TAG: "Autism"

Research finds differences in brains, behavior of girls and boys with autism

UC Davis study uses imaging technique to neuroanatomically subdivide corpus callosum.

New research by the MIND Institute finds that the brains and behavior of girls with autism differs from that of boys with autism and typically developing girls.

By Phyllis Brown, UC Davis

New research conducted by the UC Davis MIND Institute on a large cohort of preschoolers with autism spectrum disorder has found differences in the underlying biology of their brains, and in their behavior, that may help explain how the condition affects a little-studied and poorly understood population of children: girls.

Autism spectrum disorder is diagnosed much more frequently in boys than girls, at a ratio of 4 to 1. Despite recent efforts, little research has been done on girls — there are fewer of them, so fewer are represented in autism research. An estimated 1 in 42 boys has autism; in girls the statistic is 1 in 189.

The U.S. Centers for Disease Control and Prevention currently estimates the overall incidence of autism at 1 in 68 children born today.

In a brain study, the researchers found differences in the corpus callosum, the region of the brain that connects the left and right hemispheres.

That study is published online today (May 12) in the journal Molecular Autism, as part of a special issue devoted to gender differences. It adds to the growing body of evidence that suggests that in autism, there are underlying biological differences between boys and girls.

In separate research presented at the International Meeting for Autism Research (IMFAR) in Salt Lake City May 13-16, the researchers find that the behavioral differences between girls who have autism and typically developing same-age girls are much greater than the differences between boys with autism and typically developing same-age males. The finding suggests that girls with autism have greater social impairments than do boys.

The research was led by Christine Wu Nordahl, assistant professor in the UC Davis Department of Psychiatry and Behavioral Sciences and principal investigator of the Girls with Autism Imaging of Neurodevelopment (GAIN) study.

“It’s important to identify differences in underlying biology in boys and girls, because this could help us determine whether there are different etiologies of autism, and that potentially could lead us to different treatments and interventions,” Nordahl said.

Brain study

The magnetic resonance imaging (MRI) study of brain structure was conducted in a large sample of 3- to 5-year-old children, 112 boys and 27 girls — a large number for girls with autism — and 53 boys and 29 girls who were developing typically and served as control subjects.

“Previous studies have found alterations in the corpus callosum in children and adults with autism, but most were focused on males only, or had very small female sample sizes,” Nordahl said.

The study used a technique called diffusion tensor imaging (DTI), a type of magnetic resonance imaging that allowed the researchers to neuroanatomically subdivide the corpus callosum, based on where in the cerebral cortex the fibers projected.

“We found that the organization of callosal fibers was different in boys and girls with autism, particularly those projecting into the frontal lobes,” she said. “The frontal lobes are involved in many aspects of functioning, including social behavior, goal-directed behavior and executive functioning. Differences in the patterns of callosal fibers projecting to these areas may lead to differences in how autism manifests in boys and girls.”

Behavioral study

For the preliminary research presented at IMFAR, Nordahl explored behavioral differences in boys and girls with autism. Research in the area previously has been inconsistent.

“Most behavioral studies of gender differences directly compare males and females with autism. Our approach was to evaluate social impairments in a large group of children that included girls and boys with both autism and typical development,” Nordahl said. “We were interested not only in directly comparing boys and girls with autism, but also in assessing how boys and girls with autism compare in relation to their typically developing peers.”

“We found that the behavioral differences between girls with autism and typically developing girls are much larger than differences between boys with autism and typically developing boys,” she said. “In other words, girls with autism deviate further from typically developing girls than boys with autism relative to typically developing males, suggesting that girls with autism have more severe social impairments than boys.”

Nordahl said that much more works needs to be done to understand the sex differences between male and female children with autism, and particularly, increasing the numbers of female children who participate in autism research.

Future studies in Nordahl’s laboratory will include targeted recruitment of girls with autism, in order to carry out a comprehensive evaluation of behavioral and neurobiological differences in boys and girls with autism in relation to each other, as well as to their typically developing peers.

“There definitely is a need to evaluate more girls with autism, to fully understand the differences between boys and girls,” she said.

Nordahl said that the GAIN Study hopes to evaluate an additional 100 preschool-aged girls with autism during the next three years.

For further information regarding enrollment in the study contact Study Coordinator Michelle Huynh, (916) 703-0410, mmhuynh@ucdavis.edu.

The study was funded by the National Institute of Mental Health R01 MH089626, U24 MH081810, R00 MH085099 and the UC Davis MIND Institute. Statistical support was provided by the MIND Institute Intellectual and Developmental Disabilities Research Center U54 HD079125.

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UC Davis names endowed chair in autism

Marjorie Solomon named to Marvin ‘Buzz’ Oates and Family Endowed Chair

Marjorie Solomon, UC Davis

By Phyllis Brown, UC Davis

Marjorie Solomon, associate professor in the Department of Psychiatry and Behavioral Sciences, who is affiliated with the UC Davis MIND Institute and Imaging Research Center, has been named to the Marvin “Buzz” Oates and Family Endowed Chair in Lifespan Development in Autism in the UC Davis School of Medicine.

“This is an incredible honor and opportunity for UC Davis Medical Center, the MIND Institute, the Department of Psychiatry and Behavioral Sciences, and for me,” Solomon said. “This endowment will greatly accelerate my ability to study the lives of individuals with autism.”

Solomon joined the MIND Institute in 2000. Her research examines higher cognitive development in individuals with autism throughout their lifespans, using neuropsychology and cognitive neuroscience methods including functional magnetic resonance imaging. She has studied learning and memory, friendship and gender differences in these individuals.

“My father was instrumental in the formation of the MIND Institute,” said Phil Oates, chairman of the board, the Buzz Oates Group of Companies. “Autism affects our family, so we are thrilled to be able to partner with the MIND Institute and Marjorie Solomon in helping others to assimilate into our community.”

“We have always believed in what the MIND Institute does,” Oates said.

Solomon is the recipient of a recent grant award from the National Institute of Mental Health to study the relationship between early hippocampal development and intervention and later memory, cognitive control, and language in middle childhood in a cohort of individuals with autism who have been followed since they were toddlers.

From 2010 to 2012, Solomon served as an appointee of then Department of Health and Human Services Secretary Kathleen Sebelius to the InterAgency Autism Coordinating Committee, which coordinates all of the agency’s research and strategic planning efforts concerning autism.

She also is highly regarded for her extensive and highly effective Social Skills Training Group Program, which has served hundreds of higher-functioning children, youth and young adults with autism and their families, teaching skills and techniques for successful social interaction. Many children and teens with autism spectrum disorder and other social communication disorders have social difficulties, such as trouble making and keeping friends and having reciprocal, interactive conversations.

“This endowed chair is designed to accelerate research and its translation into programs that improve outcomes and enhance quality of life for people with autism and their families,” said Leonard Abbeduto, director of the MIND Institute. “I am delighted that Dr. Solomon is the inaugural appointee to this chair. She is uniquely qualified to fulfill the vision of the Oates family and of the other donors who created the endowment.”

Solomon’s ultimate goal is to apply what she learns through her neuroscience investigations to the development of effective interventions – the area where she began her career at the MIND Institute and one that she continues to develop as the director of its Social Skills Training Group Program. She and her colleagues currently are developing intervention programs for adults with autism.

“The Oates Endowed Chair will enable me to continue to conduct neuroscientific investigations that will help us to better tailor personalized intervention strategies to aid people with autism to become more successful and happy in their lives,” Solomon said.

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Exploring the ADHD-autism link

UC Irvine research is revealing similarities between the two disorders.

“This is an emerging field with great promise,” says Jean Gehricke, an associate professor of pediatrics at UC Irvine and a licensed clinical psychologist with the Center for Autism & Neurodevelopmental Disorders. “We know a bit about the underlying causes of ADHD, and through this, we may be able to improve how we treat autism.” (Photo by Jocelyn Lee, UC Irvine)

By Tom Vasich, UC Irvine

For the better part of the last decade, a growing body of research has been revealing more and more similarities between attention-deficit/hyperactivity disorder and autism.

Jean Gehricke, an associate professor of pediatrics at UC Irvine and a licensed clinical psychologist with the Center for Autism & Neurodevelopmental Disorders, is focusing on this link to better understand why people with ADHD and autism may be more prone to substance abuse and, in the process, to develop more effective behavioral therapies.

“This is an emerging field with great promise,” Gehricke says. “We know a bit about the underlying causes of ADHD, and through this, we may be able to improve how we treat autism.”

The Center for Autism & Neurodevelopmental Disorders – which provides assessment, diagnosis, treatment, care coordination, family support and education for children, teens and young adults with autism and other developmental disorders – is one of only a few in the region to deliver a continuum of services until age 22 and to conduct research aimed at transforming the approach to autism.

Gehricke, who teaches 25 students in his lab, has expertise in the assessment and treatment of autism, ADHD and co-occurring problems such as depression, anxiety and drug abuse.

He joined the center in 2013. Before that, he worked at the UCLA Neuropsychiatric Institute & Hospital, the UCI Transdisciplinary Tobacco Use Research Center and the UCI Child Development Center, where he also provided comprehensive clinical assessments and cognitive behavioral therapy.

Gehricke is well-known for his scientific work on the underlying mechanisms of ADHD and drug abuse, having published a number of breakthrough articles showing why individuals with ADHD are more prone to smoke cigarettes or get hooked on other nicotine and tobacco products.

He’s taking this knowledge and applying it to autism. While people with ADHD and high-functioning autism share certain characteristics, such as difficulty interacting with others and problems with emotional control, Gehricke is especially interested in whether these issues have similar neurobiological underpinnings.

In a December 2014 study, he and his colleagues identified a genetic trait shared by those with ADHD and those with autism that sheds light on some of the more troubling behaviors associated with the disorders.

Gehricke explains that aggression and health-risk actions are driven by distorted dopamine signaling in the brain and that the DRD4 gene is critical in regulating this function. The researchers found that one form of the gene – called the 7R allele and linked to altered dopamine regulation – is overrepresented in both individuals with ADHD and those with autism. It’s the genetic fingerprint of these types of conduct, Gehricke says.

“This study provides a conceptual model for risky behaviors, which we often see in our patients, and explores the possibility of tailoring information to reduce them,” he says. “More specifically, it points to the need to use strong visual images to induce behavioral changes.”

Gehricke is especially focused on nicotine addiction – which, he points out, is another shared ADHD-autism inclination. He believes that early behavioral intervention with autistic children could be a particularly effective deterrent to smoking – the No. 1 preventable health threat in the world – and “vaping.”

Gehricke says that the intervention should include warning labels (such as those used with nicotine and tobacco) depicting the negative consequences of health-risk behaviors and presenting distinctive imagery visually stimulating enough to alter the activities of teenagers and young adults with ADHD and autism. Testing the effectiveness of this deterrent is the next step Gehricke plans to take with his 7R allele group.

“Research – such as the projects conducted by Jean – is one of the core pillars of our mission at the Center for Autism & Neurodevelopmental Disorders,” says Catherine Brock, executive director. “Through his efforts and the families that participate, we are better able to understand the underlying mechanisms of autism spectrum disorders and ADHD.”

The Santa Ana-based center is a collaboration of the UC Irvine School of Medicine, CHOC Children’s Hospital, Chapman University’s College of Educational Studies, the Children & Families Commission of Orange County, and the William & Nancy Thompson Family Foundation.

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Brain imaging explains reason for language outcomes in autistic toddlers

Findings could help determine how and why treatments are effective for some, but not all.

By Scott LaFee, UC San Diego

Using functional magnetic resonance imaging (fMRI), UC San Diego School of Medicine researchers say it may be possible to predict future language development outcomes in toddlers with autistic spectrum disorder (ASD), even before they’ve been formally diagnosed with the condition.

The findings are published in today’s (April 9) online issue of the journal Neuron.

A major challenge of ASD diagnosis and treatment is that the neurological condition – which affects 1 in 68 children in the United States, mostly boys – is considerably heterogeneous. Early symptoms differ between each ASD toddler, as does progression of the condition. No uniform clinical phenotype exists, in part because the underlying causes for different subtypes of autism are diverse and not well-understood.

“There is no better example than early language development,” said senior author Eric Courchesne, Ph.D., professor of neurosciences and co-director of the Autism Center of Excellence at UC San Diego. “Some individuals are minimally verbal throughout life. They display high levels of symptom severity and may have poor clinical outcomes. Others display delayed early language development, but then progressively acquire language skills and have relatively more positive clinical outcomes.”

In other words, said Courchesne, in some children with ASD language improves substantially with age; but in some it may progress too slowly or even diminish. The neurodevelopmental bases for this variability are unknown, he said. Differences in treatment quantity do not fully account for it. But numerous studies have shown that early, accurate diagnoses of ASD can improve treatment benefits in many affected children.

“It’s important to develop more and new biological ways to identify and stratify the ASD population into clinical subtypes so that we can create better, more individualized treatments,” said co-author Karen Pierce, Ph.D., associate professor of neurosciences and co-director of the Autism Center of Excellence.

In the Neuron paper, Courchesne, first author Michael V. Lombardo, Ph.D., a senior researcher at the University of Cambridge and assistant professor at the University of Cyprus, Pierce and colleagues describe the first effort to create a process capable of detecting different brain subtypes within ASD that underlie and help explain varying development language trajectories and outcomes. “We wanted to see if patterns of brain activity in response to language can explain and predict how well language skills would develop in a toddler with ASD before that toddler actually began talking,” said Courchesne.

The researchers combined prospective fMRI measurements of neural systems’ response to speech in children at the earliest ages at which risk of ASD can be clinically detected in a general pediatric population (at approximately ages 1-2 years) with comprehensive longitudinal diagnostic and clinical assessments of language skills at 3-4 years of age.

They found that pre-diagnosis fMRI response to speech in ASD toddlers with relatively good language outcomes was highly similar to non-ASD comparison groups with robust responses to language in superior temporal cortices, a region of the brain responsible for processing sounds so that they can be understood as language.

In contrast, ASD toddlers with poor language outcomes had superior temporal cortices that showed diminished or abnormal inactivity to speech.

In sum, the study found entirely different neural substrates at initial clinical detection that precede and underlie later good versus poor language outcome in autism. These findings, said researchers, will open new avenues of progress towards identifying the causes and best treatment for these two very different types of autism.

“For the first time, our study shows a strong relationship between irregularities in speech-activation in the language-critical superior temporal cortex and actual, real-world language ability in ASD toddlers,” said Lombardo.

The scientists said fMRI imaging also showed that the brains of ASD toddlers with poor language development processed speech differently, including how neural regions governing emotion, memory and motor skills were involved.

“Our work represents one of the first attempts using fMRI to define a neurofunctional biomarker of a subtype in very young ASD toddlers,” said Pierce. “Such subtypes help us understand the differences between persons with ASD. More importantly, they can help us determine how and why treatments are effective for some, but not all, on the autism spectrum.”

Co-authors include Lisa Eyler, UCSD and Veterans Affairs San Diego Healthcare System; Cindy Carter Barnes, Clelia Ahrens-Barbeau, Stephanie Solso, and Kathleen Campbell, UCSD.

Funding for this research came, in part, from National Institute of Mental Health grants P50-MH081755, R01-MH080134 and R01-MH036840, the National Foundation for Autism Research and Jesus College, Cambridge and the British Academy.

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UC Davis expert named editor-in-chief of Autism Research

David Amaral, MIND Institute research director, has significant experience as journal editor.

David Amaral, UC Davis

By Phyllis Brown, UC Davis

David G. Amaral, director of research at the UC Davis MIND Institute, has been named the new editor-in-chief of Autism Research, the peer-reviewed journal of the International Society for Autism Research (INSAR) and its publishing partner, Wiley.

Amaral was president of INSAR from 2009-10 and played a central role in launching the first International Meeting for Autism Research (IMFAR) in 2001. He has significant experience as a journal editor. With Menno Witter, he started the journal Hippocampus and acted as co-editor-in-chief for nearly a decade. He also was editor-in-chief of the International Brain Research Organization journal Neuroscience.

Amaral succeeds Anthony J. Bailey, the journal’s first editor-in-chief, who steps down at the end of March.

“I look forward to the challenge of continuing the good work of Dr. Bailey and to enhancing the efficiency and usefulness of the journal for the autism research community,” Amaral said. “We are increasing the number of associate editors to deepen our coverage of all areas of modern research on autism spectrum and related disorders.”

Amaral will be joined in the enterprise by a new team of associate editors, including UC Davis Distinguished Professor Peter Mundy, also of the MIND Institute and the School of Education.

Autism Research publishes six issues a year in electronic format. INSAR is devoted to advancing knowledge about autism spectrum disorders. For more information, visit www.autism-insar.org.

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UC Davis scientist receives International Sisley-Lejeune Foundation Award

Randi Hagerman honored for her work developing treatments for fragile X syndrome.

By Phyllis Brown, UC Davis

Randi Hagerman receiving the International Sisley-Lejeuen Award 2014 in Paris.

Randi Hagerman, medical director of the UC Davis MIND Institute, has received the prestigious International Sisley-Lejeune Award 2014 from the Paris-based Jérôme Lejeune Foundation, for her groundbreaking work developing targeted treatments for individuals with fragile X syndrome, a leading cause of intellectual disability and the leading single-gene cause of autism spectrum disorder.

The award recognizes significant accomplishments in therapeutic research for Down syndrome or other genetic intellectual disabilities for researchers who have ‘contributed to creating knowledge of these pathologies and the discovery of treatments and cures.’

The Jérôme Lejeune Foundation was founded by Jérôme Lejeune, discoverer of the cause of Down syndrome, which in 1958 he renamed trisomy 21, to accurately describe the genetic abnormality. Hagerman received the award in Paris on March 10, in an event timed to coincide with World Down Syndrome Awareness Day. The award comes with a €30,000, or $33,855 prize, and a lecture.

“I am very positive about new targeted treatments that have the potential to reverse intellectual disability at a variety of ages, including childhood, adolescence and even in adulthood. My work will continue for this very important goal,” said Hagerman, distinguished professor of pediatrics and Endowed Chair in Fragile X Research and Treatment.

Hagerman is one of the world’s leading physician-scientists investigating fragile X-related disorders, including fragile X syndrome and fragile X-associated tremor/ataxia syndrome, or FXTAS, a condition affecting primarily older men that she discovered with her husband, Paul Hagerman, in 2001. In 1984 she founded the National Fragile X Foundation in the United States.

Hagerman said during her acceptance speech that she is hopeful that her ongoing trials of investigational drugs, such as ganaxolone, mGluR5 antagonists, minocycline, and sertraline, eventually may improve language, attention, socialization and learning in people with fragile X syndrome and other genetic conditions, such as Angelman syndrome. This work, she said “leads the way for treatments that may reverse neurobiological abnormalities in autism and many other neurodevelopmental disorders.” These treatments must be coupled with educational programs to ensure that patients may take advantage of their improved cognitive strengths.

Hagerman is director of the MIND Institute’s Fragile X Research and Treatment Center. She is the recipient of numerous honors, including the Jarrett Cole Clinical Award from the National Fragile X Foundation for dedicated service to families in the worldwide fragile X community; the Bonfils-Stanton Foundation Award for her pioneering work in fragile X disorders; and the Distinguished Scholarly Public Service Award from UC Davis. In 2008 she received a Lifetime Achievement Award from the National Fragile X Foundation and, in 2014, she received the C. Anderson Aldrich Award from the American Academy of Pediatrics, for her outstanding contributions to the field of child development.

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Blood-based genetic biomarkers ID young boys with autism

Proof-of-principle method suggests much-earlier diagnoses could be done with clinic test.

By Scott LaFee, UC San Diego

In a study published in the current online issue of JAMA Psychiatry, an international team of scientists, led by researchers at the UC San Diego School of Medicine, report finding a highly accurate blood-based measure that could lead to development of a clinical test for autism spectrum disorder (ASD) risk in males as young as 1 to 2 years old.

The test could be done in community pediatric settings. The degree of accuracy, they said, outperforms other behavioral and genetic screens for infants and toddlers with ASD described in literature.

The causes of ASD are complex and diverse, making it difficult to conclusively diagnose the disease much before a child’s fourth year of life. Indeed, the median age of diagnosis in the United States is 53 months.

“A major challenge is the difficulty of accurately diagnosing ASD, which is very heterogeneous, at an early enough age to implement the most effective treatment,” said principal investigator Eric Courchesne, Ph.D., professor of neurosciences and director of the Autism Center of Excellence at the UC San Diego School of Medicine.

In the proof-of-principle study, Courchesne, first author Tiziano Pramparo, Ph.D., and colleagues identified blood-based genomic biomarkers that differentiated toddlers with ASD, ranging in age from 1 to 4 years old, from a control group of toddlers without ASD. Blood samples were taken at the child’s initial clinical intake. Importantly, the control group consisted of a mix of young boys commonly seen in community clinics, with typical development, mild language delay, transient language delay and global developmental delay. Against this control group, the researchers identified a genetic signature that identified 83 percent of ASD toddlers.

The study used an unbiased systems biology-based method to search for genes and gene pathways in blood samples that best distinguished ASD infants and toddlers from typically developing toddlers and toddlers with non-autism developmental delays. Specifically, the researchers measured leukocyte (white blood cell) RNA expression levels.

“Ideally, biomarkers come from tissue affected, but in ASD this is the brain, which is obviously an inaccessible tissue,” said Courchesne. “Peripheral blood of living ASD infants and toddlers is an important alternative, and obtaining blood samples is routine and safe and, thus, is a preferable and accessible tissue for identifying signatures of ASD that could be used in clinical screening and follow-up evaluations.”

Pramparo, an associate research scientist at the UC San Diego Autism Center of Excellence, said blood is expected to carry autism-relevant molecular signatures that can be used to detect the disorder at very young ages. It might also reflect aspects of the disrupted biology underlying neural defects.

In fact, the researchers found gene expression differences between ASD and non-ASD in genes related to translation and immune/inflammation functions, as well as cell adhesion and cell cycle. These “ASD signature classifier” genes are among those that can have effect on early brain development.

“New studies point to autism beginning in the womb,” said Courchesne, who, with colleagues, published one such widely reported study last year detailing disrupted brain development in post-mortem brains of autistic children. “Our present study shows examination of the gene expression profiles at the very early age of initial clinical detection reveals both strong evidence of early biological processes in ASD and abnormal signals with the potential to serve as an early, practical biomarker of risk for the disorder in general pediatric settings.”

The scientific team conducted two different analyses of blood samples involving two cohorts of study participants: 147 toddlers (91 with ASD, 56 control) in the first group, 73 toddlers (44 ASD, 29 control) in the second group. The first assay identified an ASD genomic signature 83 percent of the time; the second had a 75 percent accuracy rate.

Young male toddlers with autism were the focus of the study because autism is far more prevalent in males.

“The genetics and molecular bases of autism may differ somewhat in affected males and females,” said Pramparo. “We reasoned, therefore, that different signatures might need to be discovered and developed in each gender in ASD.”

It was simpler to begin with boys.

“Autism is four times more common in males,” said Courchesne, “and so we were able to more quickly recruit and test samples of autism males than autism females. Our current work is aimed at recruiting sufficiently large samples of females to begin work to discover possible gene expression markers for them.”

Courchesne emphasized that this was a first step toward a possible means of diagnosing autism much earlier than current methodologies, one that would greatly boost the efficacy of intervention and remedial treatments.

Though only proof-of-principle, Courchesne said the findings are encouraging. Next steps involve further refinement of the process and identification of diagnostic risk markers for females.

“As we write in the paper, our study showed that a blood-based clinical test for at-risk male infants and toddlers could be refined and routinely implemented in pediatric diagnostic settings.”

Co-authors include Karen Pierce, Cynthia Carter Barnes, Steven Marinero, Clelia Ahrens-Barbeau and Linda Lopez, UC San Diego Autism Center of Excellence; Michael V. Lombardo, University of Cambridge and University of Cyprus; Sarah S. Murray, Scripps Translational Sciences Institute; and Ronghui Xu, UCSD.

Funding for this research came, in part, from the National Institutes of Health (grants P50-MH081755, R01-MH036840, R01-MH080134, 1U54RR025204, 1UL1RR031980-01) and UC San Diego (grant KL2T00099).

Disclosure: Pramparo and Courchesne have a patent application pending that includes data from this study.

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Newborn foals may offer clues to autism

Common link, researchers suggest, may be abnormal levels of naturally occurring neurosteroids.

Veterinary researchers at the University of California, Davis, are teaming up with their colleagues in human medicine to investigate a troubling disorder in newborn horses and are exploring possible connections to childhood autism. The common link, the researchers suggest, may be abnormal levels of naturally occurring neurosteroids.

The horse disorder, known as neonatal maladjustment syndrome, has puzzled horse owners and veterinarians for a century. Foals affected by the disorder seem detached, fail to recognize their mothers and have no interest in nursing.

“The behavioral abnormalities in these foals seem to resemble some of the symptoms in children with autism,” said John Madigan, a UC Davis veterinary professor and expert in equine neonatal health.

The maladjustment syndrome in foals also caught the attention of Isaac Pessah, a professor of molecular biosciences at the UC Davis School of Veterinary Medicine and a faculty member of the UC Davis MIND Institute, who investigates environmental factors that may play a role in the development of autism in children.

“There are thousands of potential causes for autism, but the one thing that all autistic children have in common is that they are detached,” Pessah said

Madigan, Pessah and other researchers in veterinary and human medicine recently formed a joint research group and secured funding to investigate links between the two conditions.

(See news feature story. A press kit, including video b-roll and high-resolution still images, is available.)

Maladjusted foal syndrome

In newborn foals, neonatal maladjustment syndrome, or dummy foal syndrome, occurs in 3 to 5 percent of live births. With around-the-clock bottle or tube feeding plus intensive care in a veterinary clinic for up to a week or 10 days, 80 percent of the foals recover. But for horse owners, that level of care is grueling and costly.

For years, the syndrome has been attributed to hypoxia — insufficient oxygen during the birthing process. Madigan and UC Davis veterinary neurologist Monica Aleman began sleuthing around for other potential causes, however, noting that hypoxia usually causes serious, permanent damage, while most foals with the maladjustment syndrome survive with no lingering health problems.

One of their prime suspects was a group of naturally occurring neurosteroids, which are key to sustaining pregnancies in horses, especially in keeping the foal “quiet” before birth.

Foals remain quiet in the womb

“Foals don’t gallop in utero,” Madigan is fond of saying, pointing out the dangers to the mare if a four-legged, hoofed fetus were to suddenly become active in the womb. The prenatal calm is made possible, he explains, by neurosteroids that act as sedatives for the unborn foal.

However, immediately after birth, the infant horse must make an equally important transition to consciousness. In nature, a baby horse would be easy prey for many natural enemies, so the foal must be ready to run just a few hours after it is born.

In short, somewhere between the time a foal enters the birth canal and the moment it emerges from the womb, a biochemical “on switch” must be flicked that enables the foal to recognize the mare, nurse and become mobile. Madigan and Aleman suspect that the physical pressure of the birthing process may be that important signal.

“We believe that the pressure of the birth canal during the second stage of labor, which is supposed to last 20 to 40 minutes, is an important signal that tells the foal to quit producing the sedative neurosteroids and ‘wake up,’ ” Madigan said.

Neurosteroids persist in the bloodstream

The theory, he says, is supported by the fact that the maladjusted foal syndrome appears more frequently in horses that were delivered via cesarean section or experienced unusually rapid births. Perhaps those foals do not experience significant physical pressure to trigger the change in neurosteroids, Madigan said.

Furthermore, the research team has found for the first time that sedative neurosteroids persist, and their levels often rise, in the bloodstream of foals born with symptoms of the maladjustment syndrome. These neurosteroids are known to be able to cross the blood-brain barrier and impact the central nervous system, acting on the same receptor as do sedatives and anesthetics.

The researchers also have demonstrated that maladjustment symptoms can be brought on temporarily in normal, healthy foals by administering short infusions of a neurosteroid called allopregnanolone. When the neurosteroid levels drop, the foals return to their normal state.

Foals ‘wake up’ with gentle harness pressure

Amazingly, the veterinary researchers have found that they can reduce maladjustment symptoms in foals by using several loops of a soft rope to gently squeeze the foal’s upper torso and mimic the pressure normally experienced in the birth canal. When pressure is applied with the rope, the foal lies down and appears to be asleep.

After 20 minutes — about the same time a foal would spend in the birth canal — the rope is loosened and the squeeze pressure released. In initial cases, the foals have responded well to the procedure and recovered, some rising to their feet within minutes and then bounding over to join the mare and nurse.

The researchers suspect that the pressure triggers biochemical changes in the central nervous system that are critical for transitioning the foal from a sleeplike state in the womb to wakefulness at birth.

While larger studies are underway, the researchers have presented their results at national and international meetings of equine veterinarians, and many veterinarians and clinics are treating maladjusted foals with the squeeze procedure — now called the Madigan Foal Squeeze Procedure.

Madigan cautions that, in spite of the strong observational effects, a larger, controlled clinical trial of national and international scope is now needed to reproduce those observed results and provide a better understanding of the mechanisms at work in the foals.

Foal behaviors resemble autism

The early findings have compelling implications for the health of newborn foals, and have caused the researchers to also explore possible links to autism, which includes a group of complex brain-development disorders. While the symptoms vary, these disorders are generally marked by difficulties with social interactions, verbal and nonverbal communication, and repetitive behaviors.

“The concept that a disruption in the transition of fetal consciousness may be related to children with autism is intriguing,” said Pessah, noting that the behaviors seen in the maladjusted foal syndrome truly are reminiscent of those in some autistic children.

He notes that some children with autism do outgrow autistic behaviors by the time they reach their teen years. Could this be a parallel to the recovery of the foals with the maladjustment syndrome?

Investigating possible links

A new group called the Comparative Neurology Research Group, consisting of veterinarians, physicians, epidemiologists and basic-science researchers, has formed to pursue further studies in this area. Madigan is working with researchers at the Stanford School of Medicine, exploring the mechanisms of post-birth transitions of consciousness related to neonatal care of infants.

Using data from the foal research, Pessah and Madigan are working with environmental epidemiologist Irva Hertz-Picciotto at the UC Davis MIND Institute to investigate neurosteroids in children with varying degrees of autism, ranging from some developmental delay to full-spectrum autism.

The researchers are exploring whether abnormal regulation of neurosteroids during the time around childbirth could be one of many factors that might contribute to autism and related neurodevelopmental disorders. A recent study has reported elevated levels of neurosteroids in children with autism spectrum disorder.

Pessah and colleagues will be looking to see whether there are alterations in blood levels of certain neurosteroids that may serve as a marker for the disorder. They caution, however, that the relationship right now is just a theory that remains to be validated or disproven.

More information about this research effort.

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Oxytocin shows promise for improving social skills in autistic mice

UCLA study could point way toward therapy for people with autism.

Daniel Geschwind, UCLA

By Mark Wheeler, UCLA

People with autism spectrum disorders have difficulty with social behavior and communication, which can make it challenging to form friendships, engage in routine conversations or pick up on the social cues that are second nature to most people. Similarly, mice with symptoms of autism show little interest in interacting or socializing with other mice.

A drug called risperidone has been shown to treat some symptoms of autism — including repetitive behaviors — in both humans and mice, but so far no medication has been found to help improve the ability to socialize.

In a study published online by the journal Science Translational Medicine, researchers at UCLA found that giving oxytocin to mice with autism-like symptoms restored their normal social behavior. Oxytocin is a neuropeptide, a type of molecule that helps neurons communicate with one another.

But perhaps the study’s biggest surprise was that early postnatal administration of the oxytocin led to longer-lasting positive effects, which continued into the animals’ adolescence and adulthood. “This suggests that there may be critical windows of time for treatment that are better than others,” said Daniel Geschwind, a UCLA professor of psychiatry, neurology and human genetics and senior author of the study.

In 2011, Geschwind and his colleagues developed a mouse model for autism spectrum disorders by knocking out a gene called contactin-associated protein-like 2, or CNTNAP2, which scientists believe plays an important role in the brain circuits responsible for language and speech. Previous research has linked common CNTNAP2 variants to a heightened risk for autism, while rare variants can lead to an inherited form of autism called cortical dysplasia-focal epilepsy syndrome.

“The oxytocin system is a key mediator of social behavior in mammals, including humans, for maternal behavior, mother–infant bonding, and social memory,” said Geschwind, who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and is the director of the Center for Autism Research and Treatment at the Semel Institute for Neuroscience and Human Behavior at UCLA. “So it seemed like a natural target for us to go after.”

The mice that were engineered for autism have fewer oxytocin neurons in the hypothalamus than other mice and lower-than-normal oxytocin levels throughout the brain. But after researchers treated them with oxytocin, the animals spent normal amounts of time interacting with other mice — the measure scientists used to gauge their sociability.

Separately, the researchers gave the mice melanocortin, an agonist that binds to specific receptors on a cell in order to activate it. They found that it caused a natural release of oxytocin from the mice’s brain cells, which also improved the mice’s sociability.

“The study shows that a primary deficit in oxytocin may cause the social problems in these mice, and that correcting this deficit can correct social behavior,” Geschwind said.

The next stage of the research, Geschwind said, will be to determine the lowest dosage of oxytocin that still proves effective. Because the mice in the study displayed symptoms similar to those of people on the autism spectrum, the researchers hope that this therapy may someday be applicable to humans.

The study was funded by the National Institute of Mental Health (R01 MH081754-02R, NIH/NS50220), the NIH Autism Centers of Excellence (HD055784-01 and 5R01-MH081754-04), the Simons Foundation Autism Research Initiative, Autism Speaks (7657), the NIH/National Institute of Neurological Disorders and Stroke (R01 NS049501 and R01 NS074312) and a McKnight Foundation Brain Disorders Award.

The study’s other authors were Olga Peñagarikano, María Lázaro, Xiao-Hong Lu, Hongmei Dong, Hoa Lam, Elior Peles, Nigel Maidment, Niall Murphy and X. William Yang, all of UCLA; Peyman Golshani of UCLA and the West Los Angeles V.A. Medical Center; and Aaron Gordon of Israel’s Weizmann Institute of Science.

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Century-old drug reverses autism-like symptoms

Suramin shows promise in fragile X mouse model.

By Scott LaFee, UC San Diego

Autism spectrum disorders (ASD) affect 1 to 2 percent of children in the United States. Hundreds of genetic and environmental factors have been shown to increase the risk of ASD. Researchers at UC San Diego School of Medicine previously reported that a drug used for almost a century to treat trypanosomiasis, or sleeping sickness, reversed environmental autism-like symptoms in mice.

Now, a new study published in this week’s online issue of Molecular Autism, suggests that a genetic form of autism-like symptoms in mice are also corrected with the drug, even when treatment was started in young adult mice.

The underlying mechanism, according to Robert K. Naviaux, M.D., Ph.D., the new study’s principal investigator and professor of medicine at UC San Diego, is a phenomenon he calls the cellular danger response (CDR). When cells are exposed to danger in the form of a virus, infection, toxin or even certain genetic mutations, they react defensively, shutting down ordinary activities and erecting barriers against the perceived threat. One consequence is that communication between cells is reduced, which the scientists say may interfere with brain development and function, leading to ASD.

Researchers treated a fragile X genetic mouse model, one of the most commonly studied mouse models of ASD, with suramin, a drug long used for sleeping sickness. The approach, called antipurinergic therapy or APT, blocked the CDR signal, allowing cells to restore normal communication and reversing ASD symptoms.

“Our data show that the efficacy of APT cuts across disease models in ASD. Both the environmental and genetic mouse models responded with a complete, or near complete, reversal of ASD symptoms,” Naviaux said. “APT seems to be a common denominator in improving social behavior and brain synaptic abnormalities in these ASD models.”

Weekly treatment with suramin in the fragile X genetic mouse model was started at 9 weeks of age, roughly equivalent to 18 years in humans. Metabolite analysis identified 20 biochemical pathways associated with symptom improvements, 17 of which have been reported in human ASD. The findings of the six-month study also support the hypothesis that disturbances in purinergic signaling – a regulator of cellular functions, and mitochondria (prime regulators of the CDR) – play a significant role in ASD.

Naviaux noted that suramin is not a drug that can be used for more than a few months without a risk of toxicity in humans. However, he said it is the first of its kind in a new class of drugs that may not need to be given chronically to produce beneficial effects. New antipurinergic medicines, he said, might be given once or intermittently to unblock metabolism, restore more normal neural network function, improve resilience and permit improved development in response to conventional, interdisciplinary therapies and natural play.

“Correcting abnormalities in a mouse is a long way from a cure in humans,” cautioned Naviaux, who is also co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego, “but our study adds momentum to discoveries at the crossroads of genetics, metabolism, innate immunity, and the environment for several childhood chronic disorders. These crossroads represent new leads in our efforts to understand the origins of autism and to develop treatments for children and adults with ASD.”

Co-authors include Jane C. Naviaux, Lin Wang, Kefeng Li, A. Taylor Bright, William A. Alaynick, Kenneth R. Williams and Susan B. Powell, all at UC San Diego.

This study was supported, in part, by the Jane Botsford Johnson Foundation, the UC San Diego Christini Foundation, the UC San Diego Mitochondrial Research Fund, and the Wright Family Foundation.

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Expert in translating autism research into community practice joins UC Davis

Aubyn Stahmer, a licensed clinical psychologist, will be part of the MIND Institute.

Aubyn Stahmer, UC Davis

By Phyllis Brown, UC Davis

Aubyn Stahmer, an expert in the translation of evidence-based autism research to community-based practice and delivery, has joined the UC Davis MIND Institute as an associate professor in the Department of Psychiatry and Behavioral Sciences.

Stahmer, a licensed clinical psychologist, comes to UC Davis from UC San Diego, where she was research director of the Autism Discovery Institute at Rady Children’s Hospital, San Diego, and associate director of the Child and Adolescent Services Research Center.

“We evaluate how to take evidence-based interventions that are effective in research settings and make it possible to deliver them in settings where kids are getting usual care, in schools and early-intervention settings in the community,” Stahmer said.

She is an internationally respected expert in the use of naturalistic developmental behavioral interventions which are validated treatments for autism. Derived from developmental science and applied behavioral analysis (ABA), these interventions are play-based and child-initiated. Goals include the development of communication, language and positive social behaviors.

Stahmer is the principal investigator of two U.S. Department of Education grants designed to examine methods of translating research-based interventions in collaboration with community providers. One adapted model, called Classroom Pivotal Response Teaching, is for classroom use in children 3 to 11. Another, Project ImPACT for Toddlers, provides parent coaching for very young children at risk for autism. Stahmer will continue that research, which is based in public schools and early intervention programs, at the MIND Institute, potentially including Sacramento-area public school and community settings.

At Rady Children’s Hospital Stahmer operated a preschool program for children from 18 months to five years with autism in a setting that also included typically developing peers.

“Dr. Stahmer’s expertise and interests complement and enhance our established programs of research on evidence-based practices in autism treatment,” said Leonard Abbeduto, director of the MIND Institute. “She will extend the reach of the MIND Institute even further into our community, and so ensure we help even more families affected by autism.”

Stahmer said that she plans to work closely with Sally Rogers, professor of psychiatry and behavioral sciences and developer of the Early Start Denver Model (ESDM) approach to early autism intervention. Together they will examine methods of increasing access to evidence-based care to families of children with autism in rural and underserved areas.

“I am very excited to work with Dr. Rogers to examine new ways to increase access to ESDM in the community, both locally and internationally,” Stahmer said.

Rogers said she shares Stahmer’s enthusiasm.

“I am delighted to be able to work with such a wonderful scientist and clinician,” Rogers said. “Her research and expertise in moving interventions from the lab into the community will be a great help to all the intervention scientists at UC Davis.”

Stahmer received her bachelor’s degree from the University of Colorado, Boulder. She received her master’s and doctoral degrees from UC San Diego. She will receive an annual base salary of $126,800. Additional compensation information is available upon request.

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Multiple, short learning sessions strengthen memory formation in fragile X

UC Irvine study suggests the method could aid children with the autism-related condition.

Christine Gall and Gary Lynch found that fragile X model mice trained in three short, repetitious episodes spaced one hour apart performed as well on memory tests as normal mice. (Photo by Chris Nugent, UC Irvine)

By Tom Vasich, UC Irvine

A learning technique that maximizes the brain’s ability to make and store memories may help overcome cognitive issues seen in fragile X syndrome, a leading form of intellectual disability, according to UC Irvine neurobiologists.

Christine Gall, Gary Lynch and colleagues found that fragile X model mice trained in three short, repetitious episodes spaced one hour apart performed as well on memory tests as normal mice. These same fragile X rodents performed poorly on memory tests when trained in a single, prolonged session – which is a standard K-12 educational practice in the U.S.

“These results are dramatic and never seen before. Fragile X model mice trained using this method had memory scores equal to those of control animals,” said Gall, professor of anatomy & neurobiology and neurobiology & behavior. “Our findings suggest an easily implemented, noninvasive strategy for treating an important component of the cognitive problems found in patients with fragile X syndrome.”

Fragile X syndrome is an inherited genetic condition that causes intellectual and developmental disabilities and is commonly associated with autism. Symptoms include difficulty learning new skills or information.

It’s been known since classic 19th century educational psychology studies that people learn better when using multiple, short training episodes rather than one extended session.

Two years ago, the Lynch and Gall labs found out why. They discovered a biological mechanism that contributes to the enhancing effect of spaced training: Brain synapses – which are the connection points among neurons that transfer signals – encode memories in the hippocampus much better when activated briefly at one-hour intervals.

The researchers found that synapses have either low or high thresholds for learning-related modifications and that the high-threshold group requires hourlong delays between activation in order to store new information.

“This explains why prolonged ‘cramming’ is inefficient – only one set of synapses is being engaged,” said Lynch, professor of psychiatry & human behavior and anatomy & neurobiology. “Repeated short training sessions, spaced in time, engage multiple sets of synapses. It’s as if your brain is working at full power.”

The finding was significant, Gall added, because it demonstrated that a ubiquitous and fundamental feature of psychology can, at least in part, be explained by neurobiology.

It also gave the researchers time-sequencing rules for optimizing forms of learning dependent upon the hippocampus – utilized in the current study. Results appear in the Nov. 25 issue of Proceedings of the National Academy of Sciences.

The UCI scientists stress that the new brain-based training protocols, if applied during childhood, have the potential to offset many aspects of fragile X-related autism. “We believe that synaptic memory mechanisms are used during postnatal development to build functional brain circuits for dealing with confusing environments and social interactions,” Lynch said. “Implementing the brain-based rules during childhood training could result in lifelong benefits for patients.”

He and Gall look forward to collaborating with UCI’s Center for Autism Research & Translation to further evaluate the effect of multiple, short training episodes on learning in fragile X children.

Ronald Seese led the study as part of his work toward a Ph.D. and was assisted by Kathleen Wang and Yue Qin Yao. The research was funded by the National Science Foundation (grant 1146708), the National Institutes of Health (grants MH082042 and NS04260), and the William & Nancy Thompson Family Foundation, via UCI’s Center for Autism Research & Translation.

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