Cited by 302Advanced Neuroimaging Techniques and ApplicationsFunctional Brain Connectivity StudiesCerebrovascular and genetic disorders

The DOI matches its Crossref record; 609 of the 609 references it cites were found in a registry or an index; 147 of the 332 sources its claims cite were checked for support.

Quantitative mapping of the brain’s structural connectivity using diffusion MRI tractography: A review

Open access

Abstract

Diffusion magnetic resonance imaging (dMRI) tractography is an advanced imaging technique that enables in vivo reconstruction of the brain's white matter connections at macro scale. It provides an important tool for quantitative mapping of the brain's structural connectivity using measures of connectivity or tissue microstructure. Over the last two decades, the study of brain connectivity using dMRI tractography has played a prominent role in the neuroimaging research landscape. In this paper, we provide a high-level overview of how tractography is used to enable quantitative analysis of the brain's structural connectivity in health and disease. We focus on two types of quantitative analyses of tractography, including: 1) tract-specific analysis that refers to research that is typically hypothesis-driven and studies particular anatomical fiber tracts, and 2) connectome-based analysis that refers to research that is more data-driven and generally studies the structural connectivity of the entire brain. We first provide a review of methodology involved in three main processing steps that are common across most approaches for quantitative analysis of tractography, including methods for tractography correction, segmentation and quantification. For each step, we aim to describe methodological choices, their popularity, and potential pros and cons. We then review studies that have used quantitative tractography approaches to study the brain's white matter, focusing on applications in neurodevelopment, aging, neurological disorders, mental disorders, and neurosurgery. We conclude that, while there have been considerable advancements in methodological technologies and breadth of applications, there nevertheless remains no consensus about the "best" methodology in quantitative analysis of tractography, and researchers should remain cautious when interpreting results in research and clinical applications.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review provides a high-level overview of how diffusion MRI tractography is used for quantitative mapping of brain structural connectivity, organizing methods into tractography correction, segmentation, and quantification and reviewing applications across development, aging, neurological/mental disorders, and neurosurgery. It concludes that despite methodological and application advances, there is no consensus on the “best” methodology and results should be interpreted cautiously.

Key findings

  • Quantitative tractography analyses are categorized into tract-specific, hypothesis-driven analyses of named fiber tracts and connectome-based, more data-driven analyses of whole-brain structural connectivity.
  • The review identifies three common processing steps—tractography correction, tractography segmentation, and tractography quantification—and discusses methodological choices, popularity, and pros/cons for each.
  • In applications, the review cites developmental tractography milestones including identification of fornix and cingulum parts at 13 weeks, part of the corpus callosum at 15 weeks, and prominent radial/tangential pathways at 17 weeks; it also notes parcellation scales ranging from tens to millions of parcels, with suggestions that >2000 parcels can benefit machine learning/statistical analysis and <200 parcels can improve connectome consistency.
  • The review reports no consensus on the “best” methodology for quantitative tractography analysis and emphasizes caution in biological and clinical interpretation.

Methods

  • Narrative review of dMRI tractography methods and applications, not an empirical study; no original sample or dataset is analyzed.
  • The methodology review is organized around three processing steps: correction of tractography biases, segmentation/identification of white matter pathways, and extraction of quantitative measures.
  • The applications review covers neurodevelopment, aging, neurological disorders (with multiple sclerosis and schizophrenia as exemplars), mental disorders, and neurosurgery.

Limitations

  • The paper states that there remains no consensus about the “best” methodology in quantitative tractography analysis and that researchers should remain cautious when interpreting results in research and clinical applications.
  • The paper states that reconstructed streamlines are simulated entities that do not correspond directly to nerve fibers and that basic diffusion metrics are inferences from local diffusion properties rather than direct tissue measures; it also notes ongoing false-positive and false-negative anatomical accuracy issues.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy, inclusion criteria, or quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.neuroimage.2021.118870

Cites

609 of 609 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Figures

Fig. 1. Graphic illustration of tractography. (a) Example dMRI data, also known as diffusion weighted imaging (DWI) data. (b) An individual streamline computed after performing tractography. (c) An example whole-brain tractogram that consists of streamlines covering the entire white matter. (d) A fiber bundle that consists of a set of streamlines, representing an anatomical fiber tract named the corpus callosum. The streamlines are colored by a microstructural measure, i.e., fractional anisotropy (FA) that measures the anisotropy of water diffusion. The distribution of FA along the fiber tract is provided to show the tractometry of the tract. A low FA can be seen at the endpoint region of the streamlines (near the cortex) and a high FA can be seen in the middle of the streamlines (in the deep white matter). (e) An example brain structural connectivity matrix, which is constructed based on white matter tractography from the whole brain. Each row (and column) represents a brain gray matter ROI (See Fig. 3(c) for an example brain gray matter parcellation), and the value in an element of the matrix is the strength of the white matter connection between the two corresponding ROIs (quantified as the number of streamlines in this case).
Fig. 1. Graphic illustration of tractography. (a) Example dMRI data, also known as diffusion weighted imaging (DWI) data. (b) An individual streamline computed after performing tractography. (c) An example whole-brain tractogram that consists of streamlines covering the entire white matter. (d) A fiber bundle that consists of a set of streamlines, representing an anatomical fiber tract named the corpus callosum. The streamlines are colored by a microstructural measure, i.e., fractional anisotropy (FA) that measures the anisotropy of water diffusion. The distribution of FA along the fiber tract is provided to show the tractometry of the tract. A low FA can be seen at the endpoint region of the streamlines (near the cortex) and a high FA can be seen in the middle of the streamlines (in the deep white matter). (e) An example brain structural connectivity matrix, which is constructed based on white matter tractography from the whole brain. Each row (and column) represents a brain gray matter ROI (See Fig. 3(c) for an example brain gray matter parcellation), and the value in an element of the matrix is the strength of the white matter connection between the two corresponding ROIs (quantified as the number of streamlines in this case).CC BY-NC-ND · PubMed Central
Fig. 2. Demonstrations of various forms of errors and biases in tractography, as described in Section 3. Images are exemplars only; therefore there exist many other possible manifestations of such biases and errors. 1. Low-order integration methods under-estimate bundle curvature, leading to reconstructed paths overshooting the underlying curved trajectory. 2. In the absence of tailored constraints, streamlines may terminate in locations other than those known to contain axon synapses. 3. The number of streamlines generated within a bundle may not be proportional to the underlying axonal density of that bundle. 4. Because of the low resolution of diffusion MRI relative to the complexity of gyral folding, streamline termination may accumulate at gyral crowns rather than being distributed uniformly across the cortical ribbon. 5. Where macroscopic WM bundles intersect, streamlines may erroneously traverse part of one bundle and part of another, producing trajectories that are not present in the underlying structure (Schilling et al., 2021).
Fig. 2. Demonstrations of various forms of errors and biases in tractography, as described in Section 3. Images are exemplars only; therefore there exist many other possible manifestations of such biases and errors. 1. Low-order integration methods under-estimate bundle curvature, leading to reconstructed paths overshooting the underlying curved trajectory. 2. In the absence of tailored constraints, streamlines may terminate in locations other than those known to contain axon synapses. 3. The number of streamlines generated within a bundle may not be proportional to the underlying axonal density of that bundle. 4. Because of the low resolution of diffusion MRI relative to the complexity of gyral folding, streamline termination may accumulate at gyral crowns rather than being distributed uniformly across the cortical ribbon. 5. Where macroscopic WM bundles intersect, streamlines may erroneously traverse part of one bundle and part of another, producing trajectories that are not present in the underlying structure (Schilling et al., 2021).CC BY-NC-ND · PubMed Central
Fig. 3. Tractography segmentation: (a) Example whole-brain tractogram computed by performing tractography in DWI data; (b) Example anatomical tracts extracted from the tractogram; and (c) Example structural connectivity matrix constructed by performing whole brain tractography segmentation between all pairs of FreeSurfer cortical regions.
Fig. 3. Tractography segmentation: (a) Example whole-brain tractogram computed by performing tractography in DWI data; (b) Example anatomical tracts extracted from the tractogram; and (c) Example structural connectivity matrix constructed by performing whole brain tractography segmentation between all pairs of FreeSurfer cortical regions.CC BY-NC-ND · PubMed Central
Fig. 4. Graph theoretical analysis of the human connectome. (a) Network diagram of structural connectivity, where nodes represent gray matter ROIs and connections depict white matter fiber bundles. (b) Schematics of key graph theory concepts applied to the analysis of structural connectivity. The thickness of connections indicates the strength of structural connectivity between two ROIs (e.g., NOS or integrated FA). Region-level graph measures such as degree, strength, and centrality identify ROI B as an important hub in the network. At the mesocale, two modules or communities are observed. Intra-module connectivity is dense and inter-module connectivity in sparse. At the global scale, communication paths delineate multi-step sequences linking anatomically unconnected ROIs. Two possible paths connecting ROIs A and C are highlighted in green (shortest path) and orange (alternative path).
Fig. 4. Graph theoretical analysis of the human connectome. (a) Network diagram of structural connectivity, where nodes represent gray matter ROIs and connections depict white matter fiber bundles. (b) Schematics of key graph theory concepts applied to the analysis of structural connectivity. The thickness of connections indicates the strength of structural connectivity between two ROIs (e.g., NOS or integrated FA). Region-level graph measures such as degree, strength, and centrality identify ROI B as an important hub in the network. At the mesocale, two modules or communities are observed. Intra-module connectivity is dense and inter-module connectivity in sparse. At the global scale, communication paths delineate multi-step sequences linking anatomically unconnected ROIs. Two possible paths connecting ROIs A and C are highlighted in green (shortest path) and orange (alternative path).CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

60 Partly supported · 30 No basis given · 26 Sources not found · 22 Supported · 22 No full text of the sources · 22 Own interpretation · 19 Supported so far · 12 Not checked yet · 4 Couldn’t confirm · 1 Not supported · 1 Own method · 1 Own result · accuracy not yet measured

Show all 115 claims

  • It may state two separate claims as one. 69
  • Probably not a substantial claim. 50
105 of 105
  • The authors state this as an assumption.

    Fibers are naturally organized in bundles.

    “fibers are naturally organized in bundles (Mandonnet et al., 2018; Udin and Fawcett, 1988)”
  • The authors state this as an assumption.

    The number of bundles should be low to minimize the overall wiring cost.

    “the number of bundles should be low to minimize the overall wiring cost (Bullmore and Sporns, 2012)”
  • The paper relies on this without support.

    There is no ground truth in tractography.

    “given the fact that there is no ground truth in tractography”
  • The authors state this as an assumption.

    The microstructure properties corresponding to a single streamline (or a group of axons following the same trajectory) remain constant along its path on average at achievable resolution.

    “Assuming that the microstructure properties corresponding to a single streamline remain constant along its path, these methods assign a specific microstructural property to each reconstructed pathway.”
    “we can suppose that on average the microstructure properties the magnetic resonance signal is sensitive to at achievable resolution remain constant.”
  • The paper relies on this without support.

    Pathological lesions of MS hinder basic tract reconstruction.

    “Since the pathological lesions of MS hinder basic tract reconstruction”
5 of 5

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

1 of 1

Citations

Cites

Items 201–400 of 609

Research works printed but not linked: 10

  1. Barakovic, 2021, Resolving bundle-specific intra-axonal T2 values within a voxel using diffusion-relaxation tract-based estimation, Neuroimage, 227, 117617, 10.1016/j.neuroimage.2020.117617 · DOI
  2. Bullmore, 2009, Complex brain networks: graph theoretical analysis of structural and functional systems, Nat. Rev. Neurosci., 10, 186, 10.1038/nrn2575 · DOI · Paper page
  3. Chandio, 2020, Bundle analytics, a computational framework for investigating the shapes and profiles of brain pathways across populations, Sci. Rep., 10, 1, 10.1038/s41598-020-74054-4 · DOI
  4. Colby, 2012, Along-tract statistics allow for enhanced tractography analysis, Neuroimage, 59, 3227, 10.1016/j.neuroimage.2011.11.004 · DOI
  5. Hagmann, 2008, Mapping the structural core of human cerebral cortex, PLoS Biol., 6, e159, 10.1371/journal.pbio.0060159 · DOI · Paper page
  6. Rheault, 2020, Common misconceptions, hidden biases and modern challenges of dMRI tractography, J. Neural Eng., 17, 011001, 10.1088/1741-2552/ab6aad · DOI
  7. Schilling, 2018, Confirmation of a gyral bias in diffusion MRI fiber tractography, Hum. Brain Mapp., 39, 1449, 10.1002/hbm.23936 · DOI
  8. Smith, 2020, Diffusion MRI fiber tractography, Vol. 1, 533
  9. Wu, 2020, Mitigating gyral bias in cortical tractography via asymmetric fiber orientation distributions, Med. Image Anal., 59, 101543, 10.1016/j.media.2019.101543 · DOI
  10. Zalesky, 2016, Connectome sensitivity or specificity: which is more important?, Neuroimage, 142, 407, 10.1016/j.neuroimage.2016.06.035 · DOI · Paper page

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Metadata

Authors
Zhang, F., Daducci, A., He, Y., Schiavi, S., Seguin, C., Smith, R. E., Yeh, C.-H., Zhao, T., & O’Donnell, L. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • University of Verona (IT)
  • The University of Sydney (AU)
  • The University of Melbourne (AU)
  • Chang Gung University (TW)
  • Beijing Normal University (CN)
Corresponding author
  • Zhang, Fan
  • O’Donnell, Lauren J.
Venue
NeuroImage
Publisher
Elsevier BV
Published
2022-04
Volume
249
Pages
118870
ISSN
1053-8119 (ISSN-L)
OpenAlex
W4205798776
Cited by
302
References
598
Citations by year
2026: 57 · 2025: 88 · 2024: 71 · 2023: 58 · 2022: 24
FWCI
31.00
Type
journal article
Language
en
Open access
Locations
  • NeuroImage (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • arXiv (Cornell University) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
  • arXiv (Cornell University)
Funders
  • Ministry of Science and Technology, Taiwan (109-2222-E-182-001-MY3)
  • National Natural Science Foundation of China (81620108016, 81801783)
  • National Institutes of Health (P41EB015902, R01MH074794, R01MH119222, R01MH125860)
  • National Imaging Facility
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
Keywords
diffusion MRI tractography, structural connectivity, white matter, connectome, white matter microstructure, brain development, brain aging, neurological disorders, mental illness, neurosurgery, method comparison
MeSH terms
Brain, Humans, Nerve Net, Diffusion Tensor Imaging

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