David Amaral, research director of the UC Davis M.I.N.D. Institute, and former graduate student Cynthia Mills Schumann counted and measured representative samples of neurons in the amygdala of nine postmortem brains of males who had autism and 10 postmortem brains of males who did not have autism. Both subject groups ranged in age from 10-to-44 years at the time of death. Using a technique known as "unbiased stereological analysis," Schumann and Amaral counted neurons using a computer-aided microscope system. They found significantly fewer neurons - cells responsible for creating and transmitting electrical impulses - in the whole amygdala and its lateral nucleus in the brains of people with autism.
"This is the first quantitative evidence of an abnormal number of neurons in the autistic amygdala and the first study to use modern unbiased sampling techniques for autism research," Amaral said.
"While we have known that autism is a developmental brain disorder, where, how and when the autistic brain develops abnormally has been a mystery," said Thomas R. Insel, a physician and director of the National Institute of Mental Health. "This new finding is important because it demonstrates that the structure of the amygdala is abnormal in autism. Along with other findings on the abnormal function of the amygdala, research is beginning to narrow the search for the brain basis of autism."
Now affecting 1 in every 166 children and primarily affecting males, autism is a lifelong neurodevelopmental disorder characterized by social and communication deficits. While autism has clear behavioral indicators, the neural alterations leading to the deficits have been difficult to pinpoint. In studies dating back to the mid-1980s, researchers began focusing on the amygdala because of its importance in generating appropriate emotional responses and assimilating memories that are key to social learning - functions that are impaired by autism.
"Previous magnetic resonance imaging studies from several laboratories, including the M.I.N.D. Institute, have indicated precocious enlargement of the amygdala in young children with autism," said Schumann, who is now a postdoctoral researcher at UC San Diego. "But these studies were not able to determine whether the number of neurons were different in the autistic amygdala."
Interpreting these earlier qualitative studies was hampered because many postmortem brains available for research were from individuals who had autism as well as epilepsy, a condition known to cause pathology of the amygdala.
"Back when these studies were conducted, it wasn't easy to acquire the brain of a deceased person who just had autism," Amaral explained. "We are fortunate now to have the Autism Tissue Program, funded by the National Alliance for Autism Research and the National Institutes of Health. With their help, we were able to analyze more than double the number of previously examined postmortem brains, none of which had seizure disorders or any major neurological disorder other than autism."
"A better understanding of the neurobiology of the amygdala is crucial to advance autism research, and this study helps answer many important questions about the fundamental basis of autism," said Andy Shih, chief science officer for the National Alliance for Autism Research, which is now merged with Autism Speaks. "Autism Speaks and the Autism Tissue Program were proud to support this project so that these important discoveries could be made."
By counting the actual number of neurons in tissue samples, the researchers also overcame a methodological concern raised by studies that described changes in neuronal density, or neurons per unit volume, in portions of the amygdala.
"Differences in neuron density could just indicate changes in tissue volume rather than changes in total cell number. The only way to determine the actual difference is to systematically count samples of neurons in a defined volume," Amaral said.
With this latest confirmation that the amygdala is pathological in autism, Amaral and colleagues will now determine why there are fewer neurons in the amygdala and if other parts of the brain are similarly affected.
"We need to look at other brain regions to find out if the cell loss is idiosyncratic to the amygdala or a more general phenomenon," he said. "We're in the very early stages of understanding autism and its neurological pathologies. It's clearly a process with many steps, and at least we are now one step further."
Additional research will also help identify the developmental point in time at which the neuron reduction actually occurs, which the current study does not address.
"One possibility is that there are always fewer neurons in the amygdala of people with autism. Another possibility is that a degenerative process occurs later in life and leads to neuron loss. More studies are needed to refine our findings," said Schumann.
Schumann and Amaral's research was funded by the National Alliance for Autism Research and the National Institutes of Health. A copy of the article, "Stereological Analysis of Amygdala Neuron Number in Autism," is available from Caitlin Quigley in the Society for Neuroscience Public Information Department. She can be reached at (202) 962-4000 or firstname.lastname@example.org.
The UC Davis M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) is a unique, collaborative center bringing together parents, scientists, clinicians and educators for research on autism, fragile X syndrome, learning disabilities and other neurodevelopmental disorders. For more information, visit www.mindinstitute.org.
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