Inflammation can increase risk of autism or developmental delay in children.

Ousseny Zerbo

A team of UC Davis researchers has found that mothers who had a fever during pregnancy were more than twice as likely to have a child with autism or developmental delay than mothers who did not have a fever or who took medication to counter its effect.

“Our study provides strong evidence that controlling fevers while pregnant may be effective in modifying the risk of having a child with autism or developmental delay,” said Ousseny Zerbo, lead author of the study, who was a Ph.D. candidate with UC Davis when the study was conducted and is now a postdoctoral researcher with the Kaiser Permanente Northern California Division of Research. “We recommend that pregnant women who develop fever take anti-pyretic medications and seek medical attention if their fever persists.”

Published online in the “Journal of Autism and Developmental Disorders,” the study is believed to be the first to consider how fever from any cause, including the flu, and its treatment during pregnancy could affect the likelihood of having a child with autism or developmental delay.

The results are based on data from a large, case-control investigation known as the Childhood Autism Risk from Genetics and the Environment (CHARGE) Study led by the UC Davis MIND Institute. Another recent study based on CHARGE data found that mothers who were obese or diabetic had a higher likelihood of having children with autism.

Irva Hertz-Picciotto, a professor of public health sciences at UC Davis and principal investigator of CHARGE, pointed out that fever is produced by acute inflammation — the short-term, natural immune system reaction to infection or injury — and that chronic inflammation, which no longer serves a beneficial purpose and can damage healthy tissue, may be present in mothers with metabolic abnormalities like diabetes and obesity.

“Since an inflammatory state in the body accompanies obesity and diabetes as well as fever,” said Hertz-Picciotto, “the natural question is: Could inflammatory factors play a role in autism?”

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UC CITRIS rewards student teams for developing innovative tools.

Nikita Bier (left) and Jeremy Blalock, UC Berkeley

UC’s Center for Information Technology Research in the Interest of Society (CITRIS) rewarded teams of students for developing innovative tools that may prove handy for politics, health care and seeking social services.

New virtual reality study, book series focus on elementary and secondary school students.

Peter Mundy, UC Davis

UC Davis autism researcher and education specialist Peter Mundy has received a $1 million grant from the U.S. Department of Education to apply virtual-reality technology to evaluate social attention and its relation to academic achievement among school children with autism. He also is launching “Educational Interventions for Students with Autism,” a book for elementary and secondary school teachers that shares current research and evidence-based approaches to training. The book is the first in a series on the topic, and Mundy is co-author.

In the U.S., 80 percent of children with autism spectrum disorders (ASDs) go to public schools, and at least 50 percent of them are in general education classes throughout the school day. More than 60 percent have average IQs and are not affected by intellectual disabilities, yet they have the worst graduation rates of any group.

“Schools are not very well equipped to deal with ASDs,” said Mundy, who holds the Lisa Capps Endowed Chair in Neurodevelopmental Disorders and Education and is director of educational research at the UC Davis MIND Institute. “Although we’ve made tremendous progress with ASDs at the preschool level, we haven’t focused attention on how to continue to develop optimal development for these kids in elementary and secondary schools. The new research grant and book emphasize the benefits of research and the influence teachers can have on current and future generations of children.”

Expanding on a pilot project conducted last year, the study uses virtual-reality technology to track participants’ attention to nine avatars representing fellow students. All avatars stay on the screen if the participants regularly turn their heads to look at them, while avatars not getting attention begin to fade away.

It is one of the first-ever longitudinal studies on children with autism in school. The study goals include assessing whether or not social attention is a pivotal factor in both academic achievement and interventions for children with higher-functioning forms of autism. If results are promising, a follow-up study could focus specifically on use of virtual reality as an intervention.

An additional goal is to evaluate the use of social attention as a way of illustrating differences between children with attention-deficit/hyperactivity disorder and children with autism, as those symptoms can seem similar in classroom settings.

The new study will involve 120 elementary and secondary school children affected by autism and 80 typically developing children. They will participate in exercises at the Social Attention and Virtual Reality Laboratory at UC Davis, a collaboration of the MIND Institute, School of Education and Center for Mind and Brain that Mundy established in 2009.

“Through this study, we’ll obtain new information about what might help these children graduate at higher rates and have better lives, earning more than minimum wage and living independently,” said Mundy, who holds appointments as a professor in both the UC Davis School of Education and the School of Medicine’s Department of Psychiatry and Behavioral Sciences. “We need to make the best use of the biggest intervention system we have, which is the K-12 public school system. Children with ASDs spend more time in this system than in any other.”

“Educational Interventions for Students with Autism” (Wiley, 2012) is written by nationally acclaimed experts in the field and published in collaboration with the UC Davis MIND Institute and UC Davis School of Education. Co-edited by Mundy and Ann Mastergeorge, who is now with the University of Arizona, it outlines best practices in education for children with autism to meet the practical, real-world classroom needs of teachers, school administrators and parents.

Topics include how autism affects student learning, autism and its impact on schools, a teacher’s view of autism and the classroom, working with children who have high-functioning forms of autism in schools, and successful community-school partnerships. Mundy contributes a co-written chapter titled “Effects of Autism on Social Learning and Social Attention.”

UC Davis Health System Chief Executive Officer Claire Pomeroy, UC Davis School of Education Dean Harold Levine, MIND Institute Director Leonard Abbeduto and the UC Davis Department of Psychiatry and Behavioral Sciences supported early research that led to the current grant and facilitated the production of the new book.

Mundy’s work on defining the nature of autism began more than 25 years ago at the UCLA Neuropsychiatric Institute (now the Semel Institute). Before joining UC Davis in 2008, he was professor of psychology at the University of Miami, where he was the founding director of the University of Miami Center for Autism and Related Disabilities and founding co-director of the Marino Autism Research Institute. A standing member of the National Institutes of Health Biobehavioral and Behavioral Science Subcommittee, he has published more than 100 papers on autism, early social development and developmental psychopathology.

The UC Davis MIND Institute, in Sacramento, was founded in 1998 as a unique interdisciplinary research center where parents, community leaders, researchers, clinicians and volunteers collaborate to study and treat autism and other neurodevelopmental disorders. The institute has major research efforts in autism, Tourette syndrome, fragile X syndrome, chromosome 22q11.2 deletion syndrome and attention-deficit/hyperactivity disorder (ADHD). More information about the institute, including previous presentations in its Distinguished Lecture Series, is available on the Web at mindinstitute.ucdavis.edu.

Neurological process triggered by suspected carcinogen may increase autism risk.

Isaac Pessah, UC Davis

New research from UC Davis and Washington State University shows that PCBs, or polychlorinated biphenyls, launch a cellular chain of events that leads to an overabundance of dendrites — the filament-like projections that conduct electrochemical signals between neurons — and disrupts normal patterns of neuronal connections in the brain.

“Dendrite growth and branching during early development is a finely orchestrated process, and the presence of certain PCBs confuses the conductor of that process,” said Pamela Lein, a developmental neurobiologist and professor of molecular biosciences in the UC Davis School of Veterinary Medicine. “Impaired neuronal connectivity is a common feature of a number of conditions, including autism spectrum disorders.”

Reported today (April 24) in two related studies in the journal Environmental Health Perspectives, the findings underscore the developing brain’s vulnerability to environmental exposures and demonstrate how PCBs could add to autism risk.

“We don’t think PCB exposure causes autism,” Lein said, “but it may increase the likelihood of autism in children whose genetic makeup already compromises the processes by which neurons form connections.”

The senior authors of the studies were Lein and Isaac Pessah, chair of molecular biosciences in the School of Veterinary Medicine and director of the Center for Children’s Environmental Health at UC Davis. Both are researchers with the UC Davis MIND Institute, which is dedicated to finding answers to autism and other neurodevelopmental disorders. The lead author was Gary Wayman of Washington State University’s Program in Neuroscience, who first described the molecular pathway that controls the calcium signaling in the brain that guides normal dendrite growth.

Wayman found that key cellular players, called calcium and calmodulin kinases, are activated by increased calcium levels. Activated calmodulin kinase then turns on the protein known as CREB that regulates genes that produce Wnt2, a potent molecule and the final arbiter of whether and how dendrites grow. Wnt2 directs structural proteins to construct scaffolding that supports dendrite growth and branching.

“Orderly choreography of the calmodulin kinase-to-Wnt2 pathway translates normal increases in calcium levels into normal levels of dendrite production,” said Wayman. “The wiring of billions of neurons is dependent on the health of this cellular process and is crucial to proper development of virtually all complex behaviors, learning, memories and language.”

For the current studies, the team set out to determine if that pathway was altered by exposure to PCBs, focusing on neurons of the hippocampus — the brain region linked with learning and memory and known to suffer impaired connectivity in many neurodevelopmental disorders.

The scientists also focused on the effects of an understudied PCB subset known as non-dioxin-like PCBs, which have been shown to increase calcium levels in neurons. Both non-dioxin-like PCBs and the more familiar dioxin-like subset were widely used in electrical equipment in the 1950s and 1960s. Banned in the 1970s because of the potential for dioxin-like PCBs to cause cancer, all PCBs are stable compounds that persist throughout the environment today.

One of the current UC Davis studies examined dendrite growth in rat pups born to and nursed by PCB-exposed mothers. Another study analyzed how PCBs affect rat neurons in cell cultures at developmental stages similar to those in the third trimester of pregnancy in humans. In both studies, PCB exposure levels were similar to those found in the human diet and in human tissues, including the placenta and breast milk.

Evaluation of the brains of the rats exposed to PCBs early in life showed significant overproduction of dendrites. The cellular studies showed that PCBs triggered the calcium pathway that led to the aberrant brain architecture, and that dendrite production was normal when that cellular pathway was blocked.

“We are the first to show that non-dioxin-like PCBs alter how the developing brain gets wired by hijacking the calcium signaling pathway and greatly expanding dendrite growth,” said Lein.

The experiments also helped identify for the first time the specific trigger for this cellular chain of events as the ryanodine receptor (RyR) calcium channel. Pessah, a recognized leader in calcium-channel dysfunction and neurodevelopment, previously showed that RyR is selectively activated by non-dioxin-like PCBs. The new studies prove that RyR is a necessary component in the pathway that controls dendritic growth.

“These same calcium pathways are implicated in some forms of autism and, while environmental exposures alone do not cause autism, these new findings provide good evidence that PCBs could add to autism risk in genetically predisposed children,” said Pessah. “Understanding the fundamental mechanisms by which PCBs alter neural networks sets the stage for research on environmental contaminants that are structurally related to PCBs, including flame retardants, and their risks to susceptible populations.”

In addition to Lein, Pessah and Wayman, coauthors on the papers were Dongren Yang, Diptiman Bose and Donald Bruun of UC Davis; Adam Lesiak of Washington State University; and Soren Impey and Veronica Ledoux of the Oregon Health & Science University.

Funding for the studies was provided by the National Institutes of Health (grants R01 ES014901, R01 ES017425, P42 ES04699, R01 MH086032, P01 ES011269 and T32 ES007060), the U.S. Environmental Protection Agency (grants R833292 and R829388), the Hope for Depression Research Foundation and the J.B. Johnson Foundation.

The studies — “PCB 95 Promotes Dendritic Growth via Ryanodine Receptor-Dependent Mechanisms” and “PCB 95 Modulates Calcium-Dependent Signaling Pathway Responsible for Activity-Dependent Dendritic Growth” — will be published in a future print issue of the journal with several other investigations focused on autism and the environment. Copies of the UC Davis-Washington State University studies are available online now at http://dx.doi.org/10.1289/ehp.1104832 and http://dx.doi.org/10.1289/ehp.1104833.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.

Washington State University’s Program in Neuroscience is housed in the Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology in the College of Veterinary Medicine. The program will be moving to a new state-of-the-art neuroscience research building in spring 2013. Research in the program focuses on how cellular and molecular events integrate to control organismal physiology (e.g., cardiac function, autonomics) and behavior (e.g., sleep, feeding, addiction, emotion). For more information, visit vetmed.wsu.edu/neuroscience.

UC Davis studies maternal metabolic conditions and risk of neurodevelopment disorders.

Paula Krakowiak, UC Davis

A major study conducted by researchers affiliated with the UC Davis MIND Institute has found strong links between maternal diabetes and obesity and the likelihood of having a child with autism spectrum disorder (ASD) or another developmental disorder.

The study, which investigated the relationships between maternal metabolic conditions and the risk of neurodevelopmental disorders, found that mothers who were obese were 67 percent more likely to have a child with ASD than normal-weight mothers without diabetes or hypertension, and were more than twice as likely to have a child with another developmental disorder.

Mothers with diabetes were found to have nearly 67 percent more likely to have a child with developmental delays as healthy mothers. However, the proportion of mothers with diabetes who had a child with ASD was higher than in healthy moms but did not reach statistical significance.

The study also found that the children of diabetic mothers who had ASD were more disabled — had greater deficits in language comprehension and production and adaptive communication — than were the children with ASD born to healthy mothers.

However, even children without ASD born to diabetic mothers exhibited impairments in socialization in addition to language comprehension and production, when compared with the non-ASD children of healthy women. Children without ASD of mothers with any of the metabolic conditions displayed mild deficits in problem solving, language comprehension and production, motor skills and socialization.

“Over a third of U.S. women in their childbearing years are obese, and nearly one-tenth have gestational or type 2 diabetes during pregnancy. Our finding that these maternal conditions may be linked with neurodevelopmental problems in children raises concerns and therefore may have serious public-health implications,” said Paula Krakowiak, a Ph.D. candidate in epidemiology affiliated with the MIND Institute. “And while the study does not conclude that diabetes and obesity cause ASD and developmental delays, it suggests that fetal exposure to elevated glucose and maternal inflammation levels adversely affect fetal development.”

The study, “Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders,” is published online today (April 9) in Pediatrics, the Journal of the American Academy of Pediatrics. Its authors said that it is the first study to examine the associations between neurodevelopmental disorders and maternal metabolic conditions not restricted solely to type 2 or gestational diabetes. It is also the first to include obesity and hypertension, which have similar underlying biological characteristics, and to investigate correlations between these conditions and impairments in the skills and abilities of children in specific developmental domains.

Over 60 percent of U.S. women of childbearing age are overweight; 34 percent are obese; and 16 percent have metabolic syndrome. Nearly 9 percent of U.S. women of childbearing age are diabetic, and more than 1 percent of U.S. pregnancies were complicated by chronic hypertension. In California, where the study was conducted, 1.3 percent of women had type 2 diabetes, and 7.4 percent had gestational diabetes.

Autism spectrum disorder is characterized by impairments in social interaction, communication deficits and repetitive behaviors and often is accompanied by intellectual disability. An estimated 1 in 88 children born today will be diagnosed with autism spectrum disorder, according to statistics recently released by the U.S. Centers for Disease Control and Prevention. An estimated 1 in 83 U.S. children has another developmental disorder, which includes other disorders resulting in intellectual disability.

The study included 1,004 mother/child pairs from diverse backgrounds enrolled in the Childhood Autism Risks from Genetics and the Environment Study (CHARGE), most of them living in Northern California, with a small subset living in Los Angeles. The children were between 24 and 60 months old, born in California and resided with at least one biological parent who spoke either English or Spanish. There were 517 children who had ASD; 172 who had other developmental disorders but not ASD; and 315 who were developing typically. The participants were enrolled between January 2003 and June 2010.

The researchers obtained demographic and medical information for the mothers and their children using the CHARGE Study Environmental Exposure Questionnaire, a telephone survey, the study participants’ birth files and medical records. The primary metabolic conditions of interest were type 2 diabetes or gestational diabetes.

Women were considered diabetic if the condition was noted in their medical records or if during the telephone surveys they answered “yes” to the questions “During this pregnancy were you ever told by a physician or nurse that you had gestational diabetes?” or “At any time before you became pregnant were you told by a doctor that you had [type 2] diabetes?” The same wording was used to obtain information about hypertension. BMI was calculated using height and weight prior to pregnancy from medical records or telephone interviews.

To confirm the developmental diagnoses of the children with ASD researchers used the Autism Diagnostic Interview-Revised (ADIR) and the Autism Diagnostic Observation Schedules (ADOS). All of the children were administered the Mullen Sales of Early Learning and the Vineland Adaptive Behavior Scales to assess their cognitive and adaptive development. Spanish-speaking children were administered the tests in Spanish. The participants were then divided into groups of children with ASD, developmental delay or typical development.

Among children whose mothers were diabetic during their pregnancies, the study found that the percentage of children with ASD born to women with type 2 diabetes or gestational diabetes (9.3 percent) or developmental disability (11.6 percent) was higher than the 6.4 percent of children with ASD born to women without these metabolic conditions.

Over 20 percent of the mothers of children with ASD or developmental delay were obese, compared with 14 percent of the mothers of typically developing children.

Approximately 29 percent of the children with ASD had mothers with a metabolic condition, and nearly 35 percent of the children with developmental delay had mothers with metabolic conditions. In contrast, 19 percent of the typically developing children had mothers with a metabolic condition.

The study also examined the link between hypertension and ASD or developmental disorders. The prevalence of high blood pressure was low for all groups, but more than two times higher among mothers of children with ASD or developmental delay than among mothers of children with typical development, though the finding did not reach statistical significance.

Analyses of the children’s cognitive abilities found that, among the children with ASD, children of mothers with diabetes exhibited poorer performance on tests of expressive and receptive language and communication skills of everyday living when compared with the children of healthy mothers. And the presence of any metabolic condition was associated with lower scores on all of the tests among children without ASD.

The authors note that obesity is a significant risk factor for diabetes and hypertension, and is characterized by increased insulin resistance and chronic inflammation, as are diabetes and hypertension. In diabetic, and possibility pre-diabetic pregnancies, poorly regulated maternal glucose can result in prolonged fetal exposure to elevated maternal glucose levels, which raises fetal insulin production, resulting in chronic fetal exposure to high levels of insulin.

Because elevated insulin production requires greater oxygen use this may result in depleted oxygen supply for the fetus. Diabetes also may result in fetal iron deficiency. Both conditions can adversely affect fetal brain development, the authors said.

“The sequence of events related to poorly regulated maternal glucose levels is one potential biological mechanism that may play a role in adverse fetal development in the presence of maternal metabolic conditions,” Krakowiak said.

Maternal inflammation, which accompanies metabolic conditions, may also adversely affect fetal development. Certain proteins involved in cell signaling that are produced by cells of the immune system can cross the placenta from the mother to the fetus and disturb brain development.

Other study authors are Irva Hertz-Picciotto, Cheryl Walker, Alice Baker, Sally Ozonoff and Robin Hansen of the UC Davis MIND Institute and Andrew Bremer of UC Davis and Vanderbilt University.

The study was supported by the National Institutes of Health (P01 ES11269 and R01 ES015359), the U.S. Environmental Protection Agency through the Science to Achieve Results (STAR) program (R829388 and R833292), and the UC Davis MIND Institute.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.

New technique reveals another piece of spectrum’s genetic architecture.

Daniel Geschwind, UCLA

There is little argument among experts that autism spectrum disorders (ASD), complex developmental disabilities that vary widely in their severity, are caused by both genetic and environmental factors. Advances in genome sequencing now permit scientists to uncover specific mutations in DNA that are associated with ASD at unprecedented resolution. Such data are vital to understanding the genetic basis of the disorder.

A new study co-authored by UCLA researchers has led to a better understanding of the genetic contribution to autism using this new approach. By comparing siblings with and without ASD, the researchers have discovered a single instance in the affected siblings in which two independent mutations disrupt a gene called SCN2A.

Reporting in today’s (April 4) edition of the journal Nature, Dr. Daniel Geschwind, a UCLA professor of neurology and psychiatry, and colleagues from Yale University, Carnegie Mellon University and the University of Pittsburgh completed “whole-exome sequencing” of 238 parent-child quartets. A quartet is defined as two parents and one child without ASD and one child with ASD.

Instead of the time-consuming process of searching the entire genome of an individual, the researchers turned to the newer technology of whole-exome sequencing, which searches only the protein-coding regions of the genome to pinpoint the mutation that causes a particular disorder.

The researchers compared mutation rates between unaffected individuals and those with ASD within a family, then compared the ASD mutations to the entire cohort. They found multiple variations between the unaffected and affected groups. Specifically, among a total of 279 coding mutations, they identified a single instance in individual children with ASD — and not in siblings — in which two independent mutations disrupt the gene SCN2A. That same mutation was found in all the unrelated children with ASD, confirming its importance.

In addition, the researchers found many other genes with similar mutations occurring only once — these also make promising new candidates for autism susceptibility. Finally, they were able to estimate that there are likely about 1,000 or more genes that contribute to autism risk.

“This work demonstrates that autism, in most cases, has a contribution from several genes, as the average risk imparted by one mutation is typically not sufficient,” said Geschwind, who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and directs the UCLA Center for Autism Research and Treatment. “Overall, these results substantially clarify the genomic architecture of ASD, and this is an important step in attempting to better understand the genetic basis of these disorders.”

A complete list of contributing authors and institutions is available in the Nature paper. Funding was provided by the Simons Foundation.

Autism is a complex brain disorder that strikes in early childhood. The condition disrupts a child’s ability to communicate and develop social relationships and is often accompanied by acute behavioral challenges. Autism spectrum disorders are diagnosed in one in 110 children in the United States, affecting four times as many boys as girls. Diagnoses have expanded tenfold in the last decade.

The UCLA Center for Autism Research and Treatment provides diagnosis, family counseling, clinical trials and treatment for patients with autism. UCLA is one of eight centers in the National Institutes of Health-funded Studies to Advance Autism Research and Treatment network and one of 10 original Collaborative Programs for Excellence in Autism.

New programs feature latest autism research from UC Davis’ MIND Institute.

April is National Autism Awareness Month.

UCTV celebrates National Autism Awareness Month with a slate of new programs featuring the latest research on autism and neurodevelopmental disorders from the UC Davis MIND Institute.

Programs include:

Autism Research and Policy: A Family’s Journey
First air date: April 23

Summit on Autism
First air date: March 5

A New Vision for the MIND Institute
First air date: Feb. 27

A Community Forum: Autism Spectrum Disorders
First air date: Feb. 13

Tap Into the Potential of the Multi Touch Interface
First air date: Feb. 6

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Related:
UC Davis MIND Institute holds family open house April 28 for Autism Awareness Month

UC Davis researchers seeking children and young adults to join study.

Marjorie Solomon, UC Davis

Researchers at the UC Davis MIND Institute are seeking children and young adults to participate in a groundbreaking brain-imaging study aimed at understanding one of the most critical aspects of autism: motivation in learning.

“One of the areas that is affected in many kids and adults with autism is their ability to learn in conventional settings. We believe this is because they have unique strengths and motivation patterns, which they use to tackle challenges,” said Marjorie Solomon, principal investigator for the study and associate professor of clinical psychiatry at the MIND Institute.

“We are trying to better isolate the kinds of strengths and challenges people with autism spectrum disorder have with respect to learning. We want to understand the neurobiology of those strengths and challenges so that we can help them to maximize their potential in life.”

Solomon said that many of the behavioral treatments used today with children with autism spectrum disorders depend on learning. Yet, no one really knows how the brains of children with autism spectrum disorders work during learning.

“It is ironic that one of our major therapies has never been studied in this way,” Solomon said.

Solomon and her colleagues at the MIND Institute will be using behavioral evaluations and brain scans to study what neuroscientists call cognitive control and reward processing.

Cognitive control refers to a person’s ability to flexibly process information and change actions depending on internal goals. It allows a person to read the word “green” out loud even if the word is actually printed in red. Cognitive control is important in a variety of aspects of learning, including planning, problem solving and multitasking.

“We’re trying to investigate why children and adults with autism often show deficits in cognitive control and reward processing in laboratory tasks and what brain regions are involved in these deficits,” said Jonathan Beck, the study’s coordinator. “We will use this information to  understand the many strengths they use to compensate in tasks that are difficult for them.”

To better understand the learning style of persons with autism, the MIND researchers are using computer-based behavioral testing. They will then use functional magnetic resonance imaging (fMRI) to pinpoint the areas of activity in the brain while the participant completes a learning task.

Taking part in the study involves two visits, one to the MIND Institute and one to the UC Davis Imaging Research Center. During the visits, participants fill out questionnaires, complete computer-based brainteasers and puzzles, provide blood samples, and have their brains scanned using fMRI while completing a learning task.

The brain scans show researchers which parts of the brain are involved during the tasks.

To complete this ongoing study, the MIND Institute is seeking to enroll additional participants ages 12 to 40 who are either typically developing or who have been diagnosed with autism spectrum disorder. The study already includes more than 100 children and adults with autism, but more are needed to reach the goal of enrolling 200 participants.

Study participants are compensated for their time, receive free assessments and receive a digital file of their own brain scan.

Solomon said typically developing children and adults, as well as those with autism, have something to gain from participating in this study.

“Some get the pleasure of knowing they are helping people with autism, and those with autism get free testing and may help us to better understand their unique gifts,” Solomon said. “We take the time to discuss their results and answer their questions. They also are entered into a system of care that specializes in helping people with autism. A lot of families like that.”

Those interested in participating in this should contact Jonathan Beck, the study coordinator, at (916) 703-0298.

Genetic studies find dysregulation in pathways that govern development of the prefrontal cortex in young patients with autism.

Eric Courchesne, UC San Diego

A study led by Eric Courchesne, director of the Autism Center of Excellence at the University of California, San Diego, School of Medicine, has for the first time identified in young autism patients genetic mechanisms involved in abnormal early brain development and overgrowth that occurs in the disorder. The findings suggest novel genetic and molecular targets that could lead to discoveries of new prevention strategies and treatment for the disorder.

The study, to be published today (March 22) in PLoS Genetics, uncovered differences in gene expression between brain tissue from young (2-14 years) and adult individuals with autism syndrome disorder, providing important clues why brain growth and development is abnormal in this disorder.

Courchesne first identified the link between early brain overgrowth and autism in a landmark study published by the Journal of the American Medical Association (JAMA) in 2003. Next, he tested the possibility that brain overgrowth might result from an abnormal excess of brain cells. In November 2011, his study, also published in JAMA, discovered a 67 percent excess of brain cells in a major region of the brain, the prefrontal cortex — a part of the brain associated with social, communication and cognitive development.

“Our next step was to see whether there might be abnormalities of genetic functioning in that same region that might give us insight into why there are too many cells and why that specific region does not develop normally in autism,” said Courchesne.

In the new study, the researchers looked towards genes for answers, and showed that genetic mechanisms that normally regulate the number of cortical neurons are abnormal. “The genes that control the number of brain cells did not have the normal functional expression, and the level of gene expression that governs the pattern of neural organization across the prefrontal cortex is turned down. There are abnormal numbers and patterns of brain cells, and subsequently the pattern is disturbed,” Courchesne said. “This probably leads to too many brain cells in some locations, such as prefrontal cortex, but perhaps too few in other regions of cortex as well.”

In addition, the scientists discovered a turning down of the genetic mechanisms responsible for detecting DNA defects and correcting or removing affected cells during periods of rapid prenatal development.

Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings in the brain at young ages have remained largely unknown. Until now, few studies have been able to investigate whole-genome gene expression and genotype variation in the brains of young patients with autism, especially in regions such as the prefrontal cortex that display the greatest growth abnormality.

Scientists — including co-first authors Maggie Chow and Tiziano Pramparo at UC San Diego — identified abnormal brain gene expression patterns using whole-genome analysis of mRNA levels and copy number variations from 33 autistic and control postmortem brain samples. They found evidence of dysregulation in the pathways that govern cell number, cortical patterning and cell differentiation in the young autistic prefrontal cortex. In contrast, in adult patients with autism, the study found that this area of the brain shows dysregulation of signaling and repair pathways.

“Our results indicate that gene expression abnormalities change across the lifespan in autism, and that dysregulated processes in the developing brain of autistic patients differ from those detected at adult ages,” said Courchesne. “The dysregulated genetic pathways we found at young ages in autism may underlie the excess of neurons — and early brain overgrowth — associated with this disorder.”

Additional contributors include co-senior authors Nicholas J. Schork, Ph.D., biostatistician at the Scripps Research Institute in La Jolla, and Anthony Wynshaw-Boris, professor of pediatrics at UC San Francisco; Mary E. Winn and Sarah Murray, Scripps Research Institute; Lauren Weiss and Haim Belinson, UC San Francisco; Jian-Bing Fan and Craig April, Illumina, Inc.; Cynthia Carter Barnes, Hai-Ri Li and Xiang-Dong Fu, UC San Diego.

The research was supported by funds from the Simons Foundation, The Peter Emch Family Foundation, Autism Speaks, the Thursday Club Juniors and the UCSD-NIH Autism Center of Excellence.

UCLA scientists identify 2,000 important genes.

Zebra finches

Can the song of a small bird provide valuable insights into human stuttering and speech-related disorders and conditions, including autism and stroke? New research by UCLA life scientists and colleagues provides reason for optimism.

The scientists discovered that some 2,000 genes in a region of the male zebra finch’s brain known as “Area X” are significantly linked to singing. More than 1,500 genes in this region, a critical part of the bird’s song circuitry, are being reported for the first time. Previously, a group of scientists including the UCLA team had identified some 400 genes in Area X. All the genes’ levels of expression change when the bird sings.

We did not know before that all of these genes are regulated by singing,” said Stephanie White, a UCLA associate professor of integrative biology and physiology and senior author of the new study. She believes the 2,000 genes — which are also shared by humans — are likely important for human speech.

The research is published in the online edition of the journal Neuron, a leading neuroscience journal, and will appear in an upcoming print edition.

“A method that (UCLA co-author) Steve Horvath developed lets us see what genes are changing together and, therefore, which genes are linked in a network,” White said. “We can see which are the hub genes that are the most connected to other genes, as in a social network — the popular kids. We can also identify the genetic equivalent of the lonely kids. Steve’s analysis lets us group the genes together and see who is interacting with whom.”

Many more genes are involved in vocalization than scientists had previously known. While language is uniquely human, it has components — such as the ability to create new sounds — that songbirds and other animals share with us. The zebra finch may create new sounds using the same genes as humans, said White, who is also a member of UCLA’s Brain Research Institute.

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UC Davis MIND Institute will host study on language skills and impairment in males with genetic disorder.

Leonard Abbeduto, UC Davis

Leonard Abbeduto, director of the UC Davis MIND Institute, has received a more than $3.5 million grant from the National Institutes of Health to conduct an examination of the development of language among individuals with fragile X syndrome, the leading inherited cause of intellectual disability and the foremost single-gene cause of autism spectrum disorder.

Abbeduto will lead the five-year-long multisite study, which will explore language development in a group of adolescent and young adult males with fragile X syndrome, the factors that affect their language development, and the consequences of language impairments for independent functioning in adulthood.

“Parents often ask what the future may hold for their children with fragile X syndrome. This study will help us answer that question by providing information on language skills and independent functioning in adulthood. The study also should give us clues about treatments and therapies that could improve outcomes for people with fragile X syndrome,” said Abbeduto, who also is Tsakopoulos-Vismara Endowed Chair in the Department of Psychiatry and Behavioral Sciences.

Abbeduto is an internationally respected expert on the behavioral growth of individuals with intellectual disabilities, particularly their development and use of language. He is the author of numerous studies on the development of language in children and adolescents with fragile X syndrome. The newly funded research will extend that work into adulthood.

The study will focus on a group of 15- to 22-year-old males with fragile X syndrome. It will explore the effects of behavioral, environmental and biological factors on development of language among these individuals, as well as how linguistic impairments affect adult outcomes, such as independence and participation in the community. The study also will examine how language development in fragile X differs from that in autism spectrum disorder by collecting data from a comparable group of males with autism.

Study sites for the research will be the UC Davis MIND Institute in Sacramento; the Department of Psychology at the University of South Carolina in Columbia, S.C.; and the New York State Institute for Basic Research in Developmental Disabilities in Staten Island, N.Y.

Fragile X syndrome results from a genetic mutation, a trinucleotide (cytosine-guanine-guanine) repeat expansion in a stretch of DNA on the X chromosome. People normally have five to 45 CGG repeats in this region, but the number of CGG repeats can expand beyond normal as the DNA is copied from mother to child. Fragile X syndrome results when the three nucleotides repeat more than 200 times.

The gene involved in fragile X disorders codes for a critical brain protein known as the fragile X mental-retardation protein (FMRP). This protein normally acts as a brake on the production of other proteins associated with learning and memory. When more than 200 CGG repeats are present, the gene for FMRP tends to shut down, resulting in an overproduction of the other proteins. The brain develops too many connections, or synapses, which often are immature and weak.

The resulting cognitive effects range from learning disorders to severe intellectual impairment and often include autism, epilepsy, anxiety disorders and attention-deficit/hyperactivity disorder (ADHD). Affected individuals tend to have associated physical anomalies, including an elongated face, prominent ears and enlarged testicles, as well as connective-tissue abnormalities and mitral-valve prolapse.

Abbeduto became director of the UC Davis MIND Institute in August 2011. He is the recipient of the 2010 Enid and William Rosen Research Award for outstanding contributions to understanding fragile X syndrome from the National Fragile X Foundation. He is a fellow of the American Association on Intellectual and Developmental Disabilities and the author of more than 100 research papers, books and book chapters and has made numerous presentations throughout the nation and the world.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.

UC Davis study highlights the interaction between epigenetics and genetics and exposure to a flame retardant in mice.

Rima Woods (left) and Janine LaSalle, UC Davis

Mice genetically engineered to be susceptible to autism-like behaviors that were exposed to a common flame retardant were less fertile and their offspring were smaller, less sociable and demonstrated marked deficits in learning and long-term memory when compared with the offspring of normal unexposed mice, a study by researchers at UC Davis has found. The researchers said the study is the first to link genetics and epigenetics with exposure to a flame retardant chemical.

The research was published online today (Feb. 16) in the journal Human Molecular Genetics. It will be presented during a symposium on Saturday (Feb. 18) at the annual meeting of the American Association for the Advancement of Science (AAAS) by Janine LaSalle, a professor in the Department of Medical Microbiology and Immunology in the UC Davis School of Medicine and the UC Davis Genome Center. (LaSalle will discuss her research during a news briefing with her colleagues at 9 a.m. Sunday (Feb. 19) in room 221 on the second level of the Vancouver Convention Center).

“This study highlights the interaction between epigenetics and the effects of early exposure to flame retardants,” said LaSalle, the study’s senior author and a researcher affiliated with the UC Davis MIND Institute. “Our experiments with wild-type and mutant mice indicate that exposure to flame retardants presents an independent risk of neurodevelopmental deficits associated with reduced sociability and learning.”

Epigenetics describes the heritable changes in gene expression caused by mechanisms other than those in the DNA sequence. One such mechanism is DNA methylation, in which genes are silenced when their activation no longer is required. DNA methylation is essential for normal development. The researchers chose a mouse that was genetically and epigenetically susceptible to social behavioral deficits in order to understand the potential effect of this environmental pollutant on genetically susceptible humans.

LaSalle and her colleagues examined the effects of the chemical BDE-47 (Tetrabromodiphenl ether), a member of the class of flame retardants called polybrominated diphenylethers, or PBDEs. PBDEs have been used in a wide range of products, including electronics, bedding, carpeting and furniture. They have been shown to persist in the environment and accumulate in living organisms, and toxicological testing has found that they may cause liver toxicity, thyroid toxicity and neurodevelopmental toxicity, according to U.S. Environmental Protection Agency. BDE-47 is the PBDE found at highest concentrations in human blood and breast milk, raising concerns about its potential neurotoxic effects during pregnancy and neonatal development.

The research was conducted in the offspring of mice genetically engineered for the autism phenotype found in Rett syndrome, a disorder that occurs primarily in females and causes regression in expressive language, motor skills and social reciprocity in late infancy. The condition affects about 1 in 10,000 children.

Autism spectrum disorders are a group of neurodevelopmental disabilities that can cause significant social, communication and behavioral deficits. The U.S. Centers for Disease Control and Prevention estimates that an average of 1 in 110 children born in the United States today will be diagnosed with an autism spectrum disorder.

Rett syndrome is causally linked to defects in the methyl-CpG-binding protein 2 gene MECP2 situated on the X chromosome. Mutations in MECP2 result in a nonfunctional MeCP2 protein, which is required for normal brain development. The researchers evaluated the effects of exposure to BDE-47 on mice genetically engineered to have mutations in MECP2 and their offspring, or pups. The genetically engineered Mecp2 mother mice, or dams, were bred with non-mutant wild-type males. The dams were monitored for 10 weeks — for four weeks prior to conception, three weeks during gestation and three weeks of lactation. They were then compared with a control group of normal, unexposed dams and pups over several generations and hundreds of mice.

The study found that that the weights of the pups of the lactating BDE-47-exposed dams were diminished when compared with the controls, as were their survival rates. To assess the effects of the flame retardant exposure on the pups and their genotypes, the researchers placed them through more than 10 cognitive, social and physical tests.

Female offspring of dams exposed with BDE-47 spent half as much time interacting with another mouse in a 10-minute sociability test compared to controls. The reduced sociability in BDE-47 exposed females corresponded to reduced DNA methylation in females regardless of genotype. In addition, genetic and environmental interaction effects in this study were specifically observed in females.

In a short-term memory test of social novelty, although all mice showed the expected preference for interacting with a novel over a familiar mouse, BDE-47-exposed mutant female mice spent about half as much time interacting with the familiar mouse than their non-mutant littermates. In a long-term memory test of swimming to reach a hidden platform in a cloudy pool, female mice who were both mutant and BDE-47 exposed did not learn to reach the platform faster after fourdays of training. These behavioral changes in social and cognitive learning specifically in the interaction group corresponded to changes in a known epigenetic regulator of DNA methylation in brain, DNA methyltransferase 3a (Dnmt3a).

LaSalle said that the study results are important because better understanding of the epigenetic pathways implicated in social behavior and cognition may lead to improved treatments for autism spectrum disorders.

“While the obvious preventative step is to limit the use and accumulation of PBDEs in our environment, this would likely be a long-term solution,” LaSalle said. “These pollutants are going to be hard to get rid of tomorrow. However, one important preventative that all women could do tomorrow is to start taking prenatal vitamins before becoming pregnant, as these may counteract the toxins in our environment through DNA methylation,” she said.

A study by researchers at UC Davis conducted in 2011 found that women who reported not taking a daily prenatal vitamin immediately before and during the first month of pregnancy were nearly twice as likely to have a child with an autism spectrum disorder as women who did take the supplements — and the associated risk rose to seven times as great when combined with a high-risk genetic make-up.

Other authors of the research are Rima Woods, Roxanne O. Vallero, Mari Golub, Joanne K. Suarez, Tram Anh Ta, Dag H. Yasui, Lai-Har Chi, Isaac N. Pessah and Robert F. Berman, all of UC Davis, and Paul J. Kostyniak of the Toxicology Research Center, University at Buffalo, the State University of New York.

The research was funded by grants from the National Institutes of Health and the American Recovery and Reinvestment Act, the National Institutes of Environmental Health Sciences/Environmental Protection Agency Center for Children’s Environmental Health, and the U.S. Environmental Protection Agency Science to Achieve Results (STAR) program.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.