Brain Development Initiative
The creation of effective biologically-based treatments for autism will require knowledge of the underlying brain defects. Identifying what goes awry in the developing brain of children with autism is the first step.
We must understand how, when, and why the brains of individuals with autism are thrown off track during development. The creation of effective biologically-based treatments for autism will require knowledge of the underlying brain defects. Identifying what goes awry in the developing brain of children with autism is the first step.
The search for the brain basis of autism started out as a hunt for a particular place in the brain where the problem could be located. Though the limbic system, cerebellum and other structures showed abnormalities in some studies, these findings were not always consistent or explanatory. Rather than any one structure being affected, researchers now think that the defect may lie within the neural circuitry, the way the brain is wired together. One critical link between brain circuitry may be the increasingly replicated finding of larger brain size in autism and increased white matter volume.
White Matter and Brain Development
Lead by Martha Herbert, M.D., Ph.D., of Massachusetts General Hospital, The Brain Development Initiative takes its impetus from a confluence of recent findings on abnormal brain development in autism. Although it’s become well known that children with autism can have abnormally larger brains in early childhood, it’s still unclear just what this observation may be telling us. In order to gather more specific information on these problems, Dr. Herbert has spent the past several years measuring MRI scans of people with autism.
Her work began with a Young Investigator grant from Cure Autism Now and culminated in 2004 with a Brain Development Initiative Innovator Award to enable Dr. Herbert’s continued pursuit of an understanding for the basis of brain enlargement in autism. Her recently published findings show that most of the brain overgrowth can be accounted for by volume increases in the later-developing parts of white matter, especially those in the frontal lobes. If we can understand what it is that sets volume increases off, we may have the information necessary to intervene at an early enough stage to prevent this circuitry change.
(For a summary of Dr. Herbert’s work from the Cure Autism Now archives, read the CAN Science Summary: The White Matter Story)
Even though abnormal white matter may not end up being a direct cause of autism, it gives scientists an entry point to autism’s complex web of inter-related abnormalities. By studying the possible causes and consequences of white matter changes, this initiative continues Cure Autism Now’s focus on bridging research disciplines – brain structure, function, chemistry, and genetics—to fund innovative work that approaches autism in ways not previously contemplated.
Cure Autism Now’s White Matter Think Tank held in February 2005, brought together scientists from different backgrounds and disciplines for the specific of goal of working towards a synthesis of ideas. In doing so, The Brain Development Initiative continues Cure Autism Now’s tradition of focusing on promising but undeveloped scientific questions.
As a direct result of our Brain Development Initiative and feedback from scientists at the 2005 White Matter Think Tank, in 2006 CAN formed a collaborative neuropathology workgroup to look more directly at how the brains of individuals with autism develop.
Structural and functional imaging studies have consistently found particular brain regions to be atypical in individuals with autism. However, while such experiments are essential in identifying potentially abnormal brain regions, including changes in white matter, they cannot reveal the precise nature of the cellular and molecular defects that are causing those abnormalities.
The only way to discover the underlying brain defects is to conduct studies directly on the brain tissue. Neuropathological experiments are the most direct path to providing answers to the myriad of questions surrounding the brain causes of autistic behavior. Yet, neuropathology remains one of the most under-funded areas of autism research. Coordinated, large-scale tissue analyses must absolutely be undertaken to determine what generates the anatomical and functional abnormalities witnessed in autism.
The Neuropathology Workgroup is a collaborative effort organized by Cure Autism Now that combines unbiased stereology with modern molecular neuropathology to directly examine the frontal lobes of individuals with autism. The goal is to finally reveal what accounts for the structural and functional abnormalities, including the brain enlargement and white matter volume increases that have been observed by so many previous brain imaging studies. The workgroup represents a partnership across multiple institutes/organizations, bringing together researchers with different expertise, many of whom have never worked together before.
Among the several principle investigators in this new effort are Eric Courchesne, Ph.D. and Katerina Semendeferi, Ph.D. (University of California, San Diego), Carlos Pardo, M.D. (Johns Hopkins University), Karoly Mirnics, M.D. (University of Pittsburgh), and Dan Buxhoevden, Ph.D. (University of South Carolina).
Using the largest group of brains yet assembled for postmortem analysis, the workgroup will be cohesively characterizing several parameters, including neuron numbers and the presence of abnormalities in laminar patterns, minicolumns, neuroinflammatory cells, and axonal characteristics.
In order to carry this out, the effort also includes important collaborations with the Autism Tissue Program and the New York Institute for Basic Research in Developmental Disabilities on Staten Island. The Neuropathology Workgroup is being co-funded by Autism Speaks. CAN is especially grateful to Mr. Peter Emch for his extremely generous donation toward this project.
Collaborative Neuropathology Workgroup: A Comprehensive Multilevel Analysis of Frontal Lobe Microstructure in Autism (Brain Development Initiative Award)
Eric Courchesne, Ph.D., University of California, San Diego; Carlos Pardo, M.D., Johns Hopkins University; Katerina Semendeferi, Ph.D., University of California, San Diego; Karoly Mirnics, M.D., University of Pittsburgh; and Dan Buxhoevden, Ph.D., University of South Carolina
To solve the mystery of what causes autistic behavior and to develop biologically-based treatments, it is necessary to discover the underlying neural defects. As a first step, brain imaging studies have begun to successfully identify which major regions of the brain have abnormal growth and function in autism. One of these pivotal regions is the frontal lobe. It is responsible for complex social, emotional cognitive and language abilities.
Now that brain imaging studies have pinpointed where to look, the next step is to discover why the frontal lobe is abnormal. To do that requires detailed examination of the microscopic building blocks -the molecules and cells – that make up the frontal lobe. New scientific methods allow an unprecedented opportunity to see these microscopic building blocks in autism by studying postmortem tissue.
Such quantitative neuropathological methods are the only ones able to validate and examine in detail the nature of the neuronal, neuroglial and cytoarchitectural abnormalities in autism. As such, they are the most direct path to providing answers to the myriad of questions surrounding the brain causes of autistic behavior.
A collaborative neuropathology workgroup headed by Dr. Eric Courchesne and his colleagues Drs. Pardo, Semendeferi, Mirnics, and Buxhoevden will be the first to use such quantitative methods and markers to carefully measure and identify the molecular and cellular abnormalities in frontal lobe in autism. Those discoveries are expected to point to the developmental events that ultimately caused defects in these fundamental building blocks of the brain.
In sum, careful examination of the brains of individuals with autism will allow us to finally determine the cellular and molecular underpinnings that generate autistic behavior, knowledge that is necessary for rationally-designed treatment strategies.
Research Partners: Mr. Peter Emch and Autism Speaks