Cited by 176Advanced Neuroimaging Techniques and ApplicationsAdvanced MRI Techniques and ApplicationsFunctional Brain Connectivity Studies

The DOI matches its Crossref record; 221 of the 248 references it cites were found in a registry or an index; 43 of the 99 sources its claims cite were checked for support.

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

Open access
Lazari, Alberto, Lipp, Ilona·2021·NeuroImage

Published version of a preprint

Abstract

Abstract Recent years have seen an increased understanding of the importance of myelination in healthy brain function and neuropsychiatric diseases. Non-invasive microstructural magnetic resonance imaging (MRI) holds the potential to expand and translate these insights to basic and clinical human research, but the sensitivity and specificity of different MR markers to myelination is a subject of debate. To consolidate current knowledge on the topic, we perform a systematic review and meta-analysis of studies that validate microstructural imaging by combining it with myelin histology. We find meta-analytic evidence for correlations between myelin histology and markers from different MRI modalities, including fractional anisotropy, radial diffusivity, macromolecular pool, magnetization transfer ratio, susceptibility and longitudinal relaxation rate, but not mean diffusivity. Meta-analytic correlation effect sizes range widely, between R 2 = 0.26 and R 2 = 0.82. However, formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias, thus preventing the establishment of a single most sensitive strategy to measure myelin with MRI. To facilitate further progress, we provide a detailed characterisation of the evaluated studies as an online resource. We also share a set of 12 recommendations for future studies validating putative MR-based myelin markers and deploying them in vivo in humans. Highlights Systematic review and meta-analysis of studies validating microstructural imaging with myelin histology We find many MR markers are sensitive to myelin, including FA, RD, MP, MTR, Susceptibility, R1, but not MD Formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias Results emphasize the advantage of using multimodal imaging when testing hypotheses related to myelin in vivo in humans.

Overview

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Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis of 71 MRI–histology validation studies finds that many microstructural MRI markers correlate with myelin histology, but no single marker is clearly superior. The authors recommend multimodal imaging and better reporting/statistical practices for future validation and in vivo myelin studies.

Key findings

  • Across 71 included validation studies, meta-analyses of 32 studies found evidence for correlations between myelin histology and FA, RD, susceptibility, R1, MP, and MTR, but not MD.
  • MTR showed higher within-subject meta-analytic effect sizes (95% CI for R²: 0.60–0.84) than between-subject effect sizes (95% CI for R²: 0.15–0.51).
  • No single marker had a clearly stronger effect size than others; the authors conclude that using multiple myelin-sensitive modalities in parallel is currently the best way to test myelin-related hypotheses in vivo.
  • Publication-bias checks found no abnormal p-value distribution (80% of positive results had p ≤ 0.01), but a significant correlation between sample size and effect size, and trim-and-fill suggested publication bias could inflate validation effect sizes for some markers.

Methods

  • Systematic review followed PRISMA guidelines, searching Pubmed and Scopus on February 20, 2020, plus 45 articles from the authors’ library; 386 unique articles were screened, yielding 71 included peer-reviewed validation studies.
  • From each study, the authors extracted imaging modality/metrics, species, tissue state, histology methods, ROI/coregistration, statistical design, sample size, and correlation results; data are openly available.
  • Meta-analyses used fixed-effect models with R² as the effect size, run separately for Pearson vs. Spearman correlations and for between-subject vs. within-subject designs; only markers validated in more than two independent studies and studies with more than three subjects were included. P-curve, funnel plots, and trim-and-fill were used to assess bias.

Limitations

  • The paper states that methodological variability, inconsistent reporting, and potential publication bias limit formal comparisons between MRI-based myelin markers, and that the small number of studies makes it difficult to systematically account for factors such as tissue processing, scanning temperature, and tissue type.
  • The paper notes that MWF could not be meta-analyzed because 14 studies used mixed designs, unreported correlation type, or too-small samples, and that correlative validation studies do not address precision/reliability or causation.
  • Evident from the text: many markers appear only once in the validation literature, only 21 of 70 studies used coregistration, 19 studies pooled ROIs across subjects without modeling nesting, and 8 studies did not allow deduction of which variance was modeled.

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Integrity signals

Registry

Crossref · 10.1016/j.neuroimage.2021.117744

Cites

221 of 221 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Figures

Fig. 1 Mock examples of between-subject vs within-subject design in validation studies. In between-subject validation studies (left), each data point comes from a different subject and correlations are computed separately for each ROI. In within-subject validation studies (right), each data point comes from a different brain region and correlations are computed separately for each subject. In mixed designs, data points from different subjects and different regions are pooled into one data analysis.
Fig. 1 Mock examples of between-subject vs within-subject design in validation studies. In between-subject validation studies (left), each data point comes from a different subject and correlations are computed separately for each ROI. In within-subject validation studies (right), each data point comes from a different brain region and correlations are computed separately for each subject. In mixed designs, data points from different subjects and different regions are pooled into one data analysis.CC BY · PubMed Central
Fig. 2 Flow diagram of study selection.
Fig. 2 Flow diagram of study selection.CC BY · PubMed Central
Fig. 3 Features of the MR-histology validation literature. [A] Sample size distribution of the included papers (median = 13 subjects). [B] The most frequently used histology techniques used in the articles are shown in decreasing order. [C] Due to lack of commonly agreed reporting standards, some relevant information may be missing from validation studies. The most commonly missing pieces of information on methods are reported here. [D] Pie chart of species and field strength used in each study. [E] Frequency of different statistical measures used for the validation analysis. [F] MR markers most commonly used in the literature, subdivided based on MR technique they are based on. The graphs show that DWI, MT and relaxometry are by far the most commonly explored techniques in validation studies. Within studies using DWI, tensor-based measures are predominant.
Fig. 3 Features of the MR-histology validation literature. [A] Sample size distribution of the included papers (median = 13 subjects). [B] The most frequently used histology techniques used in the articles are shown in decreasing order. [C] Due to lack of commonly agreed reporting standards, some relevant information may be missing from validation studies. The most commonly missing pieces of information on methods are reported here. [D] Pie chart of species and field strength used in each study. [E] Frequency of different statistical measures used for the validation analysis. [F] MR markers most commonly used in the literature, subdivided based on MR technique they are based on. The graphs show that DWI, MT and relaxometry are by far the most commonly explored techniques in validation studies. Within studies using DWI, tensor-based measures are predominant.CC BY · PubMed Central
Fig. 4 Meta-analysis of correlations between histology and MR markers. Forest plots from meta-analyses of 6 MR markers (FA, RD, MD, susceptibility, MTR and MP). Spearman and Pearson correlations are pooled separately; the type of correlation coefficient is indicated at the top of each forest plot. All studies included use a between-subject statistical design; meta-analyses of studies with a within-subject design are reported in Fig. 5. For each study, sample size and effect size (R²) with the respective confidence interval are provided. The fixed effect model results are reported at the bottom of each forest plot, together with pooled sample size across all included studies and with 95% Confidence Interval of the meta-analytic effect size.
Fig. 4 Meta-analysis of correlations between histology and MR markers. Forest plots from meta-analyses of 6 MR markers (FA, RD, MD, susceptibility, MTR and MP). Spearman and Pearson correlations are pooled separately; the type of correlation coefficient is indicated at the top of each forest plot. All studies included use a between-subject statistical design; meta-analyses of studies with a within-subject design are reported in Fig. 5. For each study, sample size and effect size (R²) with the respective confidence interval are provided. The fixed effect model results are reported at the bottom of each forest plot, together with pooled sample size across all included studies and with 95% Confidence Interval of the meta-analytic effect size.CC BY · PubMed Central
Fig. 5 Within-subject meta-analyses. For the three metrics R1, MP and MTR, a meta-analysis on within-subject correlations could be performed. The resulting effect size estimate for MTR is higher than its between-subject effect size (see Fig. 4).
Fig. 5 Within-subject meta-analyses. For the three metrics R1, MP and MTR, a meta-analysis on within-subject correlations could be performed. The resulting effect size estimate for MTR is higher than its between-subject effect size (see Fig. 4).CC BY · PubMed Central

Verification

Claims the paper makes

48 Own interpretation · 47 Own result · 25 No full text of the sources · 25 No basis given · 17 Partly supported · 11 Supported · 4 Supported so far · 3 Not checked yet · 2 Sources not found · 1 Own method · accuracy not yet measured

Show all 87 claims

  • Probably not a substantial claim. 50
  • It may state two separate claims as one. 66
96 of 96
  • The paper relies on this without support.

    It is currently unclear which MR marker is the most biologically accurate non-invasive measure for myelin, and how measures differ in sensitivity to specific aspects of myelination.

    “Currently, it is not clear which of these MR markers is the most biologically accurate non-invasive measure for myelin, and how the measures differ in their sensitivity to specific aspects of myelination.”
  • The paper relies on this without support.

    Neuroimaging studies conducted in vivo often use individual validation studies as evidence to justify employing a specific microstructural MRI measure to study myelination.

    “Neuroimaging studies conducted in vivo often use individual validation studies of this kind as evidence to justify employing a specific microstructural MRI measure to study myelination.”
  • The paper relies on this without support.

    The gold standard for validation studies aiming to assess the accuracy of MR markers is to compare MRI and underlying myelin content within the same tissue.

    “For this reason, the gold standard for validation studies aiming to assess the accuracy of MR markers is to compare MRI and underlying myelin content within the same tissue.”
  • The paper relies on this without support.

    Myelin histology provides a valid reference standard for myelin content in the validation studies included in the meta-analysis.

    “Our meta-analysis focussed on studies using a correlative approach to measure the accuracy of MR metrics for validation.”
4 of 4

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

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Metadata

Authors
Lazari, A., & Lipp, I.
Affiliations
  • University of Oxford (GB)
  • Max Planck Institute for Human Cognitive and Brain Sciences (DE)
Corresponding author
Lipp, Ilona
Venue
NeuroImage
Publisher
Elsevier BV
Published
2021-04
Volume
230
Pages
117744
ISSN
1053-8119 (ISSN-L)
OpenAlex
W3126596385
Cited by
176
References
248
Citations by year
2026: 15 · 2025: 30 · 2024: 38 · 2023: 32 · 2022: 41 · 2021: 18
FWCI
6.55
Type
journal article
Language
en
Open access
Locations
  • NeuroImage (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
Wellcome Trust (109062/Z/15/Z)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
myelin, fractional anisotropy, radial diffusivity, magnetization transfer ratio, susceptibility, longitudinal relaxation rate, mean diffusivity, white matter microstructure, publication bias
MeSH terms
Brain, Humans, Magnetic Resonance Imaging, Myelin Proteins, Myelin Sheath, Reproducibility of Results, Qualitative Research

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