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Article title: Autism Research: NIMH
From 1 in 500 to 1 in 2,500 Americans suffer from autism,1,2 a brain disorder that begins in early childhood and impairs thinking, feeling, language, and the ability to relate to others. Families coping with this devastating illness are searching for answers about its causes, diagnosis, prevention, and treatment. The National Institute of Mental Health (NIMH) is devoting an increasing portion of its research portfolio to this mission. NIMH's investment in autism-related science more than doubled over the past 4 years—from $9.4 million in FY 1997 to $22.6 million in FY 2000. The research is being funded through grants and contracts with investigators at universities. In addition, new Institute initiatives aimed at advancing basic knowledge of brain development and genetics also hold promise for understanding complex behavioral disorders like autism. NIMH's autism-related activities range from efforts to improve awareness, diagnosis and treatment, to studies involving brain imaging, tissue banks, animal models, genetics, developmental neurobiology, and neuropsychology.
Implementing the Children's Health Act of 2000
As part of the Children's Health Act of 2000,3 Congress recently designated the NIMH to take the lead in expanding, intensifying and coordinating NIH's autism research effort, which more than doubled between 1997 and 2000. NIMH has begun implementing provisions of this landmark legislation, in collaboration with the four other Institutes represented on the NIH Autism Coordinating Committee (NIH/ACC): National Institute of Child Health and Human Development (NICHD), National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Deafness and Other Communication Disorders (NIDCD), and National Institute of Environmental Health Sciences (NIEHS).
An NIMH Snapshot
The National Institute of Mental Health (NIMH) is a component 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 2000 NIMH budget was $974 million.
To reduce the burden of mental illness through research on mind, brain, and behavior.
How Does the Institute Carry Out Its Mission?
Centers of Excellence in Autism Research
Foremost among the Act's provisions is a collaborative effort to support development of broadly based Centers of Excellence in Autism Research. This project will build new infrastructure for autism research by bringing together critical masses of expertise and resources at five or more dedicated research centers around the country. The Centers will conduct basic and clinical research, including investigations into causes, diagnosis, early detection, prevention, control, and treatment. The Centers will also include research in the fields of developmental neurobiology, genetics, and psychopharmacology. Interdisciplinary collaborations, including the recruitment of outstanding investigators who had previously not worked in the autism field, are being sought in an initial Request for (grant) Applications in FY 2001, with the Centers being funded in stages over the next few years.
The Children's Health Act of 2000 mandates that the NIH make available information about its autism activities and facilitate public feedback to the NIH. Information Officers, Public Liaison Officers, and other staff from the NIH/ACC institutes meet annually with representatives of autism advocacy groups to exchange information and stay in touch via a list-serve. Members of the autism advocacy community also serve as public participants on NIMH scientific review committees. A searchable information clearinghouse for all NIH autism-related activities is posted on the National Library of Medicine's MedlinePlus web site ( http://medlineplus.nlm. nih.gov/medlineplus/autism.html). This links to several resources within the DHHS, including NIMH's autism web page ( http://www.nimh.nih.gov/publicat/autism.cfm).
Brain Tissue and Genetics Resources
The Children's Health Act of 2000 also calls on NIMH to take the lead in expanding a program under which samples of tissues and genetic materials are donated, collected, preserved, and made available for autism research. Post-mortem brain tissue, which has been very scarce 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 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 post-mortem tissue made possible by the new molecular methodologies, NIMH, in collaboration with the autism community and other NIH Institutes, is stepping up efforts to establish brain bank collections to study autism. Such brain banks work with families to arrange tissue donations upon the death of individuals with autism. For example, NIMH supports ongoing efforts by the Harvard Brain Tissue Resource Center, and at UCLA's West Los Angeles VA Medical Center, to collect and make this vital resource available to researchers.
Supported under a contract with Washington University, the NIMH Center for Genetic Studies at Rutgers University has been receiving data and blood samples from NIMH-funded autism genetics projects at Stanford University, New England Medical Center, Vanderbilt University, and the University of North Carolina. These data and biomaterials will be widely distributed to the scientific community to conduct analyses on the genetic basis of autism, and their availability is expected to accelerate collaborations among researchers and the discovery of genes producing disease vulnerability.
Diagnosis, Training, and Early Identification
People with autism represent a broad 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. A common diagnostic scheme for assessing the complex social and communication deficits that constitute key features of the disorder has been a critical prerequisite to scientific progress.
NIMH has supported research that has raised the quality and standardization of diagnosis in autism. Standard diagnostic interviews and observational methods developed through this research have become a 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.4
NIMH also supports research aimed at improving early diagnosis of autism. Institute-supported studies have demonstrated that a reliable diagnosis of autism spectrum can be made at age 2.5 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.
Brain Imaging—Database on Normal Brain Development
Non-invasive brain imaging techniques, such as MRI (magnetic resonance imaging), offer great potential for 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 NINDS and NICHD, a $16 million initiative that will use aMRI (anatomic magnetic resonance imaging), DTS (diffusion tensor imaging), and MRS (magnetic resonance spectroscopy) to create the world's first such large-scale database on normal brain development in children.6 The NIH MRI Study of Normal Brain Development will catalog the structural development of the brain, by age and sex, with seven major research centers scanning more than 500 infants, children, and adolescents. 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 brain structures to be charted, revealing the development of circuitry for language, thinking, and other functions. Individual brains differ enough that only broad generalizations can be made from comparisons of different individuals at different ages. But following the same brains as they mature allows scientists a much more detailed view of developmental changes. 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. These databases, being developed by an NIMH-funded data analysis center, 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.
The promise of such a normative brain database for turning up clues about childhood brain disorders was recently illustrated in a similar, but smaller-scale, NIMH intramural study.7 In this first longitudinal structural MRI study to track individual children's developing brains, the researchers were surprised to discover a second wave of overproduction of gray matter, the thinking part of the brain (neurons and their branch-like extensions) just prior to puberty. Possibly related to the influence of surging sex hormones, this thickening peaks at around age 11 in girls, 12 in boys, after which the gray matter actually thins some. Prior to this study, scientists had thought that the brain overproduced gray matter for a brief period in early development (in the womb and for about the first 18 months of life) and then underwent just one bout of pruning. The gray matter growth spurt predominates in the frontal lobe, the seat of "executive functions" (planning, impulse control and reasoning) that are impaired in childhood-onset schizophrenia, a rare (1 in 40,000 children) psychotic disorder that is sometimes confused with autism. In teens who had developed psychosis prior to puberty, the MRI scans revealed four times as much gray matter loss in the frontal lobe as normally occurs.8
In other brain imaging studies, researchers using MRI and MRS 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.9 Yet another series of MRI studies is pinpointing brain structural abnormalities associated with the severity of attention deficits in people with autism.10 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.
New autism-related research includes a study that will use MRI and MRS to investigate structural anatomy and biochemistry of the brain in developmental language disorder and autistic groups of children.11 These structural anatomical and biochemical measures would then be examined in relation to quantifiable aspects of social communication using measures of formal thought disorder and discourse. The proposed study has the potential to contribute to our knowledge of the neuroanatomical and neurochemical abnormalities associated with the social communication deficits seen in autistic and developmental language disorders in children.
A separate project will assess the relation between brain anatomy and autism through structural neuroimaging of individuals with autism and their well siblings.12 The results of these studies have the potential to allow investigators greater experimental control of those genetic and environmental factors that influence normal and abnormal brain development and may clarify biologically based subtypes of autism. Another study will use aMRI and fMRI to assess how the abnormal structure and function of the brain in autism may affect the processing of emotional information, as conveyed through faces and facial expressions.13
For ethical reasons, some studies required to understand autism cannot be conducted in humans. But careful 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.14 Such behavioral and neuroanatomical research may help to pinpoint brain circuit abnormalities in autism and ultimately lead to intervention strategies. Findings relevant to autism may also emerge from planned studies of proteins in the mammalian brain.
In December 2000, NIMH held a workshop at the Jackson Laboratory in Bel Harbor, Maine, "Genetics in the New Millennium: Modeling Autism." The meeting was designed to foster development of new animal models of autism, or components of the illness, that might eventually lead to new treatments. Among approaches discussed was to survey inbred strains of rodents for autism-related traits that could be mapped to particular locations in the genome.
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. 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 some family members of people with autism may share with them milder, but qualitatively similar, behavioral characteristics of autism.15 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.16 Other investigators are screening genetic material from 350 carefully diagnosed patients with autism for possible linkage with several already known "candidate" genes.17 Another group is using hundreds of telltale gene markers to screen 200 families in which at least two siblings are affected with the disorder.18
Recently, five research teams, including one funded by NIMH,19 published results from genome scans in autism. Regions on chromosomes 1, 2, 4, 5, 6, 7, 10, 13, 15, 16, 17, 18, 19, X, and 22 were identified as possible locations for disease vulnerability genes. This pooled data is now being analyzed. Although all studies pointed to one chromosomal region (7q) as being involved, no specific linked gene had yet been pinpointed. Now, NIMH-funded researchers have discovered that variants of a particular gene in the 7q region, expressed in human thalamus, may be associated with autism susceptibility.20 In addition to its suspect location, it is a member of a family of genes that influences brain development. Moreover, mice bred without genes essential to the functioning of this gene family show diminished social interaction, much like people with autism. Of course, this preliminary finding must be confirmed in studies by other groups.
In another set of subsequent analyses, NIMH-funded teams re-examined a genomic region on chromosome 15q and two specific genes, HOXA1 (chromosome 7p) and HOXB1 (chromosome 17q), that had been implicated in previous studies. Evidence was not found for involvement of this genomic region or for these two genes in vulnerability to autism, suggesting that their roles are at best minimal in the majority of individuals with autism.21
If 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—or in the wrong place. This may interfere with the migration and wiring of embryonic brain cells during early development, or with the way cells function. 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).22 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 location 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 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—each expressing distinctive physiological and behavioral characteristics—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.
Intricate guidance mechanisms have evolved to ensure that the brain gets wired correctly during critical periods in early development. Mistakes in this process, resulting in circuitry gone awry, are hypothesized to occur in neurodevelopmental disorders like autism. NIMH-funded researchers recently developed a way to discover the normal wiring diagram of the mammalian brain.23 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.24
Human focal cortical dysplasia (FCD) is a developmental brain malformation characterized by disorganized cell structure and layering in the cerebral cortex. FCD is associated with several mental disorders including autism. A newly funded project will test the hypothesis that FCD is the result of abnormal neuronal migration occurring because of a failure to develop appropriate and necessary genes for migration.25 Anatomical and molecular experiments will assess the presence of immature or other abnormal genes in individual abnormal cells in cortical dysplasia.
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 relationship to clinical symptoms, implications for treatment, and implications for underlying neurobiology, are the focus of these studies.
One study is examining whether adults with autism have a distinct profile of "executive" function deficits, with pronounced impairment of verbal working memory.26 Other researchers are looking into the possibility that the working memory problems may stem from an inability to use feedback from other people.27
NIMH plans an FY 2002 workshop with outstanding human statistical and molecular geneticists and neuroscientists to identify strategies for accelerating the discovery of vulnerability genes for autism and other mental disorders. Also in FY 2002, NIMH plans to bring together diverse groups of genetics researchers and develop strategies by which all available data sets may be assembled. Such efforts will enhance the power to detect vulnerability genes and elucidate their functions.
In addition to cognitive impairments, individuals with autism often suffer from multiple and severe mental and emotional problems. 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.28 Individuals with autism may also have co-occurring seizures and tuberous sclerosis.
Both psychosocial and pharmacological interventions can improve the behavioral and cognitive functioning of individuals with autism.29 The increasing use of psychotropic medications to treat 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 has established, at several research centers, a network of Research Units on Pediatric Psychopharmacology (RUPPs) 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. The RUPPs recently completed enrollment of the first multi-site controlled trial of the antipsychotic medication risperidone in children with autism, with results scheduled to become available in 2001. The Institute is also supporting a study of valproate* as a treatment for aggressive behavior in adolescents affected by the illness. In 2001, the RUPP network will launch a new protocol to test the efficacy and safety of treatments for inattention and hyperactivity in children with autism. An expansion of the network is planned for FY 2002.
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.31,32 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.
*NOTE: Valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients prescribed valproate should be monitored carefully.30
In November 2000 NIH/ACC, supported by NIMH, NICHD, NINDS, and NIDCD, issued an RFA (Request for Applications) for innovative methods and feasibility studies in the area of treatments for autism.33 The program grew out of a workshop hosted by these Institutes a year earlier. The Institutes hope to link brain and/or behavioral processes that are at least partially understood with possible interventions. The program will encourage partnerships between investigators on the frontline of treatment with basic behavioral or neuropharmacology investigators. Six new grants totaling about $1 million have been funded in FY 2001.
As NIMH and its research partners sharpen their focus on the problem, individuals and families affected by autism increasingly have new reason for hope.
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
In addition to studying autism, 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 bipolar disorder (also called 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.
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:
At the beginning of the 21st century, NIMH stands poised to surmount the burden, loss, and tragedy of mental illnesses that afflict millions of Americans.
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3Children's Health Act of 2000, Public Law
6Pediatric Study Centers (PSC) for a MRI Study of Normal Brain Development. http://grants.nih.gov/grants/guide/notice-files/not98-114.html
7Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL. Brain development during childhood and adolescence: a longitudinal MRI study. Nature Neuroscience, 1999; 2(10): 861-63.
8Rapoport JL, Giedd JN, Blumenthal J, Hamburger S, Jeffries N, Fernandez T, Nicolson R, Bedwell J, Lenane M, Zijendos A, Paus T, Evans A. Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Archives of General Psychiatry, 1999; 56(7): 649-54.
9Martin A, Giedd J. Brain imaging of childhood onset psychiatric disorders, endocrine disorders and healthy controls. NIH Protocol No. 89-M-0006. In progress. http://clinicalstudies.info.nih.gov/cgi/wais/bold032001.pl?A_1989-M-0006.html@autism
15Piven J, Palmer P, Jacobi D, Childress D, Arndt S. Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. American Journal of Psychiatry, 1997; 154(2): 185-90.
19Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Myers RM, et al. A genomic screen of autism: evidence for a multilocus etiology. American Journal of Human Genetics, 1999; 65(2): 493-507.
20Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield VC. Evidence supporting WNT2 as an autism susceptibility gene. American Journal of Medical Genetics, May 17, 2001. http://www3.interscience.wiley.com/cgi-bin/issuetoc?ID=77002064
21Salmon B, Hallmayer J, Rogers T, Kalaydjieva L, Petersen PB, Nicholas P, Pingree C, McMahon W, Spiker D, Lotspeich L, Kraemer H, McCague P, Dimiceli S, Nouri N, Pitts T, Yang J, Hinds D, Myers R, Risch N. Absence of linkage and linkage disequilibrium to chromosome 15q11-q13 markers in 139 multiplex families with autism. American Journal of Medical Genetics (Neuropsychiatric Genetics), 1999; 88(5): 551-56.
22Brain Molecular Anatomy Project. http://www.resgen.com/products/BMAP.php3
23Leighton PA, Mitchell KJ, Goodrich LV, Lu X, Pinson K, Scherz P, Skarnes WC, Tessier-Lavigne M. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature, 2001; 410(6825): 174-79.
24Giger RJ, Cloutier JF, Sahay A, Prinjha RK, Levengood DV, Moore SE, Pickering S, Simmons D, Rastan S, Walsh FS, Kolodkin AL, Ginty DD, Geppert M. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron, 2000; 25(1): 29-41.
29Bristol MM, Cohen DJ, Costello EJ, Denckla M, Eckberg TJ, Kallen R, Kraemer HC, Lord C, Maurer R, McIlvane WJ, Minshew N, Sigman M, Spence MA. State of the science in autism: report to the National Institutes Health. Journal of Autism and Developmental Disorders, 1996; 26(2): 121-54.
30Vainionpaa LK, Rattya J, Knip M, Tapanainen JS, Pakarinen AJ, Lanning P, Tekay A, Myllyla VV, Isojarvi JI. Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy, Annals of Neurology, 1999; 45(4): 444-50.
33Development of innovative treatment approaches to autism. http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-01-010.html
Updated: August 21, 2001
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