to correctly identify emotions and faces, therefore, might be an endophenotype of bipolar disorder, she said. Also, the findings suggest that part of the treatment for children with bipolar disorder might be to help them see emotions accurately in faces and interpret emotional information in their environment. Dr. Guyer has been investigating the brain mechanism that underlies the problem the children have in recognizing the emotional content of faces. She focused on the amygdala in the brain because it develops early in life and plays an important role in processing emotional stimuli. Also, other research has implicated the amygdala as being aberrant in bipolar disorder. About five studies to date have shown that children with bipolar disorder have smaller amygdalas than healthy children. Dr. Guyer also has found that in bipolar children both amygdala size and function are abnormal. Her results come from studies of children with bipolar disorder performing a face processing task while in the MRI. The children see a series of faces depicting different emotions and are asked to make different judgments about the faces. It was found that when bipolar children look at neutral faces and rate how hostile they think the face is, the amygdala shows much more activity in bipolar than in healthy children. Based on these results, Dr. Guyer is now doing the same study with children at risk for bipolar disorder. With more research, she and her colleagues hope to identify those children most at risk, and to develop better methods to treat and prevent this debilitating illness. Commentary from Dr. Mann: A lot of time usually elapses between the beginning of symptomatic bi-polar disorder and the commencement of treatment, which is alarming. Dr. Guyer mentioned that one of the complications of bipolar disorder is suicide. Indeed, bipolar disorder carries the highest risk of suicide among psychiatric illnesses. Some estimates suggest 20 percent of people with bipolar disorder ultimately die by suicide. Furthermore, every episode of mania or depression results in reverberations in the person’s life, particularly when one is young. In children, the condition can dramatically affect their situation at school and their relationships with friends. As they get older, the disease adversely affects education and employment. Relationships, marriages, financial situation and physical health often fall apart with repeated episodes of mania or depression. Thus, the earlier the condition can be diagnosed and treatment commenced, and the more consistent the treatment, the better. Clearly, the key elements of bipolar disorder are a combination of genetics and early childhood adversity, which means that the potential for the condition is laid down early in life. As such, the condition may be detectable early in life. The effects on the brain and subtle effects on behavior and on other kinds of brain functions, as Dr. Guyer described, may be detectable before the individual actually develops overt illness. If that’s true, then it may be possible to try to institute some kind of corrective interventions that will prevent the person actually getting overtly ill and avoid a lot of this costly impact on life. The field of psychiatry is looking forward to seeing studies like Dr. Guyer’s mature because of their great potential benefit. Steven F. Kendell, Ph.D., Assistant Professor of Psychiatry, Boonshoft School of Medicine, Assistant Clinical Professor of Psychiatry, Yale University School of Medicine, Staff Psychiatrist, Kettering Medical Center, Staff Psychiatrist, Connecticut Mental Health Center Role of Riluzole in Modulating the Neurotransmitter Glutamate and in Treating Drug-Resistant Depression Of the antidepressant medications available today, almost all target the monoamine neurotransmitters, which include norepinephrine, serotonin and dopamine. Recently, though, the results of a large National Institute of Mental Health-sponsored multicenter study showed that despite treatment with these available medications, almost half of patients have residual symptoms, and many patients have very little benefit at all. These results implied there’s a tremendous need to develop new drugs with novel mechanisms of action. To develop these medications, the study said, scientists should focus on continuing to understand the pathophysiology of depression. To that end, Dr. Kendell and colleagues have been studying the influence of the amino acid neurotransmitter system as a significant contributor to the pathogenesis and pathophysiology of major depressive disorder. Several studies have pointed to the dysfunction of the amino acid neurotransmitter systems in depression. Neuroimaging, for example, has shown differences in the GABA and glutamine levels (GABA being the major inhibitory amino acid neurotransmitter and glutamate being the major excitatory amino acid neurotransmitter) in the brains of depressed individuals versus controls. Depressed individuals have a much lower level of GABA than healthy controls, according to neuroimaging work by Dr. Kendell. In fact, nearly half of the patients in his study with depression had lower GABA levels, whereas glutamate levels in depressed subjects were tremendously higher than healthy controls. The findings imply that individuals with depression when assayed by neuroimaging have significant abnormalities in GABA and glutamate, the major amino acid neurotransmitters in the brain. How might abnormalities of GABA and glutamate levels be connected, and why are they both abnormal when looking at individuals with depression? To begin to answer those questions, Dr. Kendell said it is necessary to understand the tripartite model of the amino acid synapse, which includes a glutamatergic neuron, a GABAergic neuron and a glial cell. Glial cells are helper cells responsible for the metabolic processes that go on in the brain. In the glutamatergic neurons, glutamate is released from the presynaptic neuron and travels across the synaptic cleft. It attaches to postsynaptic receptors, which might be AMPA receptors or NMDA receptors. Through that attachment, an action potential is propagated down the neuron. But glutamate is also taken up by the glial cell. In fact, the vast majority of the excitatory neurotransmitter glutamate is taken up by the glial cell, not by the neurons. In the glial cell, glutamate is converted into glutamine. Glutamine is then transferred, or shuttled over to the glutamatergic neuron where it is converted back into glutamate. Glutamine is also transferred over to the GABAergic neuron and converted into GABA. This model shows there is a very intimate connection between glutamatergic neurons and GABAergic neurons via the glial cell. Recent studies have revealed a decrease in both the glial cell density as well as glial cell numbers in certain areas of the brain in depressed patients. An absence of glial cells may affect the brain’s ability to perform normal metabolic functions. Excess glutamate will build up in the synaptic cleft of glutamatergic neurons because fewer glial cells would be present to take up the glutamate to transform it into glutamine. Ultimately, the excess glutamate transports itself out of the synaptic cleft and into the extrasynaptic space. Recent evidence, however, reveals that this excess glutamate in the extrasynaptic space becomes toxic. Thus, the inability of glial cells to take up glutamate can result in neurotoxicity. Furthermore, this excess glutamate in the extrasynaptic space can feed back to the presynaptic neuron, and inhibit the release of normal glutamate for normal processes like thinking or memory. In total, a reduction of glial cells can lead to a complete breakdown of glutamate cycling and GABA synthesis. Based on this model, Dr. Kendell and colleagues began studying drugs capable of repairing glutamatergic abnormality. One of the medications under study was riluzole, also called Rilutek, currently FDA-approved for the treatment of amyotrophic lateral sclerosis, commonly called Lou Gehrig’s disease. Riluzole appears to be able to stabilize the release of glutamate from the glutamatergic neuron, Dr. Kendell has found. In addition, it may increase the uptake of glutamate from the synaptic cleft, essentially regulating the excess glutamate from the deficit of glial cells. Through these mechanisms, Dr. Kendell believes there’s a potential for riluzole to normalize glutamate cycling as well as reestablish the impairment in GABA synthesis. Dr. Kendell and his colleagues recently published a study looking at the effect of adding riluzole to current antidepressant medications in individuals with significantly treatment-resistant depression. Some of the subjects in the study had had symptoms of depression for longer than five years and had been on numerous medications. The current average was at least three. The researchers found that riluzole, added to the depression medication patients were taking, reduced these individuals’ depression symptoms as measured by the Hamilton Depression Rating Scale. Dr. Kendell found it interesting that some patients experienced a rapid response (within one to two weeks) in an amelioration of their depression symptoms. He is now studying whether those patients who had the rapid response were the same ones who had very low GABA and very high glutamate as detected in neuroimaging. He also is employing rodent models of depression, studying the influence of stress in the glutamatergic system and looking for other means of understanding the mechanism of action behind riluzole and its ability to treat treatment refractory depression. Commentary from Dr. Mann: The two major neurotransmitters in the cortex of the brain are GABA and glutamate. The notion that GABA is low and glutamate is high in depression actually fits because the GABA neurons are principally inhibitory neurons. GABA neurons inhibit glutamate, so with less GABA, there will be more glutamate because of a removal of the inhibition. In addition to that, Dr. Kendell explained the role of glial cells in that process. What’s fascinating about Dr. Kendell’s scenario is that ECT tends to improve GABA function. Moreover, one can improve GABA function by giving medications such as riluzole. Riluzole is another example of a type of a medication other than, say, an SSRI, that may restore some degree of normality to this part of the brain. What makes this kind of research unique for psychiatry is that by doing quantitative studies, abnormalities in these neurons in the cortex can be observed that are consistent with the neurotransmitter abnormalities that have been described and consistent with the mechanism of action of treatments like riluzole or ECT. These analyses form a different scenario for psychiatry than what existed a number of years ago, when investigators could not find anything much wrong with the brain biologically. Treatments were given to patients and if they worked, clinicians took guesses as to what was wrong by how the treatments improved people. Now, psychiatry has gone a long way beyond that. Dr. Kendell’s and other’s research, all performed in the past five years, show some evidence that certain cell types in the cortex are actually deficient in depression and that the neurotransmitter glutamate is deficient. Moreover, treatments that increase the levels of certain neurotransmitters related to those cell types make patients better. There is also a certain scientific continuity, in terms of knowledge that leads directly to designing new treatments, which is all very encouraging. These kinds of abnormalities may actually be present during the early phase of illness. That is not known yet, but Dr. Kendell and his colleagues are probably going to look at high-risk individuals before they become patients to see whether one can detect these kinds of things and whether early interventions can actually improve the situation. The scanner allows clinicians to seek what previously we could only see under the microscope. Jason Scalia, Ph.D., Instructor, Clinical Neuroscience, Department of Psychiatry, Columbia University Effects of Major Depressive Disorder and SSRI Medications on Cell Growth in the Hippocampus The hippocampus is a part of the brain that, like most of the organ, has the ability to respond dynamically and, in a developmental sense, to changing environmental conditions. But the hippocampus is profoundly vulnerable to stressors, such as shifts in long-term behaviors by an organism, and to the biological impact of psychiatric illness. The hippocampus is also one of the few parts of the brain that, in the adult mammal, continues to undergo neurogenesis, or new cell cell growth, possibly throughout life. Research in animal systems has shown hippocampal neurogenesis in response to antidepressant medications. As a result of these studies, investigators hypothesized that one of the underlying pathological features of major depressive disorder was impairment in hippocampal neurogenesis. And further, that one of the therapeutic targets of certain antidepressant therapies was to enhance hippocampal neurogenesis back to its normal levels. The thesis has been met with agreement and disagreement. Because the studies were done in animals, a major concern raised was the applicability of the findings to humans. Dr. Scalia’s research focuses on trying to understand the role of hippocampal neurogenesis in humans and to determine if the process plays a role in major depressive disorder. What is known about the hippocampus is that it is required for certain types of memory and has a powerful influence on cognition through the way memories are laid down. The hippocampus links experience to memory and it can also provide a degree of emotional salience to those memories, which has an effect on the way we think as we recall something. The ability of the hippocampus to provide emotional enrichment to cognitive experience is due in large part to its connections with other parts of the brain. The hippocampus interacts with and has a very powerful influence on the information that’s processed by the prefrontal cortex. The hippocampus also has pathways that project to the orbitofrontal cortex, connections from which then affect the processing of the dorsal lateral prefrontal cortex. These areas have been indicated to be affected adversely in depressive disorder. The hippocampus also is nestled behind and communicates with the amygdala, which has been implicated in affective disorders and depression. Specific to the hippocampus and to one or two other regions in the brain, is a neurogenic region. This band of cells is referred to as the granule cell layer. Beneath the band is a neurogenic zone where neurons are developed, migrate into the granule cell layer, take up residence there and then insert themselves into the local neuronal networks. This feature of neurogenesis as a plastic structure is one of the points of vulnerability that the hippocampus faces. It has been observed that hippocampal structure is altered by prolonged stressful situations not necessarily linked to depression. The arbors or neurite networks of cells throughout the hippocampus can shrink under conditions of prolonged stress. The number of new neurons added to the granule cell layer of the hippocampus is also reduced in periods of prolonged stress. Some imaging studies have shown that there is a reduction in the overall size of the hippocampus in long-term depression. Recently, a Duke University laboratory identified a protein called doublecortin that is expressed by granule cells in the hippocampus just after they begin to mature into neuronal cells. They express this protein for a short period of time, and then cease to express it. Dr. Scalia has begun to perform studies with doublecortin staining on slices of the hippocampus to reveal those cells that express the protein. Since doublecortin is expressed by a cell only in the first few weeks of its life, and since its mature counterparts no longer express it, the presence of doublecortin distinguishes the newborn, emerging population of neurons from the rest of the tissue. Dr. Scalia has been piloting this doublecortin staining research to be able to visualize and count newborn cells in the hippocampus and to extend the methodology to human tissues. He and his colleagues are now beginning to examine post-mortem hippocampus tissue taken from individuals who were diagnosed with major depressive disorder, but at the time of their deaths were not medicated. They then will compare that group with individuals who, in all other respects, were identical to those individuals, but did not suffer from any psychiatric disorder. By comparing the number of new neurons found in unmedicated depressed patients to those in healthy controls, Dr. Scalia said he can address the question of whether hippocampal neurogenesis is impaired in clinical depression. If he and his colleagues find no difference between hippocampal neurogenesis rates in depressed, un-medicated individuals versus healthy controls, then it would be fair to dismiss the thesis that a reduction in hippocampal neurogenesis is associated with depressive disorder. The tissue bank also will enable the investigators to compare individuals who were suffering from clinical depression and were medicated with SSRI drugs at the time of death with a depressed group of donors who were not medicated. A comparison between those two donor groups will examine the ability of SSRIs to alter the rates of neurogenesis. The overall goal of this work is to identify part of the pathological processes that either coexist with or foment depressive disorder. If it is demonstrated that neurogenesis is impaired in cases of depressive disorder, then it should provide a target for new therapeutic strategies. If it appears there is not a correlation between reduced rates of neurogenesis and depressive disorder, then researchers should shift their emphasis to new therapeutic strategies, Dr. Scalia said. Currently, a number of drug development teams perform screens specifically to see if pharmaceutical agents have the capacity to increase rates of neurogenesis. They then perform behavioral fingerprinting exercises to determine if behavioral modifications and neurogenic modifications together in a pharmaceutical agent might be suitable for premarket and preclinical trials as a therapeutic agent. Commentary from Dr. Mann: The hippocampus, which is involved in human memory processes, probably plays an important role in depression. Depressed patients often find it very difficult to remember things, and their concentration is poor. When they get better, their memory function improves. The hippocampus is unique in being one of perhaps only two areas in the brain where new neurons are produced in adult life. However, neurogenesis may be defining the process too narrowly, and perhaps scientists should be thinking about cell growth in general. Neurons are much more plastic in terms of increasing and decreasing in size and expanding and retracting the processes with which they connect and communicate with other neurons. In that sense, the brain is not that different from muscles. When muscles are not used, they get smaller. When muscles are exercised, they get bigger. A number of studies have shown that parts of the brain are susceptible to the effects of depression. The hippocampus is one example. The longer a person has spent in a depressed state during his or her life, the smaller the hippocampus. This suggests that it’s very important to treat people because, besides symptomatically improving the quality of their lives, there’s actually a measurable potential effect on the size of the brain. Animal studies have also shown that certain growth factors decrease during depression, a finding likewise seen in depressed patients. These animal studies of depression have also revealed that the genes for the growth factors are turned on again when the animals are treated. Dr. Scalia’s work is looking at the question of the process of brain growth of new cells in the hippocampus. It is a line of research that is actually part of a broader domain of brain growth in general, which also includes the size of neurons, their proliferation and the expansion of their processes and connections. If investigators can figure out more clearly the factors that produce the growth changes and their relationship to depression and antidepressants, then it might be possible to design new antidepressants that are much more specific in chemically targeting these brain growth processes. Hugh Brent Solvason, M.D., Ph.D., Assistant Professor, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine Managing Obesity and Diabetes Risk in the Pharmacological Treatment of Bipolar Disorder One of the main strategies for treating bipolar disorder in the maintenance, depressed and manic phases of the condition is the use of atypical antipsychotics. Clinicians cannot predict who is going to respond to what medication, but some people do extremely well with medications. Unfortunately, the drugs put patients at risk for the development of weight gain and metabolic syndrome. The question becomes how to deal with the weight and metabolic issues for people who uniquely respond to a single agent. Metabolic syndrome is a constellation of symptoms and signs that include central obesity, abnormalities in the lipid profile, elevation of triglycerides, low HDL (the good cholesterol), increased blood pres-sure (above 130/85) and elevated fasting glucose levels. Metabolic syndrome essentially identifies people who are at risk for insulin resistance. Insulin resistance means the body isn’t using glucose efficiently. As a result, the individual experiences higher insulin and higher blood glucose levels. Measuring blood glucose levels helps clinicians assess insulin resistance. But by the time someone has high glucose levels in the blood, it is an indication the person already is in a prediabetic or diabetic state. Certain atypical antipsychotics, such as clozapine and olanzapine, which are given to people with bipolar disorder and schizophrenia, increase the risk for weight gain and the development of insulin resistance and metabolic abnormalities. Risperidone and quetiapine also increase weight gain, but not to the extent of the other two. Aripiprazole and ziprasidone seem not to cause weight gain in the majority of patients and may be less likely to cause insulin resistance or be associated with a risk for diabetes. Because of the metabolic risks associated with atypical antipsychotics, psychiatrists have become more careful about monitoring the risk for heart disease and insulin resistance in patients taking the drugs. The side-effects profile also makes clinicians more careful about monitoring the impact of the drugs on people who have risk factors for diabetes or who already have diabetes. Assessing risk factors involves adding the number of risk factors together to get an overall risk: one risk factor causes a small elevation of risk, two risk factors a slight elevation of risk above that, three a little bit more, and with four it starts to increase logarithmically. For example, having a mood disorder actually is a risk factor. Being overweight, having central obesity and a little bit of high blood pressure makes four risk factors. Family history makes it five. Clinicians need to keep the factors in mind and monitor the patients taking the drugs. In Dr. Solvason’s study, he will test whether an oral hypoglycemic drug can counteract some aspects of the metabolic effects of atypical antipsychotics. The subjects in the study are bipolar patients taking olanzapine who have gained five pounds or more on the drug. This population is important to monitor because studies have shown that non-obese individuals with bipolar disorder treated with olanzapine have insulin resistance early on, Dr. Solvason said. He and his colleagues will assess whether an oral hypoglycemic will improve insulin sensitivity and glucose metabolism in the liver after three months of treatment. If the oral hypoglycemic drug can improve the insulin sensitivity in these bipolar patients taking olanzapine, then clinicians may be able to help avert the metabolic side effects of the antipsychotics. Commentary from Dr. Mann: There has been a rapid increase in the use of certain antipsychotic agents, such as olanzapine, because they can help the mania in bipolar disorder and the depression in people with treatment-resistant depression. The downside of these drugs, however, is that they seem to lead to metabolic syndrome, which includes weight gain, a change in the lipid profile and in-creased risk of diabetes. One of the key messages of Dr. Solvason’s talk is the importance of assessing a patient’s risk factors for diabetes before beginning treatment with antipsychotics, and then monitoring the patient’s metabolic profile to prevent problems from occurring. These potential effects can be manageable if the clinician and the patient are aware of them and take steps to watch weight, etc. The novel approach Dr. Solvason is taking is studying the effect of the oral hypoglycemic on insulin sensitivity in patients taking the antipsychotics. Another point, to which Dr. Solvason alluded, is the relationship between diabetes and mood disorders. It is now known that insulin affects the incorporation of the dopamine transporter into the nerve terminals: there are fewer dopamine transporters put in when there’s an alteration in the levels of insulin. The relationship between dopamine transporters and insulin may influence treatment responsiveness and be one mechanism that explains why certain patients are resistant to certain kinds of medications. It is important to remember that the medications for bipolar disorder or unipolar depression go everywhere in the body. Being aware of the specific side effects associated with certain medications allows doctors to make a more appropriate choice for the individual patient. Some would benefit more from certain types of medication because they’re more susceptible to the side effects of other types of medications. Even within the atypical antipsychotics, some are more likely to produce metabolic syndrome than others. Schizophrenia Session Dimitri Avramopoulos, M.D., Ph.D., Assistant Professor, Department of Psychiatry and Institute of Genetic Medicine, Johns Hopkins University School of Medicine The Genetics of Schizophrenia Schizophrenia is a common disorder affecting 1 percent of the population. It usually hits people when they are between 18 and 24 years of age and affects them for the rest of their lives. Genes clearly play a role. Twin studies show that if one of a pair of twins has schizophrenia, the other twin is 50 percent more likely to have the condition than an average person. Having a sibling with schizophrenia also increases the likelihood of getting the disease to 10 percent from 1 percent in the general population. These observations and other family studies make investigators suspect many genes may be involved in schizophrenia, and that each patient might have a different set of risk genes that contribute to the disease. (Some of these genes may also play a role in bipolar disorder.) Eventually, knowing the genes involved in the risk for schizophrenia would help clinicians treat the disease. It would allow doctors to know the mechanism of the disease and offer new targets for pharmaceutical intervention. Drugs based on these targets might also be more effective than current medications. For example, if clinicians can pinpoint the genes involved in the disease of a particular patient, they might be able to give a drug that would provide the best results for that person rather than using the current trial and error approach, which delays treatment and causes unnecessary side effects. Genetic information also might allow investigators to prevent the disease. By identifying the genetic makeup of people at risk, clinicians might be able to intervene earlier and not allow the disease to manifest itself. Among the many genes implicated in schizophrenia, Dr. Avramopoulos works on neuregulin-3. He and colleagues have evidence from genetic linkage studies suggesting that the area of the genome where this gene is located on chromosome 10 most likely contains the gene for schizophrenia. Other genetic association studies reveal that certain variants of DNA are more common in patients than among healthy controls. Another thing that makes neuregulin-3 interesting is that its relative, neuregulin-1, has also shown evidence of linkage and association with schizophrenia. Like neuregulin-1, neuregulin-3 is involved in the development of the brain, in the regulation of neurotransmitters and in plasticity. Unlike neuregulin-1, neuregulin-3 is more specific to the brain. Genes, which are comprised of DNA, normally work by getting transcribed into what is called messenger RNA. This mRNA, which consists of coding and non-coding DNA sequences, gets spliced together in a complicated and accurate process that allows the correct pieces of the coded gene to be brought together into one mature piece. The mature piece of mRNA becomes the template for proteins, which perform structural and enzymatic activities inside cells. In many genes, there are alternative ways to splice the mRNA to obtain a similar but slightly different gene product or protein. One of the things that can go wrong in genetic diseases is that a change or a mutation can affect the coding region of the gene, which results in a change in the protein made. The alteration affects the properties of the protein and can lead to disease. Another mechanism that leads to disease involves changes in areas of the DNA that do not directly code for the protein, but regulate this process that’s called transcription. Alterations in splicing of the mRNA can lead to disease, too. Before researchers can tackle the genetics of disease, they usually study how a gene works normally in a cell. In his research, Dr. Avramopoulos and colleagues have been characterizing the normal level of expression patterns of neuregulin-3 in the brain. They have validated that the gene is almost exclusively present there and is expressed in higher levels in the forebrain with more variability of expression there. Dr. Avramopoulos’ group also has shown extensive alternative splicing for neuregulin-3, which they had suspected might occur because neuregulin-1 also has multiple forms. They have found splice products that make proteins which do not include very important domains of this protein. A domain of a protein is a function of a small piece of that protein. One domain, call-ed EGF, on neuregulin-3, is missing in some splicing products, and these products are more abundant in the forebrain. With future research, Dr. Avramopoulos and colleagues hope to show a possible relationship be-tween the variations in DNA in the neuregulin-3 gene and schizophrenia. Commentary from Dr. Lieberman: Dr. Avramopoulos is at Johns Hopkins, one of the best institutions in the country, and is in its department of psychiatry, which has been at the forefront of bringing science to the study of mental illness. The work he described is an example of the challenges in studying the genetics of schizophrenia. Genetics offers the promise of allowing clinicians a better understanding, diagnosis and treatment for the disease. But the research is difficult. Dr. Avramopoulos is studying one of the candidate genes, neuregulin-3, which linkage and association studies implied was important in schizophrenia. Now he is trying to under-stand the gene’s normal expression in the brain and the consequences of this gene producing a different protein. Such an alteration could affect brain development, where the gene is expressed and how it is ex-pressed, each of which can lead to behavioral consequences. This research is high risk because investigators do not know where the results might lead. But it is important to do these studies to try to understand the complexity of diseases such as schizophrenia and to explain why the condition cannot be easily cured. The human genome has 30,000 genes, 99 percent of which are in all manner of lower organisms. Biological mechanisms are highly conserved, but the differences between these other species and humans accounts for our uniqueness. These mechanisms are also very complex and involve many genes and proteins. Schizophrenia, or any of the severe mental illnesses that are genetically based, produces massive behavioral changes. Clearly, someone who has symptoms of the full-blown diagnostic condition is markedly different and has abnormal patterns compared to healthy people. But unlike other conditions in which there is a devastating disturbance in the brain, such as a region that has failed to develop, schizophrenia involves certain populations of cells that have failed to connect in a way, so they do not function in the exact way that normal human behavior occurs and in response to the pressures of every day life. Dr. Avramopoulos is trying to track down how neu-regulin-3 figures in leading to schizophrenia, and he’s taking a calculated risk by pursuing this. He’s putting his most precious possession, his life, and the time that he has trained to make his career, to work on this problem. He’s making a calculated bet, just like putting money in the stock market, that it will pay off. Time will tell. Genetic research has to be done for mental illness as it has been done in other areas of medicine, such as cardiology, cancer and infectious disease. But family members need to be patient. Genes identified for other illnesses, such as Huntingon’s disease, still have not led to a treatment because of the complexity of the genetics. But this work is absolutely essential. Stefania Bonaccorso, M.D., Ph.D., Research Fellow, Department of Psychiatry, Division of Psychopharmacology, Vanderbilt University Improving Cognition in Patients with Schizophrenia Many people consider the hallucinations and delusions of schizophrenia as the condition’s major problems. But the greater the deficits in cognitive function that the patient has, the more likely he or she will have severe negative social or occupational outcomes. Cognitive function includes several mental processes that help us in almost every aspect of life. Social cognition, one such process, is the ability to recognize a happy face as happy. Attention — another ability —allows us to focus for a certain amount of time on important stimuli and to filter what’s relevant from what’s irrelevant. Working memory involves remembering one thing while doing something else. Verbal learning is the ability to absorb information from listening. All of these cognitive domains need to be organized and coordinated to achieve cognitive functioning. Clearly, deficits in any of these domains can seriously impair how we function in society. Psychiatrists have developed tests to measure these cognitive functions and have found that people with schizophrenia have significant impairment in these processes. Although antipsychotics have been routinely used to treat the psychoses of schizophrenia, recent research shows that a few of them can improve cognition in some patients. The drugs do not work in all patients, and investigators are trying to understand the biological mechanism underlying the cognitive deficits in schizophrenia to develop new drugs to treat this aspect of the disease. One explanation for these thinking problems may be an imbalance of acetylcholine and dopamine in the prefrontal cortex and the hippocampus, two regions of the brain strongly associated with cognitive function. Evidence shows imbalances in the neurotransmitters are associated with schizophrenia. To study this possible imbalance, Dr. Bonaccorso and her laboratory have studied animal models to look at the actions of the drugs clozapine (an atypical antipsychotic) and haloperidol (a typical antipsychotic medication) on these two brain regions and their impact in patients. She and her colleagues also analyzed the drugs’ effect on the nucleus accumbens, a region in the limbic system believed to be associated with delusions and hallucinations. These experiments were performed with a technique called microdialysis, which consists of placing a probe in specific brain areas of anesthetized animals and measuring the chemical changes after the injection of the two drugs clozapine and haloperidol. The results of these studies suggest that atypical antipsychotics may be able to partially correct the deficits in the medial prefrontal cortex and can take care of the positive symptoms (hallucinations and delusions) while haloperidol cannot help as much in the brain’s cognitive regions. Further studies showed that adding the mood stabilizer valproate to treatment with an atypical antipsychotic could work on acetylcholine and dopamine in the prefrontal cortex and the hippocampus. These basic studies have led to clinical research in patients. Dr. Bonaccorso and colleagues are now performing a double-blind, randomized six-week trial to test the hypothesis that patients treated with an atypical antipsychotic and 1,000 milligrams a day of valproate can perform better on cognitive tests six weeks after treatment than at baseline compared to patients treated with an atypical antipsychotic and a placebo. The study, which began in January, plans to include 60 patients with schizophrenia or schizoaffective disorder. Twenty patients have participated to date. Commentary from Dr. Lieberman: Dr. Bonaccorso is doing what is called translational research, which means taking results from animal studies and using them clinically in patients. Particularly, she is studying the importance of cognition for people with schizophrenia. Cognition problems are considered a core feature of schizophrenia because they significantly contribute to a patient being unable to figure out how to negotiate through the world and live independently. Schizophrenia has different dimensions. People with schizophrenia have psychoses, hallucinations and delusions. They also have emotional symptoms. And they have cognitive problems, which are increasingly being shown to be related to how a person can function. Therefore, even if clinicians can control the psychoses with drugs, if the cognitive deficits remain, the person still will need to have significant financial support and supervision. More research, though, needs to be done to determine whether atypical antipsychotics and other drugs are indeed able to improve cognition. Karin E. Borgmann-Winter, M.D., Clinical Associate, Department of Psychiatry, University of Pennsylvania, Attending Physician, Department of Child and Adolescent Psychiatry, Children’s Hospital of Philadelphia Role of Olfactory Neurons in Developing Early Intervention Strategies for Psychoses in Adolescents Recent studies have suggested that atypical antipsychotics may have some neuroprotective effects. How these agents exert their action remains under study. Because it is not possible to perform a systematic evaluation of the neurodevelopmental and neurotoxic effects of these drugs in living human subjects, Dr. Borgmann-Winter and her colleagues are using olfactory nerve tissue from subjects as a way to get at the question. Preliminary research findings from her laboratory have shown that haloperidol and risperidone have dif-ferent effects on the survival of olfactory neuronal tissue taken from healthy subjects. The researchers are now comparing healthy subjects with young adults diagnosed with psychoses to assess how antiipsychotics affect signaling pathways that promote cell survival or death. They focus their study on certain molecules, such as Akt, in these olfactory neurons because they have been implicated in the pathophysiology of schizophrenia. It may turn out that people with psychoses as a group have problems with the Akt signaling pathway or that there may be individual differences in patients in their Akt signaling. The latter implies that schizophrenia is not a single disease but many diseases, and that there are variations in the way medications affect signaling in different people. These olfactory cell lines have the potential to allow researchers to look at how signaling mechanisms occur in an individual and in a group and, in the future, to see how antipsychotics might affect a particular individual. Such cells might allow clinicians to be able to identify those individuals who would benefit from one medication or another. Commentary from Dr. Lieberman: Dr. Borgmann-Winter is a child psychiatrist, which is important be-cause, with the exception of dementias and geriatric depression, the majority of mental illnesses either have their origins in childhood or the groundwork for them seems to be laid in neurodevelopment, the time from gestation to infancy to childhood. Having a development perspective is valuable for the study of mental illness and particularly schizophrenia. Her approach is to look at the natural history of the condition and how it evolves. In recent years, it has been discerned that there are stages of the illness. There’s a period when people who are at risk for it are asymptomatic. In essence, the illness is latent. Then there’s a period when it begins to express itself, which is usually during late adolescence or early adulthood. What has become apparent with studies of people at the early stage of illness is that there appears to be a transition during which people go from a period when the illness is quiescent to when it’s diagnosable. Such a time is called a prodrome, or an incipient stage of the illness. Other studies of people in this phase of the illness have shown that the earlier they are treated, the better off they are in terms of capacity to respond to treatment and of less disruption to their life and prognosis. An understanding of this early aspect of the disease has led clinicians to think that if people were treated earlier, it would improve their long-term outcome and prognosis and prevent the progressive damage in their brain and life that occurs as a result of the illness. Now that it is known genes are involved, clinicians may soon have a means of early detection genetically. This concept of early identification and intervention has become a very compelling idea and a very powerful one, and I think it’s fair to say it’s really captured everyone’s imagination. The problem, though, is working out how to do it. In order to have early detection and intervention, there needs to be an understanding of what changes when people go from their silent or unexpressed phase of the illness to the prodromal or incipient stage to the active phase. Then, how can clinicians diagnose when that’s happening in a reliable and specific way. And perhaps most importantly, what do you use to treat them? Is it antipsychotic drugs, which is the treatment for the full- blown illness, or is it something else? It may not even be a medication. It may just be some type of psychosocial therapy or behavioral intervention. So what underlies the research that Dr. Borgmann-Winter and others are doing is to try to understand the progression to disease. Investigators are using imaging, electrophysiologic methods, neurocognitive assessments and behavioral assessments to determine the transition from latency to disease. The approach that Dr. Borgmann-Winter is taking is to study this question with the olfactory epithelium, the only source of peripherally available brain tissue from living subjects; a brain biopsy would require surgery. Blood samples provide white blood cells for analysis, but they may not be showing the same pattern of gene expression that occurs in brain cells. Because the brain projects into the nose, researchers can get these olfactory epithelial cells by doing a little punch biopsy in the nose, which is benign and non-invasive. The cells can be cultured and the gene expression assayed with and without treatments. Such an approach may help in understanding what causes the onset of the disease because you can follow subjects’ cells over a period of time. Researchers might actually be able to track when the cells begin to activate and change in a way that is associated with or gives rise to the illness. So this is a very neat and potentially informative technique. Steven R. Laviolette, Ph.D., Assistant Professor of Anatomy and Cell Biology, The Schulich School of Medicine, University of Western Ontario Processing and Encoding of Sensory Information in Schizophrenia Dr. Laviolette studies how the cannabinoid system in the brain might be involved in some of the emotional processing deficits commonly observed in schizophrenia. The cannabinoid system is a naturally occurring chemical circuit in the brain upon which endogenous cannabinoids and drugs such as marijuana act. It’s one of the oldest chemical systems in the brain and it has profound effects on emotional perception. The cannabinoid system is one of many ways the brain has evolved to respond to a fearful situation. If someone, for example, sees a poisonous snake, the frontal cortex has to accurately perceive the emotional significance of the stimulus. The medial temporal lobe, including the amygdala, also has to regulate how the brain controls the emotional perception of such a scary stimulus. Under normal circumstances, a person would experience an emotional reaction, such as fear or anxiety, and the brain would form an adaptive association or memory about the stimulus. The person would learn the association between the sensory stimulus and the emotional response it evokes. Both together would guide future behavior, which would be to avoid poisonous snakes. But a brain of a person with schizophrenia is different. Imagine, for example, an innocuous stimulus of a television set with a news commentator speaking. A healthy person would accurately perceive it for what it was. But if a person with schizophrenia has disturbances in emotional processing circuits in regions such as the prefrontal cortex, he or she may perceive the commentator as being abhorrently emotionally salient, develop distorted associations and possibly even delusions or psychotic ideation. Dr. Laviolette hypothesizes that delusional thinking may be a result of fundamental disturbances in frontal cortical emotional processing mechanisms and involve the cannabinoid system. If damage occurs to the frontal cortex or amygdala, it affects the ability to perceive the emotional significance of stimuli in the environment. In schizophrenia, it is known that both the frontal cortical region and the amygdala fail to show appropriate responses to emotionally salient information. Moreover, early cannabis use is linked to higher rates of schizophrenia, at least in male populations. Additionally, smoking marijuana is known to exacerbate psychotic episodes, and is also related to poor prognostic outcomes in diagnosed schizophrenics. Cannabinoid receptors are highly expressed in these regions, both in humans and other animals, and they show disturbed expression levels in schizophrenia. Higher levels of expression of the cannabinoid CB1 have been found in postmortem frontal cortex brain tissue from people with schizophrenia compared to healthy controls, suggesting a hyperactive cannabinoid system in schizophrenia. In Dr. Laviolette’s recent research, he and colleagues have used an animal model to study brain activity and emotional learning in response to either arousing or neutral stimuli. They measure activity from single neurons in the prefrontal cortex of the animals using a special electrode, studies that would be unethical in humans. The experiments are analogous to putting a small microphone in the brain and recording what it is doing. To measure the behavior of the animal, Dr. Laviolette and colleagues place the animal in a conditioning chamber where it is given an olfactory cue, such as a peppermint smell, which is then followed by a mildly aversive stimulus, such as a foot shock. Subsequently, the animal is given a second odor without the shock. The paradigm is a Pavlovian conditioning technique in which the animal learns to associate a specific sensory cue with a certain aversive or neutral emotional significance. The researchers have found that by giving a certain dose of the cannabinoid agonist drug, called WIN55, they could show enhanced emotional learning in the neuron they were recording. But when they used a drug called AM251, which is an antagonist of the cannabinoid system, they were able to block the ability of the neurons to encode the emotional significance of the stimuli. In essence, Dr. Laviolette said, that he and his team are demonstrating that by modulating these cannabinoid receptors in the animal’s prefrontal cortex, they can control how much single neurons encode emotional information. The evidence suggests to Dr. Laviolette that some of the dysregulation in schizophrenia may be due to emotional processing disturbances from a hyperactive cannabinoid system. Increased cannabinoid levels in schizophrenia may pathologically amplify the emotional significance of incoming sensory stimuli and may be related to the inability of many people with schizophrenia to filter out and accurately perceive what they should be paying attention to in terms of the emotional significance versus stimuli that would normally be ignored. Further clarifying these mechanisms could lead to improved pharmacological therapies and different options for controlling some of the emotional disturbances in schizophrenia. It may be that if cannabinoid transmission were blocked or controlled pharmacologically, some of the emotional dysregulation disorders in schizophrenia might be more controllable. Commentary from Dr. Lieberman: Dr. Laviolette has focused on emotional perception, which overlaps with an emerging area called social cognition that is relevant not just for schizophrenia, but for other conditions such as autism. He is linking emotional perception and processing — which partially occurs in the frontal cortex and the amygdala — to a specific neurotransmitter system, the cannabinoid system. Epidemiologic studies have shown that smoking marijuana is a risk factor for developing schizophrenia, and it turns out that in the brain there are cannabinoid receptors. Dr. Laviolette’s work is suggesting that the cannabinoid system may be involved in emotional perception and that a dysregulation in this circuit may have implications for schizophrenia. In his research, he uses an animal paradigm that takes into account smell as a mechanism of learning. He can show that the emotional learning is related to the cannabinoid system by using agonists or antagonists to it. While agonists enhance the response in the animal’s neuron, the antagonists do not have an effect. His work provides another neurobiologic system to test treatments that could work on the emotional processing part of schizophrenia. His test in rodents could be used to analyze other compounds that might be used someday in correcting this problem. Anita Ramani, Ph.D., Researcher, Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine Using a New MRI Technique (Diffusion Kurtosis Imaging) to Study Brain Structure in Schizophrenia There are an estimated 2.5 million people with schizophrenia in the United States, and the cost associated with caring for people with the illness is high. The features of the disease — psychosis, hallucinations, delusions and a disorder of thoughts — generally lead to a decline in social and occupational functioning. Dr. Ramani’s research uses a new type of imaging, Diffusion Kurtosis Imaging, to characterize schizophrenia earlier in the course of the disease to develop better diagnoses and interventions for the condition. Current MRI imaging is qualitative and allows clinicians to see white and grey matter and large anatomical detail, Dr. Ramani said. Her method is a more quantitative MRI, allowing visualization of smaller regions of the brain that might be undergoing changes due to the emergence of schizophrenia. Being able to identify the disease as it progresses would give clinicians the ability to better diagnose the disease and to monitor the effects of interventions on the brain. Diffusion MRI is a technique for observing micro-structural changes in MRI. If one adds a drop of ink to a glass of water, one can see the ink as it diffuses. This is essentially the principle used in diffusion MRI to see structure in brain tissue. Diffusion imaging provides indices that give clinicians information about the biophysical environment of water molecules in the brain. The most commonly used index is called the mean diffusivity, which gives data about how water molecules diffuse from one region of the brain to the other. Another index is fractional anisotropy, which gives data about how the white matter is oriented in the brain. The higher the fractional anisotropy in the brain, the more complex the white matter is oriented in that particular region. Diffusion Kurtosis Imaging gives data about the actual barriers of diffusion. It helps elucidate boundaries and the permeability of membranes in tissue on a microscopic level. Dr. Ramani and her colleagues have employed Diffusion Kurtosis Imaging to analyze the structure of the prefrontal cortex in the brains of 10 people with schizophrenia and schizoaffective disorder and eight healthy controls. They focused on the prefrontal cortex because the region is believed to be involved in both the assimilation and transfer of information in the brain. What they found was that Diffusion Kurtosis Imaging allowed for visualization of structures particular to schizophrenia. They saw decreases in the complexity of tissue in people with schizophrenia and differences in the prefrontal cortex and the superior temporal gyrus. They also found changes in the gray matter in the superior temporal gyrus. But they found that gray matter seems to be relatively preserved in the prefrontal cortex. Dr. Ramani and colleagues are still analyzing the data, which represent the first attempts at using Diffusion Kurtosis Imaging in people with schizophrenia. Commentary from Dr. Lieberman: Dr. Ramani’s work illustrates that the study of all diseases, including mental illness, requires multidisciplinary approaches and people who have a variety of expertise, who come together as teams to utilize the most advanced type of technologies and research methodologies to do effective research. Dr. Ramani could only be doing this kind of work now. Fifty years ago, imaging methods, such as what she described, were not available. It was only with the introduction of noninvasive, high-resolution imaging, beginning with CT scans and then with MRI and PET scanning, that clinicians could get into the brain non-invasively and get meaningful information. Such methods are necessary because mental illnesses do not create such massive changes in the brain as could be seen with a standard X-ray; high resolution methods are necessary. Dr. Ramani and her colleagues have developed a method, Diffusion Kurtosis Imaging, to stimulate the brain magnetically and then to take advantage of the biophysical properties of tissue to distinguish healthy from diseased brain tissue. More research will be needed to better understand the implications of the results. |
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