BRAIN DEVELOPMENT IN AUTISM:EARLY OVERGROWTH FOLLOWED BY PREMATURE ARREST OF GROWTH Eric Courchesne * Center for Autism Research, Children’s Hospital Research Center, La Jolla, California, and Neurosciences Department, School of Medicine, University of California at San Diego, La Jolla, California Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of children with autism has remained largely unstudied. The increased use of retrospective measures such as head circumference, along with a surge of MRI studies of toddlers with autism, have opened a whole new area of research and discovery. Recent studies have now shown that abnormal brain overgrowth occurs during the first 2 years of life in children with autism. By 2– 4 years of age, the most deviant overgrowth is in cerebral, cerebellar, and limbic structures that underlie higher-order cog- nitive, social, emotional, and language functions. Excessive growth is fol- lowed by abnormally slow or arrested growth. Deviant brain growth in autism occurs at the very time when the formation of cerebral circuitry is at its most exuberant and vulnerable stage, and it may signal disruption of this process of circuit formation. The resulting aberrant connectivity and dys- function may lead to the development of autistic behaviors. To discover the causes, neural substrates, early-warning signs and effective treatments of autism, future research should focus on elucidating the neurobiological defects that underlie brain growth abnormalities in autism that appear during these critical first years of life. © 2004 Wiley-Liss, Inc. MRDD Research Reviews 2004;10:106 –111. Key Words: autism; brain growth; development; neuroimaging; head circumference; MRI; postmortem T he first 2 years of life are unique and crucial in human brain development. Bateson referred to this brief period as a “window of opportunity.” Dobbing [1981] and Kinney et al. [1988] observed that it is also a time of particular vulnerability to abnormal events and conditions. As Hutten- locher [2002] points out, this early vulnerability arises from the fact that at birth, neural circuitry in the cerebral cortex is relatively sparse; and the creation of mature, complex cerebral circuitry depends heavily on neuronal growth in the first post- natal months and years. These growth events cause the brain to triple in size during the first 2 years of life [Blinkov and Glezer, 1968; Courchesne et al., 2000] and are marked by unparalleled increases in synaptic numbers, dendritic and axonal growth, and myelination [Huttenlocher, 2002; Kinney et al., 1988; Quartz and Sejnowski, 1998]. These neuronal and glial growth pro- cesses form the circuits that underlie growing neurobehavioral capacity, with early maturing neuronal systems providing sen- sory, perceptual, and basic memory functions, and later matur- ing systems providing working memory, social communication, language and speech, and self-awareness [Herschkowitz, 2000]. In humans, it is not until after this crucial phase of devel- opment is largely over that autism is clinically recognized and diagnosed, typically between 2 and 4 years of age [Baron-Cohen et al., 1992; De Giacomo and Fombonne, 1998; Lord and Risi, 2000; Rogers and DiLalla, 1990]. However, retrospective stud- ies, single case reports and parental comments indicate that signs of abnormal behavior may sometimes appear as early as the first year of life [Adrien et al., 1993; Dawson et al., 2000; Maestro et al., 2002; Osterling and Dawson, 1994]. Because its presence ordinarily goes unrecognized until a later age, brain develop- ment in autism during the crucial first 2 years of life has, with a single exception [Hashimoto et al., 1995], remained largely unstudied. Hints as to what might be happening during the first 2 years appeared for the first time in recent studies that used either head circumference [Courchesne et al., 2003] or MRI (Carper and Courchesne, submitted; Carper and Courchesne; 2000; Carper et al., 2002; Courchesne et al., 2001; Sparks et al., 2002]. Because head circumference (HC) has been shown in HC-MRI correlation studies to be a good indicator of brain size in young autistic and normal children [Bartholomeusz et al., 2002], we used HC as an indirect index of brain growth during these first 2 years of life [Courchesne et al., 2003]. The neuroanatomical state of the brain at the end of this critical 2-year period of development has been documented with MRI in prospective studies of autism at the age of first clinical concern and referral (Carper and Courchesne, submitted; Carper and Courchesne, 2000; Carper et al., 2002; Courchesne et al., 2001; Sparks et al., 2002]. HEAD CIRCUMFERENCE IN EARLY LIFE Retrospective studies of autism find HC is typically nor- mal average at birth [Gillberg and de Souza, 2002; Lainhart et Grant sponsors: This work is supported by grants from NIMH (2-ROI-MH36840) and NINDS (2-RO1-NS-19855) awarded to Eric Courchesne. Thanks to Karen Pierce and Philip Schwartzkroin for helpful comments on the article. *Correspondence to: Eric Courchesne, Center for Autism Research, 8110 La Jolla Shores Drive, La Jolla, CA 92037. E-mail: ecourchesne@ucsd.edu Received 23 June 2004; Accepted 25 June 2004 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrdd.20020 MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 10: 106 –111 (2004) © 2004 Wiley-Liss, Inc.