Objectives: The aim of this study was to test the hypothesis that subcortical structures are affected by developmental alterations and contribute to global brain developmental alterations and resulting functional deficits in autism.
Methods: To test this hypothesis of delayed and desynchronized growth of neurons in early childhood, the neuronal volume in 16 brain subcortical structures, the cerebellum and the archicortex was compared between autistic and control subjects of 4 to 8 years of age. Nineteen subregions (layers, sectors, nuclei) were examined to detect signs of desynchronized neuronal growth within individual anatomical brain subdivisions. To test the hypothesis that developmental defects of early childhood are partially corrected in late childhood and adulthood, the volume of neurons in the 4- to 8-year-old individuals with autism was compared with that of 9- to 64-year-old subjects with autism. Formalin fixed brains were dehydrated, embedded in celloidin, cut into 200-μm thick serial sections and stained with cresyl violet. The volume of the neuronal soma and the nucleus was estimated by using Nucleator. The volume of brain structures was estimated with the Cavalieri method and the number of neurons with the dissector.
Results: A significant deficit of neuronal soma volume (p < 0.001) was detected in 89% of the structures examined, including all 16 brain structures and 15 of 19 of their anatomical subdivisions in 4-8 year old children with autism. Finding a very severe volume deficit in 17%, severe in 44%, moderate in 22% and mild in 17% of the brain structures examined of the autistic subjects, we interpret as being a sign of desynchronized development of anatomically and functionally related neurons. This may help to explain the social and communication deficits, and the restricted repetitive and stereotypical patterns of behavior seen in autism. Finding a reduction of the developmental deficit from an average 19.6% in the 4-8 year old subjects to 8.8% in the over 8 year old subjects, suggests a delayed acceleration of the growth of neurons in late childhood and adulthood.
Conclusions: Brain region-specific neuron volume deficits may reflect desynchronized growth of neurons and neuronal networks in autism. The most severe delay seen in the 4-8 year old autistic children suggests that disregulation of brain development before the 4th year defines autism encephalopathy and leads to dysfunction for life.