Patches of Disorganization in the Neocortex of Children with Autism

Rich Stoner, Ph.D., Maggie L. Chow, Ph.D., Maureen P. Boyle, Ph.D., Susan M. Sunkin, Ph.D., Peter R. Mouton, Ph.D., Subhojit Roy, M.D., Ph.D., Anthony Wynshaw-Boris, M.D., Ph.D., Sophia A. Colamarino, Ph.D., Ed S. Lein, Ph.D., and Eric Courchesne, Ph.D.

N Engl J Med 2014; 370:1209-1219March 27, 2014DOI: 10.1056/NEJMoa1307491

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BACKGROUND

Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development.

METHODS

To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type–specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years.

RESULTS

We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches.

CONCLUSIONS

In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.)

Acute and Subacute Changes in Neural Activation during the Recovery from Sport-Related Concussion

Thomas A. Hammeke,1 Michael McCrea,2 Sarah M. Coats,3 Matthew D. Verber,4 Sally Durgerian,5 Kristin Flora,6 Gary S. Olsen,7 Peter D. Leo,5 Thomas A. Gennarelli,2 AND Stephen M. Rao8

1Clement J. Zablocki VA Medical Center & Department of Psychiatry & Behavioral Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
2Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin
3Rehabilitation Institute at St. Mary’s Hospital, Enid, Oklahoma

4Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 5Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin 6Department of Psychology, Franklin College, Franklin, Indiana
7Department of Neuropsychology, Marshfield Clinic, Marshfield, Wisconsin

8Schey Center for Cognitive Neuroimaging, Neurological Institute, Cleveland Clinic, Cleveland, Ohio (RECEIVED December 21, 2012; FINAL REVISION May 30, 2013; ACCEPTED June 3, 2013)

Abstract

To study the natural recovery from sports concussion, 12 concussed high school football athletes and 12 matched uninjured teammates were evaluated with symptom rating scales, tests of postural balance and cognition, and an event-related fMRI study during performance of a load-dependent working memory task at 13 h and 7 weeks following injury. Injured athletes showed the expected postconcussive symptoms and cognitive decline with decreased reaction time (RT) and increased RT variability on a working memory task during the acute period and an apparent full recovery 7 weeks later. Brain activation patterns showed decreased activation of right hemisphere attentional networks in injured athletes relative to controls during the acute period with a reversed pattern of activation (injured . controls) in the

same networks at 7 weeks following injury. These changes coincided with a decrease in self-reported postconcussive symptoms and improved cognitive test performance in the injured athletes. Results from this exploratory study suggest that decreased activation of right hemisphere attentional networks mediate the cognitive changes and postconcussion symptoms observed during the acute period following concussion. Conversely, improvement in cognitive functioning and postconcussive symptoms during the subacute period may be mediated by compensatory increases in activation of this same attentional network. (JINS, 2013, 19, 1–10) 

Journal of the International Neuropsychological Society (2013), 19, 1–10. Copyright E INS. Published by Cambridge University Press, 2013. doi:10.1017/S135561771300070