Adaptable decision making in the brain

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

Survey Finds More Evidence That Mental Disorders Often Begin in Youth

About 8 percent of U.S. teens meet current criteria for having a serious emotional disturbance, according to two NIMH-funded studies published in the April 2012 issue of the Archives of General Psychiatry. Background A September 2010 study using data from the NIMH-funded National Comorbidity Survey-Adolescent Supplement (NCS-A) found that about 20 percent of youth are affected by a mental disorder sometime in their lifetime. The NCS-A is a nationally representative, face-to-face survey of more than 10,000 teens ages 13 to 18. Parents or caregivers were also asked to complete a corroborating questionnaire after teens were interviewed. The NCS-A used criteria established by the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-IV) to assess for a wide range of mental disorders including mood and anxiety disorders, behavior disorders like attention deficit hyperactivity disorder (ADHD), eating disorders, and substance use disorders. In this most recent analysis, Kathleen Merikangas, Ph.D., of NIMH, Ron Kessler, Ph.D., of Harvard University, and colleagues examined the prevalence of mental disorders, as well as the severity of the disorders, within a 12-month period to estimate the rate of serious emotional disturbances (SED) in youth. SED was defined by the Substance Abuse and Mental Health Administration (SAMHSA) as a “mental, behavioral, or emotional disorder … that resulted in functional impairment which substantially interferes with or limits the child’s role or functioning in family, school, or community activities.” Results of the Study The researchers found that about 8 percent of all respondents had SED. Those with behavior disorders were most likely to be considered to have a severe disorder. Those with three or more coexisting disorders were also more likely to be severely affected. Similar to adults, anxiety disorders were the most common conditions in adolescents. Echoing many other studies, girls were more likely to have a mood or anxiety disorder or eating disorder, while boys were more likely to have a behavior disorder like ADHD or substance use disorder. Contrary to regional studies, this report showed a lower rate of depression among Hispanics compared to whites. Significance The findings in this study reflect the widely held belief that most psychiatric disorders first manifest in childhood or adolescence and tend to persist or recur throughout a person’s life. The researchers conclude that the high prevalence rate of mental disorders in U.S. adolescents underscores the need for more research focused on changing the trajectory of mental disorders in youth. What’s Next More research is needed to better understand the differences in prevalence rates among cultural and ethnic groups in different regions of the country ceus for nurses Citations Kessler R, Avenevoli S, Costello J, Georgiades K, Green JG, Gruber M, He J, Koretz D, McLaughlin K, Petukhova M, Sampson N, Zaslavsky A, Merikangas K. Prevalence, persistence and Sociodemographic correlates of DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Archives of General Psychiatry. April 2012; 69(4):372-380. Kessler R, Avenevoli S, Costello J, Green JG, Gruber M, McLaughlin K, Petukhova M, Sampson N, Zaslavsky A, Merikangas K. Severity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Archives of General Psychiatry. April 2012; 69(4):381-389.

Marital problems in childhood affect teen adjustment

Marital discord is a significant social problem for children, sometimes leading to problems in health and well-being. A new longitudinal study finds that the impact of marital problems on children in their kindergarten years is long lasting and can lead to emotional problems that contribute to difficulties in adolescence. The study, by researchers at the University of Notre Dame and the University of Rochester, appears in the journal Child Development ceus for social workers "The results further highlight the possibility that there will be persistent negative effects of children's early experiences when there is conflict between their parents, at least when their emotional insecurity increases as a result of the conflict," according to E. Mark Cummings, professor and Notre Dame Endowed Chair in Psychology at the University of Notre Dame, the study's lead author. "This study has important implications for clinicians and parents," he added. Cummings and his colleagues examined 235 primarily middle-class mothers, fathers, and children over seven years, focusing on the links between marital conflict when the children were in kindergarten, children's emotional insecurity in the early school years, and subsequent problems when the children were teens. Children's emotional security about family ties is related to their sense of protection, safety, and security, and has implications for how they do socially and emotionally. The researchers observed parents discussing a topic they had identified as hard to handle, rating specific conflict behaviors. They also asked parents to report on their conflicts. The study found that conflict between parents when their children are young predicted children's emotional insecurity later in childhood, which, in turn, predicted adjustment problems in adolescence, including depression and anxiety. "Emotional insecurity appears to be an explanation for the effects of marital conflict on children's later problems," Cummings explained. "This mechanism lasts across relatively long periods of time and across the transition between childhood and adolescence." ###

Less couch time equals fewer cookies

Just 2 simple changes in health behavior spurs big and lasting results CHICAGO --- Simply ejecting your rear from the couch means your hand will spend less time digging into a bag of chocolate chip cookies. That is the simple but profound finding of a new Northwestern Medicine study, which reports simply changing one bad habit has a domino effect on others. Knock down your sedentary leisure time and you'll reduce junk food and saturated fats because you're no longer glued to the TV and noshing. It's a two-for-one benefit because the behaviors are closely related. The study also found the most effective way to rehab a delinquent lifestyle requires two key behavior changes: cutting time spent in front of a TV or computer screen and eating more fruits and vegetables. "Just making two lifestyle changes has a big overall effect and people don't get overwhelmed," said Bonnie Spring, a professor of preventive medicine at Northwestern University Feinberg School of Medicine, and lead author of the study published in Archives of Internal Medicine. "Americans have all these unhealthy behaviors that put them at high risk for heart disease and cancer, but it is hard for them and their doctors to know where to begin to change those unhealthy habits," Spring said. "This approach simplifies it." With this simplified strategy, people are capable of making big lifestyle changes in a short period of time and maintaining them, according to the study. Spring wanted to figure out the most effective way to spur people to change common bad health habits: eating too much saturated fat and not enough fruits and vegetables, spending too much sedentary leisure time and not getting enough physical activity. She and colleagues randomly assigned 204 adult patients, ages 21 to 60 years old, with all those unhealthy habits into one of four treatments. The treatments were: increase fruit/vegetable intake and physical activity, decrease fat and sedentary leisure, decrease fat and increase physical activity, and increase fruit/vegetable intake and decrease sedentary leisure. During the three weeks of treatment, patients entered their daily data into a personal digital assistant and uploaded it to a coach who communicated as needed by telephone or email. Participants could earn $175 for meeting goals during the three-week treatment phase. But when that phase was completed, patients no longer had to maintain the lifestyle changes in order to be paid. They were simply asked to send data three days a month for six months and received $30 to $80 per month. "We said we hope you'll continue to keep up these healthy changes, but you no longer have to keep them up to be compensated," Spring said. The results over the next six months amazed Spring. "We thought they'd do it while we were paying them, but the minute we stopped they'd go back to their bad habits," she said. "But they continued to maintain a large improvement in their health behaviors." From baseline to the end of treatment to the end of the six-month follow-up, the average servings of fruit/vegetables changed from 1.2 to 5.5 to 2.9; average minutes per day of sedentary leisure went from 219.2 to 89.3 to 125.7 and daily calories from saturated fat from 12 percent to 9.4 percent to 9.9 percent. About 86 percent of participants said once they made the change, they tried to maintain it. There was something about increasing fruits and vegetables that made them feel like they were capable of any of these changes," Spring said. "It really enhanced their confidence." "We found people can make very large changes in a very short amount of time and maintain them pretty darn well," Spring said. "It's a lot more feasible than we thought." ceus for social workers ### Other Northwestern authors included Donald Lloyd-Jones, M.D. Arlen Moller and Juned Siddique. The research is supported by the following National Institutes of Health grants: National Institute of Heart, Lung and Blood grant HL075451, for Multiple Behavior Change in Diet and Activity; the Robert H. Lurie Comprehensive Cancer Center of Northwestern University grant from the National Institute of Mental Health P30 CA060553; the National Institute of Mental Health grant F31 MH070107.

Most Children with ASD Diagnosed After Age 5, Use Multiple Services and Medications

Fewer than one out of five school-aged children with special health care needs were diagnosed with autism spectrum disorder (ASD) by age 2, according to new data from an NIMH-funded study. These diagnoses were made by a variety of health care providers, and most children in the study used multiple health care services (such as speech or language therapy) and multiple medications social worker continuing education Background Identifying ASD at an early age allows children to start treatment sooner, which can improve their later development and learning, and may also reduce a child’s need for specialized services or treatments later in life. To determine the experiences of school-aged children with special health care needs, Lisa Colpe, Ph.D., M.P.H., and Bev Pringle, Ph.D., of the NIMH Division of Services and Intervention Research, collaborated with colleagues who conducted more than 4,000 telephone interviews with parents or guardians of a child between the ages of 6-17 who had a confirmed diagnosis of ASD, intellectual disability, and/or developmental delay. These survey interviews were a part of the Pathways to Diagnosis and Services Study, sponsored by NIMH using funds available from the American Recovery and Reinvestment Act of 2009 (Recovery Act). Additional collaborators on this project include the National Center for Health Statistics at the Centers for Disease Control and Prevention (CDC) and the Maternal and Child Health Bureau at the Health Resources and Services Administration (HRSA). Results of the Study Key findings include: The median age when school aged children with special health care needs and ASD were first identified as having ASD was 5 years. Those identified as having ASD at younger than 5 years were diagnosed most often by generalists (such as pediatricians, family physicians, and nurse practitioners) and psychologists. Those identified later than 5 years were diagnosed primarily by psychologists and psychiatrists. Nine out of ten school-aged children with special health care needs and ASD used at least one health care service, such as behavioral intervention or modification services, sensory integration therapy, cognitive based therapy, occupational therapy, physical therapy, social skills training, or speech or language therapy. Social skills training and speech or language therapy were the most commonly used service, each used by almost 60 percent, or three out of five, of these children. More than half of school-aged children with special health care needs and ASD used at least one psychotropic medication. “Psychotropic medication” refers to any medication used to treat a mental disorder. Almost 33 percent of these children used stimulant medications 25 percent used anti-anxiety or mood-stabilizing medications 20 percent used antidepressants. Further findings are available in the NCHS Data Brief and Frequently Asked Questions. Significance The new data detail the experiences of young children with ASD, describing when they are first identified as having ASD, who is making those identifications, and the services and medications the children use to meet their developmental needs. What’s Next NIMH encourages researchers to access and analyze the new dataset to produce more studies on the early life experiences and the diagnostic, service, and treatment issues relevant to children with ASD and special health care needs. The Pathways to Diagnosis and Services Study dataset can be accessed at http://www.cdc.gov/nchs/slaits/spds.htm. Reference Pringle BA, Colpe LJ, Blumberg SJ, Avila RM, Kogan MD. Diagnostic History and Treatment of School-Aged Children with Autism Spectrum Disorder and Special Health Care Needs. NCHS data brief, no 97. Hyattsville, MD: National Center for Health Statistics. 2012.

Reducing off-label use of antipsychotic medications may save money

Reducing the non-FDA-approved use of antipsychotic drugs may be a way to save money while having little effect on patient care, according to a Penn State College of Medicine study. Researchers say that 57.6 percent of patients prescribed antipsychotic medications in data from 2003 did not have schizophrenia or bipolar disorder, the conditions for which the drugs were approved for use. Use of medication for treatments that is not FDA-approved is called off-label use. "Given healthcare reform and widespread crisis in state revenues, state Medicaid programs will be under pressure to serve larger patient populations, increasing their fiscal stress," said Douglass L. Leslie, Ph.D., professor of public health sciences. "Medicaid prescription drug programs covered 75 percent of all antipsychotic prescription medications in the United States in 2002. Reducing off-label antipsychotic use may generate savings with little impact on patient outcomes." Researchers looked at data for 42 states from 2003, the latest data available at the time of analysis, from the Centers for Medicare & Medicaid Services. They report their results in a recent issue of American Journal of Managed Care. Patients in a Medicaid fee-for-service plan for the entire year were chosen using de-identified patient information that could not be traced to the individuals. The researchers chose patients without a diagnosis of either schizophrenia or bipolar disorder during 2003 who received an antipsychotic medication. During 2003, 372,038 patients received an antipsychotic medication. Of these patients, 214,113, or 57.6 percent, did not have a diagnosis of schizophrenia or bipolar disorder. Diagnoses included other mental disorders: 35 percent, minor depression -- 25.4 percent, major depression -- 23.2 percent, no mental disorder -- 18.8 percent, conduct disorder -- 18.8 percent, and anxiety disorder -- 16.2 percent. "A high rate of off-label antipsychotic use would not necessarily be of concern if there were scientific evidence supporting the effectiveness of these medications for conditions other than schizophrenia and bipolar disorder," Leslie said. Off-label use is supported in the medical community, with the American Academy of Neurology endorsing the use of quinine for treatment-resistant leg cramps, for example. Since 2003, some of the antipsychotic medications have been approved by the FDA for the treatment of other conditions, including irritability in autism and treatment-resistant depression. However, at the time the data were collected they were considered off-label. The rate of off-label use of antipsychotics is high compared to other medications. Other studies have shown off-label medication use includes cardiovascular drugs: 46 percent, anticonvulsants -- 46 percent, and antiasthmatics -- 42 percent. "Antipsychotics were the highest selling medication class at $14.6 billion in 2009," Leslie said. "Medicaid bears a significant proportion of these costs. Hence, off-label use may be responsible for a considerable portion of state Medicaid budgets, with little or no documented clinical benefit and a substantial risk of adverse effects. Off-label use may be an area of potential savings with little impact on patient outcomes." The newest antipsychotic drugs can cost up to $10 per day at doses recommended for patients with schizophrenia. According to the researchers, more research is needed to determine if off-label use of antipsychotic medications yields substantial clinical benefit and to identify how doctors decide to prescribe these drugs for non-FDA approved conditions. Reasons why drugs may be prescribed off-label include a lack of research results showing the drug's effectiveness in certain patients or for other conditions, or that the drugs may be used as a last resort for those patients who have not responded to other treatments. Further research is needed on the decision-making process of doctors to prescribe off-label. "Where there is limited evidence of clinical benefit, greater caution should probably be used before prescribing these drugs off-label because they can have hazardous side effects," Leslie said. ### This study was funded in part by a grant from the National Institute of Mental Health and by the Department of Veterans Affairs Mental Illness Research, Education and Clinical Center. Researchers are continuing their analysis by incorporating newer data that was recently released. Also part of this study is Robert Rosenheck, M.D., Yale School of Medicine. Continuing Education for Social Workers

Zebrafish study isolates gene related to autism, schizophrenia and obesity

What can a fish tell us about human brain development? Researchers at Duke University Medical Center transplanted a set of human genes into a zebrafish and then used it to identify genes responsible for head size at birth. Researchers at Duke University Medical Center transplanted a set of human genes into a zebrafish and then used it to identify genes responsible for head size at birth. Head size in human babies is a feature that is related to autism, a condition that recent figures have shown to be more common than previously reported, 1 in 88 children in a March 2012 study. Head size is also a feature of other major neurological disorders, such as schizophrenia. "In medical research, we need to dissect events in biology so we can understand the precise mechanisms that give rise to neurodevelopmental traits," said senior author Nicholas Katsanis, Ph.D., Jean and George Brumley Jr., MD, Professor of Developmental Biology, and Professor of Pediatrics and Cell Biology. "We need expert scientists to work side by side with clinicians who see such anatomic and other problems in patients, if we are to effectively solve many of our medical problems." The study was published online in Nature journal on May 16. Katsanis knew that a region on chromosome 16 was one of the largest genetic contributors to autism and schizophrenia, but a conversation at a European medical meeting pointed him to information that changes within that same region of the genome also were related to changes in a newborn's head size. The problem was difficult to address because the region had large deletions and duplications in DNA, which are the most common mutational mechanisms in humans. "Interpretation is harrowingly hard," said Katsanis, who is also director of the Duke Center for Human Disease Modeling. The reason is that a duplication of DNA or missing DNA usually involves several genes. "It is very difficult to go from 'here is a region with many genes, sometimes over 50' to 'these are the genes that are driving this pathology,'" Katsanis said. "There was a light bulb moment," Katsanis said. "The area of the genome we were exploring gave rise to reciprocal (opposite) defects in terms of brain cell growth, so we realized that overexpressing a gene in question might give one phenotype – a smaller head, while shutting down the same gene might yield the other, a larger head." The researchers transplanted a common duplication area of human chromosome 16 known to contain 29 genes into zebrafish embryos and then systematically turned up the activity of each transplanted human gene to find which might cause a small head (microcephaly) in the fish. They then suppressed the same gene set and asked whether any of them caused the reciprocal defect: larger heads (macrocephaly). The researchers knew that deletion of the region that contained these 29 genes occurred in 1.7% of children with autism. It took the team a few months to dissect such a "copy number variant" – an alteration of the genome that results in an abnormal number of one or more sections of chromosomal DNA. "Now we can go from a genetic finding that is dosage-sensitive and start asking reasonable questions about this gene as it pertains to neurocognitive traits, which is a big leap," Katsanis said. Neurocognitive refers to the ability to think, concentrate, reason, remember, process information, learn, understand and speak. Many human conditions have anatomical features that are also related to genetics, he said. "There are major limitations in studying autistic or schizophrenic behavior in zebrafish, but we can measure head size, jaw size, or facial abnormalities." The single gene in question, KCTD13, is responsible for driving head size in zebrafish by regulating the creation and destruction of new neurons (brain cells). This discovery let the team focus on the analogous gene in humans. "This gene contributes to autism cases, and probably is associated with schizophrenia and also childhood obesity," Katsanis said. Once the gene has been uncovered, researchers can examine the protein it produces. "Once you have the protein, you can start asking valuable functional questions and learning what the gene does in the animal or human," Katsanis said. Copy number variants, such as the ones this team found on chromosome 16, are now thought to be one of the most common sources of genetic mutations. Hundreds, if not thousands, of such chromosomal deletions and duplications have been found in patients with a broad range of clinical problems, particularly neurodevelopmental disorders. "Now we may have an efficient tool for dissecting them, which gives us the ability to improve both diagnosis and understanding of disease mechanisms," Katsanis said. The current study suggests that KCTD13 is a major contributor to some cases of autism, but also points to the synergistic action of this gene with two other genes in the region, named MVP and MAPK3, Katsanis said. Other authors include lead author Christelle Golzio, Jason Willer and Edwin Oh of the Duke Center for Human Disease Modeling and Department of Cell Biology; Mike Talkowski, Mei Sun and Jim Guzella from the Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital in Boston; Sebastien Jacquemont, Alexandre Reymond and Jacques Beckmann from the Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, in Lausanne, Switzerland; and Yu Taniguchi, Akira Sawa and Atsushi Kamiya from the Department of Psychiatry, Johns Hopkins University School of Medicine in Baltimore. Funding is from a Silvio O. Conte Center grant from the National Institute of Mental Health (NIMH), National Institutes of Health grants, the Simons Foundation, the Autism Consortium of Boston, the Leenaards Foundation Prize, the Swiss National Science Foundation, a National Science Foundation Sinergia grant, an NIMH National Research Service Award, and an academic study award from the University of Lausanne. NIH-related grants: Silvio O. Conte center grant from the National Institute of Mental Health, NIH MH-084018 (AS, AK, and NK), grant MH-091230 (AK), grant HD06286 (JFG) and an NIMH National Research Service Award (F32MH087123) social worker continuing education