Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development1,2. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life3,4. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6–12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

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The IBIS (Infant Brain Imaging Study) Network is an NIH funded Autism Center of Excellence (HDO55741) and consists of a consortium of 8 Universities in the US and Canada. This work was supported by an NIH Autism Center of Excellence grant (NIMH and NICHD HD055741 to J.Pi.), Autism Speaks (6020) and the Simons Foundation (140209). Further support was provided by the National Alliance for Medical Image Computing (NA-MIC), funded by the NIH through grant U54 EB005149, the IDDRC Imaging and Participant Registry cores (NICHD HD003110 to J.Pi.) and R01 MH093510 (to J.R.P.Jr). We thank M. Burchinal and K. Y. Truong for their consultation on the statistical methods and approach. Given the large commitment of time and effort required by this study, we extend our appreciation to the families who have participated in this study and the numerous research assistants and staff who have contributed to this work.

Author information


  1. Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA

    • Heather Cody Hazlett
    • , Hongbin Gu
    • , Sun Hyung Kim
    • , Martin Styner
    •  & Joseph Piven
  2. Carolina Institute for Developmental Disabilities, Chapel Hill, North Carolina 27599, USA

    • Heather Cody Hazlett
    • , Meghan R. Swanson
    •  & Joseph Piven
  3. College of Charleston, Charleston, South Carolina 29424, USA

    • Brent C. Munsell
  4. Department of Educational Psychology, University of Minnesota, Minneapolis, Minnesota 55455, USA

    • Jason J. Wolff
  5. Institute of Child Development, University of Minnesota, Minneapolis, Minnesota 55455, USA

    • Jed T. Elison
  6. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599, USA

    • Hongtu Zhu
  7. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Kelly N. Botteron
    • , John N. Constantino
    •  & John R. Pruett
  8. Department of Radiology, University of Washington, Seattle, Washington 98105, USA

    • Stephen R. Dager
    •  & Dennis W. Shaw
  9. Center on Human Development and Disability, University of Washington, Seattle, Washington 98105, USA

    • Stephen R. Dager
    • , Annette M. Estes
    •  & Dennis W. Shaw
  10. Department of Speech and Hearing Sciences, University of Washington, Seattle, Washington 98105, USA

    • Annette M. Estes
  11. Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 0G4, Canada

    • D. Louis Collins
    • , Alan C. Evans
    • , Vladimir S. Fonov
    •  & Penelope Kostopoulos
  12. Tandon School of Engineering, New York University, New York, New York 10003, USA

    • Guido Gerig
  13. Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri 63110, USA

    • Robert C. McKinstry
  14. Center for Autism Research, The Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Juhi Pandey
    •  & Robert T. Schultz
  15. Department of Psychology, Temple University, Philadelphia, Pennsylvania 19122, USA

    • Sarah Paterson
  16. Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2R3, Canada

    • Lonnie Zwaigenbaum
  17. University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • J. Piven
    • , H. C. Hazlett
    • , C. Chappell
    • , M. Styner
    •  & Core H. Gu
  18. University of Washington, Seattle, Washington 98105, USA.

    • S. R. Dager
    • , A. M. Estes
    •  & D. W. Shaw
  19. Washington University, St. Louis, Missouri 63130, USA.

    • K. N. Botteron
    • , R. C. McKinstry
    • , J. N. Constantino
    •  & J. R. Pruett Jr
  20. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

    • R. T. Schultz
    •  & S. Paterson
  21. University of Alberta, Edmonton, Alberta T6G 2R3, Canada.

    • L. Zwaigenbaum
  22. University of Minnesota, Minneapolis, Minnesota 55455, USA.

    • J. T. Elison
    •  & J. J. Wolff
  23. Montreal Neurological Institute, Montreal, Quebec H3A 0G4, Canada.

    • A. C. Evans
    • , D. L. Collins
    • , G. B. Pike
    • , V. S. Fonov
    • , P. Kostopoulos
    •  & S. Das
  24. New York University, New York, New York 10003, USA.

    • G. Gerig


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All co-authors discussed the results, made critical contributions to the work and contributed to the writing of the manuscript. H.C.H., K.N.B., S.R.D., A.M.E., R.C.M., S.P., J.Pi., R.T.S., J. Pa. and D.W.S. contributed to the data collection. A.C.E., P.K. provided support for data management. B.C.M., S.H.K., M.S., D.L.C., A.C.E., V.S.F. and G.G. conducted image processing. H.G., B.C.M., S.H.K., M.S. and H.Z. analysed the data. H.C.H. wrote the manuscript with J.Pi., H.G., B.C.M., M.S. and with J.J.W., J.T.E., M.R.S., J.N.C., J.R.P.Jr, A.M.E., R.T.S. and L.Z. providing additional feedback.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Heather Cody Hazlett.

Reviewer Information Nature thanks M. Johnson, G. Ramsay, T. Yarkoni and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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