| Autism Research at the National Institute of Mental Health

**Fact Sheet**
Affecting as many as 2 in 1,000 Americans, autism too often destines affected individuals to a lifetime of impaired thinking, feeling and social functioning - our most uniquely human attributes.  Families coping with emotionally walled-off children are searching for answers about the causes, diagnosis, prevention, and treatment of this devastating disorder. The National Institute of Mental Health (NIMH) is devoting an increasing portion of its research portfolio to answering these questions about autism. NIMH's investment in specifically targeted autism research increased from $8,735,946 in FY 1997 to $9,596,466 in FY 1998. Although a few studies are conducted in its intramural laboratories, the bulk of the Institute's autism research is funded through grants and contracts with investigators at universities. New initiatives aimed at advancing basic knowledge of the brain and genetics also hold hope for understanding complex behavioral disorders like autism. 
**Diagnosis, Training, Early Identification**
People with autism present across a spectrum of impairment, with great variability in clinical symptoms and levels of functioning.  Some people with autism have normal intelligence and develop good basic language skills, while others lag intellectually and develop little or no language.  Furthermore, the social and communication deficits that constitute key features of the disorder must be assessed within complex social situations. Until recently, lack of a common diagnostic scheme for autism, which is critical for comparing research data, has posed a major challenge to science.
 Research supported by NIMH has raised the quality and standardization of diagnosis in autism.  NIMH has underwritten the development of standard diagnostic interviews and observational methods that have become the national and international "gold standard," ensuring that what is diagnosed in one research center is comparable to that diagnosed in another.  The Institute funds a series of annual workshops for training researchers in the use of these tools.
NIMH also supports research aimed at improving early diagnosis of autism.  Institute-supported studies are demon-strating that a reliable diagnosis of autism spectrum can be made at age 2.  Yet, the exact age of onset remains elusive. Some children seem to develop normally for a couple of years and then regress; for example, they may lose language skills after developing a small, but significant, vocabulary.  Others may be affected from birth, but in such subtle ways that diagnosis is delayed. Earlier identification of children destined to develop symptoms could hold clues to the underlying neuropathology and would also facilitate early intervention.

**An NIMH Snapshot**

The National Institute of Mental Health (NIMH) is one of 25 components of the National Institutes of Health (NIH), the Government's principal biomedical and behavioral research agency.  NIH is part of the U.S. Department of Health and Human Services.  The actual total fiscal year 1999 NIMH budget was $859 million.

**NIMH Mission**

To reduce the burden of mental illness through research on mind, brain, and behavior.

**How Does the Institute Carry Out Its Mission?**
- NIMH conducts research on mental disorders and the underlying basic science of brain and behavior.	 NIMH supports research on these topics at universities and hospitals around the United States.	NIMH collects, analyzes, and disseminates information on the causes, occurrence, and treatment of mental illnesses.	
- NIMH supports the training of more than 1,000 scientists to carry out basic and clinical research.	 NIMH communicates information to scientists, the public, the news media, and primary care and mental health professionals about mental illnesses, the brain, mental health, and research in these areas.
**Brain Imaging**
Non-invasive brain imaging techniques, such as MRI (magnetic resonance imaging) and fMRI (functional magnetic resonance imaging), offer great potential in advancing understanding of the neural basis of emotional and intellectual deficits in autism and other childhood neuropsychiatric disorders.  However, scientists currently have little data on normal brain function and development to compare with data from individuals with autism.  Such norms have been lacking for brain imaging studies, leading to non-comparable findings and excessive duplication in scanning control subjects.  Therefore, NIMH is co-sponsoring, with other NIH Institutes, an initiative that will use MRI and fMRI to create the world's first such database on normal brain development in children.
 The study will initially catalog the structural development of the brain, by age and sex, with 8 to12 research centers scanning more than 500 children. These initial scans will be followed up with additional scans and clinical and behavioral reassessments at 2-year intervals. This will permit the normal growth curves of each brain structure to be charted, revealing the development of circuitry for language, thinking and other functions.  By comparing scans of children with neuropsychiatric disorders with this normative data, researchers will be able to determine the timing and developmental course of brain structural changes in childhood disorders. Similar standardized norms on the brain's functioning through the course of development will eventually become available.  These databases will ultimately facilitate early diagnosis and differentiation of various forms of autism.  It will also speed the development of targeted treatments and evaluations of their effects. 
In imaging studies already underway, researchers using MRI and magnetic resonance spectroscopy are searching for brain anatomical and biochemical abnormalities that may underlie impaired social communication in children with autism. One fMRI study is looking for malfunctioning brain circuits associated with impaired thinking about human relationships, a problem seen in autism.  While in the scanner, subjects view novel animated vignettes designed to challenge their ability to understand a social situation.  Yet another series of MRI studies is pinpointing brain structural abnormalities associated with the severity of attention deficits in people with autism.  For example, the researchers have shown that decreased volume in an area of the brain's parietal lobe correlates with the degree of behavioral impairment in detecting stimuli located outside a principal focus of visual attention.  
**Brain Tissue**
Although MRI spectroscopy can perform chemical assays of structures in the living human brain, even the most advanced brain scanners cannot substitute for postmortem brain tissue. Such tissue, which has been lacking for the study of autism, offers a unique, high-resolution window into the inner workings of brain cells.  For example, by using radioactive tracers on thinly sliced sections of brain tissue, scientists can detect and pinpoint any abnormal activity of genes within cells.  Only with access to brain tissue can the underlying neuropathology of autism be uncovered.  To take advantage of emerging opportunities for discovery in postmortem tissue made possible by the new molecular methodologies, NIMH, in collaboration with parent advocacy groups and other Institutes, is stepping up efforts to establish brain bank collections for the study of autism.  For example, NIMH supports the Harvard Brain Tissue Center's ongoing efforts to collect and make this vital resource available to researchers. Such brain banks work with families to arrange for tissue donations when individuals with autism die.
**Animal Models**
For obvious ethical reasons, some studies required to understand autism cannot be conducted in humans.  But experiments in monkeys hold great potential, since their brains resemble those of humans. For example, NIMH-funded investigators have shown in monkeys how early injury to the brain's limbic system (hippocampus) can interfere with the establishment of social and emotional bonds.  Such behavioral and neuroanatomical research may help to pinpoint brain circuit abnormalities in autism and ultimately lead to intervention strategies.
 In October l998, NIMH co-sponsored, with several other NIH Institutes and two private organizations, Cure Autism Now (CAN) and the National Alliance for Autism Research (NAAR), an interdisciplinary workshop on "Building Animal Models for Autism Through Translational Neuroscience Research." This event brought together 33 scientists engaged in basic or clinical neuroscience research with scientists working on autism.  They developed recommendations and identified opportunities for modeling in animals some of the neurobiological and behavioral features of autism.  
For example, brain mechanisms (circuitry and chemical systems) hypothesized to occur in the human disorder can be experimentally approximated for study in rodent or monkey models.  Some of the recommendations emerging from the conference focused on opportunities that exploit new molecular genetic approaches.
**Genetics**
While it is known that heredity plays a major role in complex behavioral disorders like autism, the identification of specific genes that confer vulnerability to such disorders has proven extremely difficult. Detecting multiple genes, each contributing only a small effect, requires large sample sizes and powerful technologies that can associate genetic variations with disease and pinpoint candidate genes from among the estimated 50,000 genes that are expressed in the human brain.  And even after human disease vulnerability genes are found, sophisticated tools will be needed to find out what turns them on, what brain components they code for, and how they affect behavior.  Although by no means assured, the prospect of acquiring such molecular knowledge holds great hope for the engineering of new therapies.  
Evidence suggests that family members of people with autism may share with them an irregular segment of genetic code or a small cluster of unstable genes that produces milder, but qualitatively similar behavioral characteristics of autism.  For example, they may have mild social, language or reading problems.  A multi-site team of NIMH-supported investigators is studying such families to characterize these behavioral traits in hopes of discovering sites in the genome associated with them.  Other investigators are screening genetic material from 350 carefully diagnosed patients with autism for possible linkage with several already known "candidate" genes.  Another group is using hundreds of telltale gene markers to screen 200 families in which at least two siblings are affected with the disorder.
 Assuming there is a developmental abnormality in autism, due to a gene defect or gene/environment interaction, some genes are likely to turn on too much or too little S or in the wrong place.  This will interfere with the way brain cells work, migrate to other parts of the brain during early development, and make connections with one another.  In collaboration with other NIH Institutes, NIMH has mounted an effort to vastly expand the set of available tools for discovering these molecular mistakes.
A vital resource for doing this, now under development, will be a shared scientific infrastructure called the BMAP (Brain Molecular Anatomy Project). The goals of this multidisciplinary effort are to catalog the genes that turn on in various parts of the brain at different developmental stages, and to make this information readily available to investigators via the Internet. This will include maps revealing a gene's locations and detailed breakdowns of its chemical components. 
The mouse's brain is a major initial focus of BMAP.  A Web-based digital mouse brain atlas will offer 3-D and 2-D views of this biological blueprint, covering different strains and ages of animals. A gene library of mouse brain tissue, optimized to detect rare gene variations, will speed studies of how specific genes act in both animals and humans. Studies will characterize gene expression patterns in precise brain regions in response to disease, pharmacological, or environmental influences.  In addition to advancing basic knowledge, the BMAP database promises to enhance clinical science, providing new leads for studying gene expression in post-mortem tissue, for the identification of candidate genes, and enhanced capacity to screen for individuals at who might be at risk for developing brain disorders.
A related set of developing tools also centers on the mouse: identifying the neural basis of complex behaviors.  The mouse has become a critical model in studying human disease because scientists have access to many inbred strains S each expressing distinctive physiological and behavioral characteristics S and know an enormous amount about mouse genetics.  Rapidly-evolving technologies now make it possible to insert, knock out, or mutate mouse genes, quickly breed a generation that expresses the change, and then see how it affects behavior.  When autism-linked genes are discovered, they will be inserted and expressed in mice to find out what they do at the molecular, cellular and behavioral levels.  Researchers will be able to track a wiring abnormality, a cell migration abnormality, or other anomaly that may lead to symptoms in humans.
**Cognitive Neuropsychology**
NIMH-supported neuropsychologists are dissecting the nature of cognitive deficits in autism.  Since identification of the syndrome more than 50 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 relation-ship to clinical symptoms, implications for treatment and implications for underlying neurobiology, are the focus of these studies.
One research team is using information processing tasks to compare three "executive" functions of the brain S inhibition, flexibility, and working (or short-term) memory S in children with autism, attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome. The researchers hope to differentiate each disorder on the basis of its unique profile of deficits.  A similar study is also underway in adults with autism, schizophrenia, and ADHD.  Other researchers are examining "executive function" (planning, reasoning, etc.) deficits in preschool children with autism and relating them to later-appearing symptoms of the disorder. Another group is examining the hypothesis that an attention deficit may be at the core of autistic symptoms.
**Comorbidity**
 In addition to cognitive impairments, individuals with autism often suffer from multiple and severe psychopathologies.  These include impulse-control disorders, psychoses, obsessive-compulsive disorder, mood and anxiety disorders, and mental retardation.  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. Individuals with autism may also have co-occurring seizures and tuberous sclerosis. 
**Treatment**
Both psychosocial and pharmacological interventions can improve the behavioral and cognitive functioning of individuals with autism. The increasing use of psychotropic medications to treat autism and other childhood psychiatric disorders has spotlighted an urgent need for more studies of such drugs in children.  To meet this need, NIMH has established, at several research centers, a network of Research Units on Pediatric Psychopharmacology (RUPP) that combine expertise in psychopharmacology and psychiatry.  The RUPPs are intended to become a national resource that will expedite clinical trials in children. 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. Among other medications, the RUPPs are currently examining the appropriateness of risperidone treatment for children with autism.  The Institute is also supporting a study of valproate as a treatment for aggressive adolescents affected by the illness.
  Among 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.  This new individualized approach is being compared with a more standardized treatment approach. Another group is comparing an early, intensive behavioral intervention with parent training approaches at three different sites.
 As NIMH and its research partners sharpen their focus on the problem, individuals and families affected by autism increasingly have new reason for hope.  
**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, and the National Institute of Deafness and other Communication Disorders.
**The Broad NIMH Research Program**In addition to studying anxiety disorders, NIMH supports and conducts a broad based, multidisciplinary program of scientific inquiry aimed at improving the diagnosis, prevention, and treatment of other mental disorders. These conditions include manic-depressive illness, clinical depression, and schizophrenia.
Increasingly, the public as well as health care professionals are recognizing these disorders as real and treatable medical illnesses of the brain. Still, more research is needed to examine 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 the world's largest registry of families affected by schizo-phrenia, manic-depressive illness, and Alzheimer's disease. Scientists are able to examine the genetic material of these family members with the aim of pinpointing genes involved in the diseases. Human Brain Project
This multi-agency 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 for simultaneous study by interested researchers.
Prevention Research Initiative
Prevention efforts seek to understand the development and expression of mental illness throughout life so that appropriate interventions can be found and applied at multiple points during the course of illness. Recent advances in biomedical, behavioral, and cognitive sciences have led NIMH to formulate a new plan that marries these sciences to prevention efforts.
While the definition of prevention will broaden, the aims of research will become more precise and targeted.
**More Than 2,000 Grants and Contracts**In total, NIMH supports more than 2,000 research grants and contracts at universities and other institutions across the nation and overseas. It also conducts basic research and clinical studies involving 9,000 patient visits per  year at its own facilities on the National Institutes of Health campus in Bethesda, MD, and elsewhere. NIMH research projects focus on:- basic research on behavior, emotion, and cognition to provide a knowledge base for a better understanding of mental illnesses
- basic sciences, including cellular and molecular biology, developmental neuro-biology, neurochemistry, neurogenetics, and neuropharmacology, to provide essential information about the anatomical and chemical basis of brain function and brain disorders
- neuroscience and behavioral aspects of acquired immune deficiency syndrome (AIDS) and behavioral strategies to reduce the spread of HIV (human immunodeficiency virus)
- interventions to treat, prevent, and reduce the frequency of mental disorders and their disabling consequences
- mental health services research, including mental health economics and improved methods of services delivery co-morbidity among mental disorders and with substance abuse and other medical conditions, such as depression and heart diseasethe prevalence of mental disorders
- risk factors for mental disorders differences in mental health and mental illness among special populationschildren and adolescents who suffer from or who are at risk for serious mental disorders and learning disabilities
- psychotherapies and pharmacotherapies for specific disorders  As the 21st century nears, NIMH stands poised to surmount the burden, loss, and tragedy of mental illnesses that afflict millions of Americans.
**For More Information About NIMH**- The Office of Communications and Public Liaison carries out educational activities and publishes and distributes research reports, press releases, fact sheets, and publications intended for researchers, health care providers, and the general public. A publications list may be obtained by contacting:

Office of Communications and Public	Liaison, NIMHInformation Resources and Inquiries Branch6001 Executive Blvd.,Room 8184, MSC 9663Bethesda, MD 20892-9663Phone: 301-443-4513TTY: 301-443-8431FAX: 301-443-4279Mental Health FAX 4U: 301-443-5158E-mail: [email protected]NIMH home page address: www.nimh.nih.govAnxiety Disorders Information:1-88-88-ANXIETYDepression Information: 1-800-421-4211
- Information about research opportunities at the NIMH Intramural Research Program may be obtained from:

Office of the Scientific Director, NIMH9000 Rockville PikeBuilding 10, Room 4N224, MSC 1381Bethesda, MD 20892-1381Phone: 301-496-3501FAX: 301-480-8348- Information for scientists on NIMH grants and contracts programs, including grant application and review, Requests for Applications, Requests for Proposals, program announcements, research training and career development, small business programs, program analyses of NIMH extramural research grants and applications, access to NIH Grants policy, and other material may be obtained from the NIMH home page:  www.nimh.nih.gov .

NIH Publication No. 99-4508Printed 1999 |
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