Seeing the inner workings of the brain made easier by new technique from Stanford

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"Last year Karl Deisseroth, a Stanford professor of bioengineering and of psychiatry and behavioral sciences, announced a new way of peering into a brain – removed from the body – that provided spectacular fly-through views of its inner connections. Since then laboratories around the world have begun using the technique, called CLARITY, with some success, to better understand the brain's wiring. However, Deisseroth said that with two technological fixes CLARITY could be even more broadly adopted. The first problem was that laboratories were not set up to reliably carry out the CLARITY process. Second, the most commonly available microscopy methods were not designed to image the whole transparent brain. "There have been a number of remarkable results described using CLARITY," Deisseroth said, "but we needed to address these two distinct challenges to make the technology easier to use." In a Nature Protocols paper published June 19, Deisseroth presented solutions to both of those bottlenecks. "These transform CLARITY, making the overall process much easier and the data collection much faster," he said. He and his co-authors, including postdoctoral fellows Raju Tomer and Li Ye and graduate student Brian Hsueh, anticipate that even more scientists will now be able to take advantage of the technique to better understand the brain at a fundamental level, and also to probe the origins of brain diseases. This paper may be the first to be published with support of the White House BRAIN Initiative, announced last year with the ambitious goal of mapping the brain's trillions of nerve connections and understanding how signals zip through those interconnected cells to control our thoughts, memories, movement and everything else that makes us us. "This work shares the spirit of the BRAIN Initiative goal of building new technologies to understand the brain – including the human brain," said Deisseroth, who is also a Stanford Bio-X affiliated faculty member. Eliminating fat When you look at the brain, what you see is the fatty outer covering of the nerve cells within, which blocks microscopes from taking images of the intricate connections between deep brain cells. The idea behind CLARITY was to eliminate that fatty covering while keeping the brain intact, complete with all its intricate inner wiring. The way Deisseroth and his team eliminated the fat was to build a gel within the intact brain that held all the structures and proteins in place. They then used an electric field to pull out the fat layer that had been dissolved in an electrically charged detergent, leaving behind all the brain's structures embedded in the firm water-based gel, or hydrogel. This is called electrophoretic CLARITY. The electric field aspect was a challenge for some labs. "About half the people who tried it got it working right away," Deisseroth said, "but others had problems with the voltage damaging tissue." Deisseroth said that this kind of challenge is normal when introducing new technologies. When he first introduced optogenetics, which allows scientists to control individual nerves using light, a similar proportion of labs were not initially set up to easily implement the new technology, and ran into challenges. To help expand the use of CLARITY, the team devised an alternate way of pulling out the fat from the hydrogel-embedded brain – a technique they call passive CLARITY. It takes a little longer, but still removes all the fat, is much easier and does not pose a risk to the tissue. "Electrophoretic CLARITY is important for cases where speed is critical, and for some tissues," said Deisseroth, who is also the D.H. Chen Professor. "But passive CLARITY is a crucial advance for the community, especially for neuroscience." Passive CLARITY requires nothing more than some chemicals, a warm bath and time. Many groups have begun to apply CLARITY to probe brains donated from people who had diseases like epilepsy or autism, which might have left clues in the brain to help scientists understand and eventually treat the disease. But scientists, including Deisseroth, had been wary of trying electrophoretic CLARTY on these valuable clinical samples with even a very low risk of damage. "It's a rare and precious donated sample, you don't want to have a chance of damage or error," Deisseroth said. "Now the risk issue is addressed, and on top of that you can get the data very rapidly." Fast CLARITY imaging in color The second advance had to do this rapidity of data collection. In studying any cells, scientists often make use of probes that will go into the cell or tissue, latch onto a particular molecule, then glow green, blue, yellow or other colors in response to particular wavelengths of light. This is what produces the colorful cellular images that are so common in biology research. Using CLARITY, these colorful structures become visible throughout the entire brain, since no fat remains to block the light. But here's the hitch. Those probes stop working, or get bleached, after they've been exposed to too much light. That's fine if a scientist is just taking a picture of a small cellular structure, which takes little time. But to get a high-resolution image of an entire brain, the whole tissue is bathed in light throughout the time it takes to image it point by point. This approach bleaches out the probes before the entire brain can be imaged at high resolution. The second advance of the new paper addresses this issue, making it easier to image the entire brain without bleaching the probes. "We can now scan an entire plane at one time instead of a point," Deisseroth said. "That buys you a couple orders of magnitude of time, and also efficiently delivers light only to where the imaging is happening." The technique is called light sheet microscopy and has been around for a while, but previously didn't have high enough resolution to see the fine details of cellular structures. "We advanced traditional light sheet microscopy for CLARITY, and can now see fine wiring structures deep within an intact adult brain," Deisseroth said. His lab built their own microscope, but the procedures are described in the paper, and the key components are commercially available. Additionally, Deisseroth's lab provides free training courses in CLARITY, modeled after his optogenetics courses, to help disseminate the techniques. Brain imaging to help soldiers The BRAIN Initiative is being funded through several government agencies including the Defense Advanced Research Projects Agency (DARPA), which funded Deisseroth's work through its new Neuro-FAST program. Deisseroth said that like the National Institute of Mental Health (NIMH, another major funder of the new paper), DARPA "is interested in deepening our understanding of brain circuits in intact and injured brains to inform the development of better therapies." The new methods Deisseroth and his team developed will accelerate both human- and animal-model CLARITY; as CLARITY becomes more widely used, it will continue to help reveal how those inner circuits are structured in normal and diseased brains, and perhaps point to possible therapies. ### Other arms of the BRAIN Initiative are funded through the National Science Foundation (NSF) and the National Institutes of Health (NIH). A working group for the NIH arm was co-led by William Newsome, professor of neurobiology and director of the Stanford Neurosciences Institute, and also included Deisseroth and Mark Schnitzer, associate professor of biology and of applied physics. That group recently recommended a $4.5 billion investment in the BRAIN Initiative over the next 12 years, which NIH Director Francis Collins approved earlier this month." In addition to funding by DARPA and NIMH, the work was funded by the NSF, the National Institute on Drug Abuse, the Simons Foundation and the Wiegers Family Fund. For more information on the brain, mental health, and social work topics please visit Professional Counselor Continuing Education

Brain connectivity study reveals striking differences between men and women

Penn Medicine brain imaging study helps explain different cognitive strengths in men and women PHILADELPHIA—A new brain connectivity study from Penn Medicine published today in the Proceedings of National Academy of Sciences found striking differences in the neural wiring of men and women that's lending credence to some commonly-held beliefs about their behavior. In one of the largest studies looking at the "connectomes" of the sexes, Ragini Verma, PhD, an associate professor in the department of Radiology at the Perelman School of Medicine at the University of Pennsylvania, and colleagues found greater neural connectivity from front to back and within one hemisphere in males, suggesting their brains are structured to facilitate connectivity between perception and coordinated action. In contrast, in females, the wiring goes between the left and right hemispheres, suggesting that they facilitate communication between the analytical and intuition. "These maps show us a stark difference--and complementarity--in the architecture of the human brain that helps provide a potential neural basis as to why men excel at certain tasks, and women at others," said Verma. For instance, on average, men are more likely better at learning and performing a single task at hand, like cycling or navigating directions, whereas women have superior memory and social cognition skills, making them more equipped for multitasking and creating solutions that work for a group. They have a mentalistic approach, so to speak. Past studies have shown sex differences in the brain, but the neural wiring connecting regions across the whole brain that have been tied to such cognitive skills has never been fully shown in a large population. In the study, Verma and colleagues, including co-authors Ruben C. Gur, PhD, a professor of psychology in the department of Psychiatry, and Raquel E. Gur, MD, PhD, professor of Psychiatry, Neurology and Radiology, investigated the gender-specific differences in brain connectivity during the course of development in 949 individuals (521 females and 428 males) aged 8 to 22 years using diffusion tensor imaging (DTI). DTI is water-based imaging technique that can trace and highlight the fiber pathways connecting the different regions of the brain, laying the foundation for a structural connectome or network of the whole brain. This sample of youths was studied as part of the Philadelphia Neurodevelopmental Cohort, a National Institute of Mental Health-funded collaboration between the University of Pennsylvania Brain Behavior Laboratory and the Center for Applied Genomics at the Children's Hospital of Philadelphia. The brain is a roadmap of neural pathways linking many networks that help us process information and react accordingly, with behavior controlled by several of these sub-networks working in conjunction. In the study, the researchers found that females displayed greater connectivity in the supratentorial region, which contains the cerebrum, the largest part of the brain, between the left and right hemispheres. Males, on the other hand, displayed greater connectivity within each hemisphere. By contrast, the opposite prevailed in the cerebellum, the part of the brain that plays a major role in motor control, where males displayed greater inter-hemispheric connectivity and females displayed greater intra-hemispheric connectivity. These connections likely give men an efficient system for coordinated action, where the cerebellum, which involves perception, and the front of the brain, which involves action, are bridged together, according to the authors. The female connections likely facilitate integration of the analytic and sequential processing modes of the left hemisphere with the spatial, intuitive information processing modes of the right side. The authors observed only a few gender differences in the connectivity in children younger than 13 years, but the differences were more pronounced in adolescents aged 14 to 17 years and young adults older than 17. The findings were also consistent with a Penn behavior study, of which this imaging study was a subset of, that demonstrated pronounced sexual differences. Females outperformed males on attention, word and face memory, and social cognition tests. Males performed better on spatial processing and sensorimotor speed. Those differences were most pronounced in the 12 to 14 age range. "It's quite striking how complementary the brains of women and men really are," said Dr. Ruben Gur. "Detailed connectome maps of the brain will not only help us better understand the differences between how men and women think, but it will also give us more insight into the roots of neuropsychiatric disorders, which are often sex related." Next steps are to quantify how an individual's neural connections are different from the population; identify which neural connections are gender specific and common in both; and to see if findings from functional magnetic resonance imaging (fMRI) studies fall in line with the connectome data Professional Counselor Continuing Education ### Co-authors of the study include Madhura Ingalhalikar, Alex Smith, Drew Parker, Theodore D. Satterthwaite, Mark A. Elliott, Kosha Ruparel, and Hakon Hakonarson of the Section of Biomedical Image Analysis and the Center for Biomedical Image Computing and Analytics. This study was funded by in part by the National Institutes of Mental Health: MH089983, MH089924, MH079938, and MH092862.

Clinician observations of preschoolers' behavior help to predict ADHD at school age

Consider how preschool children behave across multiple contexts to identify those at risk for later ADHD, study emphasizes Don't rely on one source of information about your preschoolers' inattention or hyperactivity. Rather, consider how your child behaves at home as well as information from his or her teacher and a clinician. This advice comes from Sarah O'Neill, of The City College of New York, based on research she conducted at Queens College (CUNY), in an article published in Springer's Journal of Abnormal Child Psychology. The study examines how well parent, teacher, and clinician ratings of preschoolers' behavior are able to predict severity and diagnosis of attention deficit hyperactivity disorder (ADHD) at age six Professional Counselor Continuing Education Characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity, ADHD is one of the most frequently diagnosed childhood psychiatric disorders. Although many studies focusing on school-aged children have shown that parents and teachers -- rather than clinician observations alone -- are more likely to assess ADHD accurately, scant evidence exists to support similar conclusions with preschoolers. To fill this gap in the research, O'Neill and colleagues followed a group of 104 hyperactive and/or inattentive three- and four-year-olds for a period of two years. Both parents and teachers rated the preschoolers' behavior. In addition, clinicians, who were blind to parent and teacher reports, completed ratings of preschoolers' behavior during a psychological testing session. By the time the children reached age six, more than half (53.8 percent) had been diagnosed with ADHD. The likelihood of such a diagnosis increased when all three informants had rated the child as high on symptoms at age three or four. Furthermore, after analyzing the reports separately, the research team found that parents' reports were critical, particularly when combined with either teacher or clinician reports. Teacher reports alone were not as useful, and the research team ascribed the relative inability of educators' reports to predict a child's ADHD status over time to possible situational variables. Preschoolers may initially have difficulty adjusting to the structured classroom setting, but this disruptive behavior is time-limited to the transition to school. Teachers' perceptions of "difficult" behavior may also be affected by factors such as classroom setting and size as well as their expectations of children's behavior. As a result of the study findings, O'Neill and her team emphasize the importance of using information from multiple informants who have seen the child in different settings. Parent reports of preschoolers' behavior appear to be crucial, but these alone are not sufficient. Augmenting the parent report with that of the teacher and/or clinician is necessary. Also important are clinician observations of preschoolers during psychological testing, which are predictive of an ADHD diagnosis and its severity over time. Being able to identify children at risk for poorer outcomes may help educators and clinicians to plan appropriate interventions. "Consider a preschool child's behavior in different contexts," O'Neill emphasized. "Although parents' reports of preschoolers' inattention, hyperactivity, or impulsivity are very important, ideally we would not rely solely on them. At least for young children, the clinician's behavioral observations appear to hold prognostic utility." ### Reference: O'Neill, S. et al. (2013). Reliable Ratings or Reading Tea Leaves: Can Parent, Teacher, and Clinician Behavioral Ratings of Preschoolers Predict ADHD at Age Six? Journal of Abnormal Child Psychology. DOI 10.1007/s10802-013-9802-4

Interactive computer program helps patients talk with their physician about depression

(SACRAMENTO, Calif.) – Patients who used an interactive computer program about depression while waiting to see their primary-care doctor were nearly twice as likely to ask about the condition and significantly more likely to receive a recommendation for antidepressant drugs or a mental-health referral from their physician, according to a new study by researchers at UC Davis. The study, published online today in the Journal of the American Medical Association, was conducted to evaluate the effectiveness of a waiting-room intervention that encourages primary- care patients to discuss depression symptoms and care with their physician. While patients who received treatment or a referral for depression did not report improved mental health 12 weeks later, the study did show that providing information to patients about depression is an effective way to start the conversation in a primary-care setting about mental health. "We have developed an easy-to-use tool to help people with depression identify the symptoms, feel more comfortable discussing it with a primary-care provider and accept treatment if it is needed," said Anthony Jerant, professor of family and community medicine at UC Davis and senior author of the study. "This brief and relatively inexpensive intervention could be easily and widely implemented in a variety of health-care settings." Depression is an underrecognized and undertreated condition that can easily be overlooked during a typical primary-care visit. While calculating the number of people suffering from untreated depression is difficult, the Centers for Disease Control estimates that nationally 1-in-10 adults has reported symptoms of depression. The National Institute of Mental Health has said that major depressive disorders affect approximately 14.8 million American adults, or about 6.7 percent of the U.S. population age 18 and older in a given year. When left untreated, depression poses high costs to society, jeopardizing relationships and employment, decreasing quality of life, prompting alcohol and drug abuse and, in some cases, leading to the higher risk of suicide Core Elements in Responding to Mental Health Crises CE Course Three waiting-room interventions tested The new study involved nearly 900 patients and 135 primary-care clinicians at seven Northern California health-care sites. Prior to their medical appointments, patients were screened for depression. All patients were then randomized to view one of three interventions: •A video – similar to a public-service announcement – focused on recognizing depression and talking with doctors about symptoms •An interactive multimedia computer program that provided patients with instant feedback and information tailored to different levels of depressive symptoms and treatment preferences •A non-depression-related video on healthy sleep The clinicians did not know which intervention their patients viewed. Immediately after the patients' appointments, the researchers determined if the patients discussed depression with their clinicians and whether they left with prescriptions for medications to treat depression and if they received a referral for mental-health services. Help for the most depressed The results showed that patients with baseline depression who either watched the informational video or used the computer program were nearly twice as likely as control subjects to request information about depression during their appointment. Those who used the interactive computer program were significantly more likely to receive a prescription or referral for depression (26 percent) than were those who viewed either the depression video (17.5 percent) or the video on sleep (16.3 percent). The computer program had the greatest impact on patients who were most depressed, according to the baseline screening. The investigators also studied the effects of the interventions on people who were not likely to be depressed according to the baseline screening. Among these patients, rates of prescribing and referral were low (about 5 percent) and did not differ by intervention group. According to Richard Kravitz, UC Davis professor of internal medicine and lead author of the study, it is important for public-health interventions to avoid inadvertently expanding unnecessary treatments that can do more harm than good and waste health-care resources. "We were concerned that the interventions could lead to treatment for depression for those who do not actually have it," said Kravitz. "Our interactive computer program, however, increased help for those who needed it the most without increasing treatment for those who didn't." According to Jerant, this study is the largest to compare "targeted" versus "tailored" interventions for stimulating people with depression to seek and accept treatment. Targeted interventions, such as the informational video used in the study, use terms and images most likely to resonate with the target audience, based on specific demographic factors. Four different versions were used in this study, targeted toward gender and income levels. The video took about three minutes to watch. Tailored interventions, such as the study's interactive computer program, integrate patient-specific answers to deliver information and guidance. The program used in the study, developed by the study investigators, prompted users to answer questions about symptoms of depression, informed users as to whether or not they were likely to be depressed, and provided guidance depending on the users' specific needs and interests. Patients assigned to the computer program spent about two to 15 minutes on it, with a median of five minutes. Kravitz speculated that the informational video did not work as well because, like a television commercial advertising a medication, it may require multiple repetitions to be effective. In contrast, the interactive computer program quickly provided a high level of personalization, which may account for its higher degree of effectiveness with a single use. The UC Davis investigators intend to further refine and study the interactive computer model to identify patients who need to receive more extensive treatment for their depression Professional Counselor Continuing Education ### Other UC Davis investigators on the study were Peter Franks, Daniel Tancredi, Christina Slee, Robert Bell, Debora Paterniti, Camille Cipri, Ana-Maria Iosif, Andrew Hudnut, Simon Dvorak and Charles Turner. Additional authors were Maga Jackson-Triche of the Northern California VA Health Care System, Steven Kelly-Reif of Kaiser Permanente Medical Group in Sacramento, Mitchell Feldman and Sarah Olson of UC San Francisco, and Ronald Epstein and Paul Duberstein of University of Rochester in New York. The study, titled "Patient Engagement Programs for Recognition and Initial Treatment of Depression in Primary Care," was supported by grants from the National Institute of Mental Health (1R01MH079387, K24MH072756 and K24MH02712).

What a difference a grade makes

First-graders with attention problems lag for years afterward; second-graders, less so DURHAM, N.C. -- When it comes to children's attention problems, the difference between first and second grade is profound, says a new study from Duke University. The study, which appears online in the November issue of the Journal of Attention Disorders, says the age at which attention problems emerge makes a critical difference in a child's later academic performance. When the problems emerged in first grade, children's performance suffered for years afterward. For instance, those children scored lower than their peers on reading achievement scores after fifth grade. The poor performance occurred even if the attention problems were fleeting and improved after first grade. By contrast, children who developed attention problems starting in second grade performed as well as their peers in later years. Other studies have noted the link between early attention problems and academic achievement. But the new study is the first to identify the impact of attention problems that emerge in first grade versus those that emerge just a year later. The research was conducted by Duke psychologists David Rabiner, Madeline Carrig and Kenneth Dodge, the William McDougall Professor of Public Policy and director of Duke's Center for Child and Family Policy. It draws on data from the Fast Track Project, a longitudinal study of the development of conduct problems that has followed 891 individuals in four different locales from kindergarten into adulthood. The attention study examined academic performance among a subsample of 386 children by looking at grades as well as reading and math scores before and after first grade, and again after fifth grade. The results may reflect the critical importance of first grade as an academic building block, Rabiner said. Children who suffer from attention problems in first grade fail to acquire key academic skills, and their performance suffers in later years as a result. Not all first-graders who struggle to focus in school have ADHD, Rabiner added. But whether they have diagnosable ADHD or not, he said it's important to help them at the outset of their academic careers, when they are acquiring essential building block skills. "Even when these children overcome their attention problems, they continue to struggle in school," Rabiner said. "The earlier we can identify children who are struggling with sustaining attention in the classroom and intervene to help them, the better." Professional Counselor Continuing Education The study emphasized first and second grades, but Rabiner noted that future researchers would do well to look at kindergarten as well. Data for the study was collected beginning in the early 1990s. Since that time, kindergarten has assumed a more important academic role in many schools. ### The research was supported by National Institute of Mental Health (NIMH) Grants R18 MH48043, R18 MH50951, R18 MH50952, R18 MH50953, K05MH00797, and K05MH01027; National Institute on Drug Abuse Grants DA016903, K05DA15226, and P30DA023026; and Department of Education Grant S184U30002. The Center for Substance Abuse Prevention also provided support through a memorandum of agreement with NIMH. CITATION: "Attention Problems and Academic Achievement: Do Persistent and Earlier-Emerging Problems Have More Adverse Long-Term Effects," David L. Rabiner, Madeline M. Carrig and Kenneth A. Dodge, Journal of Attention Disorders, October 18, 2013. DOI: 10.1177/1087054713507974

Hunger Pains: Binge-eating disorder linked to lifelong impairments in 12-country study

Binge-eating disorder linked to lifelong impairments in 12-country study Binge-eating disorder, designated only months ago by the American Psychiatric Association as a diagnosis in its Diagnostic and Statistical Manual of Mental Disorders, is associated with substantial lifelong impairments comparable to those of bulimia nervosa, according to a World Health Organization study based on community epidemiological surveys conducted in 12 nations worldwide. The publication of the results online today in Epidemiology and Psychiatric Sciences is timed to coincide with the beginning of Weight Stigma Awareness Week (September 23-27). Although both binge-eating disorder and bulimia involve recurrent episodes of excessive food consumption with experienced loss of control, it had been generally assumed that bulimia carried a greater functional burden of illness owing to its more complex symptom profile. A defining symptom of bulimia, lacking in binge-eating disorder, is inappropriate compensatory behavior such as purging or laxative use to offset the weight gain associated with bingeing. However, compared to matched populations of people with no history of eating disorders, a lifetime history of binge-eating disorder or bulimia each predicted between two- and nearly four-fold increases in current days unable to work or carry out usual activities. Despite the significant challenges that people with these disorders face, both are generally undetected by medical professionals and therefore left untreated. "Binge-eating disorder has been largely ignored by health care providers, but it has a tremendous cost to the physical and psychological well-being of people with the disorder," said Ronald Kessler, McNeil Family Professor of Health Care Policy at Harvard Medical School and senior author of the paper. "When all of the cases of the disorder are taken together, the elevated levels of depression, suicide and lost days at work represent substantial costs to society." The study found that binge-eating disorder and bulimia nervosa both typically arose during adolescence and were associated with a range of later-onset mental disorders (including depression and anxiety disorders) and physical disorders (such as musculoskeletal disorders and diabetes). Early-onset binge-eating disorder was associated with subsequent low rates of employment among men, low rates of marriage among women and high rates of work disability among both men and women. The researchers concluded that the adverse effects of binge-eating disorder and bulimia on subsequent functioning were largely the result of these later-onset comorbidities. This finding, the researchers said, raises the possibility that expanded efforts at early detection and treatment of eating disorders during the vulnerable school years might help prevent the onset of subsequent mental and physical disorders and impairments associated with these disorders. In independent commentaries published in the same journal, international experts on eating disorders Janet Treasure and Cynthia Bulik wrote that the evidence in the report argues strongly for proceeding with clinical effectiveness trials to evaluate the long-term effects on adult health and well-being of early detection and treatment of binge-eating disorder and bulimia among students. The study was based on community surveys in 12 countries. Researchers interviewed a total of 22,635 adult respondents. Binge-eating disorder was roughly twice as common as bulimia across the countries studied, which included the U.S., several countries in Latin America (Brazil, Colombia, Mexico), a number in Europe (Belgium, Italy, Netherlands, Northern Ireland, Portugal, Romania, Spain) and New Zealand Professional Counselor Continuing Education ### The analysis for this paper was carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. These activities were supported by the U.S. National Institute of Mental Health (R01MH070884) and the Mental Health Burden Study (Contract number HHSN271200700030C) and by a number of government agencies in the other participating countries, as well as by foundations and industry sponsors. This study received supplemental support from Shire Pharmaceuticals. Complete funding information is presented in the published paper. ADDITIONAL CONTACT INFORMATION/ INDEPENDENT INTERNATIONAL EXPERTS Janet Treasure King's College London, Institute of Psychiatry Psychological Medicine, Section of Eating Disorders, UK Email: janet.treasure@kcl.ac.uk Cynthia M. Bulik Distinguished Professor of Eating Disorders Department of Psychiatry University of North Carolina at Chapel Hill, USA Email: cbulik@med.unc.edu Harvard Medical School has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 16 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care, Hebrew Senior Life, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital and VA Boston Healthcare System.

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New Data Reveal Extent of Genetic Overlap Between Major Mental Disorders

Schizophrenia, Bipolar Disorder Share the Most Common Genetic Variation Press Release • August 12, 2013 The largest genome-wide study of its kind has determined how much five major mental illnesses are traceable to the same common inherited genetic variations. Researchers funded in part by the National Institutes of Health found that the overlap was highest between schizophrenia and bipolar disorder; moderate for bipolar disorder and depression and for ADHD and depression; and low between schizophrenia and autism. Overall, common genetic variation accounted for 17-28 percent of risk for the illnesses. “Since our study only looked at common gene variants, the total genetic overlap between the disorders is likely higher,” explained Naomi Wray, Ph.D., University of Queensland, Brisbane, Australia, who co-led the multi-site study by the Cross Disorders Group of the Psychiatric Genomics Consortium (PGC), which is supported by the NIH’s National Institute of Mental Health (NIMH). “Shared variants with smaller effects, rare variants, mutations, duplications, deletions, and gene-environment interactions also contribute to these illnesses.” Dr. Wray, Kenneth Kendler, M.D., of Virginia Commonwealth University, Richmond, Jordan Smoller, M.D., of Massachusetts General Hospital, Boston, and other members of the PGC group report on their findings August 11, 2013, in the journal Nature Genetics. “Such evidence quantifying shared genetic risk factors among traditional psychiatric diagnoses will help us move toward classification that will be more faithful to nature,” said Bruce Cuthbert, Ph.D., director of the NIMH Division of Adult Translational Research and Treatment Development and coordinator of the Institute’s Research Domain Criteria (RDoC) project, which is developing a mental disorders classification system for research based more on underlying causes. Earlier this year, PGC researchers – more than 300 scientists at 80 research centers in 20 countries – reported the first evidence of overlap between all five disorders. People with the disorders were more likely to have suspect variation at the same four chromosomal sites. But the extent of the overlap remained unclear. In the new study, they used the same genome-wide information and the largest data sets currently available to estimate the risk for the illnesses attributable to any of hundreds of thousands of sites of common variability in the genetic code across chromosomes. They looked for similarities in such genetic variation among several thousand people with each illness and compared them to controls – calculating the extent to which pairs of disorders are linked to the same genetic variants. The overlap in heritability attributable to common genetic variation was about 15 percent between schizophrenia and bipolar disorder, about 10 percent between bipolar disorder and depression, about 9 percent between schizophrenia and depression, and about 3 percent between schizophrenia and autism. The newfound molecular genetic evidence linking schizophrenia and depression, if replicated, could have important implications for diagnostics and research, say the researchers. They expected to see more overlap between ADHD and autism, but the modest schizophrenia-autism connection is consistent with other emerging evidence. The study results also attach numbers to molecular evidence documenting the importance of heritability traceable to common genetic variation in causing these five major mental illnesses. Yet this still leaves much of the likely inherited genetic contribution to the disorders unexplained – not to mention non-inherited genetic factors. For example, common genetic variation accounted for 23 percent of schizophrenia, but evidence from twin and family studies estimate its total heritability at 81 percent. Similarly, the gaps are 25 percent vs. 75 percent for bipolar disorder, 28 percent vs. 75 percent for ADHD, 14 percent vs. 80 percent for autism, and 21 percent vs. 37 percent for depression. Among other types of genetic inheritance known to affect risk and not detected in this study are contributions from rare variants not associated with common sites of genetic variation. However, the researchers say that their results show clearly that more illness-linked common variants with small effects will be discovered with the greater statistical power that comes with larger sample sizes. “It is encouraging that the estimates of genetic contributions to mental disorders trace those from more traditional family and twin studies. The study points to a future of active gene discovery for mental disorders” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funds the project.

Common inherited genetic variation (single nucleotide polymorphisms, or SNPs) accounted for up to about 28 percent of the risk for some disorders, such as ADHD (dark green). Among pairs of disorders (light green), schizophrenia and bipolar disorder (SCZ-BPD) shared about 16 percent of the same common genetic variation (coheritabilities). Source: Cross-Disorder Group of the Psychiatric Genomics Consortium Professional Counselor Continuing Education Reference Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics, August 11, 2013 Grants R01MH065562, R01MH43518, R01MH065554, R01MH65707, R01MH065571, R01MH65588, R01MH65578, R01MH65558 ### 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. Press Contact(s) Jules Asher NIMH Press Office 301-443-4536 NIMHPress@nih.gov More Science News about: Attention Deficit Hyperactivity Disorder (ADHD) Autism Bipolar Disorder Depression Schizophrenia Contact the Press Office Phone: 301-443-4536 Email: NIMHpress@mail.nih.gov Press Resources Mental Health Information Statistics on Mental Disorders Summaries of Scientific Meetings Information about NIMH RePORTER: Research Portfolio Online Reporting Tool Expenditures and Results PubMed Central: An Archive of Life Sciences Journals Recommendations for Reporting on Suicide News from the Field News from the Field NIMH-Funded Science on EurekAlert Teen Eating Disorders Increase Suicide Risk The Love Hormone is 2-Faced Fear Factor: Missing Brain Enzyme Leads to Abnormal Levels of Fear in Mice, Reveals New Research More news from the field... Bookmark & Share Newsletters RSS Feeds Facebook

Out of sync with the world: Body clocks of depressed people are altered at cell level

Finding of disrupted brain gene orchestration gives first direct evidence of circadian rhythm changes in depressed brains, opens door to better treatment ANN ARBOR, Mich. — Every cell in our bodies runs on a 24-hour clock, tuned to the night-day, light-dark cycles that have ruled us since the dawn of humanity. The brain acts as timekeeper, keeping the cellular clock in sync with the outside world so that it can govern our appetites, sleep, moods and much more. But new research shows that the clock may be broken in the brains of people with depression -- even at the level of the gene activity inside their brain cells. It's the first direct evidence of altered circadian rhythms in the brain of people with depression, and shows that they operate out of sync with the usual ingrained daily cycle. The findings, in the Proceedings of the National Academy of Sciences, come from scientists from the University of Michigan Medical School and other institutions. The discovery was made by sifting through massive amounts of data gleaned from donated brains of depressed and non-depressed people. With further research, the findings could lead to more precise diagnosis and treatment for a condition that affects more than 350 million people worldwide. What's more, the research also reveals a previously unknown daily rhythm to the activity of many genes across many areas of the brain – expanding the sense of how crucial our master clock is professional counselor continuing education In a normal brain, the pattern of gene activity at a given time of the day is so distinctive that the authors could use it to accurately estimate the hour of death of the brain donor, suggesting that studying this "stopped clock" could conceivably be useful in forensics. By contrast, in severely depressed patients, the circadian clock was so disrupted that a patient's "day" pattern of gene activity could look like a "night" pattern -- and vice versa. The work was funded in large part by the Pritzker Neuropsychiatric Disorders Research Fund, and involved researchers from the University of Michigan, University of California's Irvine and Davis campuses, Weill Cornell Medical College, the Hudson Alpha Institute for Biotechnology, and Stanford University. The team uses material from donated brains obtained shortly after death, along with extensive clinical information about the individual. Numerous regions of each brain are dissected by hand or even with lasers that can capture more specialized cell types, then analyzed to measure gene activity. The resulting flood of information is picked apart with advanced data-mining tools. Lead author Jun Li, Ph.D., an assistant professor in the U-M Department of Human Genetics, describes how this approach allowed the team to accurately back-predict the hour of the day when each non-depressed individual died – literally plotting them out on a 24-hour clock by noting which genes were active at the time they died. They looked at 12,000 gene transcripts isolated from six regions of 55 brains from people who did not have depression. This provided a detailed understanding of how gene activity varied throughout the day in the brain regions studied. But when the team tried to do the same in the brains of 34 depressed individuals, the gene activity was off by hours. The cells looked as if it were an entirely different time of day. "There really was a moment of discovery," says Li, who led the analysis of the massive amount of data generated by the rest of the team and is a research assistant professor in U-M's Department of Computational Medicine at Bioinformatics. "It was when we realized that many of the genes that show 24-hour cycles in the normal individuals were well-known circadian rhythm genes – and when we saw that the people with depression were not synchronized to the usual solar day in terms of this gene activity. It's as if they were living in a different time zone than the one they died in." Huda Akil, Ph.D., the co-director of the U-M Molecular & Behavioral Neuroscience Institute and co-director of the U-M site of the Pritzker Neuropsychiatric Disorders Research Consortium, notes that the findings go beyond previous research on circadian rhythms, using animals or human skin cells, which were more easily accessible than human brain tissues. "Hundreds of new genes that are very sensitive to circadian rhythms emerged from this research -- not just the primary clock genes that have been studied in animals or cell cultures, but other genes whose activity rises and falls throughout the day," she says. "We were truly able to watch the daily rhythm play out in a symphony of biological activity, by studying where the clock had stopped at the time of death. And then, in depressed people, we could see how this was disrupted." Now, she adds, scientists must use this information to help find new ways to predict depression, fine-tune treatment for each depressed patient, and even find new medications or other types of treatment to develop and test. One possibility, she notes, could be to identify biomarkers for depression – telltale molecules that can be detected in blood, skin or hair. And, the challenge of determining why the circadian clock is altered in depression still remains. "We can only glimpse the possibility that the disruption seen in depression may have more than one cause. We need to learn more about whether something in the nature of the clock itself is affected, because if you could fix the clock you might be able to help people get better," Akil notes. The team continues to mine their data for new findings, and to probe additional brains as they are donated and dissected. The high quality of the brains, and the data gathered about how their donors lived and died, is essential to the project, Akil says. Even the pH level of the tissue, which can be affected by the dying process and the time between death and freezing tissue for research, can affect the results. The team also will have access to blood and hair samples from new donors. ### The researchers note that the Pritzker funding in combination with federal research funding made it possible for the scientists to study this issue in an exploratory way. The research was historically funded by a Conte Center grant from the National Institute of Mental Health, and partly funded by the William Lion Penzner Foundation, the Della Martin Foundation, the Office of Naval Research (N00014-09-1-059 and N00014-12-1-0366), the National Alliance for Research on Schizophrenia and Depression's Abramson Family Foundation Investigator Award, and an International Mental Health Research Organization – Johnson & Johnson Rising Star Translational Research Award. In addition to Li and Akil, the study's authors are Blynn G. Bunney, Fan Meng, Megan H. Hagenauer, David M. Walsh, Marquis P. Vawter, Simon J. Evans, Prabakhara V. Choudary, Preston Cartagena, Jack D. Barchas, Alan F. Schatzberg, the late Edward G. Jones, Richard M. Myers, U-M MBNI co-director Stanley J. Watson, Jr., and William E. Bunney. Reference: PNAS Early Edition, http://www.pnas.org/cgi/doi/10.1073/pnas.1305814110

Brain scans might predict future criminal behavior

Low anterior cingulate activity linked to repeat offenses ALBUQUERQUE, NM and DURHAM, NC--A new study conducted by The Mind Research Network in Albuquerque, N.M., shows that neuroimaging data can predict the likelihood of whether a criminal will reoffend following release from prison. The paper, which is to be published in the Proceedings of the National Academy of Sciences, studied impulsive and antisocial behavior and centered on the anterior cingulate cortex (ACC), a portion of the brain that deals with regulating behavior and impulsivity. You can view the paper by clicking here: http://www.pnas.org/cgi/doi/10.1073/pnas.1219302110. The study demonstrated that inmates with relatively low anterior cingulate activity were twice as likely to reoffend than inmates with high-brain activity in this region. "These findings have incredibly significant ramifications for the future of how our society deals with criminal justice and offenders," said Dr. Kent A. Kiehl, who was senior author on the study and is director of mobile imaging at MRN and an associate professor of psychology at the University of New Mexico. "Not only does this study give us a tool to predict which criminals may reoffend and which ones will not reoffend, it also provides a path forward for steering offenders into more effective targeted therapies to reduce the risk of future criminal activity." The study looked at 96 adult male criminal offenders aged 20-52 who volunteered to participate in research studies. This study population was followed over a period of up to four years after inmates were released from prison. "These results point the way toward a promising method of neuroprediction with great practical potential in the legal system," said Dr. Walter Sinnott-Armstrong, Stillman Professor of Practical Ethics in the Philosophy Department and the Kenan Institute for Ethics at Duke University, who collaborated on the study. "Much more work needs to be done, but this line of research could help to make our criminal justice system more effective." The study used the Mind Research Network's Mobile Magnetic Resonance Imaging (MRI) System to collect neuroimaging data as the inmate volunteers completed a series of mental tests. "People who reoffended were much more likely to have lower activity in the anterior cingulate cortices than those who had higher functioning ACCs," Kiehl said. "This means we can see on an MRI a part of the brain that might not be working correctly -- giving us a look into who is more likely to demonstrate impulsive and anti-social behavior that leads to re-arrest." The anterior cingulate cortex of the brain is "associated with error processing, conflict monitoring, response selection, and avoidance learning," according to the paper. People who have this area of the brain damaged have been "shown to produce changes in disinhibition, apathy, and aggressiveness. Indeed, ACC-damaged patients have been classed in the 'acquired psychopathic personality' genre." Kiehl says he is working on developing treatments that increase activity within the ACC to attempt to treat the high-risk offenders. ### The four-year study was supported by grants from the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and pilot funds by the John D. and Catherine T. MacArthur Foundation Law and Neuroscience Project. The study was conducted in collaboration with the New Mexico Corrections Department. ABOUT THE MIND RESEARCH NETWORK The Mind Research Network (MRN), headquartered in Albuquerque, N.M., is committed to advancing the diagnosis and treatment of mental illness and other brain disorders. MRN is a 501(c)3 non-profit organization consisting of an interdisciplinary association of scientists located at universities, national laboratories and research centers around the world and is focused on imaging technology and its emergence as an integral element of neuroscience investigation. The Mind Research Network is a part of the Lovelace Respiratory Research Institute family of companies Professional Counselor Continuing Education Learn more at http://www.mrn.org

NIH Study Shows People with Serious Mental Illnesses Can Lose Weight

People with serious mental illnesses such as schizophrenia, bipolar disorder and major depression can lose weight and keep it off through a modified lifestyle intervention program, a National Institute of Mental Health (NIMH)-funded study reported online today in The New England Journal of Medicine. Over 80 percent of people with serious mental illnesses are overweight or obese, which contributes to them dying at three times the rate of the overall population. They succumb mostly to the same things the rest of the population experiences—cardiovascular disease, diabetes and cancer. Although antipsychotic medications increase appetite and cause weight gain in these patients, it is not the only culprit. Like the general population, sedentary lifestyle and poor diet also play a part. Lifestyle modifications such as diet and exercise should work for these patients, yet they are often left out of weight loss studies. “People with serious mental illnesses are commonly excluded from studies to help them help themselves about their weight,” said Gail L. Daumit, M.D., of Johns Hopkins University, Baltimore, and the study’s lead author. “We’re showing that serious mentally ill patients can make successful, sustained changes with proper interventions.” This study could usher in new forms of weight loss treatment for people with serious mental illness. “Until now, obesity among those with serious mental illnesses has not received adequate attention,” said NIMH Director Thomas R. Insel, M.D. “People with serious mental illnesses need more attention to their physical health. This study provides convincing evidence these individuals can make substantial lifestyle changes and therefore should suffer fewer medical complications as they age.” Other factors that preclude people with serious mental illnesses from losing weight include memory impairments or residual psychiatric symptoms that impede learning and adopting new behaviors such as counting calories. Socioeconomics are also a factor as many can’t afford or can’t get to physical activity programs like fitness gyms. Some patients additionally suffer from social phobia or have poor social interactions, and are simply afraid to work out in a public area. Daumit’s group attempted to solve these issues by bringing the gyms and nutritionists to places most of these patients frequent—psychiatric rehabilitation outpatient programs. Under the trial name ACHIEVE, the researchers randomized 291 participants in 10 rehab centers around Maryland to receive the usual care, consisting of nutrition and physical activity information, or six months of intensive intervention consisting of exercise classes three times a week along with individual or group weight loss classes once a week. Both groups were followed for an additional year, during which the weight loss classes of the intervention arm tapered down but the exercise classes remained constant. The intervention arm included goals such as reducing caloric intake by avoiding sugar-sweetened beverages and junk food; eating five servings of fruits and vegetables daily; choosing smaller portions and healthy snacks; and moderate intensity aerobic exercise. Participants in the specially tailored weight loss program lost seven pounds more than the controls—and continued to lose weight and did not regain, despite the reduced frequency of classes and counseling sessions. In contrast, the general population tends to experience peak weight loss in the first six months and then rebound and gain part or all of their weight back. On average, each participant was on three psychotropic medications, with half on lithium or mood stabilizers, all known to cause weight gain. But no matter what they were on, they lost the weight. “We’re showing behavioral interventions work regardless of what they’re taking,” Daumit said. Her group is now looking for ways to spread the program. VIDEO Project Achieve is the first weight loss clinical trial to include people with serious mental illnesses. Reference Effects of a behavioral weight loss intervention in persons with serious mental illness. Daumit GL, Dickerson FB, Wang N-Y, Dalcin A, Jerome GJ, Anderson CAM, Young DR, Frick KD, Yu A, Gennusa III JV, Oefinger M, Crum RM, Charleston J, Casagrande SS, Guallar E, Goldberg RW, Campbell LM, Appel LJ. NEJM, March 21, 2013 Professional Counselor Continuing Education Grant number: MH080964 ### 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.

Mapping Brain Circuits Provides Clues to Schizophrenia, Earlier Detection of Psychosis

Two regions in the brain have been linked to schizophrenia and psychosis, which may lead to earlier detection of this disorder and symptom, reported an imaging study funded by the National Institute of Mental Health (NIMH) that was published online last month in Biological Psychiatry. Background Patients with schizophrenia experience decreased activity in the prefrontal cortex ( blue, top figure) and excess activity in the basal ganglia (red, bottom figure). The greater the disconnect between these two regions, the higher the level of psychosis seen in these patients. Psychosis is a loss of contact with reality that usually includes false beliefs about what is taking place or who one is (delusions) and seeing or hearing things that aren’t there (hallucinations). Numerous medical problems can cause psychosis such as substance abuse, brain tumors, and certain mental disorders such as schizophrenia and bipolar disorder. Treatment approaches include hospitalization, antipsychotic drugs, and various psychosocial treatments. Too often, psychosis is not diagnosed or treated early enough. The longer this duration of untreated psychosis, the poorer the patient’s long-term functioning and response to treatment. In the United States, the average time between the first onset of psychotic symptoms and the initiation of treatment is about 110 weeks, or over 2 years. Disordered thinking and psychosis often go hand-in-hand in patients with the chronic brain disorder schizophrenia. A popular and long-standing theory in the field implicates the prefrontal cortex, the brain area just behind the forehead that normally supports higher-order capabilities such as prioritizing, categorizing, and strategizing. Damage to this area causes not only disordered thinking but also leads to psychosis from the excess release of the neurotransmitter dopamine into regions deep inside the brain. While this theory offers a compelling explanation for the co-occurrence of these two symptoms in schizophrenia, there have been only a small handful of studies that have directly supported this theory. Identification of the exact circuit(s) involved has so far remained elusive Professional Counselor Continuing Education “Schizophrenia is a very complex condition, involving a constellation of diverse symptoms. This diversity presents both a challenge and a constraint for figuring out the neurobiological root causes of schizophrenia. There is likely not just one lesion but a number of lesions that are present across different brain regions that are the proximal causes for these symptoms.” explained Jong H. Yoon, M.D., at the University of California, Davis, and lead author of the study. Yoon’s study focused on the prefrontal cortex and the basal ganglia. The basal ganglia is a subcortical collection of neuron clusters, including the ventral tegmental area and substantia nigra, which produce the majority of the brain’s dopamine, and the striatum, an important site of action of dopamine. Using functional magnetic resonance imaging (fMRI), the researchers examined the brain activity within the prefrontal cortex and basal ganglia of 18 individuals with schizophrenia and 19 healthy controls. The subjects completed a memory task in which they had to remember images of faces across a brief delay period to determine if subsequently presented faces were the same faces; it was hypothesized that patients with schizophrenia would have more difficulty performing this task. Results of the Study Patients with schizophrenia experienced excess activity in the substantia nigra, decreased activity in the prefrontal cortex, and diminished functional connectivity between these regions, suggesting that communication among these regions was out of sync. Additionally, the higher the level of connectivity between the substantia nigra and the striatum, the higher the level of psychosis seen in the patients with schizophrenia. Significance These findings suggest that the prefrontal cortex-basal ganglia circuit may be a common pathway linking cognitive deficits and psychosis in schizophrenia. It also points to a more widespread use of fMRI in diagnosis and treatment. Compared to other neuroimaging techniques such as positron emission tomography (PET), fMRI yields more detailed images, does not use radiation, and is relatively widely available since most university-based brain imaging centers have this technology. These findings could also lead to the creation of a better animal model of psychosis, of which there currently are few. Biomedical research has shown that early detection and intervention could preempt later stages of diseases. This concept of “treatment as prevention” is seen in the NIMH-supported North American Prodrome Longitudinal Study (NAPLS), which is using biological assessments, such as neuroimaging, to predict who will convert to psychosis and to develop new treatment and prevention approaches. Another NIMH study, Recovery After an Initial Schizophrenia Episode (RAISE), supports the development and testing of two complementary models for early intervention in schizophrenia. Research is also underway to identify genes and environmental elements associated with schizophrenia. What’s Next Because the study involved patients with established illness who are already on antipsychotic medications, it needs replication in patients with schizophrenia who are not medicated and/or in the early phases of illness. The study should also be performed in individuals at high risk of developing psychosis to see if these findings could help identify individuals in the earliest stages of illness when interventions to prevent or significantly ameliorate schizophrenia can be instituted. To obtain greater precision in localizing brain regions, the study also warrants replication with high-resolution fMRI. Furthermore, the techniques in this study could also be applied to other disorders that can have psychosis as one of its symptoms, such as mood disorders, and post-traumatic stress disorder. Reference Yoon JH, Minzenberg MJ, Raouf S, D’Esposito M, Carter CS. Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia. Biological Psychiatry, published online January 14, 2013.

Psychotropic Medications Are Prescribed Appropriately Among U.S. Teens, National Study Finds

Prescribed psychotropic medications are not being misused or overused among U.S. youth, according to a study using nationally representative data sponsored by NIMH. The study was published December 3, 2012, online ahead of print in the Archives of Pediatric and Adolescent Medicine. Background Psychotropic medications affect the brain chemicals associated with mood and behavior. Some studies and media reports have raised concerns about their use among youth. However, much of the concern stems from information found in anecdotal reports, small clinical samples, or insurance databases rather than on representative samples of U.S. youth with clinical assessments of emotional and behavioral disorders. Studies from regional community samples have found widely varying rates, which can lead to skewed perceptions. For example, different studies have found a wide range of stimulant medication use for attention deficit hyperactivity disorder (ADHD)—from 7 percent to 72 percent—likely due to methodological and regional differences. As a result, it has been difficult to get a clear, accurate understanding of medication use among youth. Kathleen Merikangas, Ph.D., of NIMH and colleagues collected information on specific medication use in the National Comorbidity Study-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey from 2004 of more than 10,000 teens ages 13 to 18.The teens were asked questions that helped to ascertain information about mental disorders and service use. A previous report published in October 2010 using data from the NCS-A indicated that about 20 percent of U.S. youth are affected by some type of mental disorder during their lifetime serious enough to affect their functioning. In this most recent analysis, the researchers examined patterns of prescribed medication use among youth who met criteria for a wide range of mental disorders. Psychotropic medications that were examined include antipsychotics, antidepressants, and stimulants Professional Counselor Continuing Education Results of the Study Among those youth who met criteria for any mental disorder, 14.2 percent reported that they had been treated with a psychotropic medication. Teens with ADHD had the highest rates of prescribed medication use at 31 percent, while 19.7 percent of those with a mood disorder like depression or bipolar disorder were taking psychotropic medication. Among those with eating disorders, about 19 percent were taking a psychotropic medication, and 11.6 percent of those with anxiety disorders reported taking medication. Very few youth reported use of antipsychotic medications. They were most frequently used by youth with severe bipolar disorder (1.7 percent) or a neurodevelopmental disorder such as autism (2.0 percent). Approximately 2.5 percent of teens without a diagnosed mental disorder were prescribed a psychotropic medication. Among these youth, 78 percent reported having a previous mental or neurodevelopmental disorder and associated psychological distress or impairment. Significance The data suggest that most adolescent youth who are taking psychotropic medications have serious behavioral, cognitive or emotional disturbances. The findings also showed that youth being treated by a mental health professional were more likely to be receiving appropriate medication as opposed to those being treated within general medicine or other settings. However, more research is needed on medication use among children younger than age 13. Reference Merikangas K, He J, Rapoport J, Vitiello B, Olfson M. Medication use in US Youth with Mental Disorders. Archives of Pediatric and Adolescent Medicine. Online ahead of print Dec 3, 2012.

WSU researchers find the missing link between mental health disorders and chronic diseases in Iraq war refugees

October 15, 2012Subjects who fled Iraq after Gulf War were 43 times more likely to suffer from obstructive sleep apneaDETROIT – Wayne State University School of Medicine researchers may have discovered why people exposed to war are at increased risk to develop chronic problems like heart disease years later. And the culprit that links the two is surprising.Beginning in the mid-2000s, WSU researchers interviewed a random sample of 145 American immigrants who left Iraq before the 1991 Gulf War, and 205 who fled Iraq after the Gulf War began. All were residing in metropolitan Detroit at the time of the study. Study subjects were asked about socio-demographics, pre-migration trauma, how they rated their current health, physician-diagnosed and physician-treated obstructive sleep apnea, somatic disorders and psychosomatic disorders. Those who left Iraq after the war began and suffered from mental disorders such as post-traumatic stress disorder (PTSD) and depression, and self-rated their physical health as worse than their actual health, were 43 times more likely than pre-Gulf War immigrants to report obstructive sleep apnea (30.2 percent versus 0.7 percent) and later develop major chronic health issues such as cardiovascular disease.“I was surprised, but we had a specific theory we wanted to test. Changes in the stress system would contribute to sleep apnea. What happens? Maybe it’s the stress that leads to this fractured sleep,” said Bengt Arnetz, M.D., Ph.D., M.P.H., School of Medicine professor of occupational and environmental health, deputy director of the Institute of Environmental Health Sciences at Wayne State, and the study’s principal investigator and first author. “No one had explored this possible link before, although basic research suggests it as plausible.”The results are featured in the October 2012 issue of Psychosomatic Medicine, the peer-reviewed journal of the American Psychosomatic Society.According to the article, “Obstructive Sleep Apnea, Post-traumatic Stress Disorder, and Health in Immigrants,” obstructive sleep apnea occurs when the muscles supporting the soft palate at the back of the throat relax, but less is known about the reasons behind this neuromuscular malfunctioning.“It’s a known fact that the more exposure to violence you have, the more likely you are to report PTSD and depression, and the worse your self-rated health is, the more likely your actual health will suffer in five to 10 years,” Arnetz said.Hikmet Jamil, M.D., Ph.D., professor of occupational and environmental health in WSU’s School of Medicine, and Thomas Templin, Ph.D., research professor in WSU’s College of Nursing, also contributed to the article.The obstructive sleep apnea and chronic disase link has been observed among many trauma-exposed populations, including refugees, Arnetz said.“Iraqis were exposed to harsh conditions during the entirety of Saddam Hussein’s more than 20 years of reign. However, trauma and environmental exposures increased measurably and dramatically after the initiation of the 1991 Gulf War,” the article states.The study can now be used as a model for other populations, including U.S. soldiers returning home from battle.The multidisciplinary study brought together mental health research, sleep research and chronic disease research, Arnetz said.He and Jamil were partially supported by the National Institute of Mental Health of the National Institutes of Health (award number R01MH085793).To further test their ideas, the researchers plan to apply for funding from the National Institutes of Health to collaborate with Safwan Badr, M.D., professor and chief of the School of Medicine’s Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, and Thomas Roth, Ph.D., director of the Henry Ford Sleep Disorders and Research Center.###Wayne State University is one of the nation’s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit http://www.research.wayne.edu.Founded in 1868, the Wayne State University School of Medicine is the largest single-campus medical school in the nation, with more than 1,000 medical students. In addition to undergraduate medical education, the school offers master’s degree, Ph.D. and M.D.-Ph.D. programs in 14 areas of basic science to about 400 students annually Professional Counselor Continuing Education

NIH researchers use brain imaging to understand genetic link between Parkinson's and a rare disease

Role of Gaucher disease-gene alterations is clarified by six-year study By Steven Benowitz Special to NHGRI A Composite PET scan showing how the areas with decreased dopamine synthesis (yellow) in patients with Gaucher disease and Parkinson's disease (left) and in typical Parkinson's disease (right) are very similar. A rare metabolic disorder is helping researchers at the National Human Genome Research Institute (NHGRI) and the National Institute of Mental Health (NIMH) uncover new clues about the biology underlying Parkinson's disease. The results of their six-year study, published online in the July 30, 2012, issue of the journal Brain, may explain how people with alterations in the gene involved in Gaucher disease are more likely to develop Parkinson's — and provide a window to potential inner workings of Parkinson's itself professional counselor continuing education "It's important to understand why having a mutation in this gene predisposes someone to Parkinson's," said Ellen Sidransky, M.D., co-senior author and senior investigator in NHGRI's Medical Genetics Branch. "Clinically, we've seen that people with Gaucher mutations are at increased risk of developing Parkinson's and have noted that these patients can have earlier and more progressive symptoms, but these new findings provide biological evidence to support those differences." Gaucher disease is an inherited disease caused by mutations in the GBA gene, which codes for the enzyme glucocerebrosidase, which breaks down fatty molecules in the cell for disposal. When this housekeeping enzyme doesn't work properly, the fatty molecules pile up and ultimately can damage the spleen, liver, bones and other organs. The most severe form results in severebrain damage and early death. People affected by Gaucher disease inherit two defective gene copies; those who carry only one gene mutation do not have the disease. Parkinson's disease is a neurodegenerative disorder that affects about 1.5 million Americans, causing tremors and motor impairment. It results from a combination of age, environmental factors and genetic susceptibility. Both patients with Gaucher disease and those who carry one mutation in this gene are at increased risk for developing Parkinson's. In 2009, Dr. Sidransky and her team coordinated a large, international study of the association between the two disorders. The results, published in The New England Journal of Medicine, showed that those with Gaucher-related gene mutations had a five-times greater risk of developing Parkinson's. "We didn't expect this metabolic disorder to be linked to an unrelated neurodegenerative disorder, and we've been working to understand the mechanisms involved and their implications," Dr. Sidransky said. Previous research showed that people with GBA mutations and Parkinson's tend to develop the disease earlier and have more cognitive difficulties than generally seen in Parkinson's. In the current study, the researchers set out to determine if the brain biology of GBA-associated Parkinson's is different from that observed in others with Parkinson's disease. Investigators looked at 107 study participants divided into four groups: people with both diseases; those with Parkinson's and no Gaucher mutations; people with Gaucher disease and a family history of Parkinson's; and healthy GBA-mutation carriers with a family history of Parkinson's. Each test group was matched with a comparison group of healthy people who were examined the same way. The researchers used two types of an imaging technique called positron emission tomography (PET) to study the brains of participants. One type measured the amount and distribution of dopamine, an important message-carrying brain chemical lacking in people with Parkinson's. The second technique gauged blood flow in the brain, which reflects brain function. The researchers found that people with Parkinson's disease — both those with and those without Gaucher disease — had a similar reduction in dopamine levels, indicating damage to certain nerve cells in the brain in both groups. "We're fairly early along in understanding how mutations in the GBA gene predispose people to Parkinson's," said Karen Berman, M.D., co-senior author and chief of NIMH's Clinical Brain Disorders Branch. "We now need to investigate the mechanisms by which mutations in this gene may affect dopamine function and the health of dopamine neurons in the brain." They also found striking differences in blood flow, which was significantly reduced in the people with GBA mutations. They saw this blood flow reduction in specific brain regions where people with different forms of dementia, including Alzheimer's disease, are affected. "This different blood flow distribution has been seen in other disorders that involve cognitive impairment," Dr. Sidransky said. "This provides biologic confirmation of our clinical impression of problems with cognition in some patients with GBA-associated Parkinson's disease. This observation may help us to better understand the causes of dementia that can develop in Parkinson's disease and related disorders and could ultimately lead to strategies to target these problems." The investigators also examined dopamine distribution and brain blood flow/brain activity in the two groups thought be at high-risk for developing Parkinson's — people with a family history of Parkinson's who either have Gaucher disease or are healthy yet carry a GBA mutation. They looked at the PET scans to identify any significant, early brain changes compared to people in the study control groups. Among seven mutation carriers and 14 patients with Gaucher without Parkinson's, only two had reduced dopamine levels. Dr. Sidransky said that while long-term follow-up is needed to see if any of these people develop Parkinson's, the observation that most of the patients with GBA mutations didn't have early signs of Parkinson's may be reassuring to those considered at risk. "Not everyone with GBA alterations will develop Parkinson's," Dr. Sidransky said. "Identifying an early marker associated with disease may show us who might go on to develop Parkinson's, and help identify a population that could benefit from pre-symptomatic management. In addition, discovering why other at-risk individuals do not develop Parkinson's disease may also help us to understand factors that protect people from developing this disease." The researchers plan to continue to follow people in their study with GBA mutations and a family history of Parkinson's to monitor their dopamine levels and cerebral blood flow to see whether they develop Gaucher disease. The researchers also will assess whether these clinical data might predict which patients will eventually develop Parkinson's disease.

Mothers and OCD children trapped in rituals have impaired relationships

News Release: Tuesday, April 10, 2012

A new study from Case Western Reserve University finds mothers tend to be more critical of children with obsessive-compulsive disorder than they are of other children in the family. And, that parental criticism is linked to poorer outcomes for the child after treatment.

Parent criticism has been associated with child anxiety in the past, however, researchers wanted to find out if this is a characteristic of the parent or something specific to the relationship between the anxious child and the parent.

“This suggests that mothers of anxious children are not overly critical parents in general. Instead they seem to be more critical of a child with OCD than they are of other children in the home,” said Amy Przeworski, assistant professor of psychology. She is the lead author of the study, “Maternal and Child Expressed Emotion as Predictors of Treatment Response in Pediatric Obsessive-Compulsive Disorder,” in the recent journal, Child Psychiatry & Human Development.

OCD is found in one in 200 children, according to the American Academy of Child and Adolescent Psychiatry. The psychological disorder overcomes individuals with repetitive thoughts that lead to anxiety, which is then acted out in exacting routines or behaviors that can range from foot tapping to eating rituals to school or bedtime preparations.

This research evolved from other studies that found parental criticism is associated with less success in therapy and a relapse of behavior.

“Parents’ criticism may be a reaction to the child’s anxiety. This research is not blaming the parent for the child’s OCD. But it does suggest that the relationship between parents and children with OCD is important and should be a focus of treatment. This means that parents can help children with OCD to get better.” Przeworski says.

“OCD sneaks up on the kids and parents,” Przeworski says.

The psychology professor, who specializes in anxiety disorders, says some parents become concerned when their children show some early warning signs for OCD:

• Rigidity in a child, with things routinely done or said in exactly the same way or order.
• Asking for reassurance many times in the day.
• Repetition of a task from tapping the foot, checking on the stove, washing hands that the child cannot stop when asked.
• Routines that have prescribed patterns or are excessive lengthy: An example is a two-hour shower or raw and chapped hands that look like the child is wearing red gloves.
• Bedtime or dinner rituals, where there is a prescribed order for eating food, placement of food on the plate, etc.
• Temper tantrums where the child goes beyond being stubborn but has anxiety associated with them.
• Children want symmetry in appearance or things around them.

Parents initially may think it is a phase, a habit or stubbornness. Over time, the behaviors become so exacting that the child and family members have to act in prescribed ways. Parents may end up criticizing the child in an effort to get them to drop obsessive-compulsive behaviors.

The researchers videotaped interviews with 62 mother-child pairs just before the child’s OCD treatment began. Children either had medication, therapy, a combination of the two, or a placebo. The children were between the ages of 7 and 17.

Because most mothers bring their children for treatment appointments, the researchers focused on the mother’s view of their children. Mothers were asked to give a five-minute description of their relationship with the child with OCD and the mother’s relationship with the sibling closest in age to the child with OCD. The researchers asked the children to describe their relationships with their mothers and fathers.

The researchers examined the presence of criticism and emotional over-involvement (over-protection or excessive self-sacrificing) in these descriptions. The tone of the OCD child and parent tended toward criticism, they said. The other sibling received more loving expressions. Parent criticism was associated with poorer child functioning after treatment.

Przeworski said treatment of OCD has good results, but many times parents misjudge these rigid routines as stubbornness or “just going through a phase” until the behavior takes over family life. Then parents realize the behavior requires therapy professional counselor continuing education

Collaborating with Przeworski were: Lori Zoellner from University of Washington; Martin E. Franklin and Edna B. Foa, University of Pennsylvania School of Medicine; and Abbe Garcia and Jennifer Freeman, Brown University. The study was supported with funds from the National Institute of Mental Health.


Posted by: Susan Griffith, April 10, 2012 01:19 PM | News Topics: Official Release

Our brains are made of the same stuff, despite DNA differences

Gene expression databases reveal “consistent molecular architecture”

Despite vast differences in the genetic code across individuals and ethnicities, the human brain shows a “consistent molecular architecture,” say researchers supported by the National Institutes of Health. The finding is from a pair of studies that have created databases revealing when and where genes turn on and off in multiple brain regions through development counselor ceus

“Our study shows how 650,000 common genetic variations that make each of us a unique person may influence the ebb and flow of 24,000 genes in the most distinctly human part of our brain as we grow and age,” explained Joel Kleinman, M.D., Ph.D., of the National Institute of Mental Health (NIMH) Clinical Brain Disorders Branch.

Kleinman and NIMH grantee Nenad Sestan, M.D., Ph.D. of Yale University, New Haven, Conn., led the sister studies in the Oct. 27, 2011 issue of the journal Nature.

“Having at our fingertips detailed information about when and where specific gene products are expressed in the brain brings new hope for understanding how this process can go awry in schizophrenia, autism and other brain disorders,” said NIMH Director Thomas R. Insel, M.D.

Both studies measured messenger RNAs or transcripts. These intermediate products carry the message from DNA, the genetic blueprint, to create proteins and differentiated brain tissue. Each gene can make several transcripts, which are expressed in patterns influenced by a subset of the approximately 1.5 million DNA variations unique to each of us. This unique set of transcripts is called our transcriptome – a molecular signature that is unique to every individual. The transcriptome is a measure of the diverse functional potential that exists in the brain.

Both studies found that rapid gene expression during fetal development abruptly switches to much slower rates after birth that gradually decline and eventually level off in middle age. These rates surge again as the brain ages in the last decades, mirroring rates seen in childhood and adolescence, according to one of the studies. The databases hold secrets to how the brain’s ever-changing messenger chemical systems, cells and development processes are related to gene expression patterns through development.

For example, if a particular version of a gene is implicated in a disorder, the new resources might reveal how that variation affects the gene’s expression over time and by brain region. By identifying even distant genes that may be turning on and off in-sync, the databases may help researchers discover whole modules of genes involved in the illness. They can also reveal how variation in one gene influences another’s expression.

Prefrontal cortex

Kleinman’s team focused on how genetic variations are linked to the expression of transcripts in the brain’s prefrontal cortex, the area that controls insight, planning and judgment, across the lifespan. They studied 269 postmortem, healthy human brains, ranging in age from two weeks after conception to 80 years old, using 49,000 genetic probes. The database on prefrontal cortex gene expression alone totals more than 1 trillion pieces of information, according to Kleinman.

Among key findings in the prefrontal cortex:
Individual genetic variations are profoundly linked to expression patterns. The most similarity across individuals is detected early in development and again as we approach the end of life.

Different types of related genes are expressed during prenatal development, infancy, and childhood, so that each of these stages shows a relatively distinct transcriptional identity. Three-fourths of genes reverse their direction of expression after birth, with most switching from on to off.

Expression of genes involved in cell division declines prenatally and in infancy, while expression of genes important for making synapses, or connections between brain cells, increases. In contrast, genes required for neuronal projections decline after birth – likely as unused connections are pruned.

By the time we reach our 50s, overall gene expression begins to increase, mirroring the sharp reversal of fetal expression changes that occur in infancy.

Genetic variation in the genome as a whole showed no effect on variation in the transcriptome as a whole, despite how genetically distant individuals might be. Hence, human cortexes have a consistent molecular architecture, despite our diversity.


In previous studies, Kleinman and colleagues have found that all genetic variations implicated to date in schizophrenia are associated with transcripts that are preferentially expressed in the fetal brain. This adds to evidence that the disorder originates in prenatal development. By contrast, he and his colleagues are examining evidence that genetic variation implicated in affective disorders may be associated with transcripts expressed later in life. They are also extending their database to include all transcripts of all the genes in the human genome, examining 1000 post-mortem brains, including many of people who had schizophrenia or other brain disorders.

Multiple brain regions

Sestan and colleagues characterized gene expression in 16 brain regions, including 11 areas of the neocortex, from both hemispheres of 57 human brains that spanned from 40 days post-conception to 82 years – analyzing the transcriptomes of 1,340 samples. Using 1.4 million probes, the researchers measured the expression of exons, which combine to form a gene’s protein product. This allowed them to pinpoint changes in these combinations that make up a protein, as well as to chart the gene’s overall expression.

Among key findings:
Over 90 percent of the genes expressed in the brain are differentially regulated across brain regions and/or over developmental time periods. There are also widespread differences across region and time periods in the combination of a gene’s exons that are expressed.

Timing and location are far more influential in regulating gene expression than gender, ethnicity or individual variation.

Among 29 modules of co-expressed genes identified, each had distinct expression patterns and represented different biological processes. Genetic variation in some of the most well-connected genes in these modules, called hub genes, has previously been linked to mental disorders, including schizophrenia and depression.

Telltale similarities in expression profiles with genes previously implicated in schizophrenia and autism are providing leads to discovery of other genes potentially involved in those disorders.

Sex differences in the risk for certain mental disorders may be traceable to transcriptional mechanisms. More than three-fourths of 159 genes expressed differentially between the sexes were male-biased, most prenatally. Some genes found to have such sex-biased expression had previously been associated with disorders that affect males more than females, such as schizophrenia, Williams syndrome, and autism.


The Sestan study was also funded by NIH’s National Institute on Child Health and Human Development, National Institute on Neurological Disorders and Stroke, and National Institute on Drug Abuse. Data for the Sestan study are posted at www.humanbraintranscriptome.org and at http://www.developinghumanbrain.org, as part of a larger ongoing study, BrainSpan, funded by NIMH under the American Recovery and Reinvestment Act to create an Atlas of Human Brain Development.

The Kleinman study data on genetic variability are accessible to qualified researchers at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v1.p1, while the gene expression data can be found at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc5GSE30272. In addition, BrainCloud, a web browser application developed by NIMH to interrogate the Kleinman study data, can be downloaded at http://www.libd.org/braincloud.


Our brains are all made of the same stuff. Despite individual and ethnic genetic diversity, our prefrontal cortex shows a consistent molecular architecture. For example, overall differences in the genetic code (“genetic distance”) between African -Americans (AA) and caucasians (cauc) showed no effect on their overall difference in expressed transcripts (“transcriptional distance”). The vertical span of color-coded areas is about the same, indicating that our brains all share the same tissue at a molecular level, despite distinct DNA differences on the horizontal axis. Each dot represents a comparison between two individuals. The AA::AA comparisons (blue) generally show more genetic diversity than cauc::cauc comparisons (yellow), because caucasians are descended from a relatively small subset of ancestors who migrated from Africa, while African Americans are descended from a more diverse gene pool among the much larger population that remained in Africa. AA::cauc comparisons (green) differed most across their genomes as a whole, but this had no effect on their transcriptomes as a whole.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Individual genetic variation likely affects the expression of genes. For example, across all ages and ethnicities studied, expression of a gene called ZSWIM7 stays low, medium or high in the prefrontal cortex, depending on which of three versions (A/A, A/G, G/G) is inherited. The versions are created by a tiny variation in the letters of the genetic code (DNA) at a location in the gene called rs1045599.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Overall gene expression plummets 5-fold in infancy and 90-fold in childhood from its prenatal peak. The decline levels-off during the middle years, but expression surges again in the last decades of life, as the brain ages. Note: The fetal/infant graph at left is based on a different scale than the lifespan graph at right, so the two are not visually comparable.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Males show more sex-biased gene expression. More genes differentially expressed (DEX) between the sexes were found in males than females, especially prenatally. Some genes found to have such sex-biased expression had previously been associated with disorders that affect males more than females, such as schizophrenia, Williams syndrome, and autism. Eleven of the brain areas shown are in the neocortex (NCX), or outer mantle.
Source: Nenad Sestan, M.D., Ph.D., Yale University Department of Neurobiology and Kavli Institute for Neuroscience


Profiling developmental processes. The expression data can be used to create trajectories for the expression of genes involved in particular processes, such as the development of synapses (structures that underlie communication between neurons). These expression trajectories can be compared for different regions, such as the NCX and cerebellar cortex (CBC).
Source: Nenad Sestan, M.D., Ph.D., Yale University Department of Neurobiology and Kavli Institute for Neuroscience

References

Colantuoni c, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, Colantuoni EA, Elkahloun AG, Herman MM, Weinberger DR, Kleinman JE. Temporal Dynamics and Genetic Control of Transcription in the human prefrontal cortex. Nature 2011. Oct 27

Kang HJ, Kawasawa1YI, Cheng F, Zhu Y, Xu X, Li M, Sousa1 AMM, Pletikos M, Meyer KA, Sedmak G, Guennel G, Shin Y, Johnson MB, Krsnik Z, Fertuzinhos MS, Umlauf S, Lisgo SN, Vortmeyer A, Weinberger DR, Mane S, Hyde TM, Huttner A, Reimers M, Kleinman JE, Šestan N. Spatiotemporal transcriptome of the human brain. Nature 2011. Oct 27.

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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.

The National Institute on Drug Abuse is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world's research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to inform policy and improve practice. Fact sheets on the health effects of drugs of abuse and information on NIDA research and other activities can be found on the NIDA home page at www.drugabuse.gov. To order publications in English or Spanish, call NIDA's new DrugPubs research dissemination center at 1-877-NIDA-NIH or 240-645-0228 (TDD) or fax or email requests to 240-645-0227 or drugpubs@nida.nih.gov. Online ordering is available at http://drugpubs.drugabuse.gov. NIDA's new media guide can be found at http://drugabuse.gov/mediaguide/.

NINDS is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease — a burden borne by every age group, by every segment of society, by people all over the world.

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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.

The activities described in this release are funded in part through the American Recovery and Reinvestment Act. More information about NIH's Recovery Act grant funding opportunities can be found at http://grants.nih.gov/recovery/. To track the progress of HHS activities funded through the Recovery Act, visit www.hhs.gov/recovery. To track all federal funds provided through the Recovery Act, visit www.recovery.gov.