One of the most replicated findings in autism research is the tendency for children with autism to have larger heads. Recently we've heard a lot about white matter increases and the work of Dr. Martha Herbert. This week's article is a research update on recent work by Ruth Carper, Ph.D and Eric Courchesne, Ph.D. about the part of the brain which is complementary and inextricably linked to white matter: gray matter.
Just as evidence has accumulated showing specific white matter volume increases in autistic children, a series of papers beginning in 2000 and including a paper published earlier this year in the Journal of Biological Psychiatry, describes clear and localized increases in gray matter volume. Below I will describe their recently published work and how the newest data may fit in with the white matter increases we've previously discussed.
As always, by profiling research which may otherwise have flown under the radar, we hope to help you follow the rapid progress being made in autism biology research.
Generally-speaking, the largest part of the brain, the cerebrum, can be divided into gray matter and white matter. Gray matter contains the "cell bodies" of the nerve cells, where information is processed and actual calculations take place, while the white matter contains their "axons." The axons are like the wires or cable extensions that connect the billions of information processors. Gray matter thus performs calculations, turning simple sensations of light and sound into an awareness of our environment and into abstract thoughts, while white matter moves that information to where it is needed. Several studies have shown that there is a trend for enlarged white matter in autistic individuals, especially in the front of the brain (the 'frontal lobe'). In studies that began in 2000, Ruth Carper, Ph.D. and Eric Courchesne, Ph.D. of the University of California, San Diego and Children's Hospital have focused on evaluating both white and gray matter volume changes in autistic children. Their work has revealed that toddlers with autism have increased gray matter as well as white matter, particularly in certain areas in the front of the brain.
In a previous study from 2002, the UCSD team used Magnetic Resonance Imaging (MRI) to measure white and gray matter volumes of each of the four major lobes of the brain. They discovered that there are both gray and white matter increases in children with autism, and that these changes are biggest at the front of the brain. In their newest study published earlier this year, Dr. Carper and Dr. Courchesne chose to look in more detail at the gray matter in the frontal lobes of 25 autistic children. By dividing the frontal lobe into four smaller regions and calculating their sizes, they found that the gray matter volume increases are greatest in two sub-regions, called the dorsolateral prefrontal cortex and medial frontal cortex. These regions include areas that are important for language abilities, social abilities, and the difficult task of keeping multiple concepts in mind at once (referred to as 'working memory'). In contrast, the motor cortex, an area responsible for directing intentional movements of the body, was not affected.
The second major finding of their work became apparent when they compared the gray matter volumes in autistic and typically-developing children over different age ranges. Dr. Carper and Dr. Courchesne found that, relative to controls, the enlargement in the autistic children was present at the youngest ages examined (2-5 years old) but, surprisingly, not at the older ages (5-9 years old). To explain this, they generated gray matter growth curves. Their data suggests that the brains of autistic children begin to grow earlier and/or faster than normal. Over time, however, the accelerated growth rate slows down, while the brains of normal children continue to grow and will eventually catch up, which is why they do not see any significant size difference at the later ages (although subtle abnormalities may still remain).
Interestingly, a very similar story on another gray matter brain structure was reported last year by Cynthia Schumann, Ph.D. and David Amaral, Ph.D. from The M.I.N.D. Institute. When analyzing the size of the amygdala (another gray matter structure - this one is important for the processing of emotion) in autistic individuals and controls, the M.I.N.D. Institute team found that the amygdala was approximately 20% bigger than controls in autistic children ages 7-12, yet no significant size difference was seen in the adolescent groups. Although the exact timing of overgrowth may be different depending on what brain structure is examined, both groups conclude that there appears to be a change in the rate of gray matter growth of some structures in autistic children, with an accelerated early growth followed by an abnormal growth slowing. This highlights the important need for longitudinal imaging studies, which track individual children repeatedly over a period of time, in order to confirm the abnormal brain growth patterns.
Scientifically, these studies are illuminating for the field of autism for a number of reasons. Most importantly, just as in the white matter abnormalities, the gray matter volume changes are biggest in the front of the brain, again focusing our attention on the part of the brain which is thought to be responsible for some of our most complicated and integrated mental processes. This work therefore provides even more anatomical significance to an area of the brain that has recently been shown through functional imaging to be operationally abnormal as well. Additionally, as with the white matter increases, the changes are not absolute, but vary in severity across the brain. Finally, this research helps us pinpoint a period during which development seems to be going off-course, at least in some children with autism. Whatever is causing the brain overgrowth, in these cases it must be occurring at or prior to 2 years of age because the gray matter changes detected by Dr. Carper and Dr. Courchesne were already evident at this age.
As the pace of autism research increases, every new piece of data provides us with more clues and further focuses our efforts. These findings are important for scientists studying the development of the brains of autistic children for a number of reasons. By determining where these abnormalities occur in the brain and when they begin during development, scientists are better prepared to research questions about the genetic and non-genetic factors that may underlie the disorder. This information will help with determining the brain processes which may have been affected, and generate ideas about how to diminish the long term effects. Findings from this most recent paper also offer at least one possible explanation for the white matter increases because, as explained above, gray matter consists of the nerve cell bodies that are forming the axons found in white matter. Thus, gray and white matter are intricately related. Early volume increases in the gray matter could be because there are too many nerve cell bodies. If this were the case, then as the extra nerve cells begin to grow axons, this would be seen over time as an increase in the white matter also. This may account for the white matter increases that Dr. Courchesne found in autistic children as young as 2 years, and which Dr. Herbert found when she studied MRI images from 7-9 year old children with autism. Of course, this is just one of many possible hypotheses, but it helps direct the efforts of the researchers. By studying the brains at earlier and earlier ages, the scientists hope to hone in on the problem as it is occurring.
Identifying the mechanism behind the unusual brain growth patterns in autism will absolutely inform us of how to aim our treatments, regardless of what the initial trigger or timing of that trigger may have been. Therefore, many experts in the field, including Drs. Herbert, Carper and Courchesne, have told us that the crucial next study must be close examination of the cellular architecture of the gray and white matter to tell us what is behind the well-documented volume increases. Through continued funding of our Brain Development Initiative, Cure Autism Now aims to answer these questions in as directed a fashion as possible. Critical to this ongoing investigation is the participation of the many individuals with autism and control subjects in these and other studies. The UCSD researchers have specifically asked that we again express their thanks to the more than 40 families in the San Diego area who allowed this research to be possible. Working together, we will gather the answers we need to improve the lives of our loved ones with autism.
Carper RA, Courchesne, E. (2005) Localized enlargement of the frontal cortex in early autism. Biol Psychiatry, 57: 126-33.
Carper RA, Moses P, Tigue ZD, Courchesne E. (2002) Cerebral lobes in autism: early hyperplasia and abnormal age effects. Neuroimage, 16: 1038-51.
Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA, Tigue ZD, Chisum HJ, Moses P, Pierce K, Lord C, Lincoln AJ, Pizzo S, Schreibman L, Hass RH, Akshoomoff NA,
Courchesne RY. (2001) Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology, 57: 245-54.
Carper RA, Courchesne, E. (2000) Inverse correlation between frontal lobe and cerebellum sizes in children with autism. Brain, 123: 836-44.
Schumann CM, Hamstra J, Goodlin-Jones, BL, Lotspeich, LJ, Kwon, H, Buonocore MH, Lammers, CR, Reiss, AL, Amaral, DG. (2004) The amygdale is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci., 24: 6392-401.