Autism Spectrum Disorders Research at the National Institute of Mental Health - Part 2

Developmental Neurobiology

To function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process, resulting in circuitry gone awry, are hypothesized to occur in neuro-developmental disorders like autism. NIMH-funded researchers recently developed a way to discover the normal wiring diagram of the mammalian brain.³⁵ The technique, a type of "gene trap," provides a shortcut for identifying from among the tangled trillions of neural connections just the machinery involved in brain wiring. The trick for finding the needle in a haystack: attach a molecular tag to the needle. Through genetic engineering, lines of mice are bred to express telltale mutations. Brain neurons harboring particular wiring molecules are revealed by a blue tint, while their tentacle-like extensions, or axons, are colored purple.

By breeding strains of mice in which particular genes are knocked-out, other Institute-funded researchers have been discovering the molecular machinery of the guidance systems used by such migrating embryonic neurons. When they knocked-out the cell's antennae for receiving vital signals from guidance chemicals, the tentacle-like axons failed to make the proper connections.³⁶

After reviewing evidence pointing to abnormal brain development in autism, researchers at the University of California, supported in part by NIMH, have proposed that the disorder stems from mechanisms gone awry that normally regulate brain growth. This "growth dysregulation hypothesis" holds that the anatomical abnormalities seen in autism are caused by genetic defects in brain growth factors. Due to abnormal timing in the starting and stopping of growth in neurons and supportive tissue, there is premature overgrowth in some brain structures and reduced growth or excessive cell loss in others, the researchers suggest.³⁷ Although the head size and brains of children with autism are slightly smaller than normal at birth, they undergo a spurt of excessive brain growth soon thereafter. Increased head circumference by the end of the first year predicted an enlarged cerebrum and cerebellum by 2 to 5 years of age. Sudden, rapid head growth in an infant may signal for risk of developing autism, the researchers propose.³⁸

Neuropsychology

NIMH-supported neuropsychologists are dissecting the nature of cognitive deficits in autism and related disorders. Since identification of the syndrome more than 60 years ago, clinicians and researchers have been intrigued with the uneven ability profiles of individuals with autism. While many affected individuals show generalized deficits, many also show areas of intact functioning. The nature of these deficits and strengths, their relationship to clinical symptoms, implications for treatment, and implications for underlying neurobiology, are the focus of these studies.

Adults with autism show more executive function deficits than those with other developmental disabilities. Executive functions include the ability to plan ahead, work toward a goal and to hold a mental representation "on-line" in working memory. To see if such deficits might underlie the syndrome, NIMH-funded researchers at the University of Denver compared the performance of preschoolers with autism with age-matched controls on eight executive function tasks. Surprisingly, the children with autism performed as well or better than the control group, suggesting that developmental lags in this area are not specific to autism. A second study that tracked children's progress in performing a spatial reversal task over a year found no evidence that children with autism were growing into an executive deficit over time. Rather, the children without autism seemed to be growing out of a deficit. The two groups seemed to be on diverging developmental trajectories. These results cast doubt on the notion that autism stems exclusively from executive function deficits.³⁹

Co-occurring Disorders

In addition to cognitive impairments, individuals with autism and other ASDs often suffer from multiple and severe mental and emotional problems. These include impulse-control disorders, obsessive-compulsive disorder, mood and anxiety disorders, mental retardation, and genetic disorders such as Fragile X. Such co-existing problems start early in life, are chronic, and account for a substantial portion of outpatient, inpatient and residential services. They present immense challenges to clinicians and families, and the complexity of the psychopathology presents enormous research challenges. NIMH is developing and testing treatment and rehabilitative interventions for such co-occurring psychopathology.⁴⁰ Individuals with autism may also have co-occurring seizures and tuberous sclerosis, a genetic disorder that causes benign tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs.

A key set of proteins involved in synaptic plasticity and neuronal growth, some of them likely implicated in ASDs, has been discovered by an NIMH-funded scientific team. Researchers at the University of Pennsylvania and the University of Illinois developed a new technique that revealed, in living neurons, a swath of secondary damage caused by the primary protein defect in Fragile X syndrome, the most common inherited form of mental retardation. Mental retardation is common in people with autism, and the new findings suggest that ASDs too may be traceable to this protein pathway. Gene knockout mice modeling the protein defect showed abnormalities in the distribution and quantities of some of the affected secondary proteins and the genetic material that makes them. A melding of genomics and proteomics, the new method, called Antibody Positioned RNA Amplification (APRA), can be applied in similar studies of other systems and cells.⁴¹

Defective fragile X mental retardation protein (FMRP) can have devastating effects because as an "RNA binding protein" it influences many other proteins in critical brain centers, like the hippocampus, a memory hub. FMRP regulates the synthesis and transport of a bevy of here to fore unknown associated proteins. Like a dispatcher in a truck depot, FMRP manages the shuttling of these "cargo proteins" from the cell's nucleus to supply the needs of its working parts, or cytoplasm. Much of the cargo turns out to be the genetic material (RNA) that makes proteins vital to synaptic maturation and communication between neurons which breaks down if the 'dispatcher' can't do its job.

To discover FMRP's cargo proteins in cultured mouse hippocampal neurons, the researchers devised an intricate methodology (APRA) that takes advantage of the specific affinity that antibodies and short strands of genetic material have for particular genes and proteins. They joined an antibody that binds to FMRP with genetic material that, in turn, binds to genes associated with FMRP. The antibody positions the molecular probe close to the FMRP cargo so that it can be detected. Among genes expressed in the human brain, about 60 percent detected by the probe were directly associated with FMRP again, many involved in synaptic plasticity and neuronal maturation.

Since some people with Fragile X syndrome show autistic behavior, the researchers suspected that some FMRP cargo proteins might also be associated with autism. Among the 81 proteins, 15 mapped to the same chromosomal locations as candidate autism genes. Mutations in some of the genes that code for these proteins may contribute to autism and other disorders characterized by autistic-like social impairment and stereotyped behavior.

Treatment

Both psychosocial and pharmacological interventions can improve the behavioral and cognitive functioning of individuals with ASDs.⁴² The increasing use of psychotropic medications to treat symptoms of autism and other childhood-onset psychiatric disorders has spotlighted an urgent need for more studies of such drugs in children. To meet this need, NIMH established a network of Research Units on Pediatric Psychopharmacology (RUPPs) in 1997 that combined expertise in psychopharmacology and psychiatry at several research sites. The network was expanded to include psychosocial interventions with the funding of additional network projects called the RUPP-PI (Research Units on Pediatric Psychopharmacology and Psychosocial Interventions) network. The RUPP and RUPP-PI networks are intended to become a national resource that will expedite clinical trials in children.^43,44,45 They include five groups specifically funded to evaluate treatments for autism. Studies are examining dose range and regimen of medications, and their mechanisms of action, safety, efficacy, and effects on cognition, behavior, and development. The RUPP network is nearing completion of a study examining the efficacy of methylphenidate for treating hyperactivity and impulsivity in children and adolescents with a variety of behavioral disorders. In one recent study, risperidone, one of a newer class of anti-psychotic medications, was successful and well tolerated for the treatment of serious behavioral disturbance in children with autism aged 5-17.⁴⁶

The RUPP-PI network has launched a multi-site study investigating the effect of combined parent training and medication treatment on disruptive behavior in children with autism spectrum disorders. The study will test whether adding a program to teach parents behavior management techniques to a regimen of risperidone will add to treatment response and/or maintain treatment effects after discontinuation of the medication.^{47,48, 49}

Among other studies of psychosocial treatments in autism, two NIMH-funded research teams are evaluating parent training interventions that are tailored to the particular characteristics of the child and family. The investigators have demonstrated that an individualized approach enhances the effectiveness of their Pivotal Response Model, and that this, in turn, leads to positive changes in parents' confidence and feelings of empowerment.^50,51,52 The investigators are continuing their line of research on interventions development with a study investigating the efficacy of visual augmentation strategies for teaching communication skills to nonverbal children with autism.^53,54,55

The NIH Autism Coordinating Committee (NIH/ACC) coordinates efforts of NIMH, NICHD, NINDS, NIDCD, and NIEHS to facilitate research on interventions for individuals with autism and autism spectrum disorders. In November 2000, six grants were funded in response to an RFA (Request for Applications)⁵⁶ for innovative methods and feasibility studies. These projects included behavioral and pharmacological treatments and are nearing completion. The STAART Centers funded in 2002 and 2003 (described above) include eight treatment projects that are in development or underway. Foci of the intervention projects include efficacy of early interventions, efficacy of treatments for social deficits, efficacy trials for pharmacotherapy, and understanding the variability of response to treatments. Through these and other initiatives, the Institutes hope to encourage multi-disciplinary partnerships to develop and improve treatments for individuals with autism spectrum disorders.

The NIH/ACC sponsored a workshop "Research on Psychosocial and Behavioral Interventions in Autism: Confronting the Methodological Challenges" in September 2002.³⁷ The purpose of the meeting was to review the state-of-the-science with regard to psychosocial, behavioral, and educational interventions for children with autism; to examine the barriers to progress in the field; and to discuss potential strategies for overcoming the barriers. An outcome of the meeting was the formation of ongoing working groups of scientists focusing on methodology and design issues.

Services

As part of its initiative on Child and Adolescent Interdisciplinary Research Networks, NIMH awarded a grant in FY03 to the University of California-Davis, "Enhancing Mental Health Services to Children with Autism." This innovative effort will create, for the first time, a formal, interdisciplinary research network of faculty and community representatives focused on an understudied population, children with autism and their families in rural communities. The network will review barriers and develop guidelines for implementing telehealth technologies such as clinical telemedicine, distance learning, and information distribution for the delivery of high quality, empirically supported, coordinated mental health services.

NIH Collaboration

NIMH supports research on autism in collaboration with the National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, and the National Institute of Environmental Health Sciences.

The Broad NIMH Research Program

NIMH supports and conducts a broad-based, multidisciplinary program of scientific inquiry aimed at improving the diagnosis, prevention, and treatment of mental disorders in people of all ages. Increasingly the public, as well as health care professionals, are recognizing these disorders as real and treatable medical illnesses of the brain. Still, there is a need for more research that examines in greater depth the relationships among genetic, behavioral, developmental, social, and other factors to find the causes of these illnesses. NIMH is meeting this need through a series of research initiatives.

NIMH Human Genetics Initiative

This project has compiled a large repository of clinical information and DNA obtained from families affected by schizophrenia, bipolar disorder, autism, Alzheimer's disease, and other mental disorders. Qualified scientists are given access to these data and genetic materials in order to characterize the genetic bases of mental disorders.

Neuroinformatics: Human Brain Project

This Federal effort is using state-of-the-art computer science technologies to organize the immense amount of data being generated through neuroscience and related disciplines, and to make this information readily accessible through the World Wide Web for simultaneous study by interested investigators. Because the scope of the Human Brain Project extends to all facets of brain and behavioral research and includes a range of technology sciences, this initiative is sponsored, in a coordinated fashion, by fifteen Federal organizations across four Federal agencies: the National Institutes of Health, National Aeronautics and Space Administration, National Science Foundation, and U.S. Department of Energy.

Prevention Research Initiative

Prevention research can be broadly characterized as seeking to understand the development and expression of mental illness throughout the course of life so that appropriate interventions can be designed and applied in order to prevent mental disorders and promote mental health. Advances in biomedical, behavioral, and cognitive sciences led NIMH to formulate a plan, Priorities for Prevention Research at NIMH, which marries these sciences to prevention efforts. Focusing on the expansion of prevention research to include the prevention of relapse, disability, and co-occurring conditions, the plan provides a blueprint for NIMH prevention research in the years to come.

For More Information

The NIMH Office of Communications carries out educational activities, such as the Real Men Real Depression campaign, and publishes and distributes research reports, press releases, fact sheets, and informational materials intended for researchers, health care providers, and the general public. All of these materials, and this fact sheet, are in the public domain and may be copied or reproduced without permission from the Institute, although citation of NIMH as the source is appreciated. Materials may be downloaded directly from the NIMH Web site, or hard copies may be ordered through the mail.

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⁵⁶Development of innovative treatment approaches to autism.

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All material in this fact sheet is in the public domain and may be reproduced or copied without permission from the Institute. Citation of the National Institute of Mental Health as the source is appreciated.

NIH Publication No. 04-4508