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Fumiko Hoeft, MD, PhD; Amy A. Lightbody, PhD; Heather Cody Hazlett, PhD; Swetapadma Patnaik, MS; Joseph Piven, MD; Allan L. Reiss, MD

Arch Gen Psychiatry. 2008;65(9):1087-1097.

Context  Brain maturation starts well before birth and occurs as a unified process with developmental interaction among different brain regions. Gene and environment play large roles in such a process. Studies of individuals with genetic disorders such as fragile X syndrome (FXS), which is a disorder caused by a single gene mutation resulting in abnormal dendritic and synaptic pruning, together with healthy individuals may provide valuable information.

Objective  To examine morphometric spatial patterns that differentiate between FXS and controls in early childhood.

Design  A cross-sectional in vivo neuroimaging study.

Setting  Academic medical centers.

Participants  A total of 101 children aged 1 to 3 years, comprising 51 boys with FXS, 32 typically developing boys, and 18 boys with idiopathic developmental delay.

Main Outcome Measures  Regional gray matter volume as measured by voxel-based morphometry and manual tracing, supplemented by permutation analyses; regression analyses between gray and white matter volumes, IQ, and fragile X mental retardation protein level; and linear support vector machine analyses to classify group membership.

Results  In addition to aberrant brain structures reported previously in older individuals with FXS, we found reduced gray matter volumes in regions such as the hypothalamus, insula, and medial and lateral prefrontal cortices. These findings are consistent with the cognitive and behavioral phenotypes of FXS. Further, multivariate pattern classification analyses discriminated FXS from typical development and developmental delay with more than 90% prediction accuracy. The spatial patterns that classified FXS from typical development and developmental delay included those that may have been difficult to identify previously using other methods. These included a medial to lateral gradient of increased and decreased regional brain volumes in the posterior vermis, amygdala, and hippocampus.

Conclusions  These findings are critical in understanding interplay among genes, environment, brain, and behavior. They signify the importance of examining detailed spatial patterns of healthy and perturbed brain development.

Author Affiliations: Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, Stanford, California (Drs Hoeft, Lightbody, and Reiss and Ms Patnaik); and the Neurodevelopmental Disorders Research Center and Department of Psychiatry, University of North Carolina, Chapel Hill (Drs Hazlett and Piven).

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