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Cited by 345Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersFetal and Pediatric Neurological Disorders

Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder

Open access
Shen, Mark D., Nordahl, Christine W., Young, Gregory S., Wootton-Gorges, Sandra L., Lee, Aaron, Liston, Sarah E., Harrington, Kayla R., Ozonoff, Sally +1 more·2013·Brain
DOI 10.1093/brain/awt166PMC PMC3754460
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Abstract

Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 'high-risk' infants having an older sibling with autism spectrum disorder and 22 'low-risk' infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.

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Crossref · 10.1093/brain/awt166

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 62 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Lateral ventricles · p. 7

    Male infants had larger lateral ventricles than females after controlling for age and total cerebral volume.

    “there was a significant effect of gender on lateral ventricle volume, with male infants having larger lateral ventricles than females ( 2 = 5.80, df = 1, P 5 0.05).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Total cerebral volume · p. 5

    The ASD group showed a significantly faster growth trajectory of total cerebral volume than the other groups.

    “which indicates that the ASD group had a significantly faster growth trajectory of total cerebral volume than the other groups”
    Quote in the paperSubstantial claim
  • Findingown data
    § Total cerebral volume · p. 5

    By 12-15 months, infants who developed ASD had 7% larger total cerebral volume than low-risk typical infants.

    “Infants who developed ASD had 7% larger total cerebral volume than low-risk typical infants by 12-15 months ( P 5 0.05)”
    Quote in the paperSubstantial claim
  • Findingown data
    § Total cerebral volume · p. 5

    At 18-24 months, infants who developed ASD had 8% larger total cerebral volume than low-risk typical infants.

    “8% larger total cerebral volume at 18-24 months ( P 5 0.01)”
    Quote in the paperSubstantial claim
  • Findingown data
    § Head circumference · p. 7

    Extra-axial fluid had an independent and unique effect on head circumference.

    “Adding extra-axial fluid was also found to have an independent and unique effect on head circumference ( 2 = 7.03, df = 1, P 5 0.01).”
    Quote in the paperSubstantial claim
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 27

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    Findingown data
    § Head circumference · p. 7

    Head circumference correlated with body size, total cerebral volume, and extra-axial fluid.

    “Table 3 shows that head circumference is correlated with body size, total cerebral volume, and extra-axial fluid.”
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    Findingown data
    § Total cerebral volume · p. 5

    Total cerebral volume was higher for children who weighed more.

    “and was higher for children who weighed more ( 2 = 22.93, df = 1, P 5 0.0001).”
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    Findingown data
    § Lateral ventricles · p. 7

    The ASD group had slightly larger lateral ventricles than all other groups, a marginally significant effect.

    “There was also a marginally significant effect of outcome group, above and beyond age, total cerebral volume, and gender, with the ASD group having slightly larger lateral ventricles compared to all other groups ( 2 = 6.75, df = 3, P = 0.08).”
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    Findingown data
    § Outcome classifications · p. 5

    Ten infants, all high-risk, received an ASD classification at 24 months, representing 30.3% of the high-risk group.

    “Ten infants (eight male, two female; all high-risk; 30.3% of high-risk group) received an ASD classification at 24 months.”
    Quote in the paperNot a substantial claim

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    Findingown data
    § Outcome classifications · p. 5

    Eight of the 10 infants with ASD at 24 months had their diagnosis confirmed at 36 months, and no ASD diagnosis changed.

    “Eight of the 10 infants have reached 36 months and have had their ASD diagnosis confirmed at this visit. None of the ASD diagnoses made at 24 months were changed at 36 months.”
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    Findingown data
    § Total cerebral volume · p. 5

    There were no interactions with gender for total cerebral volume.

    “There were no interactions with gender.”
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    Findingown data
    § Quantified volume of extra-axial fluid · p. 6

    There was no significant effect or interaction of gender on extra-axial fluid, suggesting the ASD elevation was present in both girls and boys.

    “There was no significant effect or interactions of gender, suggesting that the elevated extra-axial fluid in the ASD group was present in both girls and boys.”
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    Findingown data
    § Total cerebral volume · p. 5

    Total cerebral volume was higher in males than females.

    “was higher in males than females ( 2 = 19.26, df = 1, P 5 0.0001)”
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    Findingown data
    § Discussion · p. 9

    Both brain volume and extra-axial fluid volume contribute to infant head circumference.

    “We found that both brain and extra-axial fluid volumes contribute to infant head circumference.”
    Quote in the paperSubstantial claim

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    Findingown data
    § Discussion · p. 8

    Elevated extra-axial fluid during early infancy was associated with both an autism spectrum disorder diagnosis and more severe autism symptoms.

    “Our finding that elevated extra-axial fluid during early infancy was associated with both a diagnosis of ASD and more severe autism symptoms”
    Quote in the paperSubstantial claim

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    Study design and conductown data
    § Sample description · p. 4

    The high-risk and low-risk groups did not differ significantly on gender, age at Time 1 MRI, interval between MRI time points, or age at outcome assessment.

    “The groups comprised of the remaining 33 high-risk and 22 low-risk infants did not differ significantly on gender, age at Time 1 MRI, interval between MRI time points, or age at outcome assessment (Table 1).”
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    Premisecitation
    § Introduction · p. 3

    An additional 20-30% of infant siblings of children with ASD will have other developmental delays.

    “An additional 20-30% of infant siblings of children with ASD will have other developmental delays (Gamliel et al ., 2007; Constantino et al ., 2010).”
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    Premisecitation
    § Introduction · p. 3

    The recurrence rate of ASD in siblings is 18.7%, nearly 20-fold greater than in the general population.

    “The recurrence rate of ASD in siblings is 18.7% (Ozonoff et al ., 2011), a nearly 20-fold greater risk than in the general population.”
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    Study design and conductown data
    § Sample description · p. 4

    The nine infants who dropped out did not differ in developmental quotient from the remaining sample.

    “There were no differences in developmental quotient between the nine infants who were dropped from the study and the remaining sample ( n = 55).”
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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Introduction · p. 3

    Early intervention is effective in decreasing impairments and may improve long-term outcomes for children with ASD.

    “Early intervention is effective in decreasing impairments (Dawson et al ., 2010) and may result in more positive long-term outcomes for the child (Rogers and Vismara, 2008).”
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    Premisecitation
    § Introduction · p. 3

    There is evidence for alterations in event-related potentials and in microstructural organization of white matter tracts in infants later diagnosed with ASD.

    “There is also evidence for alterations in event-related potentials (Elsabbagh et al ., 2012) and in the microstructural organization of white matter tracts (Wolff et al ., 2012) in infants later diagnosed with ASD.”
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    Premisecitation
    § Discussion · p. 7

    Lateral ventricles in children with extra-axial fluid are either normal or mildly enlarged.

    “The lateral ventricles of these children are either normal or mildly enlarged (Sahar, 1978; Alvarez et al ., 1986; Odita, 1992)”
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    Premisenone given
    § Introduction · p. 3

    It remains unclear whether MRI analyses could detect clinically significant structural anomalies in infants at risk for ASD and whether these would be associated with developing ASD.

    “It remains unclear, however, whether MRI analyses could detect clinically significant structural anomalies in infants at risk for ASD and whether these would be associated with developing ASD.”
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    Premisecitation
    § Discussion · p. 7

    The presenting symptom of extra-axial fluid is usually rapid head growth in the first year of life, with greatest increase around 6 months.

    “The presenting symptom is usually rapid head growth in the first year of life, with the greatest increase in head circumference around 6 months (Sahar, 1978; Barlow, 1984; Alvarez et al ., 1986).”
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    Premisecitation
    § Introduction · p. 3

    Symptoms more fully diagnostic of ASD appear to develop gradually between 12 and 24 months.

    “Symptoms more fully diagnostic of ASD appear to develop gradually between 12 and 24 months of age (Zwaigenbaum et al ., 2005; Ozonoff et al ., 2010; Landa et al ., 2012).”
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    Interpretationown data
    § Head circumference · p. 7

    Both total cerebral volume and extra-axial fluid contribute to individual variability in head circumference.

    “This indicates that both total cerebral volume and extra-axial fluid contribute to individual variability in head circumference.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion · p. 9

    Accumulation of extra-axial fluid may begin before birth, as prenatal MRI has shown that infants with extra-axial fluid had prominent cerebrospinal fluid-filled subarachnoid spaces during the foetal period.

    “In fact, it is possible that the accumulation of extra-axial fluid begins before birth, since prenatal MRI has shown that infants with extra-axial fluid had prominent CSF-filled subarachnoid spaces during the foetal period (Girard and Raybaud, 2001).”
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    Interpretationreasoning
    § Discussion · p. 9

    There may be an imbalance between cerebrospinal fluid production and drainage in infants with excessive extra-axial fluid.

    “However, there may be an imbalance between CSF production and CSF drainage in infants with excessive extra-axial fluid.”
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  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion · p. 9

    Cerebrospinal fluid production increases markedly in the first year of life.

    “There is a marked increase in CSF production in the first year of life (Yasuda et al ., 2002)”
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    Premisecitation
    § Discussion · p. 9

    Cerebrospinal fluid is recycled more slowly in early life, and the higher ratio of cerebrospinal fluid to brain volume gives the developing brain less ability to eliminate harmful metabolites and toxins, making it more vulnerable to damage.

    “CSF is recycled at a much slower rate in early life (Johanson et al ., 2008), and coupled with a higher ratio of CSF to brain volume (Yasuda et al ., 2002), these factors give the developing brain less ability to eliminate harmful metabolites and toxins, thus making it more vulnerable to damage (Johanson et al ., 2008).”
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    Premisecitation
    § Discussion · p. 9

    Parental concerns at 12 months have 82% sensitivity and 60% specificity in predicting autism spectrum disorder diagnosis.

    “By comparison, parental concerns at 12 months have 82% sensitivity and 60% specificity in predicting ASD diagnosis (Ozonoff et al ., 2009).”
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    Premisecitation
    § Discussion · p. 9

    Stagnation of cerebrospinal fluid flow in animal models leads to altered neurogenesis and premature migration of progenitor cells.

    “For example, stagnation of CSF flow in animal models leads to an alteration of neurogenesis and premature migration of progenitor cells (Mashayekhi et al ., 2002).”
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    Premisecitation
    § Discussion · p. 8

    Increased extra-axial fluid is usually found in the absence of severe ventricular enlargement.

    “which is consistent with reports that increased extra-axial fluid is usually found in the absence of severe ventricular enlargement (Sahar, 1978; Alvarez et al ., 1986; Odita, 1992).”
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    Premisecitation
    § Discussion · p. 8

    In typical brain development, the subarachnoid space increases from birth to 7 months, declines between 12 and 24 months, and is minimal by 24 months.

    “In typical brain development, on the other hand, the subarachnoid space increases from birth to 7 months, declines between 12-24 months, and is minimal by 24 months (Kleinman et al ., 1983; Lam et al ., 2001).”
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    Premisecitation
    § Discussion · p. 9

    Cerebrospinal fluid from the subarachnoid space in infants with extra-axial fluid has a markedly higher protein concentration than cerebrospinal fluid from the ventricles or lumbar puncture, and than cerebrospinal fluid in normal infants.

    “Indeed, the composition of CSF drawn from the subarachnoid space in infants with extra-axial fluid has a markedly higher protein concentration than CSF drawn from the ventricles or from lumbar puncture (Chazal et al ., 1985), and also compared to CSF in normal infants (Briner and Bodensteiner, 1981).”
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    Premisecitation
    § Discussion · p. 7

    Intracranial pressure in children with extra-axial fluid is normal or slightly elevated.

    “and intracranial pressure is normal or slightly elevated (Sahar, 1978; Chazal et al ., 1985).”
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    § Discussion · p. 9

    An imbalance of cerebrospinal fluid production and absorption alters the concentration of these factors and could lead to serious consequences on cortical development.

    “An imbalance of CSF production and absorption alters the concentration of these factors and could lead to serious consequences on cortical development (Mashayekhi et al ., 2002).”
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    Premisecitation
    § Discussion · p. 8

    In the mature brain, cerebrospinal fluid returns to the venous circulation through reabsorption into arachnoid granulations located along the superior sagittal sinus.

    “In the mature brain, return of CSF to the venous circulation takes place through re-absorption into arachnoid granulations that are located along the superior sagittal sinus (Kapoor et al ., 2008).”
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    § Discussion · p. 8

    Arachnoid granulations are absent at birth and mature over the first 18 months of life.

    “However, arachnoid granulations are not present at birth and only mature over the first 18 months of life (Le Gros Clark, 1920; Go ´ mez et al ., 1981).”
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    § Discussion · p. 9

    Cerebrospinal fluid absorption occurs through lymphatic pathways, primarily through the cribriform plate and into extracranial lymphatics in the paranasal region.

    “Human and animal studies demonstrate that CSF absorption occurs through lymphatic pathways, primarily through the cribriform plate and ultimately into the extracranial lymphatics located in the paranasal region (Johnston et al ., 2004).”
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    § Discussion · p. 7

    Boys comprise about two-thirds of infants detected with extra-axial fluid.

    “Boys comprise about two-thirds of the infants detected with extra-axial fluid (Sahar, 1978; Nickel and Gallenstein 1987; Hellbusch, 2007).”
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    Premisecitation
    § Discussion · p. 9

    Stagnation of cerebrospinal fluid could lead to accumulation of waste byproducts and neuromodulators in brain tissue, potentially altering the extracellular environment of neurons and impacting their function.

    “Stagnation of CSF could lead to the accumulation of waste byproducts and neuromodulators in brain tissue that may alter the extracellular environment of neurons and impact their function (Del Bigio, 2010).”
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    § Discussion · p. 9

    Cerebrospinal fluid removes potentially harmful byproducts of brain metabolism.

    “CSF has many important functions, including the removal of potentially harmful byproducts of brain metabolism (Johanson et al ., 2008).”
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    Premisecitation
    § Discussion · p. 9

    Individuals with autism spectrum disorder are born with normal head size, but head growth accelerates compared to typically developing children sometime during the first year of life.

    “One of the most often cited and replicated findings of the neuropathology of ASD is that individuals with ASD are born with normal head size, but that head growth accelerates, compared to typically developing children, sometime during the first year of life (Lainhart et al ., 1997; Courchesne et al ., 2003).”
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    § Discussion · p. 9

    Lymphatic drainage may be the primary pathway for cerebrospinal fluid absorption during the neonatal period.

    “In fact, lymphatic drainage may be the primary pathway for CSF absorption during the neonatal period (Johnston, 2003).”
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    Premisecitation
    § Discussion · p. 7

    Extra-axial fluid in infancy has been considered benign because it is not currently associated with a clinical syndrome or gross anatomical abnormality and because excess fluid typically resolves without intervention later in infancy.

    “The presence of extra-axial fluid in infancy has been considered 'benign' because it is not currently associated with a clinical syndrome or gross anatomical abnormality (stroke, trauma, tumour) and because excess fluid typically resolves without intervention later in infancy (Maytal et al ., 1987; Odita, 1992).”
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    Premisecitation
    § Discussion · p. 7

    Extra-axial fluid is associated with co-occurrence of seizures and motor delays.

    “However, several reports have associated extra-axial fluid with a co-occurrence of seizures (Sahar, 1978; Chazal et al ., 1985; Hellbusch, 2007) and motor delays (Sahar, 1978; Nickel and Gallenstein, 1987; Lorch et al ., 2004; Hellbusch, 2007)”
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    § Discussion · p. 7

    Previous findings of increased cerebrospinal fluid in autism spectrum disorder were in older children and adults and did not focus on the subarachnoid space.

    “There are some previous findings of increased CSF in ASD, but these reports of older children and adults did not focus on the subarachnoid space (McAlonan et al ., 2005; Hallahan et al ., 2009).”
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43 of 43

  • The paper relies on this without support.

    The 55 infants who completed the first MRI and outcome assessment are representative of all infants who develop ASD or typical development.

    “Analyses included these 55 infants who were successfully scanned at Time 1 (6-9 months).”

  • The paper relies on this without support.

    The nine infants lost to follow-up did not differ from the analyzed sample in any characteristic relevant to the MRI measures.

    “There were no differences in developmental quotient between the nine infants who were dropped from the study and the remaining sample ( n = 55).”
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Cites

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Research works printed but not linked: 8

  1. American Psychiatric Association (APA), Diagnostic and statistical manual of mental disorders (text revision)
  2. Centers for Disease Control and Prevention (CDC), 2012, Prevalence of autism spectrum disorders–autism and developmental disabilities monitoring network, 14 sites, United States, 2008, MMWR Surveill Summ, 61, 1
  3. Hellbusch, 2007, Benign extracerebral fluid collections in infancy: clinical presentation and long-term follow-up, J Neurosurg, 107, 119
  4. Le Gros Clark, 1920, On the pacchionian bodies, J Anat, 55, 40
  5. Lord, 2002, Autism diagnostic observation schedule: generic
  6. Mullen, 1995, Mullen scales of early learning
  7. Ozonoff, 2010, A prospective study of the emergence of early behavioral signs of autism, J Am Acad Child Adolesc Psychiatry, 49, 256
  8. SAS Institute Inc, 2012, JMP® 10 Modeling and Multivariate Methods

Cited by

Sorted by citations

Authors
Shen, M. D., Nordahl, C. W., Young, G. S., Wootton-Gorges, S. L., Lee, A., Liston, S. E., Harrington, K. R., Ozonoff, S., & Amaral, D. G.
Affiliations
University of California, Davis (US)
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2013-08-09
Volume
136
Issue
9
Pages
2825-2835
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awt166
PMC
PMC3754460
OpenAlex
W2116471897
Cited by
345
References
53
Citations by year
2026: 12 · 2025: 30 · 2024: 22 · 2023: 19 · 2022: 28 · 2021: 32 · 2020: 56 · 2019: 22 · 2018: 21 · 2017: 27 · 2016: 25 · 2015: 27 · 2014: 17 · 2013: 7
FWCI
13.89
Type
journal article
Language
en
Open access
Locations
  • Brain (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • MIND Institute, University of California, Davis
  • National Institutes of Health (P51OD011107)
  • University of California, Davis
  • National Institute of Mental Health (R01MH068398, K99MH085099)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
Keywords
autism spectrum disorder, infant brain development, cerebrospinal fluid, brain enlargement, brain volume, brain growth trajectories, high-risk infants, sibling risk, frontal lobe, neuroimaging biomarkers, developmental delay, longitudinal MRI follow-up
MeSH terms
Age Factors, Brain, Developmental Disabilities, Child Development Disorders, Pervasive, Child, Preschool, Female, Head, Humans, Image Processing, Computer-Assisted, Infant, Functional Laterality, Longitudinal Studies, Magnetic Resonance Imaging, Male, Time Factors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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