In a small, preliminary study that included 13 male children, those with autism had an average 67 percent more prefrontal brain neurons and larger than average brain weight, than children without autism, according to a study in the November 9 issue of JAMA.

Brain and head overgrowth in children with autism and neural dysfunction are evident at young ages in multiple brain regions, including the prefrontal cortex (PFC), that are involved in higher-order social, emotional, communication, and cognitive development. "Therefore, knowledge of the neural basis of overgrowth could point to early causal mechanisms in autism and elucidate the neural functional defects that engender autistic symptoms. In the first magnetic resonance imaging (MRI) report of early brain overgrowth in autism a decade ago, it was theorized that excess numbers of neurons could be an underlying cause, perhaps due to prenatal dysregulation of proliferation, apoptosis [cell death], or both. However, the neural basis of early overgrowth remains unknown and can only be known from direct quantitative studies of the young postmortem autistic brain," according to background information in the article.

Eric Courchesne, Ph.D., of the NIH-UCSD School of Medicine Autism Center of Excellence, La Jolla, Calif., and colleagues examined whether early brain overgrowth in children with autism involves excess neuron numbers in the PFC. The study included postmortem prefrontal tissue from 7 autistic and 6 control male children, ages 2 to 16 years, which was examined by expert anatomists who were blinded to diagnostic status. Number and size of neurons were quantified within the dorsolateral (DL-PFC) and mesial (M-PFC) subdivisions of the PFC. Cases were from the eastern and southeastern United States and died between 2000 and 2006.

The researchers found statistically significant differences in neuron counts in the PFC in the autistic children compared with controls. There were 79 percent more neurons in DL-PFC in the autistic cases compared with the control cases and 29 percent more in M-PFC. The average DL-PFC count in the autistic children was 1.57 billion neurons compared with an average of 0.88 billion neurons in control children. The average M-PFC count in the autistic group was 0.36 billion neurons compared with an average of 0.28 billion neurons in controls. "Together, these 2 subdivisions gave a total combined prefrontal neuron count that was 67 percent greater in the autistic children compared with controls," the authors write.

The researchers also found that the brain weight in the autistic sample deviated from normative average weight for age by 17.6 percent, while control brains deviated from age-based norms by 0.2 percent.

"Our sample of autistic children was not large enough to statistically examine brain-behavior relationships. Future studies with many more cases of autistic children might reveal important relationships between neuron counts and symptom severity or intellectual ability," the authors write.

"To our knowledge, this study is the first direct quantitative test and confirmation of the theory that a pathological overabundance of neurons in critical brain regions is present at a young age in autism. Because cortical neurons are generated in prenatal, not postnatal life, pathological overabundance of neurons indicates early developmental disturbances in molecular and genetic mechanisms that govern proliferation, cell cycle regulation, and apoptosis. Therefore, the finding has significance for understanding the etiological and neural development and functional origins of autism."

Editorial: Increased Neuron Number and Head Size in Autism

"The results of the study by Courchesne et al show that the relationship between increased neuron count, brain overgrowth, and increased brain weight in autism is complex," writes Janet E. Lainhart, M.D., of the University of Utah, Salt Lake City, and Nicholas Lange, Sc.D., of the Harvard University Schools of Medicine and Public Health, Boston, in an accompanying editorial.

"Prefrontal neuron number and brain weight were increased in the autism group but were not significantly correlated. Future studies of prefrontal neuron numbers are needed in children and adolescents with autism who do not have brain overgrowth and in nonautistic children with benign megalencephaly [an abnormally large brain] to determine if increased prefrontal neuron count in autism is associated with autism only, brain overgrowth only, or some combination of both. Neuroimaging studies suggest that other regions of the brain, including the temporal lobe, deserve further investigation by postmortem tissue analysis. Because neurons in all brain areas except the olfactory bulb and hippocampus are generated before birth, the present findings add significantly to mounting biological evidence that the developmental neuropathology of idiopathic autism begins before birth in some, possibly all, cases. The study by Courchesne et al also adds to frequently reported findings in neuroanatomical studies of autism, including increased variance and loss of typical relationships between measured components of the brain. Factors that normally organize the brain appear to be disrupted."