Intervention in 6-month-olds with autism eliminates symptoms, developmental delay

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'Infant Start' therapy removes disabling delay before most children are diagnosed "Treatment at the earliest age when symptoms of autism spectrum disorder (ASD) appear – sometimes in infants as young as 6 months old – significantly reduces symptoms so that, by age 3, most who received the therapy had neither ASD nor developmental delay, a UC Davis MIND Institute research study has found. The treatment, known as Infant Start, was administered over a six-month period to 6- to 15-month-old infants who exhibited marked autism symptoms, such as decreased eye contact, social interest or engagement, repetitive movement patterns, and a lack of intentional communication. It was delivered by the people who were most in tune with and spent the most time with the babies: their parents. “Autism treatment in the first year of life: A pilot study of Infant Start, a parent-implemented intervention for symptomatic infants,” is co-authored by UC Davis professors of Psychiatry and Behavioral Sciences Sally J. Rogers and Sally Ozonoff. It is published online today in the Journal of Autism and Developmental Disorders. "Most of the children in the study, six out of seven, caught up in all of their learning skills and their language by the time they were 2 to 3," said Rogers, the study's lead author and the developer of the Infant Start therapy. "Most children with ASD are barely even getting diagnosed by then." "For the children who are achieving typical developmental rates, we are essentially ameliorating their developmental delays," Rogers said. "We have speeded up their developmental rates and profiles, not for every child in our sample, but for six of the seven." Rogers credited the parents in the small, pilot study with making the difference. "It was the parents – not therapists – who did that," she said. "Parents are there every day with their babies. It's the little moments of diapering, feeding, playing on the floor, going for a walk, being on a swing, that are the critical learning moments for babies. Those moments are what parents can capitalize on in a way that nobody else really can." Early identification crucial Children diagnosed with autism typically receive early intervention beginning at 3 to 4 years, six to eight times later than the children who participated in the study. But the earliest symptoms of autism may be present before the child’s first birthday. Infancy is the time when children first learn social interaction and communication, so autism researchers and parents of children with the condition have been working to identify autism and begin intervention sooner. Effective autism treatment relies on early detection so that a child can begin therapy as soon as possible, to prevent or mitigate the full onset of symptoms and sometimes severe and lifelong disability. "We were very fortunate to have this treatment available for the affected infants identified through our study," said Ozonoff, who directs the MIND Institute's Infant Sibling Study, an early detection project that follows babies at risk for autism or ADHD from birth through age 3. "We want to make referrals for early intervention as soon as there are signs that a baby might be developing autism," Ozonoff said. "In most parts of the country and the world, services that address autism-specific developmental skills are just not available for infants this young." Of the seven babies in the study, four were part of the Infant Sibling Study. In addition to these four, the other three children were referred by community parents. The treatment group was compared with four other groups of children that included: High-risk children with older siblings with autism who did not develop autism Low-risk children who were the younger siblings of typically developing children Infants who developed autism by the age of 3 Children who also had early autism symptoms but chose to receive treatment at an older age Treatment based on Early Start Denver Model The treatment was based on the highly successful Early Start Denver Model (ESDM) intervention developed by Rogers and her colleague, Geraldine Dawson, professor of psychiatry, psychology and pediatrics at Duke University in North Carolina. ESDM is usually provided in the home by trained therapists and parents during natural play and daily routines. Parents were coached to concentrate their interactions on supporting their infants’ individualized developmental needs and interests, and embedded these practices into all of their play and caretaking, focusing on creating pleasurable social routines to increase their children’s opportunities for learning. Parents were encouraged to follow their infants’ interests and subtle cues and gauge activities in ways that optimized their child's attention and engagement. The intervention focused on increasing: Infant attention to parent faces and voices Parent-child interactions that attract infants' attention, bringing smiles and delight to both Parent imitation of infant sounds and intentional actions Parent use of toys to support, rather than compete with, the child's social attention The treatment sessions included: Greeting and parent progress sharing A warm-up period of parent play, followed by discussion of the activity and intervention goals Discussion of a new topic, using a parent manual Parents interacting in a typical daily routine with their child while fostering social engagement, communication and appropriate play, with coaching from therapists Parents practicing the approach with their child across one or two additional home routines with toys or caregiving activities Autism scores lowered by 18 to 36 months All of the participants who received treatment were between 6 and 15 months old, lived within a one-hour drive of the MIND Institute, and came from families where English was the primary language. They had normal vision and hearing and no significant medical conditions. All received assessments prior to their participation and at multiple points throughout the study. The treatment group of seven children received scores on the Autism Observation Scale for Infants (AOSI) and the Infant-Toddler Checklist that indicated they were highly symptomatic and at risk of developing ASD. Their symptoms also elicited clinical concern from professors Rogers and Ozonoff. The study measured the children’s and parents’ responses to the intervention. Treatment began immediately after enrollment and consisted of 12 one-hour sessions with infant and parent. It was followed by a six-week maintenance period with biweekly visits, and follow-up assessments at 24 and 36 months. The treatment sessions focused on parent–child interactions during typical daily life and provided parent coaching as needed to increase infant attention, communication, early language development, play and social engagement. The children who received the intervention had significantly more autism symptoms at 9 months, but significantly lower autism severity scores at 18- to 36-months of age, when compared with a small group of similarly symptomatic infants who did not receive the therapy. Overall, the children who received the intervention had less impairment in terms of autism diagnosis, and language and development delays than either of the other affected groups. Treating severe disability Given the preliminary nature of the findings, the study only suggests that treating these symptoms so early may lessen problems later. Larger, well controlled studies are needed to test the treatment for general use. However, the researchers said that this initial study is significant because of the very young ages of the infants, the number of symptoms and delays they exhibited early in life, the number of comparison groups involved, and because the intervention was low intensity and could be carried out by the parents in everyday routines. “I am not trying to change the strengths that people with ASD bring to this world," Rogers said when asked whether she is seeking to "cure" autism. "People with ASD contribute greatly to our culture," she said. "The diversity of human nature is what makes us a powerful and strong species. We are trying to reduce the disability associated with ASD." “My goal is for children and adults with autism symptoms to be able to participate successfully in everyday life and in all aspects of the community in which they want to participate: to have satisfying work, recreation, and relationships, education that meets their needs and goals, a circle of people they love, and to be generally happy with their lives.” ### Other study authors are Laurie Vismara of UC Davis and York University, Toronto; and A.L. Wagner, C. McCormick and Gregory Young, all of UC Davis. The study was funded by grants from the National Institute of Child Health and Human Development R21 HD 065275 to Sally Rogers and National Institute of Mental Health grant MH068398 to Ozonoff. At the UC Davis MIND Institute, world-renowned scientists engage in collaborative, interdisciplinary research to find the causes of and develop treatments and cures for autism, attention-deficit/hyperactivity disorder (ADHD), fragile X syndrome, 22q11.2 deletion syndrome, Down syndrome and other neurodevelopmental disorders. For more information, visit mindinstitute.ucdavis.edu." For more informationon this topic and other related subjects, please visit Counselor CEUs

Autism Spectrum Disorder: Uncovering Clues to a Complicated Condition

Autism Spectrum Disorder Uncovering Clues to a Complicated Condition Autism is a complex brain disorder that first appears during early childhood. It affects how a person behaves and interacts with others. People with autism might not look you in the eye when talking. They may spend a lot of time lining up toys or other objects. Or they may say the same sentence over and over. The disorder is so variable—affecting each person in very different ways—that it can be difficult to diagnose and treat. This variability is why autism is called a “spectrum” disorder. It spans the spectrum from mild to severe and includes a wide range of symptoms. NIH-funded scientists have been working to uncover the secrets of autism. They’ve identified genes that may boost the risk for autism. They’ve developed therapies that can help many of those affected. And they’ve found that starting treatment as early as possible can lead to better outcomes. Still, there’s much more we need to learn about this complicated condition. About 1 in 88 children may have autism spectrum disorder, according to the U.S. Centers for Disease Control and Prevention. The number of affected children has been growing in recent years. Many researchers believe this increase is due to better diagnosis and awareness. Others suspect that yet-unknown factors may be partly to blame. Although the exact causes of autism are unclear, research suggests that both genes and the environment play important roles. Autism affects a child’s development in different ways, and so it’s known as a developmental disorder. Parents are often the first to suspect that something may not be quite right with their child’s development. They may notice their baby doesn’t make eye contact, becomes overly focused on certain objects or isn’t “babbling” like other children the same age. “A parent may first have concerns when a child is under 2 years of age,” says Dr. Connie Kasari, a child development expert at the University of California, Los Angeles. “A more certain diagnosis can usually be made by age 2, but some cases might not be clear until much later.” There are no direct tests, like blood tests or brain scans, that can identify autism. Instead, the condition is diagnosed by looking at a child’s behaviors and development. “All affected children have some sort of social impairment, but symptoms vary along a continuum,” Kasari says. “Impairment can range from kids who are in their ‘own world’ and seemingly unaware of others to high-functioning individuals who are just awkward and seem to miss the point of social interactions.” In May 2013, the American Psychiatric Association updated an important book that’s used to diagnose and classify mental disorders. The DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) includes an updated definition for autism spectrum disorder. The condition is now identified by looking for 2 broad categories of symptoms: problems with social communication and the presence of “stereotyped” behaviors, such as walking in certain patterns or insisting on specific or unusual routines. To be diagnosed with autism, these symptoms must arise during early childhood, even if they’re not noticed until later, when social demands increase. “The new DSM-5 definition moves all the disorders into a single spectrum, rather than the 4 separate autistic disorders described in the past,” says NIH pediatrician and neuroscientist Dr. Susan Swedo. She chaired the expert panel that updated the DSM-5 definition of autism spectrum disorders. “The new criteria are also more inclusive of minorities, adolescents and young adults with autism than the previous edition, which focused more on boys ages 4 to 9.” Getting diagnosed as early as possible is crucial. “Autism is treatable even though it’s not curable,” says Dr. David Mandell, an expert in autism and health services at the University of Pennsylvania. “If we intervene early enough with appropriate and intensive care, we can reduce a lot of impairments for many kids who have autism.” Research has shown that therapies focusing on behavior and communication can be helpful. Some drugs can also reduce certain related symptoms, but no medications have been approved by the U.S. Food and Drug Administration specifically for treating the main symptoms of autism. “Because autism is such a complicated disorder, no one therapy fits everyone,” Kasari explains. Kasari and her colleagues developed and tested several treatments that focus on improving social skills and communication. In one study, preschoolers with autism received intense training in basic skills such as playing and sharing attention. Five years later, these children tended to have stronger vocabularies and better communication skills than children who received standard therapy. “We’ve found that if we can improve these basic skills, we can also improve language learning for these kids,” Kasari says. “We’re now studying 2 potential therapies in at-risk babies, ages 12- to 21-months old, to see if we can push language development along faster for the children.” Scientists are also looking for ways to predict likely outcomes for children with autism. One NIH-funded team found that the brain waves of some 2-year-olds with autism can have a distinctive pattern when they listen to familiar words. The children with more severe social symptoms didn’t have a typical focused response in the brain region that processes language. Follow-up studies showed that these brain responses predicted the children’s developmental abilities 2 and 4 years later. “In the future, we’d like to be able to assess a child based on brain function or their genetic profile and then identify the intervention that might be best for that particular kid,” Mandell says. A growing number of studies are looking at autism in older age groups. “While we think about autism as a disorder of childhood, it actually continues through adolescence and into adulthood,” Mandell says. “Some adults with autism have been misdiagnosed, and they can find themselves being treated for other conditions. We’d like to develop better screening tools and ultimately provide these adults with skills and supports to help them become happy and productive citizens.” While research is ongoing, it’s clear that early diagnosis and treatment can improve outcomes for those with autism. If you’re concerned about your child’s social communication and behaviors, don’t wait. Talk with your child’s doctor. You may be referred to a specialist who can do a thorough evaluation. The earlier autism is diagnosed, the sooner specific therapy can begin Social Worker Continuing Education

Aging and gene expression -- possible links to autism and schizophrenia in offspring

Advanced paternal age has been associated with greater risk for psychiatric disorders, such as schizophrenia and autism. With an increase in paternal age, there is a greater frequency of certain types of mutations that contribute to these disorders in offspring. Mutations are changes in the genetic code. Recent research, however, looks beyond the genetic code to "epigenetic effects", which do not involve changes in the genes themselves, but rather in how they are expressed to determine one's characteristics. Such epigenetic changes in sperm, related to ageing, have been linked with psychiatric disorders in offspring. Maria Milekic, PhD, reported today, at the American College of Neuropsychopharmacology annual meeting in Hollywood Florida, that old mice have an epigenetic change ‒ a loss of DNA methylation at the locations where the genetic code starts being transcribed. DNA methylation is a biochemical process that plays an important regulatory role in development and disease. The work was done by a research team in the Department of Psychiatry at Columbia University. Offspring of old fathers showed the same deficit in DNA methylation, and they differed in their behavior from the offspring of the young fathers. They showed less exploratory activity and differed in the startle response and in habituation. Two groups, with 10 breeder mice per group, were tested. The breeders were either old (12 month) or young (3 month) males, each bred with two young (3 month) female mice. Then the behavior of the offspring was tested when they were 3 months old. DNA methylation also was tested in the young and old fathers' sperm, and brains of the offspring were tested for DNA methylation as well as gene expression. "We were interested in understanding the mechanism of the paternal age effect", said Dr. Milekic."The risk for schizophrenia increases 2-fold when a father is over 45 years of age, and the risk for autism increases 2-5-fold. It seemed unlikely that mutation alone could account for this. We therefore speculated that DNA methylation could provide an alternative mechanism." Not only did the offspring of the old fathers differ from their counterparts with young fathers in DNA methylation, they also showed significant differences in the expression of genes that have been implicated in autism spectrum disorders and that are known to regulate the development and function of the brain. These findings point to possible factors that can lead to autism spectrum disorders and schizophrenia, and ultimately may lead to more effective therapeutic interventions. With respect to studies in the immediate future, Dr. Milekic said,"We are trying to evaluate changes in different brain regions. Our studies before did not compare brain regions. Most of the genes that have altered expression are in the cerebellum. We are interested in how DNA methylation in the cerebellum is affected by paternal age." Social Worker CEUs ### The work was supported by grants from NIMH and the Simon Foundation to Jay Gingrich, MD, PhD, and a NARSAD Young Investigator Awa rd from the Brain and Behavior Research Foundation to Dr. Milekic.

Focusing on faces

Researchers find neurons in amygdala of autistic individuals have reduced sensitivity to eye region of others' faces Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals. "We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team's findings. "We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally." The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD. By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown. "It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment." "We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs. To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs. "At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says MHC Continuing Education ### Funding for the research outlined in the Neuron paper, titled "Single-neuron correlates of abnormal face processing in autism," was provided by the Simons Foundation, the Gordon and Betty Moore Foundation, the Cedars-Sinai Medical Center, Autism Speaks, and the National Institute of Mental Health. Additional coauthors were Caltech postdoctoral scholar Oana Tudusciuc and graduate student Shuo Wang.

New study identifies signs of autism in the first months of life

Scientists at Marcus Autism Center, Children's Healthcare of Atlanta and Emory University School of Medicine identify markers of social disability present in 2 to 6-month-old infants later diagnosed with autism Researchers at Marcus Autism Center, Children's Healthcare of Atlanta and Emory University School of Medicine have identified signs of autism present in the first months of life. The researchers followed babies from birth until 3 years of age, using eye-tracking technology, to measure the way infants look at and respond to social cues. Infants later diagnosed with autism showed declining attention to the eyes of other people, from the age of 2 months onwards. The results are reported in the Nov. 6, 2013 advanced online publication of the journal Nature. The study followed two groups of infants, one at low and one at high risk for having autism spectrum disorders. High-risk infants had an older sibling already diagnosed with autism, increasing the infant's risk of also having the condition by 20 fold. In contrast, low-risk infants had no first, second, or third degree relatives with autism. "By following these babies from birth, and intensively within the first six months, we were able to collect large amounts of data long before overt symptoms are typically seen," said Warren Jones, Ph.D., the lead author on the study. Teams of clinicians assessed the children longitudinally and confirmed their diagnostic outcomes at age 3. Then the researchers analyzed data from the infants' first months to identify what factors separated those who received an autism diagnosis from those who did not. What they found was surprising MFT Intern Continuing Education "We found a steady decline in attention to other people's eyes, from 2 until 24 months, in infants later diagnosed with autism," said co-investigator Ami Klin, Ph.D., director of Marcus Autism Center. Differences were apparent even within the first 6 months, which has profound implications. "First, these results reveal that there are measurable and identifiable differences present already before 6 months. And second, we observed declining eye fixation over time, rather than an outright absence. Both these factors have the potential to dramatically shift the possibilities for future strategies of early intervention." Jones is director of research at Marcus Autism Center and assistant professor in the Department of Pediatrics at Emory University School of Medicine. Klin is director of Marcus Autism Center, chief of the Division of Autism & Related Disorders in the Department of Pediatrics at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar. The researchers caution that what they observed would not be visible to the naked eye, but requires specialized technology and repeated measurements of a child's development over the course of months. "To be sure, parents should not expect that this is something they could see without the aid of technology," said Jones, "and they shouldn't be concerned if an infant doesn't happen to look at their eyes at every moment. We used very specialized technology to measure developmental differences, accruing over time, in the way that infants watched very specific scenes of social interaction." Before they can crawl or walk, babies explore the world intensively by looking at it, and they look at faces, bodies, and objects, as well as other people's eyes. This exploration is a natural and necessary part of infant development, and it sets the stage for brain growth. The critical implications of the study relate to what it reveals about the early development of social disability. Although the results indicate that attention to others' eyes is already declining by 2 to 6 months in infants later diagnosed with autism, attention to others' eyes does not appear to be entirely absent. If infants were identified at this early age, interventions could more successfully build on the levels of eye contact that are present. Eye contact plays a key role in social interaction and development, and in the study, those infants whose levels of eye contact diminished most rapidly were also those who were most disabled later in life. This early developmental difference also gives researchers a key insight for future studies. "The genetics of autism have proven to be quite complex. Many hundreds of genes are likely to be involved, with each one playing a role in just a small fraction of cases, and contributing to risk in different ways in different individuals," said Jones. "The current results reveal one way in which that genetic diversity may be converted into disability very early in life. Our next step will be to expand these studies with more children, and to combine our eye-tracking measures with measures of gene expression and brain growth." ### The study, Attention to Eyes is Present But In Decline in 2-6 Month-Olds Later Diagnosed with Autism was funded by the Simons Foundation, the National Institute of Mental Health, the Marcus Foundation and the Whitehead Foundation. More information can be found at http://www.marcus.org/infants. Marcus Autism Center Marcus Autism Center is a not-for-profit organization and an affiliate of Children's Healthcare of Atlanta that treats more than 5,500 children with autism and related disorders a year. As one of the largest autism centers in the U.S. and one of only three National Institutes of Health Autism Centers of Excellence, Marcus Autism Center offers families access to the latest research, comprehensive evaluations and intensive behavior treatments. With the help of research grants, community support and government funding, Marcus Autism Center aims to maximize the potential of children with autism today and transform the very nature of autism for future generations. Visit marcus.org for more information.

Autism Risk Unrelated to Total Vaccine Exposure in Early Childhood

A child’s risk for developing an autism spectrum disorder (ASD) is not increased by receiving “too many vaccines too soon,” according to a new study published in The Journal of Pediatrics. Although previous scientific evidence has shown that vaccines do not cause autism, more than 1 in 10 parents refuse or delay vaccinations for their young children. A main safety concern of these parents is the number of vaccines administered, both on a single day and over the course of a child’s first 2 years of life. In the first study of its kind, researchers from the CDC and Abt Associates, Inc. compared vaccine records for over 1000 children born from 1994–1999, some of whom were later diagnosed with ASD. The researchers calculated the total number of vaccine antigens each child received between birth and age 2, as well as the maximum number of antigens each child received on a single day. The study found that the total number of vaccine antigens received was the same between children with ASD and those without ASD. Additionally, antigen number was also found to be unrelated to the development of two sub-categories of ASD—autistic disorder and ASD with regression LCSW Continuing Education The researchers concluded, “The possibility that immunological stimulation from vaccines during the first 1 or 2 years of life could be related to the development of ASD is not well-supported by what is known about the neurobiology of ASDs.”

5 Most Common Mental Illnesses Share the Same Genes

From Autism to Depression: Largest Genetic Study Shows Mental Disorders Share Genetic Kinks --Associated Press Mental Illnesses Share Common DNA Roots, Study Finds --nbcnews.com An NIMH-funded study published online today in Lancet reveals that the five most common disorders—autism, attention deficit hyperactivity disorder, bipolar disease, schizophrenia, and major depression—all share similar genetic components. “These disorders that we thought of as quite different may not have such sharp boundaries,” said Dr. Jordan W. Smoller of Massachusetts General Hospital, one of the lead study authors. The results suggest that a rethink in how these disorders are defined might be in order. Rather than focusing on symptoms, which can be attributed to one or more disorder, physicians could one day start to rely on specific gene mutations or biologic pathways to make a formal diagnosis Aspira Continuing Education Online Courses And it also could lead to better treatments, said Dr. Bruce Cuthbert, director of the NIMH’s Division of Adult Translational Research and Treatment Development. “We are finally starting to make inroads where we have actual physiological mechanisms that we can target,” he said. “We can really start to understand the biology instead of having to guess at it.” Reference Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of Risk Loci with Shared Effects on Five Major Psychiatric Disorders: A Genome-wide Analysis. Lancet, published online February 28, 2013.

Autism early intervention found to normalize brain activity in children as young as 18 months

An intensive early intervention therapy that is effective for improving cognition and language skills among very young children with autism also normalizes their brain activity, decreases their autism symptoms and improves their social skills, a nationwide study has found. The researchers said the study is the first to demonstrate that an autism early intervention program can normalize brain activity. "We know that infant brains are quite malleable and previously demonstrated that this therapy capitalizes on the potential of learning that an infant brain has in order to limit autism's deleterious effects," said study author Sally Rogers, professor of psychiatry and behavioral sciences and a researcher with the UC Davis MIND Institute. "The findings on improved behavioral outcomes and the ability to normalize brain activity associated with social activities signify that there is tremendous potential for the brains of children with autism to develop and grow more normally," Rogers said. Published online today in the Journal of the American Academy of Child & Adolescent Psychiatry, the randomized, case-controlled, multi-centered study titled "Early behavioral intervention is associated with normalized brain activity in young children with autism," found that the children who received the intervention exhibited greater brain activation when viewing faces rather than objects, a response that was typical of the normal children in the study, and the opposite of the children with autism who received other intervention counselor ceus The U.S. Centers for Disease Control and Prevention estimates that 1 in 88 children born today will be diagnosed with autism spectrum disorder. Hallmarks of the neurodevelopmental condition include persistent deficits in social communication and relatedness, and repetitive or restrictive patterns of interest that appear in early childhood and impair everyday functioning. Named the Early Start Denver Model (ESDM), the intervention method was developed by Rogers and Geraldine Dawson, chief science officer of the research and advocacy organization Autism Speaks. The therapy fuses a play-based, developmental, relationship-based approach and the teaching methods of applied behavioral analysis. "This may be the first demonstration that a behavioral intervention for autism is associated with changes in brain function as well as positive changes in behavior," said Thomas R. Insel, director of the National Institute of Mental Health, which funded the study. "By studying changes in the neural response to faces, Dawson and her colleagues have identified a new target and a potential biomarker that can guide treatment development." For the present study, the researchers recruited 48 diverse male and female children diagnosed with autism between 18 and 30 months in Sacramento, Calif., and in Seattle, as well as typically developing case controls. The ratio of male-to-female participants was more than 3-to-1. Autism is five times more common among boys than girls. Approximately half of the children with autism were randomly assigned to receive the ESDM intervention for over two years. The participants received ESDM therapy for 20 hours each week, and their parents also were trained to deliver the treatment, a core feature of the intervention. The other participants with autism received similar amounts of various community-based interventions as well as evaluations, referrals, resource manuals and other reading materials. At the study's conclusion, the participants' brain activity was assessed using electroencephalograms (EEGs) that measured brain activation while viewing social stimuli -- faces -- and non-social stimuli -- toys. Earlier studies have found that typical infants and young children show increased brain activity when viewing social stimuli rather than objects, while children with autism show the opposite pattern. Twice as many of the children who received the ESDM intervention showed greater brain activation when viewing faces rather than when viewing objects -- a demonstration of normalized brain activity. Eleven of the 15 children who received the ESDM intervention, 73 percent, showed more brain activation when viewing faces than toys. Similarly, 12 of the 17 typically developing children, or 71 percent, showed the same pattern. But the majority -- 64 percent -- of the recipients of the community intervention showed the opposite, "autistic" pattern, i.e., greater response to toys than faces. Only 5 percent showed the brain activation of typical children. Further, the children receiving ESDM who had greater brain activity while viewing faces also had fewer social-pragmatic problems and improved social communication, including the ability to initiate interactions, make eye contact and imitate others, said MIND Institute researcher Rogers. Use of the ESDM intervention has been shown to improve cognition, language and daily living skills. A study published in 2009 found that ESDM recipients showed more than three times as much gain in IQ and language than the recipients of community interventions. "This is the first case-controlled study of an intensive early intervention that demonstrates both improvement of social skills and normalized brain activity resulting from intensive early intervention therapy," said Dawson, the study's lead author and professor of psychiatry at the University of North Carolina, Chapel Hill. "Given that the American Academy of Pediatrics recommends that all 18- and 24-month-old children be screened for autism, it is vital that we have effective therapies available for young children as soon as they are diagnosed." "For the first time," Dawson continued, "parents and practitioners have evidence that early intervention can alter the course of brain and behavioral development in young children. It is crucial that all children with autism have access to early intervention which can promote the most positive long-term outcomes." Rogers, Dawson and Laurie J. Vismara, also a researcher with the MIND Institute, have authored two books on the intervention. One for professionals is titled "Early Start Denver Model for Young Children with Autism: Promoting Language, Learning, and Engagement" and one for parents titled "An Early Start for Your Child with Autism: Using Everyday Activities to Help Kids Connect, Communicate, and Learn." The ESDM intervention is available in Sacramento through the MIND Institute clinic and in a number of locations throughout the U.S. and other nations. Training in delivering the ESDM method is provided through the MIND Institute and the University of Washington. ### Other study authors include Emily J.H. Jones, Kaitlin Venema, Rachel Lowy, Susan Faja, Dana Kamara, Michale Murias, Jessica Greenson, Jamie Winter, Milani Smith and Sara J. Webb, all of the University of Washington, and Kristen Merkle of Vanderbilt University. The study was funded by a grant from the National Institute of Mental Health and by a postdoctoral fellowship to Jones from Autism Speaks. Autism Speaks is the world's leading autism science and advocacy organization. It is dedicated to funding research into the causes, prevention, treatments and a cure for autism; increasing awareness of autism spectrum disorders; and advocating for the needs of individuals with autism and their families. At the UC Davis MIND Institute, world-renowned scientists engage in collaborative, interdisciplinary research to find the causes of and develop treatments and cures for autism, attention-deficit/hyperactivity disorder (ADHD), fragile X syndrome, 22q11.2 deletion syndrome, Down syndrome and other neurodevelopmental disorders. For more information, visit mindinstitute.ucdavis.edu

Studying sex differences in autism focus of $15 million NIH award to Yale center

The reasons why autism spectrum disorders are almost five times more common among boys than among girls may soon be revealed, thanks to a five-year, $15 million National Institutes of Health (NIH) grant awarded to Yale School of Medicine for the Autism Centers of Excellence (ACE) research program. Led by principal investigator Kevin Pelphrey of Yale Child Study Center, the Yale ACE award is part of a $100 million National Institutes of Health grant to nine institutions investigating sex differences in autism spectrum disorders, or ASD, as well as studying ASD and limited speech. Pelphrey and a collaborative team of researchers from Yale, UCLA, Harvard, and the University of Washington, will investigate the poorly understood nature of autism in females. The team will study an unprecedented number of girls with autism and will focus on genes, brain function, and behavior throughout childhood and adolescence. The objectives are to identify causes of autism and develop novel treatments.

ASDs are complex developmental disorders that affect how a person behaves, interacts with others, communicates, and learns. According to the Centers for Disease Control and Prevention, ASD affects approximately 1 in 88 children in the United States. "This award represents an innovative collaboration among three laboratories at Yale led by Drs. Matthew State, James McPartland, and myself," said Pelphrey, the Harris Associate Professor in the Child Study Center, and associate professor of psychology, and director of the Child Neuroscience Laboratory. "It is my hope that this award will invigorate research in autism at Yale and allow us to maintain our outstanding history of cutting edge work in this field." Alcoholism and Drug Abuse Counselors Continuing Education ### NIH created the ACE Program in 2007 to launch an intense and coordinated research program into the causes of ASD and to find new treatments. The program supports large collaborative efforts to advance the broad research goals. The program expanded this year to examine such issues as children and adults who have limited or no speech, possible links between ASD and other genetic syndromes, potential treatments, and the possible reasons why ASDs are more common among boys than girls, according to Alice Kay of the Intellectual and Developmental Disabilities Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), one of five institutes funding the ACE program. In addition to the NICHD, the NIH institutes that support the ACE program are the National Institute on Deafness and Other Communication Disorders, the National Institute of Environmental Health Sciences, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. The eight other researchers to receive ACE funding hail from the following institutions: University of California, Emory University, Boston University, University of North Carolina at Chapel Hill, Mount Sinai School of Medicine, and Harvard Medical School. *Research reported here was supported by the National Institute Of Mental Health (NIMH) of the National Institutes of Health under Award Number R01MH100028.

Social Brain Circuits Disrupted in Autism

In a study of high-functioning adolescents with an autism spectrum disorder, scientists using functional brain imaging have found reduced connectivity selectively affecting parts of the brain that form circuits supporting social behavior. The findings sharpen the focus of previous reports suggesting disruptions in connectivity across the brain in autism, and offer a target for future studies to search for the genes that shape the development of these circuits and how they become disrupted in the disorder. Background Difficulties with communication and social interactions are central features of autism spectrum disorders (ASD), and are universally present in those with an ASD. In an effort to determine how brain function is disrupted in autism, scientists have used noninvasive functional brain imaging to explore connectivity in the brain—the extent to which patterns of activity in functionally related parts of the brain correlate with each other. Scientists increasingly see the brain and its disorders in terms of circuits, with a given behavior engaging multiple centers across the brain, functioning in tandem. Functional imaging of people with an ASD has suggested that there are disruptions in connectivity across the brain. Narrowing the search to determine if losses in connectivity affect only specific circuits has been difficult, however. Mapping which centers of the brain are tightly connected in most people but disrupted in illness potentially involves comparisons in activity between thousands of points in different brain regions. Accordingly, previous studies have focused on a predetermined, small handful of regions to evaluate connectivity differences in ASD. This Study Stephen Gotts, Alex Martin and colleagues at the National Institute of Mental Health developed an approach to identify regions throughout the entire brain for which connectivity was reduced in ASD, and measure the magnitude of the reductions. The scans were done on 31 adolescents with ASD and 29 without the disorder, while they were at rest, not engaged in any task. Scan results revealed decreases in connectivity among those with ASD compared to individuals without ASD, concentrated in areas of the brain involved in social functions. In particular, the greatest decreases occurred between a cluster of brain regions involved in the emotional aspects of social behavior (the limbic brain) and two other clusters: one involved in language and communication and the other in the interplay between visual perception and movement. Moreover, participants in the study who had the greatest difficulties with social interactions were those in whom the decreases in connectivity were the most marked. Significance These data offer evidence in terms of brain activity to confirm what scientists have suspected but have been unable to examine systematically, that disruptions in connectivity in autism are concentrated in social centers of the brain. According to Dr. Gotts, what they found was not that this circuit was inactive, but that, among participants with ASD, patterns of activity in the three clusters of brain centers did not correlate with each other. “So a circuit that is normally in sync with the rest of the social brain has become decoupled. The limbic brain is composed of areas and structures that mediate emotional and affective components of our social interactions, so you can understand the social rules about how other people are behaving and acting. These brain regions are active in autism spectrum disorders and are coordinated amongst themselves, but they are not interacting appropriately with the rest of the social brain.” The clusters of brain centers identified in the study as functionally connected are also anatomically connected circuits. One of the most exciting aspects of the research, says Gotts, is that in humans, this brain circuit shows a different developmental growth trajectory relative to the rest of the brain's cortex during typical development. Since genes are responsible for guiding growth during development, these findings provide a target for searching for genes that drive abnormal growth and limbic circuit functioning in ASD. The differences in connectivity also offer the possibility of a “systems-level” marker—an indicator reflecting function across the brain—to use in developing and testing possible treatment. Local abnormalities in cell signaling or, alternatively, loss of longer range neuronal connections could explain the differences reported. If the differences can be traced to more local dynamics, it may be possible to identify new medications or behavioral therapies; variations in circuit activity as shown by functional brain imaging could be used as markers of whether therapy was effective.

Brain regions showing decreases in connectivity in high functioning adolescents with an autism spectrum disorder (ASD) are shown to the left: Limbic-related regions involved in emotional/affective aspects of social behavior (shown in red), regions involved in social communication and comprehension (shown in blue), and regions involved in visual, somatosensory and motor aspects of social behavior (shown in green). In typically developing adolescents, these circuits are interactive and coordinated, exhibiting correlated patterns of brain activity over time (traces of neural activity would appear as illustrated in upper right plot). In adolescents with an ASD, the activity in the limbic circuit has become decoupled from the other social brain regions (see red activity trace in lower right plot). Activity within the limbic circuit itself remains coordinated but no longer interacts appropriately with the other two circuits nursing ceus Reference Gotts, S.J., Simmons, W.K., Milbury, L.A., Wallace, G.L., Cox, R.W., and Martin, A. Fractionation of Social Brain Circuits in Autism Spectrum Disorders. Brain 2012 doi:10.1093/brain/aws160.

UCLA study uncovers new tools for targeting genes linked to autism

Findings could lead to future therapeutic targets UCLA researchers have combined two tools – gene expression and the use of peripheral blood -- to expand scientists' arsenal of methods for pinpointing genes that play a role in autism. Published in the June 21 online edition of the American Journal of Human Genetics, the findings could help scientists zero in on genes that offer future therapeutic targets for the disorder. "Technological advances now allow us to rapidly sequence the genome and uncover dozens of rare mutations," explained principal investigator Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics and a professor of neurology at the David Geffen School of Medicine at UCLA. "But just because a particular genetic mutation is rare doesn't mean it's actually causing disease. We used a new approach to tease out potential precursors of autism from the occasional genetic glitch." Geschwind and his colleagues studied DNA contained in blood samples from 244 families with one healthy child and one child on the autism spectrum. The team used a hybrid method that blended tests that read the order of DNA bases with those that analyze gene expression, the process by which genes make cellular proteins. "Monitoring gene expression provides us with another line of data to inform our understanding of how autism develops," said Geschwind, who is also director of the Center for Autism Research and Treatment at the Semel Institute for Neuroscience and Behavior at UCLA. "Integrating this method with the sequencing of DNA bases expands our ability to find mutations leading to the disease." Gene expression offers a molecular signpost pointing scientists in the right direction by narrowing the field and highlighting specific areas of the genome. For example, if a gene is expressed at substantially higher or lower levels in a patient, researchers will review the patient's DNA to check if that gene has changed. "We found that we can use gene expression to help understand whether a rare mutation is causing disease or playing a role in disease development," said Geschwind. "A true mutation will alter a gene's sequence, modifying the protein or RNA it produces -- or preventing the gene from producing them entirely. "A gene mutation accompanied by a change in expression clues us to a hot spot on the genome and directs us where to look next," he added. "Not all mutations will influence gene expression, but this approach improves our ability to pinpoint those that do." The researchers used the combined method to prioritize gene targets that merit closer investigation, potentially explaining why one person develops autism and their sibling does not. Their search turned up new regions in the genome where genetic variations showed strong links to autism and altered expression patterns. Genes in these regions were more likely to be mutated in the autistic children than in their unaffected siblings. "When we looked at genes associated with nervous-system function we found significantly more genes were expressed at higher or lower levels in the children diagnosed with autism than we did in their siblings unaffected by the disorder," said Geschwind. Finally, the research team discovered that the DNA contained in peripheral blood can help shed light on diseases of the central nervous system. Brain cells and genes related to synaptic function are expressed in the blood, offering a window into gene expression. "Brain tissue from people with autism is not readily available for study, and some people are reluctant to use non-neural tissue in psychiatric disease," explained Geschwind. "But our study demonstrates that even peripheral blood can expand our knowledge of neurological disease." The team's next step will be to replicate their findings in a larger population. ### 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 research was supported by grants from the Simons Foundation, the National Institute of Mental Health (5R01 MH081754-04), the Wellcome Trust and Autism Speaks. Geschwind's coauthors included first author Rui Luo, Irina Voineagu, Lambertus Klei, Chaochao Cai, Jing Ou, Jennifer Lowe and Matthew State of UCLA; Stephan Sanders of Yale University; Ni Huang and Matthew Hurles of the Wellcome Trust Sanger Institute; and Su Chu and Bernie Devlin of Carnegie Mellon University. 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 social worker ceus

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.

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

Agent Reduces Autism-like Behaviors in Mice

Press Release • April 25, 2012

Agent Reduces Autism-like Behaviors in Mice Boosts Sociability, Quells Repetitiveness – NIH Study National Institutes of Health researchers have reversed behaviors in mice resembling two of the three core symptoms of autism spectrum disorders (ASD). An experimental compound, called GRN-529, increased social interactions and lessened repetitive self-grooming behavior in a strain of mice that normally display such autism-like behaviors, the researchers say. GRN-529 is a member of a class of agents that inhibit activity of a subtype of receptor protein on brain cells for the chemical messenger glutamate, which are being tested in patients with an autism-related syndrome. Although mouse brain findings often don’t translate to humans, the fact that these compounds are already in clinical trials for an overlapping condition strengthens the case for relevance, according to the researchers. “Our findings suggest a strategy for developing a single treatment that could target multiple diagnostic symptoms,” explained Jacqueline Crawley, Ph.D., of the NIH’s National Institute of Mental Health (NIMH). “Many cases of autism are caused by mutations in genes that control an ongoing process – the formation and maturation of synapses, the connections between neurons. If defects in these connections are not hard-wired, the core symptoms of autism may be treatable with medications.” Crawley, Jill Silverman, Ph.D., and colleagues at NIMH and Pfizer Worldwide Research and Development, Groton, CT, report on their discovery April 25th, 2012 in the journal Science Translational Medicine. "These new results in mice support NIMH-funded research in humans to create treatments for the core symptoms of autism,” said NIMH director Thomas R. Insel, M.D. “While autism has been often considered only as a disability in need of rehabilitation, we can now address autism as a disorder responding to biomedical treatments." social worker ceus Crawley’s team followed-up on clues from earlier findings hinting that inhibitors of the receptor, called mGluR5, might reduce ASD symptoms. This class of agents – compounds similar to GRN-529, used in the mouse study – are in clinical trials for patients with the most common form of inherited intellectual and developmental disabilities, Fragile X syndrome, about one third of whom also meet criteria for ASDs. To test their hunch, the researchers examined effects of GRN-529 in a naturally occurring inbred strain of mice that normally display autism-relevant behaviors. Like children with ASDs, these BTBR mice interact and communicate relatively less with each other and engage in repetitive behaviors – most typically, spending an inordinate amount of time grooming themselves. Crawley’s team found that BTBR mice injected with GRN-529 showed reduced levels of repetitive self-grooming and spent more time around – and sniffing nose-to-nose with – a strange mouse. Moreover, GRN-529 almost completely stopped repetitive jumping in another strain of mice. “These inbred strains of mice are similar, behaviorally, to individuals with autism for whom the responsible genetic factors are unknown, which accounts for about three fourths of people with the disorders,” noted Crawley. “Given the high costs – monetary and emotional – to families, schools, and health care systems, we are hopeful that this line of studies may help meet the need for medications that treat core symptoms.” Reference: Silverman JL, Smith DG, Rizzo SJS, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley, JN. Negative allosteric modulation of the MGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. April 25, 2012, Science Translational Medicine.

Spontaneous Gene Glitches Linked to Autism Risk with Older Dads

Non-Inherited Mutations Spotlight Role of Environment – NIH-Supported Study, Consortium ceus for nurses

Researchers have turned up a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders. Moreover, the number of such transmitted genetic glitches increased with paternal age. The discovery may help to explain earlier evidence linking autism risk to older fathers.

The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs. One of the studies determined that having such glitches boosts a child’s risk of developing autism five to 20 fold.

Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. They reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not. While the changes identified don’t account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum.

“These results confirm that it’s not necessarily the size of a genetic anomaly that confers risk, but its location – specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it’s this kind of knowledge that will yield potential targets for new treatments,” explained Thomas, R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

Multi-site research teams led by Mark Daly, Ph.D., of the Harvard/MIT Broad Institute, Cambridge, Mass., Matthew State, M.D., Ph.D., of Yale University, New Haven, Conn., and Evan Eichler, Ph.D., of the University of Washington, Seattle, report on their findings online April 4, 2012 in the journal Nature.

The study by Daly and colleagues was supported by NIMH – including funding under the American Recovery and Reinvestment Act. The State and Eichler studies were primarily supported by the Simons Foundation Autism Research Initiative. The studies also acknowledge the NIH’s National Human Genome Research Institute, National Heart Lung and Blood Institute, and National Institute on Child Health and Human Development and other NIH components.

All three teams sequenced the protein coding parts of genes in parents and an affected child – mostly in families with only one member touched by autism. One study also included comparisons with healthy siblings. Although these protein-coding areas represent only about 1.5 percent of the genome, they harbor 85 percent of disease-causing mutations. This strategy optimized the odds for detecting the few spontaneous errors in genetic transmission that confer autism risk from the “background noise” generated by the many more benign mutations.

Like larger deletions and duplications of genetic material previously implicated in autism and schizophrenia, the tiny point mutations identified in the current studies are typically not inherited in the conventional sense – they are not part of parents’ DNA, but become part of the child’s DNA. Most people have many such glitches and suffer no ill effects from them. But evidence is building that such mutations can increase risk for autism if they occur in pathways that disrupt brain development.

State’s team found that 14 percent of people with autism studied had suspect mutations – five times the normal rate. Eichler and colleagues traced 39 percent of such mutations likely to confer risk to a biological pathway known to be important for communications in the brain.

Although Daly and colleagues found evidence for only a modest role of the chance mutations in autism, those pinpointed were biologically related to each other and to genes previously implicated in autism.

The Eichler team turned up clues to how environmental factors might influence genetics. The high turnover in a male’s sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process. These can be passed-on to the offspring’s DNA, even though they are not present in the father’s DNA. This risk may worsen with aging. The researchers discovered a four-fold marked paternal bias in the origins of 51 spontaneous mutations in coding areas of genes that was positively correlated with increasing age of the father. So such spontaneous mutations could account for findings of an earlier study that found fathers of boys with autism were six times – and of girls 17 times – more likely to be in their 40’s than their 20’s.

“We now have a path forward to capture a great part of the genetic variability in autism – even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness,” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium. “These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence.”

References

Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. April 5, 2012. Nature.

O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. April 5, 2012.

Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shair K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 5, 2012.

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

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

Autism may be linked to abnormal immune system characteristics and novel protein fragment

University of South Florida researchers made the discoveries using mouse models of autism

Tampa, FL (Jan 3, 2012) – Immune system abnormalities that mimic those seen with autism spectrum disorders have been linked to the amyloid precursor protein (APP), reports a research team from the University of South Florida's Department of Psychiatry and the Silver Child Development Center.

The study, conducted with mouse models of autism, suggests that elevated levels of an APP fragment circulating in the blood could explain the aberrations in immune cell populations and function – both observed in some autism patients. The findings were recently published online in the Journal of the Federation of American Societies for Experimental Biology nursing ceus.

The USF researchers concluded that the protein fragment might be both a biomarker for autism and a new research target for understanding the physiology of the disorder.

"Autism affects one in 110 children in the United States today," said research team leader Jun Tan, MD, PhD, professor of psychiatry and the Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at USF's Silver Child Development Center. "While there are reports of abnormal T-cell numbers and function in some persons affected with autism, no specific cause has been identified. The disorder is diagnosed by behavioral observation and to date no associated biomarkers have been identified."

"Not only are there no associated biomarkers, but the prognosis for autism is poor and the costs associated with care are climbing," said Francisco Fernandez, MD, department chair and head of the Silver Center. "The work of Dr. Tan and his team is a start that may lead to earlier diagnosis and more effective treatments."

The amyloid precursor protein is typically the focus of research related to Alzheimer's disease. However, recent scientific reports have identified elevated levels of the particular protein fragment, called, sAPP-α, in the blood of autistic children. The fragment is a well-known growth factor for nerves, and studies imply that it plays a role in T-cell immune responses as well.

To study the autism-related effects of this protein fragment on postnatal neurodevelopment and behavior, Dr. Tan and his team inserted the human DNA sequence coding for the sAPP-α fragment into the genome of a mouse model for autism. While the studies are ongoing, the researchers documented the protein fragment's effects on the immune system of the test mice.

"We used molecular biology and immunohistochemistry techniques to characterize T-cell development in the thymus and also function in the spleen of the test animals," Dr. Tan said. "Then we compared transgenic mice to their wild-type littermates."

The researchers found that increased levels of sAPP-α in the transgenic mice led to increased cytotoxic T-cell numbers. The investigators also discovered subsequent impairment in the recall function of memory T-cells in the test mice, suggesting that the adaptive immune response is negatively affected in the presence of high levels of the protein fragment.

"Our work suggests that the negative effects of elevated sAPP-α on the adaptive immune system is a novel mechanism underlying certain forms of autism," concluded Dr. Tan, who holds the Silver Chair in Developmental Neurobiology. "The findings also add support to the role of sAPP-α in the T-cell response."


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Other researchers involved in the study were Antoinette Bailey, Dr. Huayan Hou, Dr. Demian Obregon, Jun Tian, Dr. Yuyan Zhu, Dr. Qiang Zou, Dr. William Nikolic, Dr. Michael Bengston, Dr. Takashi Mori (Saitama Medical Center/Saitama Medical University, Japan) and Dr. Tanya Murphy.

The work was supported by the Silver Endowment and a grant from the National Institutes of Health/National Institute of Mental Health.

Citation: Aberrant T-lymphocyte development and function in mice overexpressing human secreted amyloid precursor protein-α: implications for autism; A. Bailey, H. Hou, D. Obregon, J. Tian, Y. Zhu, Q. Zou, W. Nikolic, M. Bengston, T. Mori, T. Murphy, J. Tan; The FASEB Journal; published online Nov. 15, 2011.

USF Health's mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician's Group. The University of South Florida is a global research university ranked 34th in federal research expenditures for public universities.

NDAR Federation Creates Largest Source of Autism Research Data to Date

NIH-funded Database Sets Standard for Collaboration and Data Sharing

Source: NDAR

A data partnership between the National Database for Autism Research (NDAR), and the Autism Genetic Resource Exchange (AGRE) positions NDAR as possibly the largest repository to date of genetic, phenotypic, clinical, and medical imaging data related to research on autism spectrum disorders (ASD)LPC Continuing Education

“The collaboration between AGRE and NDAR exemplifies the efforts of government and stakeholders to work together for a common cause,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health, part of NIH. “NDAR continues to be a leader in the effort to standardize and share ASD data with the research community, and serves as a model to all research communities.”

NDAR is supported by the National Institutes of Health; AGRE is an Autism Speaks program.

NDAR’s mission is to facilitate data sharing and scientific collaboration on a broad scale, providing a shared common platform for autism researchers to accelerate scientific discovery. Built around the concept of federated repositories, NDAR integrates and standardizes data, tools, and computational techniques across multiple public and private autism databases. Through NDAR, researchers can access results from these different sources at the same time, using the rich data set to conduct independent analyses, supplement their own research data, or evaluate the data supporting published journal articles, among many other uses.

Databases previously federated with NDAR include Autism Speaks’ Autism Tissue Program, the Kennedy Krieger Institute’s Interactive Autism Network (IAN), and the NIH Pediatric MRI Data Repository. AGRE currently houses a clinical dataset with detailed medical, developmental, morphological, demographic, and behavioral information from people with ASD and their families.

Approved NDAR users will have access to data from the 25,000 research participants represented in NDAR, as well as 2,500 AGRE families and more than 7,500 participants who reported their own information to IAN.

NDAR is supported by NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, the National Institute of Environmental Health Sciences, and the NIH Center for Information Technology.

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

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

Training Peers Improves Social Outcomes for Some Kids with ASD

NIH-funded Study Finds Engaging Peers in Social Skills Intervention May Be More Helpful than Training Children with ASD Directly

Children with autism spectrum disorder (ASD) who attend regular education classes may be more likely to improve their social skills if their typically developing peers are taught how to interact with them than if only the children with ASD are taught such skills. According to a study funded by the National Institutes of Health, a shift away from more commonly used interventions that focus on training children with ASD directly may provide greater social benefits for children with ASD. The study was published online ahead of print on November 28, 2011, in the Journal of Child Psychology and Psychiatry.

"Real life doesn't happen in a lab, but few research studies reflect that," said Thomas R. Insel, director of the National Institute of Mental Health (NIMH), a part of NIH. "As this study shows, taking into account a person’s typical environment may improve treatment outcomes." CEUs for Counselors

The most common type of social skills intervention for children with ASD is direct training of a group of children with social challenges, who may have different disorders and may be from different classes or schools. The intervention is usually delivered at a clinic, but may also be school-based and offered in a one-on-one format. Other types of intervention focus on training peers how to interact with classmates who have difficulty with social skills. Both types of intervention have shown positive results in studies, but neither has been shown to be as effective in community settings.

Connie Kasari, Ph.D., of the University of California, Los Angeles, and colleagues compared different interventions among 60 children, ages 6-11, with ASD. All of the children were mainstreamed in regular education classrooms for at least 80 percent of the school day.

These children were randomly assigned to either receive one-on-one training with an intervention provider or to receive no one-on-one intervention. The children were also randomized to receive a peer-mediated intervention or no peer-mediated intervention. The two-step randomization resulted in four intervention categories, each with 15 children who had ASD:
Child-focused: direct, one-on-one training between the child with ASD and intervention provider to practice specific social skills, such as how to enter a playground game or conversation
Peer-mediated: group training with the intervention provider for three typically developing children from the same classroom as the student with ASD; the affected student did not receive any social skills training. The participating children were selected by study staff and teachers and were taught strategies for engaging students with social difficulties.
Both child-focused and peer-mediated interventions
Neither intervention.

All interventions were given for 20 minutes two times a week for six weeks. A follow-up was conducted 12 weeks after the end of the study. After the follow up phase, all children with ASD who had received neither intervention were re-randomized to one of the other treatment categories.

Children with ASD whose peers received training—including those who may also have received the child-focused intervention—spent less time alone on playgrounds and had more classmates naming them as a friend, compared to participants who received the child-focused interventions. Teachers also reported that students with ASD in the peer-mediated groups showed significantly better social skills following the intervention. However, among all intervention groups, children with ASD showed no changes in the number of peers they indicated as their friends.

At follow-up, children with ASD from the peer-mediated groups continued to show increased social connections despite some of the children having changed classrooms due to a new school year and having new, different peers.

According to the researchers, the findings suggest that peer-mediated interventions can provide better and more persistent outcomes than child-focused strategies, and that child-focused interventions may only be effective when paired with peer-mediated intervention.

In addition to the benefits of peer-mediated interventions, the researchers noted several areas for improvement. For example, peer engagement especially helped children with ASD to be less isolated on the playground, but it did not result in improvement across all areas of playground behavior, such as taking turns in games or engaging in conversations and other joint activities. Also, despite greater inclusion in social circles and more frequent engagement by their peers, children with ASD continued to cite few friendships. Further studies are needed to explore these factors as well as other possible mediators of treatment effects.

The study was supported by NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Institute on Deafness and Other Communication Disorders through the Studies to Advance Autism Research and Treatment (STAART) network program and received additional funding from the Health Resources and Services Administration (HRSA).

Reference

Kasari C, Rotheram-Fuller E, Locke J, Gulsrud A. Making the Connection Randomized Controlled Trial of Social Skills at School for Children with Autism Spectrum Disorders. J Ch Psychol Psychiatry. 2011 Nov 28. [epub ahead of print]

Clinical Trials Number: NCT00095420

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

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