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Cited by 267Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersFetal and Pediatric Neurological Disorders

A Meta-Analysis of the Corpus Callosum in Autism

Open access
Frazier, Thomas W., Hardan, Antonio Y.·2009·Biological Psychiatry
DOI 10.1016/j.biopsych.2009.07.022PMC PMC2783565
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Abstract

Background Several previous MRI studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the presence, magnitude, and/or region contributing to CC reductions. The primary aim of the present study was to determine the significance and magnitude of reduction in CC total and regional area measures in patients with autism. Method PubMed and PsycInfo databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (Mean age=14.58, SD=6.00) and 250 healthy controls (M age=14.47, sd=5.31). Of these ten studies, eight reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), with six studies reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify autism versus healthy control differences in total and region CC area measurements. Demographics and study characteristics were examined as moderators of total CC area. Results Total CC area was reduced in autism and the magnitude of the reduction was medium (Weighted Mean d=.48, 95% CI=.30-.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d=.49, mid/body d=.43, posterior d=.37). Witelson sub-division 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing pre-/supplementary motor neurons. Conclusions CC reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions.

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2009.07.022

Cites

71 of 71 references verified0 citation errors · 0 not checkable

Statistics

9 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 45 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The funnel plot showed a relatively even representation of small and moderate N studies across the range of effect sizes.

    “Inspection of the funnel plot indicated a relatively even representation of small and moderate N studies across the range of effect sizes (figure available from the first author).”
    Quote in the paperNot a substantial claim
  • Findingown data

    No pooled effect size had a significant Q statistic.

    “None of the pooled effect sizes had a significant Q statistic (see Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Among corpus callosum subdivisions, Witelson subdivision 3 (rostral body) has the largest effect size, weighted mean d=0.66.

    “Witelson sub-division 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing pre-/supplementary motor neurons.”
    • Also stated in: § Results · hedged
      “Visual inspection of Figure 2 indicates that the rostral body of the CC (Witelson subdivision 3) showed the largest difference (weighted mean d=.66).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The samples in the included studies are representative of the broader population of individuals with autism.
  • Findingown data

    Meta-regression using weighted least squares significantly predicted total corpus callosum area weighted effect sizes (adjusted R2=.89, F(5,4)=15.76, p=.010).

    “Meta-regression using weighted least squares indicated a significant overall prediction of weighted effect sizes, adjusted R2=.89, F(5,4)=15.76, p=.010.”
    Quote in the paperSubstantial claim
  • Findingown data

    Publication date is positively and significantly related to total corpus callosum area effect sizes (β=.76, t(8)=3.26, p=.012).

    “Contrary to expectation, publication date was positively related to total CC area effect sizes and the effect was significant (β=.76, t(8)=3.26, p=.012).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    The anterior-to-posterior linear trend in corpus callosum area reductions is large (d=1.36) but not statistically significant (F(1,7)=3.23, p=.115).

    “Consistent with expectation, area reductions in CC regions showed a very large linear trend (anterior vs. posterior F(1,7)=3.23, p=.115, d=1.36), and did not reach significance probably due to the small sample (k=8).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The observed total corpus callosum effect size is slightly smaller than anticipated and close to the medium range.

    “In the present study the weighted mean effect size for the CC was slightly smaller than anticipated. It is close to the medium range and does not appear to be a result of publication bias.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The correlation between Witelson subdivision number and weighted mean effect sizes is large (r=−.52, d=−1.22) but not statistically significant (p=.23).

    “Similarly, the correlation between Witelson subdivision (numbered 1-7 anterior to posterior) and weighted mean effect sizes was large (r = −.52, d=−1.22, df=5, p=.23), but did not reach significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fourteen additional null-effect studies would be needed to reduce the total corpus callosum weighted mean effect size to d=.20, and 86 would be needed to reduce it to d=.05.

    “Fourteen additional studies each contributing a null effect size (d=.00) would be needed to reduce the observed weighted mean effect size for total CC area to a small effect (d=.20). Eighty-six new studies would be needed to reduce the observed effect size to a negligible effect (d=.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Every corpus callosum region examined (anterior, mid/body, posterior) and every Witelson subdivision shows a significant area reduction in autism.

    “All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d=.49, mid/body d=.43, posterior d=.37).”
    • Also stated in: § Results · plain
      “Areas for each CC region and Witelson subdivision were also significantly reduced in autism (smallest z = 3.07, p<.001).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The samples in the included studies are representative of the broader population of individuals with autism.

  • May combine two claims.

    Findingown data

    In individuals with autism compared with healthy controls, total corpus callosum area is significantly reduced, with a medium weighted mean effect size of d=0.48 (95% CI 0.30-0.66).

    “Total CC area was reduced in autism and the magnitude of the reduction was medium (Weighted Mean d=.48, 95% CI=.30-.66).”
    • Also stated in: § Results · plain
      “Consistent with expectation, total CC area was significantly reduced in autism patients (z = 5.17, p<.0001).”
    • Also stated in: § Discussion · hedged
      “The present meta-analytic results indicate that total CC area is smaller in autism”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The samples in the included studies are representative of the broader population of individuals with autism.

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

    Study design and conductcitation

    Publication bias was examined by creating a funnel plot and calculating the fail safe N.

    “The file drawer problem (publication bias) was examined by creating a funnel plot and calculating the fail safe N (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Orwin, 1983, A fail-safe N for effect size in meta analysis, J Educ Stat source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Despite evidence of moderate group-level corpus callosum area reductions, not all individuals with autism exhibit reduction in the size of this structure.

    “Despite evidence suggesting moderate reductions in CC area at the group level, not all individuals with autism exhibit reduction in the size of this structure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The data suggest that brain connectivity is likely impaired in most regions, as shown by alterations of all corpus callosum subdivisions and supported by functional studies.

    “These data suggest that brain connectivity is likely to be impaired in most regions as evidenced by alterations of all CC subdivisions and is supported by several functional studies implicating multiple cortical including frontal, and parietal regions (17, 19, 20, 51).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Just, 2007, Functional and anatomical cortical underconnectivity in autism: Evidence from an fMRI study of an executive function task and corpus callosum morphometry, Cereb Cortex source

      Not checked in the free run.

    • cites [19] Koshino, 2005, Functional connectivity in an fMRI working memory task in high functioning autism, Neuroimage source

      Not checked in the free run.

    • cites [20] Just, 2004, Cortical activation and synchronization during sentence comprehension in high-functioning autism: Evidence of underconnectivity, Brain source

      Not checked in the free run.

    • cites [51] Kana, 2006, Sentence comprehension in autism: Thing in pictures with decreased functional connectivity, Brain source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The present data may suggest reduced functional output of mirror neuron regions or decreased hemispheric cross-talk between mirror neuron regions, which may contribute to reduced attunement to others' intentions.

    “Thus, the present data may suggest reduced functional output of mirror neuron regions or decreased hemispheric cross-talk between mirror neuron regions. In turn, reduced output or cross-talk of these regions may contribute to reduced attunement to others’ intentions (56).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Oberman, 2007, The simulating social mind: The role of the mirror neuron system and simulation in the social and communicative deficits of autism spectrum disorders, Psychol Bull source

      Not checked in the free run.

    • cites [56] Gallese, 2007, Intentional attunement: Mirror neurons and the neural underpinnings of interpersonal relations, J Am Psychoanal Assoc source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    Several studies did not include Witelson subdivisions, reducing the ability to statistically examine finer grained differences among corpus callosum regions.

    “Several studies did not include Witelson subdivisions, reducing the ability to statistically examine finer grained differences among CC regions.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Future studies using newer imaging methodologies and higher magnet strength are likely to yield larger differentiation between individuals with autism and healthy controls.

    “Interestingly, the effect size was found to be large in a recent study using a 3T magnet (d=.73) (23), suggesting that future studies applying newer imaging methodologies (e.g., diffusion tensor imaging or related novel white matter tractography methods) and higher magnet strength are likely to yield larger differentiation of individuals with autism and healthy controls.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Studies of other neuropsychiatric disorders have reported alterations of corpus callosum size.

    “In fact, studies of other neuropsychiatric disorders have reported alterations of CC size (65).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Hutchinson, 2008, Corpus callosum morphology in children and adolescents with attention deficit hyperactivity disorder: A meta-analytic review, Neuropsychology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The findings are concordant with studies using other imaging methods and support the aberrant connectivity hypothesis in autism.

    “Findings were concordant with studies applying other imaging methods, supporting the aberrant connectivity hypothesis in autism (15-18).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] Herbert, 2004, Localization of white matter volume increase in autism and developmental disorder, Ann Neurol source

      Not checked in the free run.

    • cites [16] Horwitz, 1988, The cerebral metabolic landscape in autism: Intercorrelations of regional glucose utilization, Arch Neurol source

      Not checked in the free run.

    • cites [17] Just, 2007, Functional and anatomical cortical underconnectivity in autism: Evidence from an fMRI study of an executive function task and corpus callosum morphometry, Cereb Cortex source

      Not checked in the free run.

    • cites [18] Castelli, 2002, Autism, Asperger syndrome, and brain mechanisms for the attribution of mental states to animated shapes, Brain source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Random effects models indicated little change in weighted mean effect sizes and negligible widening of confidence intervals relative to fixed effects models.

    “Random effects models indicated little change in weighted mean effect sizes and negligible widening of confidence intervals relative to fixed effects models.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Heterogeneity of study methods and samples complicates interpretation of moderating factors.

    “Similarly, as in any meta-analysis, the heterogeneity of study methods and samples complicate interpretation of moderating factors.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Meta-regression analyses were restricted to a priori hypotheses regarding average age, correction for total brain volume, functional level of autism participants, magnet strength, and method index as moderators of total corpus callosum effect sizes.

    “These analyses were restricted to a priori hypotheses regarding average age, correction for total brain volume, functional level of autism participants, magnet strength, and method index as moderators of total CC effect sizes.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Recent imaging studies in autism have shown that the most abnormal aspect of brain development in this disorder is often the time course and trajectory rather than the final product.

    “This is particularly relevant since recent imaging studies in autism have shown that the most abnormal aspect of brain development in this disorder is often the time course and trajectory rather the final product (2, 39).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Amaral, 2008, Neuroanatomy of autism, Trends Neurosci source

      Not checked in the free run.

    • cites [39] Pardo, 2007, The neurobiology of autism, Brain Pathol source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The body of included studies contained a number of methodologically rigorous reports, with 6 of 10 studies scoring 12.5 or above on the method index (median=12.75).

    “Importantly, the body of studies included a number of methodologically rigorous reports, with 6 of the 10 studies receiving scores of 12.5 or above (out of 15) on the method index (median=12.75).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The corpus callosum is the main fiber tract connecting the hemispheres and is topographically organized.

    “The corpus callosum (CC) is the main fiber tract connecting the hemispheres and is topographically organized (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Witelson, 1989, Hand and sex differences in the isthmus and genu of the human corpus callosum, Brain source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Aberrant connectivity theory posits dysfunction in long-distance connections between cortical brain regions in autism, resulting in impairments in complex cognitive processes such as executive functions, social cognition, and language.

    “Aberrant connectivity theory posits dysfunction in the long-distance connections between cortical brain regions in autism, resulting in impairments in complex cognitive processes such as executive functions, social cognition, and language (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Williams, 2007, Understanding autism and related disorders: What has imaging taught us?, Neuroimaging Clin N Am source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anterior corpus callosum regions represent fibers from prefrontal cortices; mid/body regions contain fibers from premotor, motor, parietal, and superior temporal cortices; and the posterior region represents fibers from inferior temporal and occipital cortices.

    “Anterior CC regions represent fibers from pre-frontal cortices; mid/body regions are composed of fibers from pre-motor, motor, parietal, and superior temporal cortices; and the posterior region represents fibers from inferior temporal and occipital cortices (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Hardan, 2000, Corpus callosum size in autism, Neurology source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The corpus callosum provides integrated inter-hemispheric communication between homotopic and heterotopic cortical regions.

    “The CC provides integrated inter-hemispheric communication between homotopic and heterotopic cortical regions (50).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Paul, 2007, Agenesis of the corpus callosum: Genetic, developmental and functional aspects of connectivity, Nat Rev Neurosci source

      Not checked in the free run.

23 of 23

  • The paper relies on this without support.

    Pre-/supplementary motor regions are crucial for motor planning.

    “Pre-/supplementary motor regions are crucial for motor planning and disruption of these regions may be the neural substrate for impairments in fine motor skills and imitation observed in autism.”

  • The paper relies on this without support.

    The samples in the included studies are representative of the broader population of individuals with autism.

    “CC reductions are present in autism and support the aberrant connectivity hypothesis.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Patients with agenesis of corpus callosum show difficulties in language and social communication, and decreased volume of the corpus callosum has been found in ASD.

    “Patients with agenesis of corpus callosum show difficulties in language and social communication [45, 276, 357], and decreased volume of the corpus callosum has been found in ASD (see meta-analysis in [114]).”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [114]

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • Inconsistent p-value: t(4)=1.95, p = .112

    Minor

    The paper reports p = .112 here; recomputing from the test statistic and its degrees of freedom gives p = .123 (two-tailed). The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .112 · recomputed p = .123

  • Inconsistent p-value: z = 3.07, p < .001

    Minor

    The paper reports p < .001 here; recomputing from the test statistic and its degrees of freedom gives p = .002 (two-tailed). The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p < .001 · recomputed p = .002

2 of 2

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upz = 3.07reported p < .001 · recomputed p = .002

    “z = 3.07, p < .001”

  • Doesn’t add upt(4) = 1.95reported p = .112 · recomputed p = .123

    “t(4)=1.95, p = .112”

  • Consistentz = 5.17reported p < .0001 · recomputed p < .001

    “(z = 5.17, p < .0001”

  • ConsistentF(1, 7) = 3.23reported p = .115 · recomputed p = .115

    “F(1,7)=3.23, p = .115”

  • ConsistentF(5, 4) = 15.76reported p = .01 · recomputed p = .010

    “F(5,4)=15.76, p = .010”

  • Consistentt(4) = 4.32reported p = .012 · recomputed p = .012

    “t(4)=4.32, p = .012”

  • Consistentt(4) = 2.68reported p = .055 · recomputed p = .055

    “t(4)=2.68, p = .055”

  • Consistentt(8) = 3.26reported p = .012 · recomputed p = .012

    “t(8)=3.26, p = .012”

  • Consistentt(8) = 1.43reported p = .192 · recomputed p = .191

    “t(8)=1.43, p = .192”

9 of 9

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

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2 of the 73 references couldn’t be matched to a known paper.

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Related

Authors
Frazier, T. W., & Hardan, A. Y.
Affiliations
  • Cleveland Clinic (US)
  • Stanford Medicine (US)
Corresponding author
Frazier, Thomas W.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2009-11
Volume
66
Issue
10
Pages
935-941
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2009.07.022
PMC
PMC2783565
OpenAlex
W2030458571
Semantic Scholar
b6f5dab1bca29deadfa1b8d942ac33b176b86b75
Cited by
267
References
73
Citations by year
2026: 6 · 2025: 5 · 2024: 11 · 2023: 15 · 2022: 14 · 2021: 18 · 2020: 16 · 2019: 18 · 2018: 11 · 2017: 19 · 2016: 17 · 2015: 22 · 2014: 15 · 2013: 20 · 2012: 27
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (K23MH064027, MH-64027, R01MH083972, MH-083972)
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, corpus callosum
MeSH terms
Adolescent, Autistic Disorder, Child, Corpus Callosum, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Databases, Factual

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