Autism Spectrum Disorders Research at NIMH, Page 2
This overview summarizes research into the causes, diagnosis, prevention, and treatment of autism spectrum disorders.
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. For example, NIMH, NINDS and NIDCD are mounting a joint effort to develop a National Autism Brain Bank at the Harvard Brain Tissue Resource Center, which is primarily funded by NIMH and NINDS. It will store and disseminate postmortem human brain specimens for the study of autism.9
Diagnosis, Training, and Early Identification
People with ASDs show a broad range of impairment, with great variability in clinical symptoms and levels of functioning. For example, 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 screening and 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, and is funding further investigation of measurement tools.10,11
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 2.12 Yet, the 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 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. NIMH is funding studies that focus on young children at heightened risk for the disorder, such as younger siblings of children with autism.13,14,15
Brain Imaging
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 NICHD, NIDA and NINDS, a $28 million initiative that is using aMRI (anatomic magnetic resonance imaging), DTI (diffusion tensor imaging), and MRS (magnetic resonance spectroscopy) to create the world’s first such large-scale database on normal brain development in children.16
The NIH MRI Study of Normal Brain Development is cataloging the structural development of the brain, by age and sex, with seven major research centers scanning more than 500 infants, children, and adolescents. Children age five and older are being followed up with additional scans and clinical and behavioral reassessments at 2-year intervals. Younger children are being re-scanned at more frequent intervals 3-12 months to capture more rapid brain maturational changes occurring at these ages.
This study 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.17 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 (neurons) 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. This type of normative data will help researchers contrast typical growth with that in autism spectrum disorders. A wave of abnormal brain enlargement seen in MRI studies of young children with autism follows a back-to-front pattern, similar to a wave of abnormal gray matter loss seen in childhood onset schizophrenia. This may suggest a process in which the timing and trajectory of various abnormalities parallels clinical outcome.18,38 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 animated cartoons designed to challenge their ability to understand a social situation. High-functioning individuals with autism are being scanned to sort out the neural circuitry of social versus mechanical knowledge.19,20
Yet another series of MRI studies is pinpointing brain structural abnormalities associated with the severity of attention deficits in people with autism.21 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.
A project at the University of North Carolina has been assessing the relation between brain anatomy and autism through MRI scans of very young children with autism.22 The aim is to get a better picture of the development and timing of the brain enlargement that occurs in autism between 18 and 35 months. To relate these findings to another developmental disorder of known origin, the researchers have joined forces with colleagues at Stanford University to similarly follow the brain development of children with Fragile X syndrome.23,24 These studies will illuminate genetic and environmental factors that influence normal and abnormal brain development and may help to clarify subtypes of autism.
