Evidence against the "normalization" prediction of the early brain overgrowth hypothesis of autism.

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TitleEvidence against the "normalization" prediction of the early brain overgrowth hypothesis of autism.
Publication TypeJournal Article
Year of Publication2020
AuthorsYankowitz, LD, Herrington, JD, Yerys, BE, Pereira, JA, Pandey, J, Schultz, RT
JournalMol Autism
Date Published2020 Jun 18

BACKGROUND: The frequently cited Early Overgrowth Hypothesis of autism spectrum disorder (ASD) postulates that there is overgrowth of the brain in the first 2 years of life, which is followed by a period of arrested growth leading to normalized brain volume in late childhood and beyond. While there is consistent evidence for early brain overgrowth, there is mixed evidence for normalization of brain volume by middle childhood. The outcome of this debate is important to understanding the etiology and neurodevelopmental trajectories of ASD.

METHODS: Brain volume was examined in two very large single-site samples of children, adolescents, and adults. The primary sample comprised 456 6-25-year-olds (ASD n = 240, typically developing controls (TDC) n = 216), including a large number of females (n = 102) and spanning a wide IQ range (47-158). The replication sample included 175 males. High-resolution T1-weighted anatomical MRI images were examined for group differences in total brain, cerebellar, ventricular, gray, and white matter volumes.

RESULTS: The ASD group had significantly larger total brain, cerebellar, gray matter, white matter, and lateral ventricular volumes in both samples, indicating that brain volume remains enlarged through young adulthood, rather than normalizing. There were no significant age or sex interactions with diagnosis in these measures. However, a significant diagnosis-by-IQ interaction was detected in the larger sample, such that increased brain volume was related to higher IQ in the TDCs, but not in the ASD group. Regions-of-significance analysis indicated that total brain volume was larger in ASD than TDC for individuals with IQ less than 115, providing a potential explanation for prior inconsistent brain size results. No relationships were found between brain volume and measures of autism symptom severity within the ASD group.

LIMITATIONS: Our cross-sectional sample may not reflect individual changes over time in brain volume and cannot quantify potential changes in volume prior to age 6.

CONCLUSIONS: These findings challenge the "normalization" prediction of the brain overgrowth hypothesis by demonstrating that brain enlargement persists across childhood into early adulthood. The findings raise questions about the clinical implications of brain enlargement, since we find that it neither confers cognitive benefits nor predicts increased symptom severity in ASD.

Alternate JournalMol Autism
PubMed ID32552879
PubMed Central IDPMC7301552
Grant ListR01MH073084 / MH / NIMH NIH HHS / United States
RC1MH088791 / MH / NIMH NIH HHS / United States
R21MH098153 / MH / NIMH NIH HHS / United States
R21MH092615 / MH / NIMH NIH HHS / United States
5U54HD086984 / / National Institute of Child Health and Human Development /
DGE-132185 / / National Science Foundation /
SAP #4100042728 / / Pennsylvania Department of Health /
SAP # 4100047863 / / Pennsylvania Department of Health /
66727 / / Robert Wood Johnson Foundation /