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Cited by 38Autism Spectrum Disorder ResearchAdvanced Neuroimaging Techniques and ApplicationsGenetics and Neurodevelopmental Disorders

Opposite development of short- and long-range anterior cingulate pathways in autism

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Zikopoulos, Basilis, Liu, Xuefeng, Tepe, Justin, Trutzer, Iris, John, Yohan J., Barbas, Helen·2018·Acta Neuropathologica
DOI 10.1007/s00401-018-1904-1PMC PMC6208731
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Abstract

Autism has been linked with the changes in brain connectivity that disrupt neural communication, especially involving frontal networks. Pathological changes in white matter are evident in adults with autism, particularly affecting axons below the anterior cingulate cortices (ACC). It is still unknown whether axon pathology appears early or late in development and whether it changes or not from childhood through adulthood. To address these questions, we examined typical and pathological development of about 1 million axons in post-mortem brains of children, adolescents, and adults with and without autism (ages 3-67 years). We used high-resolution microscopy to systematically sample and study quantitatively the fine structure of myelinated axons in the white matter below ACC. We provide novel evidence of changes in the density, size and trajectories of ACC axons in typical postnatal development from childhood through adulthood. Against the normal profile of axon development, our data revealed lower density of myelinated axons that connect ACC with neighboring cortices in children with autism. In the course of development the proportion of thin axons, which form short-range pathways, increased significantly in individuals with autism, but remained flat in controls. In contrast, the relative proportion of thick axons, which form long-range pathways, increased from childhood to adulthood in the control group, but decreased in autism. Our findings provide a timeline for profound changes in axon density and thickness below ACC that affect axon physiology in a direction suggesting bias in short over distant neural communication in autism. Importantly, measures of axon density, myelination, and orientation provide white matter anisotropy/diffusivity estimates at the level of single axons. The structural template established can be used to compare with measures obtained from imaging in living subjects, and guide analysis of functional and structural imaging data from humans for comparison with pathological states.

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  • The short- and long-range prefrontal axons, particularly those from the ACC, are affected in their guidance to subcortical targets and may underlie the network disruption characteristic for ASD.

    “The short- and long-range prefrontal axons, particularly those from the ACC, are affected in their guidance to subcortical targets and may underlie the network disruption characteristic for ASD [377, 378].”

    From Development of prefrontal cortex (2022) · cites this paper as [378]

    The Introduction and Discussion (pages unavailable) report altered short- and long-range ACC axons in ASD and suggest these changes disrupt neural communication. They do not establish impaired axon guidance to subcortical targets; the Results say axon trajectory distributions did not differ significantly between ASD and control groups. (LLM, conf=0.86)

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Research works printed but not linked: 2

  1. [13]Conel JL Postnatal development of the human cerebral cortex 1941 Cambridge Harvard University Press
  2. [73]von Economo C, Koskinas GN (1925/2008) Atlas of cytoarchitectonics of the adult human cerebral cortex. Translated from the German original, revised and edited with an Introduction and additional appendix material by L. C. Triarhou. Karger

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Authors
Zikopoulos, B., Liu, X., Tepe, J., Trutzer, I., John, Y. J., & Barbas, H.
Affiliations
Boston University (US)
Corresponding author
Zikopoulos, Basilis
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2018-09-06
Volume
136
Issue
5
Pages
759-778
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-018-1904-1
PMC
PMC6208731
OpenAlex
W2892175952
Cited by
38
References
88
Citations by year
2026: 3 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 7
FWCI
2.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OpenBU (Boston University) (submittedVersion, cc-by)
Funders
  • National Institute of Mental Health (R01MH101209)
  • Autism Speaks (2156)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
autism spectrum disorder, anterior cingulate cortex, white matter, axon development, myelinated axons, axon density, axon diameter, postmortem brain, developmental trajectories, white matter anisotropy, white matter diffusivity, axon orientation, frontal network
MeSH terms
Adolescent, Adult, Aged, Autistic Disorder, Autopsy, Axons, Child, Child, Preschool, Female, Gyrus Cinguli, Humans, Male, Middle Aged, Nerve Net, Neuroglia, Neurons, Microscopy, Electron, Transmission, Young Adult, White Matter

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