By Darold Treffert, MD
An unusually important article, in my view, on the origins of autism was printed in the July 26, 2003 issue of the Journal of the American Medical Association (JAMA). While the possible relationship of autistic disorder to head size and brain volume in infants has been raised before in a number of prior studies, in this study Dr. Eric Courchesne and his coworkers in San Diego, did careful historical, clinical indices and MRI studies on 48 children between the ages of 2 to 5 who were diagnosed as having Autistic Spectrum Disorder (ASD), comparing them to normal youngsters on a number of variables but chiefly focusing on head circumference (HC) at birth, head measurements between ages 2 to 5, and MRI measures of brain volume during that same interval. The chief findings can be summarized as follows:
- Head circumference at birth in the autistic group tended to be smaller, actually, than averages for all infants at birth. Length and weight averages were the same.
- In the autistic youngsters however, in contrast to all children in similar age groups, there was a rapid and excessive increase in head size beginning several months after birth correlating with increases in both cerebral and cerebellar volumes by ages 2 to 5.
- This excessive brain growth in children with autism slows by middle to late childhood to where by adolescence and adulthood head and brain size of autistic persons does not differ significantly from the healthy average.
- The earlier the onset, the faster the rate, and the longer the period of excessive brain growth, the more severe the Autistic Spectrum Disorder.
- There appear to be four phases to abnormal brain growth in autism:
- slight undergrowth of the brain before birth compared to averages.
- sudden and excessive increase in head size between 1 to 2 months and 6 to 14 months.
- a gradual slowing in rate of brain growth between ages 2 to 4 so that by ages 4 to 5 brain size in autism reaches its near maximum (8 years sooner than that of non-autistic children).
- a gradual decline in overall brain size extending from middle or late childhood to adults so that by those ages brain size in autism is not significantly different from the healthy average.
Why is this study important?
For several reasons. First, it correlates well with a number of prior studies (see below) suggesting a relationship between unusually rapid and excessive brain growth in autistic youngsters in the first several years of life compared to norms for this age group. Further, this study examines both head size and brain volume in the same individuals over a period of time.
Second, this rapid proliferation in head and brain size occurs early in post-natal life, either some time before or concurrent with the typical time that the behavioral symptoms in autistic youngsters emerge. According to the authors of the study this early brain change could represent “aberrant compensatory responses to adverse prenatal conditions or deviant biological mechanisms that are first expressed in early postnatal life. Events and conditions, such as measles, mumps, and rubella vaccinations, childhood exposure to environmental toxins or pathogens, or unusual gastrointestinal or allergic reactions to food, that occur after the overgrowth are not logical plausible causes. Although some may argue that such later occurring events might be important as aggravating factors, the key questions remains — what triggers the abnormal brain overgrowth in the first months of life initially?” In short, this data suggests autistic disorder has its onset early in life in all such persons, and later events, often reported as perhaps causal, seem unlikely as the basic cause of the disorder.
Third, these findings, if confirmed in larger studies, could be used as an “early warning risk for autism,” and as an early indicator — marker — of the condition.
Fourth, as the authors point out, such brain changes, if they are significant in the etiology of autistic disorder, whatever their cause, would argue for early, early intervention as one way of ameliorating damage, and fostering compensatory and remedial pathways, perhaps, taking advantage of the extreme plasticity of the brain in these early years. The authors put it this way: “Further research may identify a combination of biological (eg, biochemical, MRI, genetic) and behavioral signs that together compose an accurate and early diagnostic prognosis, which might make it possible to begin treatment 2 or 3 years earlier than is now commonly the protocol.”
A Couple of Caveats
While I consider this a very important study, several caveats, and reassurances, need to be made. First, the sample is small, only 48 individuals and the results need to be replicated on a much larger sample. With respect to head circumference at birth and in the early years, this should be data that can be fairly easily assembled since such measurements are done quite routinely in typical pediatric practice on all infants. Brain volume data will be more scarce, but could be quite readily collected in prospective studies and pooled with a fair amount of retrospective data already available from prior studies.
Second, also important, by way of reassurance to all parents, not all children with extreme head circumference increases turn out to have autistic disorder as pointed out in this study. Such increases do sometimes occur in some healthy developing infants (6%) who do not go on to develop autistic spectrum disorders. The authors of the study put it this way: “Although an abnormally large increase in head circumference cannot be viewed as a certain and unique marker of autism, it nonetheless does appear to be an important signal that an infant is as significantly heightened risk for the disorder.” But, it needs to be remembered that at least 6% of healthy infants do not go on to develop autistic disorder.
Third, just as not all infants with these rapid head circumference and brain volume changes turn out to have autistic spectrum disorder, so it is that not all children with autistic spectrum disorder demonstrate these changes. According to the study, “88% showed early postnatal brain overgrowth with HC measurements exceeding the 87th percentile by 6-14 months, and 59% showed extreme (>2.0 SD) increases during the first year.” But 88%, and 59%, while impressive, are not 100%. So not all infants demonstrating these head size and brain volume disorders turn out to have autistic disorder, and not all children with autistic disorder demonstrate these changes during infancy and childhood. Nevertheless the correlation is at an impressive, though not absolute, level.
Some Prior Studies
While this is not an exhaustive list, several prior studies warrant mention because this present study is not an isolated one, and correlates well with earlier reported research. An article in Lancet in 1997 was one of the early reports documenting macrocephaly in autism, yet documenting normal head size at birth. Another 1997 study done at the University of Utah measured head circumference of autistic persons at birth, early childhood and time of the examination. Those investigators concluded: “macrocephaly is an independent clinical trait in autism” and rates of head growth may be abnormal in early and middle childhood in some (37%) children with autism.” A 2000 study from the University of Missouri-Columbia found occipitofrontal circumference in 137 autistic persons varied significantly from that of a normal population and that macrocephaly was an independent clinical trait in autism. In a 2002 study reported in Neurology, investigators at the University of Washington in Seattle measured head circumference and brain volume in 67 persons with autistic disorder and 83 healthy community volunteers ranging from age 8 to 46 years. They concluded: “Brain development in autism follows an abnormal pattern, with accelerated growth in early life that results in brain enlargement in childhood. Brain volume in adolescents and adults with autism is, however, normal, and appears to be due to a slight decrease in brain volume for these individuals at the same time the normal children are experiencing a slight increase.”
What’s Going on Here?
It may be that this early brain enlargement, if confirmed in even larger autistic populations, can serve as an early marker of the condition and result in earlier intervention. But beyond that, what is happening within the child’s CNS itself during this period of rather massive enlargement, followed by slowed growth? That remains to be discovered. Dr. Courchesne suggests several possibilities: excessive numbers or rates of growth of neurons and/or glial cells; excessive numbers of minicolumns; excessive and premature expansion of dendritic and axonal arbors, excessive numbers of axonal connections, and/or premature myelination.
Dr. G. Robert DeLong of Duke University Medical School takes this one step further in an article in Neurology, March, 1999. He points out that studies have demonstrated that autistic children produce far less serotonin (a brain neurotransmitter) than normal children. PET studies, further, have shown in male autistic children, at least, that lower serotonin synthesis is left-sided, compared to the normal right hemisphere synthesis, and is coupled with increased serotonin synthesis in the right dentate nucleus of the cerebellum which leads him to conclude: “These images indicate that the concept of idiopathic autism as a left-hemisphere syndrome is not over-simplified.” His article presents other data in support of his left-hemisphere serotonin deficit hypothesis, and its neuropsychologic manifestation of complex left-hemisphere dysfunction with sparing of right hemisphere (complex visual-spatial) function. He postulates that “serotonin deficiency, by permitting excessive neuronal growth, might account for the postnatal brain enlargement seen in some autistic children.” He notes autism has its onset at a time of prodigious neurite growth and synaptogenesis. He notes further that “serotonin has an important role in corticogenesis, particularly in modulating the branching and spread of thalamocortical axons. Serotonergic axons have direct inhibitory synapses onto thalamocortical branches transiently during cortical development, which appear to inhibit neurite growth and modulate transmission of action potentials. With serotonin deficiency, thalamocortical axon branches may spread excessively, resulting in lower information-transmitting capability of the cortex.” It is this excessive spreading of branches, he postulates, that might account for the overall brain enlargement.
So What Does This Have to Do with Savant Syndrome?
Several things perhaps. Clearly some persons with savant syndrome who are not autistic (approximately 50%) show clear evidence of a typical type of left hemisphere damage (on imaging studies) and/or other left hemisphere dysfunction on neuropsychological testing. This left hemisphere damage and dysfunction follows CNS injury or disease before, during, or after birth including, in the case of Dr. Miller’s FTD patients, even adult, previously non-disabled persons. In my view, in these cases, the right hemisphere compensates for left hemisphere damage and the typical right-hemisphere/habit memory constellation of savant symptoms is seen as elaborated upon in detail elsewhere on this site. In short, the right hemisphere (right mode) compensates for damage to left hemisphere (left mode), and lower level (habit memory/cortical striatal) circuits compensate for corresponding damage to higher level (cognitive memory/cortical limbic) damage and impairment producing the typical right brain/rote memory constellation so common in savant syndrome.
But in persons with autistic spectrum disorder with savant syndrome (approximately 50%) in general there is less evidence of typical left hemisphere damage of the characteristic type documented, in the above group. Could it be that the ‘brain damage’ in these persons is occurring, from whatever cause, during this very early in life period of excessive, and apparently disorganized brain growth? And could it be that the ‘brain damage’ here is not just left hemisphere, but also includes the connecting system of the brain — the corpus collosum and other structures — which otherwise are the mediator, modulators, and connectors between the two hemispheres and their more harmonious interaction? Why that possibility?
Taking Dr. DeLong’s work, above, one step further is work done by Dr. Michael Gazzaniga of Dartmouth College, particularly on ‘split-brain’ patients. These are persons who have had surgical sections done on the corpus callosum for treatment of certain neurologic and neurosurgical conditions. In a far-reaching review of the topic, Dr. Gazzaniaga has written a paper entitled “Cerebral specialization and interhemispheric communication Does the corpus callosum enable the human condition?” which appears in Brain, (2000) Volume 123, 1293-1326.
These split-brain patients confirm and re-emphasize the importance of hemispheric specialization in the brain both respect to left brain/right brain function, and split memory function as well. The role of the corpus callosum and allied structures “as a great communicator” between the two hemispheres is particularly critical to integration of brain function overall. In some savants corpus callosum abnormalities, including absence of that structure entirely, are evident on imaging studies. It may be that the ‘brain damage’ in the left hemisphere so evident in those savants with more typical CNS damage from pre, peri, or post-natal, shows up instead, in the autistic savant, as ‘damage’ of a different type involving not so much the hemispheres themselves, but the lack or coordination or intergration between them because of dysfunction in the corpus callosum and allied structures. And it may be also, that the period of rapid and excessive brain growth in autistic occurs during, and accounts for, the now rather widely reported head size changes that take place in autistic children during those early months and years. Why are both autism and savant syndrome seen more often males than females? That may go back to the work of Geschwind and Galaburda on the effects of circulating testosterone in the male fetus on the longer exposed, and more vulnerable, left hemsphere described elsewhere on this site.
In short, the search for the cause of savant syndrome, which does involve some of the left brain/right brain research embodied in all of the above, is going to have to extend beyond the brain hemispheres themselves to other allied structures and the period of rapid, excessive and disorganized brain growth described in these studies will need to be studied closely as the possible culprit for the unique brain circuitry and altered brain function seen in savant syndrome.
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For more information, please contact:
Darold A. Treffert, MD
St. Agnes Hospital, Fond du Lac, Wisconsin
Clinical Professor, Department of Psychiatry
University of Wisconsin Medical School, Madison
Personal Web site: http://www.daroldtreffert.com