Elsevier

Brain Research

Volume 1380, 22 March 2011, Pages 175-186
Brain Research

Review
Bridging the gap between MRI and postmortem research in autism

https://doi.org/10.1016/j.brainres.2010.09.061Get rights and content

Abstract

Autism is clearly a disorder of neural development, but when, where, and how brain pathology occurs remain elusive. Typical brain development is comprised of several stages, including proliferation and migration of neurons, creation of dendritic arbors and synaptic connections, and eventually dendritic pruning and programmed cell death. Any deviation at one or more of these stages could produce catastrophic downstream effects. MRI studies of autism have provided important clues, describing an aberrant trajectory of growth during early childhood that is both present in the whole brain and marked in specific structures such as the amygdala. However, given the coarse resolution of MRI, the field must also look towards postmortem human brain research to help elucidate the neurobiological underpinnings of MRI volumetric findings. Likewise, studies of postmortem tissue may benefit by looking to the findings from MRI studies to narrow hypotheses and target specific brain regions and subject populations. In this review, we discuss the strengths, limitations, and major contributions of each approach to autism research. We then describe how they relate and what they can learn from each other. Only by integrating these approaches will we be able to fully explain the neuropathology of autism.

Introduction

Investigators searching for the neuropathology of autism have typically taken one of two parallel paths: either a macroscopic approach with magnetic resonance imaging (MRI) or a microscopic approach with postmortem brain tissue. There are unique advantages and limitations to each approach; though the road forward would benefit from better communication across disciplines. MRI studies have contributed significantly to our understanding of how the brains in people with autism deviate from early typical development and function. We now know that the brain undergoes an abnormal developmental time course that appears to include a period of early overgrowth followed by a deceleration in age-related growth in some individuals with autism, which is particularly noted in the frontal and temporal cortices and the amygdala (for reviews see Courchesne et al. (2007) and Amaral et al. (2008)). But what is leading to this deviant developmental trajectory? Is there excessive prenatal neurogenesis due to genetic or environmental alteration? Do dendrites and synapses develop in an excessive, dysregulated manner which results in aberrant connectivity of neurons? Or is there perhaps an inflammatory response leading to excessive microglial activation? Currently, only postmortem brain studies can answer these questions, providing a critical link to the etiology of, and potential treatments for, autism. We will review the strengths and limitations of MRI and postmortem research and the contributions that each has made toward our understanding of autism. We propose that better communication between the two fields would greatly enhance our progress toward understanding this devastating disorder.

Section snippets

What can MRI studies tell us about autism?

Because MRI is safe and non-invasive, it can be used repeatedly in large numbers of living subjects. This allows MRI studies to provide a framework for when, where, and in whom there is a deviation from typical brain development. Common types of structural MRI images include T1-weighted images, which provide the greatest level of anatomical detail, and T2-weighted images, which highlight cerebrospinal fluid and edema. Volumetric MRI studies typically utilize high-resolution T1-weighted images

What can postmortem studies tell us about autism?

Postmortem brain tissue, acquired from individuals who had autism during life, is an important tool for understanding the underlying neurobiology and genetics of autism. Although postmortem techniques have been used for hundreds of years to probe the structure of the human brain, the use of systematic, quantitative tools in the field is still very much in its infancy. Indeed, it is largely only in the last five years that these tools have been applied to the study of autism.

It is common

What's in an MRI voxel?

The answer depends on many factors, including the resolution of the MRI scan, the age of the individual being scanned, and the brain region being examined. Currently, the typical voxel resolution of a T1-weighted scan is 1 mm3. To give some perspective, a typical pyramidal neuron in the cerebral cortex is 10–50 μm in diameter (a micron, μm, is 1/1000 of a millimeter). An interneuron is ~ 10 μm in diameter. Fig. 1 depicts the scale between a standard 1 mm3 MRI voxel and the underlying neuroanatomy.

Bridging the gap — translating between MRI and postmortem research

Using as an example the notion that the brain grows too big too fast in autism, we explore how the MRI and postmortem research fields may look to one another for guidance. If the rate of brain growth is indeed accelerated, which factors are likely to account for this growth? If brain size is an indication of aberrant neurological development, what does this really tell us about the neuropathology of autism? Is it likely that volume differences reflect a single cellular alteration?

Closing the gap

Independently, MRI and postmortem studies have made significant contributions towards elucidating the neuropathology of autism. Greater communication and understanding between the fields could lead to even more significant progress being made. MRI and postmortem researchers working in the field of autism could learn much from each other's work and use findings from each field to better guide specific hypotheses about certain brain areas and periods of development. For example, MRI studies

Acknowledgments

Original research reviewed here was supported by NIMH grant MH 041479 and NINDS grant NS 16980 (CMS) and NIMH K99MH085099 (CWN). We are grateful to Aaron Lee, Jeff Bennett, and Brian Moon for their help with manuscript and figure preparation. Dr. John Morgan and Dr. Melissa Bauman provided helpful feedback on previous drafts of this manuscript.

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