Autism at the beginning: Microstructural and growth abnormalities underlying the cognitive and behavioral phenotype of autism

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Abstract
Autistic symptoms begin in the first years of life, and recent magnetic resonance imaging studies have discovered brain growth abnormalities that precede and overlap with the onset of these symptoms. Recent postmortem studies of the autistic brain provide evidence of cellular abnormalities and processes that may underlie the recently discovered early brain overgrowth and arrest of growth that marks the first years of life in autism. Alternative origins and time tables for these cellular defects and processes are discussed. These cellular and growth abnormalities are most pronounced in frontal, cerebellar, and temporal structures that normally mediate the development of those same higher order social, emotional, speech, language, speech, attention, and cognitive functions that characterize autism. Cellular and growth pathologies are milder and perhaps nonexistent in other structures (e.g., occipital cortex), which are known to mediate functions that are often either mildly affected or entirely unaffected in autistic patients. It is argued that in autism, higher order functions largely fail to develop normally in the first place because frontal, cerebellar, and temporal cellular and growth pathologies occur prior to and during the critical period when these higher order neural systems first begin to form their circuitry. It is hypothesized that microstructural maldevelopment results in local and short distance overconnectivity in frontal cortex that is largely ineffective and in a failure of long-distance cortical–cortical coupling, and thus a reduction in frontal–posterior reciprocal connectivity. This altered circuitry impairs the essential role of frontal cortex in integrating information from diverse functional systems (emotional, sensory, autonomic, memory, etc.) and providing context-based and goal-directed feedback to lower level systems. The authors were supported by funds from the National Institute of Mental Health (2-ROI-MH36840) and National Institute of Neurological Disorders and Stroke (2-ROI-NS19855) awarded to Eric Courchesne.