Study of 38 Brain Regions Demonstrates Alterations Restricted Mainly to Structures Involved in Repetitive Behaviors and Social Deficits

Background: Individual brain structures have distinct developmental profiles during brain development (Caviness et al 1996, Herbert et al 2003, Piven et al 1996). MRI and postmortem studies indicate that autism is associated with selective alterations of the developmental profiles of some brain structures.

Objectives: The aim of our study was to detect the global pattern of developmental abnormalities and to establish whether the function of developmentally modified structures matched the autism diagnostic behavioral alterations. Detection of a global pattern required examination of 38 brain cytoarchitectonic subdivisions, including 15 brain structures and their 23 subdivisions, representing subcortical and cortical structures, cerebellum and brainstem in 4- to 60-year-old autistic and control subjects.

Methods: To achieve this aim, 14 autistic and 14 age-matched controls were selected on the basis of clinical inclusion and neuropathological exclusion criteria. The Cavalieri method was applied to estimate brain subdivision volumes. The numerical density and total number of neurons per region of interest were estimated using the MicroBrightfield software. 

Results:  Application of the Cavalieri method revealed significant volume alterations in the autism group in the caudate nucleus and nucleus accumbens only. In the autistic group, the caudate nucleus volume was larger by 22% (2,107 mm³) than in the control cohort (1,727 mm³; p < 0.026). The nucleus accumbens was larger in the autistic group by 34% (244 mm³) compared to in the control cohort (182 mm³; p < 0.026). The observed pattern of neuronal number changes in the striatum does not support the concept that there is increased volume of the brain subdivisions due to impaired neuronal pruning resulting in an increase in the number of neurons. In contrast, the numerical density of neurons in the autistic putamen was 13% less than in control subjects (24,302/mm³ and 27,838/mm³, respectively; p < 0.04), and of neurons in the autistic nucleus accumbens was 15% less (34,258/mm³ versus 40,459/mm³; p < 0.01). The numerical density of neurons was also reduced in two other striatal subdivisions, the caudate nucleus (-7%) and the globus pallidus (-10%), but these differences did not reach significance. The 12% reduction detected in the numerical density of neurons in the lateral nucleus of the amygdala in autistic subjects (24,282/mm³) in comparison to controls (27,632/mm³; p < 0.006) and the 17% reduction in the total number of neurons resemble the selective 13% reduction of the number of neurons in the lateral nucleus reported by Schumann and Amaral (2006).

Conclusions: This postmortem study of 38 brain subdivisions demonstrates that in autism, alterations in the number of neurons and in the volume of brain structures are limited to a few brain regions, including the nuclei of the striatum and amygdala. These findings support and expand MRI data (Sears at al 1994, 1999; Hollander et al 2005) and indicate that increased striatal volume and decreased number of neurons likely contribute to restricted, repetitive, and stereotypical behaviors. The results also support studies by Schumann and Amaral (2006) that showed a link between alterations in the amygdala and social deficits.