Global Pattern of Delayed and Desynchronized Neuron Growth in the Brain of Autistic Subjects

Background:  The abundance of research focused on the cortex has resulted in a mainly corticocentric theory of autism [Frith 2004, Geschwind and Levitt 2007]. However, the three diagnostic domains of autism engage subcortical structures including  (a) the amygdala, involved in processing social information, emotional interpretation, fear, and anxiety [Amaral et al 2003, Baron-Cohen et al 1999, Winston et al 2002]; (b) the thalamus, involved in language functions, attention, anxiety and obsessive thinking [Ojemann and Ward 1971, Oke et al 1978]; (c) the striatum, linked to repetitive motor behaviors, compulsions and rituals [Day and Carelli 2007]; and (d) the brainstem and cerebellar deep nuclei, integrating a cerebellar role in motor functions, language and cognition, and eye motion control [Leyung et al 2000].

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.