Alcohol, tobacco, drug use far higher in severely mentally ill

In the largest ever assessment of substance use among people with severe psychiatric illness, researchers at Washington University School of Medicine in St. Louis and the University of Southern California have found that rates of smoking, drinking and drug use are significantly higher among those who have psychotic disorders than among those in the general population. The study is published online in the journal JAMA Psychiatry. The finding is of particular concern because individuals with severe mental illness are more likely to die younger than people without severe psychiatric disorders. "These patients tend to pass away much younger, with estimates ranging from 12 to 25 years earlier than individuals in the general population," said first author Sarah M. Hartz, MD, PhD, assistant professor of psychiatry at Washington University. "They don't die from drug overdoses or commit suicide — the kinds of things you might suspect in severe psychiatric illness. They die from heart disease and cancer, problems caused by chronic alcohol and tobacco use." The study analyzed smoking, drinking and drug use in nearly 20,000 people. That included 9,142 psychiatric patients diagnosed with schizophrenia, bipolar disorder or schizoaffective disorder — an illness characterized by psychotic symptoms such as hallucinations and delusions, and mood disorders such as depression. The investigators also assessed nicotine use, heavy drinking, heavy marijuana use and recreational drug use in more than 10,000 healthy people without mental illness. The researchers found that 30 percent of those with severe psychiatric illness engaged in binge drinking, defined as drinking four servings of alcohol at one time. In comparison, the rate of binge drinking in the general population is 8 percent. Among those with mental illness, more than 75 percent were regular smokers. This compares with 33 percent of those in the control group who smoked regularly. There were similar findings with heavy marijuana use: 50 percent of people with psychotic disorders used marijuana regularly, versus 18 percent in the general population. Half of those with mental illness also used other illicit drugs, while the rate of recreational drug use in the general population is 12 percent. "I take care of a lot of patients with severe mental illness, many of whom are sick enough that they are on disability," said Hartz. "And it's always surprising when I encounter a patient who doesn't smoke or hasn't used drugs or had alcohol problems." Hartz said another striking finding from the study is that once a person develops a psychotic illness, protective factors such as race and gender don't have their typical influence. Previous research indicates that Hispanics and Asians tend to have lower rates of substance abuse than European Americans. The same is true for women, who tend to smoke, drink and use illicit drugs less often than men. "We see protective effects in these subpopulations," Hartz explained. "But once a person has a severe mental illness, that seems to trump everything." That's particularly true, she said, with smoking. During the last few decades, smoking rates have declined in the general population. People over age 50 are much more likely than younger people to have been regular smokers at some point in their lives. For example, about 40 percent of those over 50 used to smoke regularly. Among those under 30, fewer than 20 percent have been regular smokers. But among the mentally ill, the smoking rate is more than 75 percent, regardless of the patient's age. "With public health efforts, we've effectively cut smoking rates in half in healthy people, but in the severely mentally ill, we haven't made a dent at all," she said. Until recently, smoking was permitted in most psychiatric hospitals and mental wards. Hartz believes that many psychiatrists decided that their sickest patients had enough problems without having to worry about quitting smoking, too. There also were concerns about potential dangers from using nicotine-replacement therapy, while continuing to smoke since smoking is so prevalent among the mentally ill. Recent studies, however, have found those concerns were overblown. The question, she said, is whether being more aggressive in trying to curb nicotine, alcohol and substance use in patients with severe psychiatric illness can lengthen their lives. Hartz believes health professionals who treat the mentally ill need to do a better job of trying to get them to stop smoking, drinking and using drugs. "Some studies have shown that although we psychiatrists know that smoking, drinking and substance use are major problems among the mentally ill, we often don't ask our patients about those things," she said. "We can do better, but we also need to develop new strategies because many interventions to reduce smoking, drinking and drug use that have worked in other patient populations don't seem to be very effective in these psychiatric patients." CADC I & II Continuing Education ### Funding for this research comes from the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Mental Health (NIMH) and the National Cancer Institute (NCI) of the National Institutes of Health (NIH), and the American Cancer Society. NIH grant numbers R01 DA032843, R01 DA025888, U10 AA008401, UL1 RR024992, P01 CA089392, R01 MH085548, R01 MH085542, K08 DA032680-1, Kl2 RR024994, K01 DA025733. Hartz SM, Pato CN, Medeiros H, Cavazos-Rehg P, Sobell JL, Knowles JA, Bierut LJ, Pato MT and the Genomic Psychiatry Cohort Consortium. JAMA Psychiatry Published online Jan. 1, 2014. doi:10.1001/jamapsychiatry.2013.3276 Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Gene found to foster synapse formation in the brain

Implications for language development, autism, epilepsy Researchers at Johns Hopkins say they have found that a gene already implicated in human speech disorders and epilepsy is also needed for vocalizations and synapse formation in mice. The finding, they say, adds to scientific understanding of how language develops, as well as the way synapses — the connections among brain cells that enable us to think — are formed. A description of their experiments appears in Science Express on Oct. 31. A group led by Richard Huganir, Ph.D., director of the Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, set out to investigate genes involved in synapse formation. Gek-Ming Sia, Ph.D., a research associate in Huganir's laboratory, first screened hundreds of human genes for their effects on lab-grown mouse brain cells. When one gene, SRPX2, was turned up higher than normal, it caused the brain cells to erupt with new synapses, Sia found. When Huganir's team injected fetal mice with an SRPX2-blocking compound, the mice showed fewer synapses than normal mice even as adults, the researchers found. In addition, when SRPX2-deficient mouse pups were separated from their mothers, they did not emit high-pitched distress calls as other pups do, indicating they lacked the rodent equivalent of early language ability. Other researchers' analyses of the human genome have found that mutations in SRPX2 are associated with language disorders and epilepsy, and when Huganir's team injected the human SRPX2 with the same mutations into the fetal mice, they also had deficits in their vocalization as young pups. Another research group at Institut de Neurobiologie de la Méditerranée in France had previously shown that SRPX2 interacts with FoxP2, a gene that has gained wide attention for its apparently crucial role in language ability. Huganir's team confirmed this, showing that FoxP2 controls how much protein the SRPX2 gene makes and may affect language in this way. "FoxP2 is famous for its role in language, but it's actually involved in other functions as well," Huganir comments. "SRPX2 appears to be more specialized to language ability." Huganir suspects that the gene may also be involved in autism, since autistic patients often have language impairments, and the condition has been linked to defects in synapse formation. This study is only the beginning of teasing out how SRPX2 acts on the brain, Sia says. "We'd like to find out what other proteins it acts on, and how exactly it regulates synapses and enables language development." Roger Clem of the Mount Sinai School of Medicine also participated in the study CADC I & II Continuing Education ### This study was supported by the National Institute of Mental Health (grant number P50MH084020) and the National Institute of Neurological Disorders and Stroke (grant number NS050274). Related stories: Study Refutes Accepted Model of Memory Formation Johns Hopkins Scientists Reveal Molecular Sculptor of Memories Johns Hopkins Researchers Discover How to Erase Memory

Medicare beneficiaries overspend by hundreds, Pitt Public Health finds

PITTSBURGH, Oct. 9, 2012 – Medicare beneficiaries are overpaying by hundreds of dollars annually because of difficulties selecting the ideal prescription drug plan for their medical needs, an investigation by University of Pittsburgh Graduate School of Public Health researchers reveals. Only 5.2 percent of beneficiaries chose the least-expensive Medicare prescription drug benefit (Part D) plan that satisfied their medical needs in 2009, overspending on Part D premiums and prescription drugs by an average of $368 a year. The evaluation, published in the October issue of the journal Health Affairs, takes a national look at how well beneficiaries were making plan choices in the fourth year of the Medicare Part D program and could help guide changes to health insurance programs. "People need assistance in choosing the least expensive plan for their medical needs," said lead author Chao Zhou, Ph.D., a post-doctoral associate at Pitt Public Health. "Educational programs that help people navigate the dozens of plans available would make it easier to select plans that best meet their health care needs without overspending." "In particular, government officials could recommend the three most appropriate Part D plans for each person, based on their medication history," said co-author Yuting Zhang, Ph.D., associate professor of health economics at Pitt Public Health. "Alternatively, they could assign beneficiaries to the best plan for them based on their medication needs, while offering them the option to choose another plan instead." The results of this study could be useful in designing health insurance exchanges, which are state-regulated organizations created under health care reform to offer standardized health care plans. "In designing health insurance exchanges, models with more active assistance would be more helpful than models with large numbers of plans and information," Dr. Zhang said. "For example, health insurance exchanges could actively screen plans on quality and negotiate premiums to reduce the number of plans." Implemented in 2006, Part D cost the federal government $65.8 billion in 2011, according to the Congressional Budget Office. The researchers looked at the difference in a patient's total spending, including the plan premium and out-of-pocket payment for the prescriptions filled, between the plan the patient chose and the cheapest alternative option in the region that would satisfy the patient's medication needs. The study looked at data for 412,712 people, with an average age of 75. Beneficiaries tend to overprotect themselves by purchasing plans with more generous features, such as generic drug coverage in the coverage gap. A few other trends emerged: As beneficiaries aged, they increasingly chose more expensive plans, with people older than 85 overspending by $30 more than people 65 to 69 years old. Blacks, Hispanics and Native Americans chose less expensive plans than whites. People with common medical conditions, such as diabetes and chronic heart failure, were not significantly more likely to choose more expensive plans. People with cognitive deficits or mental health issues, such as Alzheimer's disease, tended to choose less expensive plans, spending an average of $10 less than those without such conditions. The researchers could not determine if those people had assistance from caregivers. As the number of plan options increased in a region, the amount of overspending increased by $3.20 for every additional plan available. "A previous study showed that in 2006, beneficiaries could have saved nearly 31 percent of their total drug spending by switching to the lowest cost plan," Dr. Zhou said. "Since our results are similar, this suggests people are not learning to reduce overspending." One possible explanation for these consistent results over time is the impact of inertia and bias toward maintaining the status quo, she noted. "When Medicare Part D started in 2006, the majority of beneficiaries did not choose the least expensive plan," Dr. Zhou said. "Over time, they may have simply stuck to their original plan and never switched to a better one. Beneficiaries might not spend much time researching and adjusting their plan choices based on changes in their medication needs and in plan options." Findings from the private health insurance market support the authors' conclusion that people keep their current plan instead of spending time researching and optimizing their plan choices based on their insurance use and prescription spending in the previous year CADC I & II Continuing Education ### About the University of Pittsburgh Graduate School of Public Health The University of Pittsburgh Graduate School of Public Health, founded in 1948 and now one of the top-ranked schools of public health in the United States, conducts research on public health and medical care that improves the lives of millions of people around the world. Pitt Public Health is a leader in devising new methods to prevent and treat cardiovascular diseases, HIV/AIDS, cancer and other important public health problems. For more information about Pitt Public Health, visit the school's Web site at www.publichealth.pitt.edu. http://www.upmc.com/media

Predicting how patients respond to therapy

Brain scans could help doctors choose treatments for people with social anxiety disorder CAMBRIDGE, MA -- A new study led by MIT neuroscientists has found that brain scans of patients with social anxiety disorder can help predict whether they will benefit from cognitive behavioral therapy. Social anxiety is usually treated with either cognitive behavioral therapy or medications. However, it is currently impossible to predict which treatment will work best for a particular patient. The team of researchers from MIT, Boston University (BU) and Massachusetts General Hospital (MGH) found that the effectiveness of therapy could be predicted by measuring patients' brain activity as they looked at photos of faces, before the therapy sessions began. The findings, published this week in the Archives of General Psychiatry, may help doctors choose more effective treatments for social anxiety disorder, which is estimated to affect around 15 million people in the United States. "Our vision is that some of these measures might direct individuals to treatments that are more likely to work for them," says John Gabrieli, the Grover M. Hermann Professor of Brain and Cognitive Sciences at MIT, a member of the McGovern Institute for Brain Research and senior author of the paper. Lead authors of the paper are MIT postdoc Oliver Doehrmann and Satrajit Ghosh, a research scientist in the McGovern Institute. Choosing treatments Sufferers of social anxiety disorder experience intense fear in social situations that interferes with their ability to function in daily life. Cognitive behavioral therapy aims to change the thought and behavior patterns that lead to anxiety. For social anxiety disorder patients, that might include learning to reverse the belief that others are watching or judging them. The new paper is part of a larger study that MGH and BU ran recently on cognitive behavioral therapy for social anxiety, led by Mark Pollack, director of the Center for Anxiety and Traumatic Stress Disorders at MGH, and Stefan Hofmann, director of the Social Anxiety Program at BU. "This was a chance to ask if these brain measures, taken before treatment, would be informative in ways above and beyond what physicians can measure now, and determine who would be responsive to this treatment," Gabrieli says. Currently doctors might choose a treatment based on factors such as ease of taking pills versus going to therapy, the possibility of drug side effects, or what the patient's insurance will cover. "From a science perspective there's very little evidence about which treatment is optimal for a person," Gabrieli says. The researchers used functional magnetic resonance imaging (fMRI) to image the brains of patients before and after treatment. There have been many imaging studies showing brain differences between healthy people and patients with neuropsychiatric disorders, but so far imaging has not been established as a way to predict patients' responses to particular treatments CADC I & II Continuing Education Measuring brain activity In the new study, the researchers measured differences in brain activity as patients looked at images of angry or neutral faces. After 12 weeks of cognitive behavioral therapy, patients' social anxiety levels were tested. The researchers found that patients who had shown a greater difference in activity in high-level visual processing areas during the face-response task showed the most improvement after therapy. Gabrieli says it's unclear why activity in brain regions involved with visual processing would be a good predictor of treatment outcome. One possibility is that patients who benefited more were those whose brains were already adept at segregating different types of experiences, Gabrieli says. The researchers are now planning a follow-up study to investigate whether brain scans can predict differences in response between cognitive behavioral therapy and drug treatment. "Right now, all by itself, we're just giving somebody encouraging or discouraging news about the likely outcome" of therapy, Gabrieli says. "The really valuable thing would be if it turns out to be differentially sensitive to different treatment choices." ### The research was funded by the Poitras Center for Affective Disorders Research and the National Institute of Mental Health. Written by Anne Trafton, MIT News Office

Research at UH finds cognitive-behavioral therapy effective in combatting anxiety disorders

Combination of treatments provides improvement for disorders such as fear of flying, public speaking or spiders Whether it is a phobia like a fear of flying, public speaking or spiders, or a diagnosis such as obsessive compulsive disorder, new research finds patients suffering from anxiety disorders showed the most improvement when treated with cognitive-behavioral therapy (CBT) in conjunction with a "transdiagnostic" approach – a model that allows therapists to apply one set of principles across anxiety disorders Anxiety Disorders CE Course The combination was more effective than CBT combined with other types of anxiety disorder treatments, like relaxation training according to Peter Norton, associate professor in clinical psychology and director of the Anxiety Disorder Clinic at the University of Houston (UH) CADC I & II Continuing Education Norton concludes that therapists treating people with anxiety disorders may effectively use a treatment that applies one set of principals across all types of anxiety disorders. The findings are the result of a decade of research, four separate clinical trials and the completion of a five-year grant funded by the National Institute of Mental Health. Norton defines anxiety disorders as when anxiety and fear are so overwhelming that it can start to negatively impact a person's day-to-day life. He notes anxiety disorders include: panic disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), social anxiety disorder, specific phobias and generalized anxiety disorder. Often anxiety disorders occur with a secondary illness, such as depression, substance or alcohol abuse. Norton says there are targeted treatments for each diagnosis, but there has been little recognition that the treatments don't differ much, and they only differ in very specific ways. IMAGE:This is Peter Norton, associate professor in clinical psychology and director of the Anxiety Disorder Clinic at the University of Houston. Click here for more information. "The Diagnostic and Statistical Manual of Mental Disorders (DSM) has been an important breakthrough in understanding mental health, but people are dissatisfied with its fine level of differentiation," said Norton. "Panic disorders are considered something different from social phobia, which is considered something different from PTSD. The hope was that by getting refined in the diagnosis we could target interventions for each of these diagnoses, but in reality that just hasn't played out." As a graduate student in Nebraska, Norton couldn't get enough people together on the same night to run a group treatment for social phobia, and that marked the beginning 10 years of work on the transdiagnostic treatment approach. "What I realized is that I could open a group to people with anxiety disorders in general and develop a treatment program regardless of the artificial distinctions between social phobia and panic disorder, or obsessive-compulsive disorder, and focus on the core underlying things that are going wrong," said Norton. Norton finds cognitive-behavioral therapy (CBT), a type of treatment with a specific time frame and goals, helps patients understand the thoughts and feelings that influence behaviors to be the most effective treatment. The twist for him was using CBT in conjunction with the transdiagnostic approach. The patients receiving the transdiagnostic treatment showed considerable improvement, especially with treating comorbid diagnoses, a disease or IMAGE:This is the cover of "Group Cognitive-Behavioral Therapy of Anxiety. A Transdiagnostic Treatment Manual, " by Peter J. Norton. Click here for more information. condition that co-exists with a primary disease and can stand on its own as a specific disease, like depression. "What I have learned from my past research is that if you treat your principal diagnosis, such as social phobia and you hate public speaking, you are going to show improvement on some of your secondary diagnosis. Your mood is going to get a little better, your fear of heights might dissipate. So there is some effect there, but what we find is when we approach things with a transdiagnostic approach, we see a much bigger impact on comorbid diagnoses," said Norton. "In my research study, over two-thirds of comorbid diagnoses went away, versus what we typically we find when I'm treating a specific diagnosis such as a panic disorder, where only about 40 percent of people will show that sort of remission in their secondary diagnosis. The transdiagnostic treatment approach is more efficient in treating the whole person rather than just treating the diagnosis, then treating the next diagnoses." Norton notes the larger contributions of the studies are to guide further development and interventions for how clinical psychologists, therapists and social workers treat people with anxiety disorders. The data collected will be useful for people out on the front lines to effectively and efficiently treat people to reduce anxiety disorders. ### Norton is the author of the book, "Group Cognitive-Behavioral Therapy of Anxiety. A Transdiagnostic Treatment Manual," and co-author of "The Anti-Anxiety Workbook: Proven Strategies to Overcome Worry, Phobias, Panic and Obsessions." He has authored more than 90 research papers on such topics as anxiety disorders, CBT and chronic pain, and he serves on the editorial boards of two scientific journals. He has received early career awards and research grants for his work on studying and treating anxiety from the National Institute of Mental Health, the University of Nebraska – Lincoln, UH, the Anxiety Disorders Association of America and the American Psychological Association. About the Anxiety Disorder Clinic The Anxiety Disorder Clinic (ADC) is a specialty treatment and research clinic at the University of Houston. The goal of the ADC is to help clients overcome their problems with anxiety without medication by using the most effective psychological therapies available. Both research opportunities and low-cost clinical services based on the latest scientific evidence are offered to individuals. For more information about research opportunities and clinical services at ADC, please call 713-743-8600 or visit the ADC website www.uh.edu/anxiety About the University of Houston The University of Houston is a Carnegie-designated Tier One public research university recognized by The Princeton Review as one of the nation's best colleges for undergraduate education. UH serves the globally competitive Houston and Gulf Coast Region by providing world-class faculty, experiential learning and strategic industry partnerships. Located in the nation's fourth-largest city, UH serves more than 39,500 students in the most ethnically and culturally diverse region in the country.

Adaptable decision making in the brain

Front-most part of the cortex involved in making short-term predictions about what will happen next Researchers at the University of Iowa, together with colleagues from the California Institute of Technology and New York University, have discovered how a part of the brain helps predict future events from past experiences. The work sheds light on the function of the front-most part of the frontal lobe, known as the frontopolar cortex, an area of the cortex uniquely well developed in humans in comparison with apes and other primates. Making the best possible decisions in a changing and unpredictable environment is an enormous challenge. Not only does it require learning from past experience, but it also demands anticipating what might happen under previously unencountered circumstances. Past research from the UI Department of Neurology was among the first to show that damage to certain parts of the frontal lobe can cause severe deficits in decision making in rapidly changing environments. The new study from the same department on a rare group of patients with damage to the very frontal part of their brains reveals a critical aspect of how this area contributes to decision making. The findings were published June 19 in the Journal of Neuroscience. "We gave the patients four slot machines from which to pick in order to win money. Unbeknownst to the patients, the probability of getting money from a particular slot machine gradually and unpredictably changed during the experiment. Finding the strategy that pays the most in the long run is a surprisingly difficult problem to solve, and one we hypothesized would require the frontopolar cortex," explains Christopher Kovach, Ph.D., a UI post-doctoral fellow in neurosurgery and first author of the study. Contrary to the authors' initial expectation, the patients actually did quite well on the task, winning as much money, on average, as healthy control participants. "But when we compared their behavior to that of subjects with intact frontal lobe, we found they used a different set of assumptions about how the payoffs changed over time," Kovach says. "Both groups based their decisions on how much they had recently won from each slot machine, but healthy comparison subjects pursued a more elaborate strategy, which involved predicting the direction that payoffs were moving based on recent trends. This points towards a specific role for the frontopolar cortex in extrapolating recent trends." Kovach's colleague and study author Ralph Adolphs, Ph.D., professor of neuroscience and psychology at the California Institute of Technology, adds that the study results "argue that the frontopolar cortex helps us to make short-term predictions about what will happen next, a strategy particularly useful in environments that change rapidly -- such as the stock market or most social settings." Adolphs also hold an adjunct appointment in the UI Department of Neurology. The study's innovative approach to understanding the function of this part of the brain uses model-based analyses of behavior of patients with specific and precisely characterized areas of brain damage. These patients are members of the UI's world-renowned Iowa Neurological Patient Registry, which was established in 1982 and has more than 500 active members with selective forms of damage, or lesions, to one or two defined regions in the brain. "The University of Iowa is one of the few places in the world where you could carry out this kind of study, since it requires carefully assessed patients with damage to specific parts of their brain," says study author Daniel Tranel, Ph.D., UI professor of neurology and psychology and director of the UI Division of Behavioral Neurology and Cognitive Neuroscience. In a final twist to the finding, the strategy taken by lesion patients was actually slightly better than the one used by comparison subjects. It happened that the task was designed so that the trends in the payoffs were, in fact, random and uninformative. "The healthy comparison subjects seemed to perceive trends in what was just random noise," Kovach says. This implies that the functions of the frontopolar cortex, which support more complex and detailed models of the environment, at times come with a downside: setting up mistaken assumptions. "To the best of my knowledge this is the first study which links a normal tendency to see a nonexistent pattern in random noise, a type of cognitive bias, to a particular brain region," Kovach notes. The researchers next want to investigate other parts of the frontal cortex in the brain, and have also begun to record activity directly from the brains of neurosurgical patients to see how single cells respond while making decisions. The work is also important to understand difficulties in decision making seen in disorders such as addiction. ### The study, "Anterior prefrontal cortex contributes to action selection through tracking of recent reward trends," also included authors David Rudrauf from the University of Iowa, John O'Doherty from the California Institute of Technology, and Nathaniel Daw from New York University. The research was funded in part by grants from the National Institute of Neurological Disorders and Stroke (Grant P50 NS19632), the National Institute on Drug Abuse (Grant DA022549), the National Institute of Mental Health (Grant MH080721) and the Tamagawa University Global Centers of Excellence Program of the Japanese Ministry of Education, Culture, Sports, and Technology CADC I & II Continuing Education

A walk in the park gives mental boost to people with depression

Study suggests nature walks improve cognitive abilities for people with clinical depression Toronto, CANADA – A walk in the park may have psychological benefits for people suffering from depression. In one of the first studies to examine the effect of nature walks on cognition and mood in people with major depression, researchers in Canada and the U.S. have found promising evidence that a walk in the park may provide some cognitive benefits. The study was led by Marc Berman, a post-doctoral fellow at Baycrest's Rotman Research Institute in Toronto, with partners from the University of Michigan and Stanford University. It is published online this week, ahead of print publication, in the Journal of Affective Disorders. "Our study showed that participants with clinical depression demonstrated improved memory performance after a walk in nature, compared to a walk in a busy urban environment," said Dr. Berman, who cautioned that such walks are not a replacement for existing and well-validated treatments for clinical depression, such as psychotherapy and drug treatment. "Walking in nature may act to supplement or enhance existing treatments for clinical depression, but more research is needed to understand just how effective nature walks can be to help improve psychological functioning," he said. Dr. Berman's research is part of a cognitive science field known as Attention Restoration Theory (ART) which proposes that people concentrate better after spending time in nature or looking at scenes of nature. The reason, according to ART, is that people interacting with peaceful nature settings aren't bombarded with external distractions that relentlessly tax their working memory and attention systems. In nature settings, the brain can relax and enter a state of contemplativeness that helps to restore or refresh those cognitive capacities. In a research paper he published in 2008 in Psychological Science, Dr. Berman showed that adults who were not diagnosed with any illness received a mental boost after an hour-long walk in a woodland park – improving their performance on memory and attention tests by 20 percent – compared to an hour-long stroll in a noisy urban environment. The findings were reported by The Wall Street Journal, The Boston Globe, The New York Times, and in the Pulitzer Prize finalist book by Nicholas Carr, The Shallows: What the internet is doing to our brains. In this latest study, Dr. Berman and his research team explored whether a nature walk would provide similar cognitive benefits, and also improve mood for people with clinical depression. Given that individuals with depression are characterized by high levels of rumination and negative thinking, the researchers were skeptical at the outset of the study that a solitary walk in the park would provide any benefit at all and may end up worsening memory and exacerbating depressed mood. For the study, 20 individuals were recruited from the University of Michigan and surrounding Ann Arbor area; all had a diagnosis of clinical depression. The 12 females and eight males (average age 26) participated in a two-part experiment that involved walking in a quiet nature setting and in a noisy urban setting. Prior to the walks, participants completed baseline testing to determine their cognitive and mood status. Before beginning a walk, the participants were asked to think about an unresolved, painful autobiographical experience. They were then randomly assigned to go for an hour-long walk in the Ann Arbor Arboretum (woodland park) or traffic heavy portions of downtown Ann Arbor. They followed a prescribed route and wore a GPS watch to ensure compliance. After completing their walk, they completed a series of mental tests to measure their attention and short-term/working memory and were re-asssessed for mood. A week later the participants repeated the entire procedure, walking in the location that was not visited in the first session. Participants exhibited a 16 percent increase in attention and working memory after the nature walk relative to the urban walk. Interestingly, interacting with nature did not alleviate depressive mood to any noticeable degree over urban walks, as negative mood decreased and positive mood increased after both walks to a significant and equal extent. Dr. Berman says this suggests that separate brain mechanisms may underlie the cognitive and mood changes of interacting with nature CADC I & II Continuing Education ### The study was supported by a grant from the National Institute of Mental Health and a private grant from the TKF Foundation. At Baycrest's Rotman Research Institute, Marc Berman's research explores the brain mechanisms involved in controlling thoughts, feeling and behaviors, and how to improve those abilities. Prior to joining Baycrest in 2011, Dr. Berman received his Ph.D. in Cognitive Neuroscience and Industrial and Operations Engineering at the University of Michigan.

Most Children with Rapidly Shifting Moods Don’t Have Bipolar Disorder

Relatively few children with rapidly shifting moods and high energy have bipolar disorder, though such symptoms are commonly associated with the disorder. Instead, most of these children have other types of mental disorders, according to an NIMH-funded study published online ahead of print in the Journal of Clinical Psychiatry on October 5, 2010. Background Some parents who take their child to a mental health clinic for assessment report that the child has rapid swings between emotions (usually anger, elation, and sadness) coupled with extremely high energy levels. Some researchers suggest that this is how mania—an important component of bipolar disorder—appears in children. How mania and bipolar disorder are defined in children is important because rapid mood swings and high energy are common among youth. Furthermore, many experts believe that overdiagnosis and misdiagnosis of bipolar disorder in youth may play a role in the increasing numbers of children being diagnosed with and treated for bipolar disorder. In choosing proper treatment, it is important to know whether children with rapid mood swings and high energy have an early or mild form of bipolar disorder, or instead have a different mental disorder CADC I & II Continuing Education In the Longitudinal Assessment of Manic Symptoms (LAMS) study, Robert Findling, M.D., of Case Western Reserve University, and colleagues assessed 707 children, ages 6-12, who were referred for mental health treatment. Of the participants, 621 were rated as having rapid swings between emotions and high energy levels, described as "elevated symptoms of mania" (ESM-positive). Parents of the other 86 children did not report rapid mood swings. These participants were deemed ESM-negative. Results of the Study At baseline, all but 14 participants had at least one mental disorder, and many had two or more. Attention deficit hyperactivity disorder (ADHD) was the most frequent diagnosis, affecting roughly 76 percent in both the ESM-positive and ESM-negative groups. However, only 39 percent were receiving treatment with a stimulant, the most common medication treatment for ADHD, at the start of the study. Only 11 percent of those with rapid mood swings and high energy (69 out of 621) and 6 percent of those without these symptoms (5 out of 86) had bipolar disorder, meaning that only this small percentage had ever experienced a manic episode, as defined by the current diagnostic system. Of the children with rapid mood swings and high energy, another 12 percent (75 children) had a form of bipolar disorder that includes much shorter manic episodes. Compared to children without rapid mood swings and high energy, those with these symptoms: Reported more symptoms of depression, anxiety, manic symptoms, and symptoms of ADHD Had lower functioning at home, school, or with peers Were more likely to have a disruptive behavior disorder (oppositional defiant disorder and/or conduct disorder). Significance Given that 75 percent of ESM-positive youth did not meet the diagnostic criteria for any bipolar disorder, the researchers suggest that bipolar disorder may not be common among children who experience rapid swings between emotions and high energy levels. Nevertheless, children with these symptoms experience significant impairments due to mood and behavior problems. The researchers also noted that ESM-positive and ESM-negative youth were prescribed psychotropic medications—including antipsychotics—at similar rates. Further study may provide insight into how serious mental illnesses should be treated in children. What's Next The study participants will be re-assessed every 6 months for up to 5 years, allowing the LAMS researchers to determine which children with rapid mood swings and high energy develop bipolar disorder later in life. Such research may inform efforts to identify early markers or predictors of the illness as well as possible protective factors. Reference Findling RL, Youngstrom EA, Fristad MA, Birmaher B, Kowatch RA, Arnold E, Frazier TW, Axelson D, Ryan N, Demeter CA, Gill MK, Fields B, Depew J, Kennedy SM, Marsh L, Rowles BM, Horwitz SM. Characteristics of Children With Elevated Symptoms of Mania: The Longitudinal Assessment of Manic Symptoms (LAMS) Study. J Clin Psychiatr. Epub 2010 Oct 5.

Friendly-to-a-Fault, Yet Tense: Personality Traits Traced in Brain

Scans Reveal How Genes Alter Circuit Hub to Shape Temperament – NIH Study

A personality profile marked by overly gregarious yet anxious behavior is rooted in abnormal development of a circuit hub buried deep in the front center of the brain, say scientists at the National Institutes of Health. They used three different types of brain imaging to pinpoint the suspect brain area in people with Williams syndrome, a rare genetic disorder characterized by these behaviors. Matching the scans to scores on a personality rating scale revealed that the more an individual with Williams syndrome showed these personality/temperament traits, the more abnormalities there were in the brain structure, called the insula CADC I & II Continuing Education

“Scans of the brain’s tissue composition, wiring, and activity produced converging evidence of genetically-caused abnormalities in the structure and function of the front part of the insula and in its connectivity to other brain areas in the circuit,” explained Karen Berman, M.D., of the NIH’s National Institute of Mental Health (NIMH).

Berman, Drs. Mbemda Jabbi, Shane Kippenhan, and colleagues, report on their imaging study in Williams syndrome online in the journal Proceedings of the National Academy of Sciences.

“This line of research offers insight into how genes help to shape brain circuitry that regulates complex behaviors – such as the way a person responds to others – and thus holds promise for unraveling brain mechanisms in other disorders of social behavior,” said NIMH Director Thomas R. Insel, M.D.

Williams syndrome is caused by the deletion of some 28 genes, many involved in brain development and behavior, in a particular section of chromosome 7. Among deficits characteristic of the syndrome are a lack of visual-spatial ability – such as is required to assemble a puzzle – and a tendency to be overly-friendly with people, while overly anxious about non-social matters, such as spiders or heights. Many people with the disorder are also mentally challenged and learning disabled, but some have normal IQs.

Previous imaging studies by the NIMH researchers found abnormal tracts of the neuronal fibers that conduct long-distance communications between brain regions -- likely resulting from neurons migrating to the wrong destinations during early development.

Evidence suggests that genes influence our temperament and the development of mental disorders via effects on brain circuits that regulate behavior. Yet direct demonstration of this in humans has proven elusive. Since the genetic basis of Williams syndrome is well known, it offers a unique opportunity to explore such effects with neuroimaging, reasoned the researchers.

Although the insula had not previously been studied in such detail in the disorder, it was known to be related to brain circuitry and certain behaviors, such as empathy, which is also highly prominent in the disorder. Berman and colleagues hypothesized that the insula’s anatomy, function and connectivity would predict patients’ scores for Williams syndrome-associated traits on personality rating scales. Fourteen intellectually normal Williams syndrome participants and 23 healthy controls participated in the study.

Magnetic resonance imaging (MRI) revealed that patients had decreased gray matter – the brain’s working tissue – in the bottom front of the insula, which integrates mood and thinking. By contrast, they had increased gray matter in the top front part of the insula, which has been linked to social/emotional processes.

Diffusion tensor imaging, which by detecting the flow of water in nerve fibers can identify and measure the connections between brain areas, showed reduced white matter – the brain’s long-distance wiring – between thinking and emotion hubs.

Tracking radioactively-tagged water in order to measure brain blood flow at rest, via positron emission tomography (PET), exposed activity aberrations consistent with the MRI abnormalities. The PET scans also revealed altered functional coupling between the front of the insula and key structures involved in thinking, mood and fear processing. These structural and functional abnormalities in the front of the insula correlated with the Williams syndrome personality profile.

“Our findings illustrate how brain systems translate genetic vulnerability into behavioral traits,” explained Berman.

The severity of abnormalities in insula (red structure near bottom of brain) gray matter volume (left) and brain activity (right) predicted the extent of aberrant personality traits in Williams syndrome patients – as reflected in their scores (red dots) on personality rating scales (WSPP).

Source: Karen Berman, M.D., NIMH Clinical Brain Disorders Branch


Long distance connections, white matter, between the insula and other parts of the brain are aberrant in Williams syndrome. Neuronal fibers of normal controls (left) extend further than those of Williams syndrome patients (right). Picture shows diffusion tensor imaging data from each patient superimposed on anatomical MRI of the median patient.

Source: Karen Berman, M.D., NIMH Clinical Brain Disorders Branch


Reference:

The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and function. Jabbi M, Kippenhan JS, Kohn P, Marenco S, Mervis CB, Morris CA, Meyer-Lindenberg A, Berman KF. Proc Natl Acad Sci U S A. 2012 Mar 12. [Epub ahead of print] PMID: 22411788

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Gene Regulator in Brain’s Executive Hub Tracked Across Lifespan – NIH study

Mental illness suspect genes are among the most environmentally responsive

For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain’s executive hub. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.

Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make – what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.

“Developmental brain disorders may be traceable to altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”

Lipska and colleagues report on the ebb and flow of the human prefrontal cortex’s (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.

“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.

In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old CADC I and II Continuing Education

In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. Lipska’s team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.

For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.

Different genes – and subsets of genes – methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.

Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers at: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v2.p1. BrainCloud, a web browser application developed by NIMH to interrogate the study data, can be downloaded at http://BrainCloud.jhmi.edu.

Two representative genes show strikingly opposite trajectories of PFC methylation across the lifespan. Each dot represents a different brain. Usually, the more methylation, the less gene expression.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch


A representative gene showing how sex can influence levels of methylation across the lifespan. Each dot represents a different brain.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch

Reference:

Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex. American Journal of Human Genetics, 2011. Feb 2.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Turning on Dormant Gene May Hold Key for Correcting a Neurodevelopmental Defect

Finding Shows Therapeutic Potential of Small-Molecule Targeting Strategy

Scientists working in cell culture and in mice have been able to correct the loss of gene activity underlying a rare but severe developmental disorder by turning on a gene that is normally silenced in brain cells. Further testing of the identified compound that activates the gene will determine whether it has potential as a genetically-based treatment for the disorder, Angelman syndrome.

Background

Infants with Angelman syndrome appear normal at birth, but show developmental delays by 6 to 12 months. Features of the disorder include impaired speech, seizures, hyperactivity, and motor difficulties. No effective treatment exists CADC I & II Continuing Education

In the late 1990s, researchers found that the disorder results from changes or deletions in the maternal gene for the enzyme ubiquitin protein ligase E3A (Ube3a). Most genes are inherited in sets of two, one from the mother and one from the father. In some cases, either the maternal or paternal gene is silenced, or prevented from being translated into protein. This normal silencing based on inheritance from a mother or father is called imprinting. The Ube3a gene is an example of genetic imprinting, as the paternal gene is normally silenced in neurons. With the maternal gene out of action, infants with Angelman syndrome lack the enzyme, leading to changes in the brain that underlie the symptoms of the disorder.

This Study

This research is reported online in the journal Nature, and was carried out by scientists at the University of North Carolina School of Medicine at Chapel Hill, led by the labs of Ben Philpot, Bryan Roth, and Mark Zylka. In an effort to restore the absent Ube3a enzyme in neurons, the research team screened thousands of compounds for their ability to “wake up” the paternal Ube3a gene. The investigators used neurons from genetically engineered mice to test whether compounds could activate the gene; the neurons fluoresce if the paternal Ube3a gene is expressed, or translated into protein. The team screened 2,306 candidate small molecules from multiple molecular libraries. If fluorescence was detected, that meant that the test compound activated the Ube3a gene. The screening and access to the molecular libraries was made possible through NIMH’s Psychoactive Drug Screening Program, funded by contract to perform pharmacological and functional screening of novel compounds. Bryan Roth at UNC Chapel Hill is the project director and a coauthor of the Nature paper.

The investigators found that a class of compounds—topoisomerase inhibitors—could unsilence the paternal gene. They chose one, topotecan, and tested it to see whether it could do the same thing in vivo in a mouse. They administered topotecan directly into the brain and later into spinal fluid; in both cases it was able to activate paternal Ube3a. Activation persisted for 12 weeks after delivery of the compound had stopped.

Significance

"This is the first time anyone has used a small molecule to successfully target activation of a disease-relevant gene," said senior author Benjamin Philpot. "The work demonstrates that turning on a dormant gene could represent a therapeutic intervention for Angelman syndrome."

NIMH helped to fund this project and has issued a grant to the UNC team to continue studies of topotecan, initially in mice. Although topotecan is already in use in both children and adults as a cancer chemotherapeutic agent, further testing is essential to determine the dosage of the agent that would be needed to be effective, the best means of administering the medication, and whether side-effects at the necessary dosage level are within a range that make it feasible to use. The authors emphasize that much work remains before this or related agents can or should be used for treatment of this condition.

Reference

Huang, H.-S., Allen, J., Mabb, A., King, I., Miriyala, J., Taylor-Blake, B., Sciaky, N., Dutton, J. Jr., Lee, H.M., Chen, X., Jin, J. Bridges, A., Zylka, M., Roth, B., Philpot, B. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. Published online ahead of print December 21, 2011, doi: 10.1038/nature10726.


This image shows Ube3a staining in a neurotypical mouse brain and its absence in the Angelman syndrome model mouse brain.

Source: Ben Philpot, Ph.D., University of North Carolina School of Medicine