Category: Autism

Neuroscientists at New York University have devised a method that has reduced several afflictions associated with Fragile X syndrome (FXS) in laboratory mice. Their findings, which are reported in the journal Neuron, offer new possibilities for addressing FXS, the leading inherited cause of autism and intellectual disability.

Those afflicted with FXS do not possess the protein FMRP, which is a suppressor of protein synthesis. Absent this suppressor, protein synthesis is exaggerated, producing a range of mental and physical disorders.

Previous research has indirectly targeted protein synthesis by seeking to temper, but not block, this process. The NYU researchers, by contrast, sought a more fundamental intervention — removing the enzyme, p70 ribosomal S6 kinase 1, or S6K1, which has previously been shown to regulate protein synthesis in FXS mice. By addressing this phenomenon at the molecular level, they hoped to diminish many of the conditions associated with FXS.

To determine the impact of this intervention, the researchers compared the behaviors of these FXS mice with those normal mice while also observing the physical attributes of these same FXS mice.

Their results showed that protein synthesis in the FXS mice lacking S6K1 became similar to that of normal mice. Moreover, through a series of experiments and other measurements (e.g., navigating a maze, interacting with other mice), they found both physical and behavioral improvements in the FXS mice:

• The FXS mice missing the S6K1 enzyme showed greater ability than other FXS mice to adjust their behaviors when facing conditions that were similar, but not identical, to previous experiences. This attribute, behavioral flexibility, is typically diminished is those afflicted with FXS. In this experiment, the FXS mice missing the S6K1 enzyme were more successful than other FXS mice to navigate a maze that was similar to a maze they had previously mastered.
• The FXS mice missing the S6K1 enzyme showed enhanced social behaviors, which are measured through a commonly used "social novelty test." Under this method, mice interact with each other multiple times to gauge familiarity. In this experiment, the FXS mice missing the S6K1 enzyme showed greater familiarity with mice they previously encountered than did other FXS mice. Humans afflicted with FXS have diminished abilities for social interaction.
• The FXS mice missing the S6K1 enzyme showed a correction in three physical traits often associated with this condition: immature dendritic spine morphology, which indicates abnormal connections between neurons, excessive weight gain, and macro-orchidism, or enlarged testicles.

However, the researchers did not find uniform improvements in the tested FXS mice — they still engaged in excessive repetitive behaviors (i.e., repeatedly burying marbles in an experiment), a common trait among those afflicted with FXS.

Nonetheless, the research team said the findings showed remarkable promise.

"We think these results set the stage for a viable pharmacological approach to target S6K1, with the aim of diminishing or even reversing the afflictions associated with Fragile X syndrome," said Eric Klann, a professor in NYU's Center for Neural Science and the study's senior author.

The study's other co-authors were: Aditi Bhattacharya, Hanoch Kaphzan, Amanda Alvarez-Dieppa, and Jaclyn Murphy of NYU's Center for Neural Science and Philippe Pierre of Université de la Méditerranée in Marseille, France.

The research was supported by grants from the National Institutes of Health and the FRAXA Research Foundation.

Autism is a disorder well known for its complex changes in behavior — including repeating actions over and over and having difficulty with social interactions and language. Current approaches to understanding what causes these atypical behaviors focus primarily on specific brain regions associated with these specific behaviors without necessarily linking back to fundamental properties of the brain's signaling abilities.

New research led by Carnegie Mellon University neuroscientists takes the first step toward deciphering the connection between general brain function and the emergent behavioral patterns in autism. Published in the journal Neuron, the study shows that autistic adults have unreliable neural sensory responses to visual, auditory and somatosensory, or touch, stimuli. This poor response reliability appears to be a fundamental neural characteristic of autism.

"Within the autism research community, most researchers are looking for the location in the brain where autism happens," said Ilan Dinstein, a postdoctoral researcher in Carnegie Mellon's Department of Psychology and lead author of the study. "We're taking a different approach and thinking about how a general characteristic of the brain could be different in autism — and how that might lead to behavioral changes."

For the study, 14 adults with autism and 14 without — all between the ages of 19 and 39 — completed sensory experiments while inside a functional magnetic resonance imaging (fMRI) machine located at CMU's Scientific Imaging and Brain Research center. To test the visual system's neural response, participants were shown a pattern of moving dots. The auditory stimulation consisted of pure tones presented to both ears, and short air puffs were used to stimulate the somatosensory senses. The fMRI measured each individual's brain activity during the experiments.

In all of the primary cortices, visual, auditory and somatosensory, the within-individual response reliability was significantly lower — by 30-40 percent — in autism; meaning, there was not a typical, predictable response from trial to trial. Thus, in the individuals with autism, there was significant intra-individual variability, with responses varying from strong to weak. Non-autistic adults had replicable and consistent responses from trial to trial.

"This suggests that there is something very fundamental that is altered in the cortical responses in individual's with autism," said Marlene Behrmann, professor of psychology at CMU and a leading expert on using brain imaging to understand autism. "It also begins to build a bridge between the kind of genetic changes that might have given rise to autism in the first place — and the kind of changes in the brain that are responsible for autistic behavioral patterns.

"And, what I think is so powerful is that we sampled visual, auditory and somatosensory senses. We were unbelievably thorough and attacked every sensory modality and showed the same pattern of unreliability across all three senses."

The study also presents the first time that researchers have investigated multiple sensory systems — at a primary brain function level — within the same autistic individual.

"One of the problems with autism is that there is considerable variability in symptoms across individuals," Dinstein said. "In this case, we have a tremendous amount of data on each individual and each of their three sensory systems. And, we see the same unreliability across all of them in autism relative to the controls."

While this study focused on adults, the team plans on taking the research further to study how the details of sensory unreliability play out in younger autistic groups.

"We are not suggesting that unreliable sensory — visual, auditory, touch — responses cause autism," said David Heeger, professor of psychology and neural science at New York University. "But rather that autism might be a consequence of unreliable activity throughout the brain during development. We've measured it in sensory areas of the brain but we hypothesize that the same kind of unreliability might be what's limiting the development of social and language abilities in the brain areas that subserve those functions."

In addition to expanding autism research to determine when and how basic neural processing affects autism, the research may have clinical implications.

"The poor cortical response reliability observed in the individuals with autism in this study may represent a biomarker which could contribute to better define Autism Spectrum Disorder (ASD) subtypes," said Pauline Chaste, a visiting research scholar at the University of Pittsburgh Medical Center who was not affiliated with the research but studies how genetic mutations affect psychiatric disorders. "This is very important because of the great heterogeneity of phenotype in ASD which makes the definition of subphenotypes critical for genetic studies as well as for treatment studies. Thus, the use of this biomarker may help to define new targets for treatment but also to assess efficacy. Moreover this study brings new insight into understanding atypical sensory sensitivity in autism, which is a major concern for a vast majority of patients and remains sorely underexplored."

Lauren Lorenzi, a research associate at Carnegie Mellon, Nancy Minshew from the Department of Neurology at the University of Pittsburgh and Rafael Malach, the Morris and Barbara Levinson Professor of Brain Research at the Weizmann Institute of Science, were also part of the research team.

The Simons Foundation, Pennsylvania Department of Health and the National Institute of Health and National Institute of Child and Human Development's Autism Center of Excellence at the University of Pittsburgh funded this research.

This study will appear as the cover story of the October 2012 print issue of Neuron. The issue's cover design was created by Carnegie Mellon's Communication Design team.

For more information, watch Dinstein and Behrmann discuss this study at http://youtu.be/0eSdOjMaGO8.

Journal Reference:

1. Ilan Dinstein, David J. Heeger, Lauren Lorenzi, Nancy J. Minshew, Rafael Malach, Marlene Behrmann. Unreliable Evoked Responses in Autism. Neuron, 2012; 75 (6): 981 DOI: 10.1016/j.neuron.2012.07.026

— One in 88 children has been diagnosed with an autism spectrum disorder (ASD) in the United States, according to the Centers for Disease Control and Prevention. A new study by a University of Missouri researcher found that many children with ASD also experience anxiety, chronic gastrointestinal (GI) problems and atypical sensory responses, which are heightened reactions to light, sound or particular textures. These problems appear to be highly related and can have significant effects on children's daily lives, including their functioning at home and in school.

Micah Mazurek, an assistant professor of health psychology and a clinical child psychologist, found in her study of 2,973 children and adolescents with ASD that nearly one-fourth also had chronic GI problems, such as constipation, abdominal pain, bloating, diarrhea or nausea. The results also showed that children with chronic GI problems were more likely to experience anxiety and sensory problems.

"These problems can have a very real impact on daily life. Children with anxiety may be distressed or reluctant to engage in new activities, and those with sensory problems may have trouble paying attention or participating in over-stimulating enviornments," Mazurek said. "These children may also suffer uncomfortable GI problems that they may not be able to communicate about to adults."

Clinicians should be aware that anxiety, GI problems and sensory sensitivity often co-occur in individuals with ASD. Effectively managing these concurrent issues may improve children's quality of life and their responses to treatment, Mazurek said.

"Parents need to be aware that these problems may underlie some of their children's difficulties, so if they notice any symptoms, they should talk to their doctors or therapists about treatment options," Mazurek said. "Practitioners who work with children with ASD need to be mindful that there is a pretty high rate of these problems, so if children are treated for one issue, it may helpful to screen for these additional symptoms."

This is the first study to examine the relationships among anxiety, GI problems and sensory over-responsivity in a large, nationally representative sample of children and adolescents with ASD. Participants in the study were enrolled in the Autism Treatment Network, a network of 17 autism centers throughout North America that are focused on best practices for medical treatment of children with ASD.

— Researchers in Georgia Tech's Center for Behavior Imaging have developed two new technological tools that automatically measure relevant behaviors of children, and promise to have significant impact on the understanding of behavioral disorders such as autism.

One of the tools — a system that uses special gaze-tracking glasses and facial-analysis software to identify when a child makes eye contact with the glasses-wearer — was created by combining two existing technologies to develop a novel capability of automatic detection of eye contact. The other is a wearable system that uses accelerometers to monitor and categorize problem behaviors in children with behavioral disorders.

Both technologies already are being deployed in the Center for Behavior Imaging's (CBI) ongoing work to apply computational methods to screening, measurement and understanding of autism and other behavioral disorders.

Children at risk for autism often display distinct behavioral markers from a very young age. One such marker is a reluctance to make frequent or prolonged eye contact with other people. Discovering an automated way to detect this and other telltale behavioral markers would be a significant step toward scaling autism screening up to much larger populations than are currently reached. This is one goal of the five-year, $10 million "Expeditions" project, funded in fall 2010 by the National Science Foundation under principal investigator and CBI Director Jim Rehg, also a professor in Georgia Tech's School of Interactive Computing.

The eye-contact tracking system begins with a commercially available pair of glasses that can record the focal point of their wearer's gaze. Researchers took video of a child captured by a front-facing camera on the glasses, worn by an adult who was interacting with the child. The video was then processed using facial recognition software available from a second manufacturer. Combine the glasses' hard-wired ability to detect wearer gaze with the facial-recognition software's ability to detect the child's gaze direction, and the result is a system able to detect eye contact in a test interaction with a 22-month-old with 80 percent accuracy. The study was conducted in Georgia Tech's Child Study Lab (CSL), a child-friendly experimental facility richly equipped with cameras, microphones and other sensors.

"Eye gaze has been a tricky thing to measure in laboratory settings, and typically it's very labor-intensive, involving hours and hours of looking at frames of video to pinpoint moments of eye contact," Rehg said. "The exciting thing about our method is that it can produce these measures automatically and could be used in the future to measure eye contact outside the laboratory setting. We call these results preliminary because they were obtained from a single subject, but all humans' eyes work pretty much the same way, so we're confident the successful results will be replicated with future subjects."

The other new system, developed in collaboration with the Marcus Autism Center in Atlanta and Dr. Thomas Ploetz of Newcastle University in the United Kingdom, is a package of sensors, worn via straps on the wrists and ankles, that uses accelerometers to detect movement by the wearer. Algorithms developed by the team analyze the sensor data to automatically detect episodes of problem behavior and classify them as aggressive, self-injurious or disruptive (e.g., throwing objects).

Researchers first developed the algorithms by putting the sensors on four Marcus clinic staff members who together performed some 1,200 different behavior instances, and the system detected "problem" behaviors with 95 percent accuracy and classified all behaviors with 80 percent accuracy. They then used the sensors with a child diagnosed along the autism spectrum, and the system detected the child's problem-behavior episodes with 81 percent accuracy and classified them with 70 percent accuracy.

"These results are very promising in leading the way toward more accurate and reliable measurement of problem behavior, which is important in determining whether treatments targeting these behaviors are working," said CSL Director Agata Rozga, a research scientist in the School of Interactive Computing and co-investigator on the Expeditions award. "Our ultimate goal with this wearable sensing system is to be able to gather data on the child's behavior beyond the clinic, in settings where the child spends most of their time, such as their home or school. In this way, parents, teachers and others who care for the child can be potentially alerted to times and situations when problem behaviors occur so that they can address them immediately."

"What these tools show is that computational methods and technologies have great promise and potential impact on the lives of many children and their parents and caregivers," said Gregory Abowd, Regents' Professor in the School of Interactive Computing and a prominent researcher in technology and autism. "These technologies we are developing, and others developed and explored elsewhere, aim to bring more effective early-childhood screening to millions of children nationwide, as well as enhance care for those children already diagnosed on the autism spectrum."

Both technologies were presented in early September at the 14th ACM International Conference on Ubiquitous Computing (Ubicomp 2012). Among the other devices under study at CSL are a camera/software system that can track children's facial expressions and customized speech analysis software to detect vocalization patterns.

An investigational compound that targets the core symptoms of fragile X syndrome is effective for addressing the social withdrawal and challenging behaviors characteristic of the condition, making it the first such discovery for fragile X syndrome and, potentially, the first for autism spectrum disorder, a study by researchers at the UC Davis MIND Institute and Rush University Medical Center, Chicago, has found.

The finding is the result of a clinical trial in adult and pediatric subjects with fragile X syndrome. It suggests, however, that the compound may have treatment implications for at least a portion of the growing population of individuals with autism spectrum disorder, as well as for those with other conditions defined by social deficits. The study is published online today in the journal Science Translational Medicine. A second study by the manufacturer of the compound is included in the same issue.

The "first-in-patient" drug trial was led by internationally recognized fragile X researchers Elizabeth Berry-Kravis of Rush University Medical Center and Randi Hagerman of the UC Davis MIND Institute. It examined the effects of the compound STX 209, also known by the name arbaclofen.

The study was conducted collaboratively with Seaside Therapeutics, a Cambridge, Mass., pharmaceutical company that is focused on translating bench research on fragile X and autism into therapeutic interventions. Seaside Therapeutics produces the compound.

"This study shows that STX 209 is an important part of the treatment for fragile X syndrome, because it improved symptoms in those with significant social deficits or autism as well as fragile X syndrome," said Hagerman, medical director of the MIND Institute. "Additional studies also are suggesting that STX 209 can be helpful for autism without fragile X syndrome. Until now, there have been no targeted treatments available for autism. This appears to be the first."

Fragile X syndrome is the most common known cause of inherited intellectual impairment, formerly referred to as mental retardation, and the leading known single-gene cause of autism. Social impairment is one of the core deficits in both fragile X and autism. The U.S. Centers for Disease Control and Prevention (CDC) estimates that about 1 in 4,000 males and 1 in 6,000 to 8,000 females have the disorder. An estimated 1 in 88 children born today will be diagnosed with autism, according to the CDC.

"There are no Food and Drug Administration-approved treatments for fragile X syndrome, and the available options help secondary symptoms, but do not effectively address the core impairments in fragile X. This is the first large-scale study that is based on the molecular understanding of fragile X and suggests that the core symptoms may be amenable to pharmacologic treatment," said lead study author Elizabeth Berry-Kravis, professor of pediatrics, neurological sciences and biochemistry at Rush University Medical Center.

"This study will help to signal the beginning of a new era of targeted treatments for genetic disorders that have historically been regarded as beyond the reach of pharmacotherapy," Berry-Kravis said. "It will be a model for treatment of autism, intellectual disability and developmental brain disorders based on understanding of dysfunction in brain pathways, as opposed to empiric treatment of symptoms. We hope mechanistically based treatments like STX209 ultimately will be shown to improve cognitive functioning in longer-term trials."

Studies in mice genetically engineered to exhibit features of fragile X, including social impairment, have suggested that the behavioral abnormalities in fragile X result from deficiencies in the neurotransmitter gamma-amino butyric acid (GABA). Decreased GABA has been observed in a mouse model of fragile X in many areas of the brain including the hippocampus, and has been hypothesized to be a basis of the social anxiety and avoidance characteristic of fragile X sufferers, the study says.

Arbaclofen is an agonist for gamma-amino butyric acid type B, or GABA-B, receptors. An agonist is a chemical that effectively combines with a receptor on a synapse to effect a physiologic reaction typical of a naturally occurring substance. Anxiety-driven repetitive behavior and social avoidance have been reduced in fragile X-engineered mice treated with arbaclofen. The current, first-of-its-kind study investigated whether arbaclofen would produce similar results in human subjects.

The double-blind, placebo-controlled clinical trial initially recruited 63 male and female subjects at 12 sites across the United States for the research, conducted between December 2008 and March 2010. The participants ranged in age from 6 to 39 years. Of the initial participants, 56 completed the clinical trial. There were no withdrawals related to drug tolerability. The majority of the subjects were treated with what was assessed as the optimum tolerated dosage of the study drug, 10 milligrams twice a day in younger patients and three times a day in adults. Compliance was monitored by patient guardians, who filled out a dosing form on a daily basis.

The study subjects returned for evaluations at two- and four-week intervals after beginning the six-week-long treatment. The drug then was tapered down over a one- to two-week period.

The effects of the medication were scored on variables of the Aberrant Behavior Checklist (ABC), a behavior-rating scale for the assessment of drug-treatment effects. The checklist includes variables for irritability, lethargy/withdrawal, stereotypic (repetitive) behavior and hyperactivity, among other factors.

The study found improvement for the full study population on the social-avoidance subscale, an analysis validated by secondary ratings from parent observation of improvement in subjects' three most problematic behaviors. It found that the medication was the same as placebo, however, on the subscale for irritability.

The study is one of several at the MIND Institute aiming to help improve behavior and cognition for individuals with fragile X syndrome and autism spectrum disorder.

"We are looking forward to further studies utilizing STX 209 in both autism and fragile X syndrome because the fragile X mouse studies demonstrate long-term strengthening of synaptic connections with continued use of this medication," Hagerman said.

Other study authors include David R. Hessl, Yi Mu and Danh V. Nguyen of UC Davis; Barbara Rathmell, Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, Paul P. Wang and Randall L. Carpenter of Seaside Therapeutics; Joseph Gonzalez-Heydrich of Boston Children's Hospital; and Mark F. Bear of the Massachusetts Institute of Technology.

Approximately 19 percent of children with a sibling diagnosed with Autism Spectrum Disorder (ASD) will develop Autism due to shared genetic and environmental vulnerabilities, according to previous studies. For that reason, University of Miami (UM) psychologists are developing ways to predict the occurrence of ASD in high-risk children, early in life, in hopes that early intervention will lead to better outcomes in the future. Their findings are published in the journal Infancy.

The study is one of the first to show that measures of non-verbal communication in children, as young as eight months of age, predict autism symptoms that become evident by the third year of life. The results suggest that identifying children, who are having difficulties early enough, can enhance the effects of interventions.

"For children at risk of developing an ASD, specific communication-oriented interventions during the first years of life can lessen the severity of autism's impact," says Daniel Messinger, professor of Psychology in the College of Arts and Sciences at UM and principal investigator of the study. Before children learn to talk, they communicate non-verbally by using eye contact and gestures. These abilities are called referential communication and are in development by eight months of age. However, "impairments in non-verbal referential communication are characteristic of older children with ASD," says Caroline Grantz a doctoral candidate in the Department of Psychology at UM and co-author of the paper.

In the study, a team of researchers tested two groups of children. One group was at high-risk for ASD and the second group was at low-risk. The evaluations took place during 15 to 20 minutes sessions, at 8, 10, 12, 15 and 18 months of life. The team measured the development of three forms of non-verbal communication:

• Initiating Joint Attention (IJA) — the way an infant shows interest in an object or event to a partner. For example, making eye contact and pointing to show a toy.
• Initiating Behavioral Requests (IBR)-the manner in which an infant requests help from a partner, by making eye contact to request a toy, reaching toward, pointing to, or giving the examiner a desired toy.
• Responding to Joint Attention (RJA)-the way infants respond and follow the behavior of a partner. For example, when the examiner points to something and the child follows the experimenter's gaze to look at that an object. The results show that lower levels of IJA and IBR growth between eight and 18 months predicted the severity of ASD symptoms for children that had a sibling with Autism.

"Overall, infants with the lowest rates of IJA at eight months showed lower social engagement with an examiner at 30 months of age," says Lisa Ibañez, research scientist at the University of Washington Autism Center and first author of the paper. Ibañez conducted the study as part of her dissertation research in the Department of Psychology at UM.

These results are important enough that the research team is following up the study with collaborator Wendy Stone, Professor of Psychology and Director of the University of Washington Autism Center.

The project was funded by the National Institute of Child Health and Human Development.