The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index; 14 of the 27 sources its claims cite were checked for support.
Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure
Open accessAbstract
Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at least in isolation) to draw strong reverse inferences about white matter microstructure, but based on the continued application and interpretation of these metrics in the broader biomedical/neuroscience literature, it appears that this has perhaps not yet become common knowledge among diffusion imaging end-users. Therefore, this paper will briefly discuss the complex biophysical underpinnings of these measures in the context of crossing fibers, provide some intuitive “thought experiments” to highlight how conventional interpretations can lead to incorrect conclusions, and suggest that future studies refrain from using (over-interpreting) FA, AD, and RD values as standalone biomarkers of cerebral white matter microstructure.
Overview
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Written from the paper’s full text.
TL;DR
This paper argues that fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are problematic as standalone biomarkers of cerebral white matter microstructure because most white matter voxels contain crossing fibers. It uses thought experiments to show that conventional interpretations can lead to incorrect reverse inferences, and recommends avoiding over-interpretation of these metrics in isolation.
Key findings
- Most cerebral white matter voxels contain multiple fiber populations: the proportion is now thought to be at least 33% (Behrens et al., 2007) and more likely between 60 and 90% (Jeurissen et al., 2013), with many regions containing 3 or more intersecting fiber bundles.
- Because FA is a relative, unitless measure scaled between 0 and 1, it can paradoxically increase when one or more fiber bundles degenerate while others are preserved, or remain unchanged when all three eigenvalues increase proportionally despite net tissue loss; AD and RD are confounded for similar reasons in crossing-fiber voxels.
- Conventional reverse inferences from FA, AD, and RD can lead to Type I (false positive) and/or Type II (false negative) errors, and the paper states there is no way to control for these effects or estimate their prevalence.
- MD and Trace are proposed as more robust DTI metrics because they equally weight diffusion along all three tensor axes; advanced dMRI methods (DKI, NODDI, tensor-valued diffusion encoding/μFA, fixel-based analysis) and non-dMRI methods (T1w/T2w ratio, ihMT, myelin water imaging) are suggested as alternatives likely more robust to crossing fibers.
Methods
- Narrative/commentary review with no new empirical data or sample; it synthesizes prior literature and presents two intuitive “thought experiments.”
- The thought experiments use cartoon voxels containing three crossing fibers (vertical, horizontal, and through-plane) and corresponding diffusion tensor eigenvalues to illustrate how FA can increase despite net fiber reduction, or remain constant despite proportional tissue changes.
- Main analysis is conceptual and biophysical, supported by references to prior simulation and empirical work (e.g., Pierpaoli et al., 2001; Wheeler-Kingshott and Cercignani, 2009; Jeurissen et al., 2013).
Limitations
- The authors state that all MRI methods have limitations and that their list of alternatives is not comprehensive; they also note that they focused on FA for simplicity, though AD and RD are confounded similarly.
- The authors state there is no way to control for crossing-fiber effects or estimate the prevalence of Type I and Type II errors, which could even occur simultaneously in different brain regions.
- Evident from the text: this is not an original data study or systematic review, and the recommendations are conceptual rather than validated by new experiments in this paper.
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Claims the paper makes
17 Own interpretation · 7 Supported · 6 No full text of the sources · 5 Partly supported · 1 Supported so far · 1 Sources not found · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Abstract
What the sources say
- Partly supportedcites Behrens et al., 2007 sourceExperimental — accuracy not yet measured
The Abstract says that multiple fibre populations occur across large regions of white matter. But Results (Local fitting of the complex fibre model; page unavailable) reports that only one third of voxels with fractional anisotropy above 0.1 supported more than one orientation in the 60-direction dataset. This supports the presence of multiple populations, not the claim that they occur in a majority of cerebral white matter voxels. (LLM, conf=0.88)
- Supportedcites Jeurissen et al., 2013 source
In Vivo Estimation of Fiber Orientations (Table I) reports two or more fiber orientations in approximately 90% of white matter voxels using CSD and 63% using bedpostx. Both estimates support the claim that a majority contain multiple fiber populations with different trajectories. (LLM, conf=0.94)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“and is more likely somewhere between 60 and 90% (Jeurissen et al., 2013)”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Introducing the Problem (Pitfall)
What the sources say
- Supportedcites Jeurissen et al., 2013 source
The In Vivo Estimation of Fiber Orientations section (Table I) reports multiple fiber orientations in approximately 90% of white-matter voxels using CSD and complex configurations in approximately 63% using bedpostx. The Discussion repeats both estimates, supporting the cited 60–90% range. The percentages are method-dependent estimates, not a single measured proportion. (LLM, conf=0.94)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“with many regions thought to contain as many as 3 or more intersecting fiber bundles with different trajectories (Figure 1)”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Introducing the Problem (Pitfall)
What the sources say
- Supportedcites Jeurissen et al., 2013 source
The In Vivo Estimation of Fiber Orientations section reports large clusters of voxels with three fiber populations, including a region where three named bundles interdigitate. It also reports that CSD detected three or more orientations in about 45% of white-matter voxels, supporting the claim's hedged wording. (LLM, conf=0.93)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the proportion of cerebral white matter voxels containing complex fiber geometries and/or multiple fiber bundles in different orientations (i.e., crossing fibers, kissing fibers, etc.) is now thought to be at least 33% (Behrens et al., 2007)”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Introducing the Problem (Pitfall)
What the sources say
- Partly supportedcites Behrens et al., 2007 sourceExperimental — accuracy not yet measured
The Results (Local fitting of the complex fibre model) and Discussion report detectable complex fibre architecture in approximately one third of voxels with fractional anisotropy greater than 0.1 using a 60-direction dataset; page numbers are not supplied. This supports the approximate proportion, but not a lower bound of at least 33% for all cerebral white matter voxels. (LLM, conf=0.88)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in the case of ihMT and MWI likely also provide more myelin-specific information than can be obtained with more general measures based on DTI or T1w/T2w ratio metrics (Mädler et al., 2008; Ercan et al., 2018; Uddin et al., 2019).”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
What the sources say
- Not checked — no full text of the sourcecites Mädler et al., 2008 source
- Not checked — no full text of the sourcecites Ercan et al., 2018 source
- Partly supportedcites Uddin et al., 2019 sourceExperimental — accuracy not yet measured
The Introduction calls MWF a myelin-specific measure and DTI metrics general measures of tissue microstructure; the Conclusions also say T1w/T2w ratios should not be interpreted as myelin-specific in subcortical structures. The paper mentions an earlier ihMTR comparison but does not establish that ihMT is more myelin-specific than DTI or T1w/T2w. Page numbers are unavailable in our copy. (LLM, conf=0.86)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“as pointed out by Jeurissen et al. (2013), even regions with crossing fibers, many observed differences/changes in FA, AD and/or RD are likely to reflect actual anatomical and biophysical phenomena, as long as other pitfalls in the acquisition and analysis have been avoided (Jones and Cercignani, 2010).”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > General Discussion
What the sources say
- Partly supportedcites Jeurissen et al., 2013 sourceExperimental — accuracy not yet measured
In “Implications for DTI” (page not provided), the paper says that, if known analysis pitfalls are avoided, an observed FA change is highly likely to reflect a true underlying biophysical phenomenon—even though its meaning is ambiguous in crossing-fiber regions. It discusses axial and radial diffusivity as similarly difficult to interpret, but does not explicitly extend that likelihood statement to changes in AD or RD. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites Jones and Cercignani, 2010 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“ex vivo MRI and histological studies of the macaque brain have revealed that white matter crossing fibers become even more apparent upon higher resolution and more detailed examination”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > General Discussion
What the sources say
- Supportedcites Schilling et al., 2017 source
The Introduction describes ex vivo MRI of a macaque brain followed by histological analysis of the same specimen. The Conclusion reports that crossing fibers became more frequent at higher spatial resolutions in both MRI and histology, supporting the citing sentence’s paraphrase. (LLM, conf=0.94)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“DKI data acquired using conventional hardware and reasonable scan times can resolve crossing fibers significantly better than conventional DTI (Glenn et al., 2016)”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
What the sources say
- Partly supportedcites Glenn et al., 2016 sourceExperimental — accuracy not yet measured
The Conclusion (page unavailable) says DKI directly resolves crossing fibers and improves tractography accuracy relative to DTI; the Methods report use of a 3T MRI system. However, the Discussion says this study’s scan time was relatively long compared with typical clinical protocols. It cites shorter DKI protocols as feasible but does not establish the same crossing-fiber performance at those scan times. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“suggesting that this is a fundamental problem that cannot be overcome by scanning at higher resolution to reduce partial volume effects (Schilling et al., 2017).”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > General Discussion
What the sources say
- Supportedcites Schilling et al., 2017 source
The Discussion says the crossing fiber problem is a fundamental limitation of diffusion MRI that cannot be overcome by increased spatial resolution. It also reports that crossing fibers remained in more than 50% of white-matter voxels at 32 µm, despite reduced partial-volume averaging. (LLM, conf=0.94)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“other quantitative MRI techniques such as calibrated T1w/T2w ratio mapping (Ganzetti et al., 2014; Uddin et al., 2018), inhomogeneous magnetization transfer (ihMT) imaging (Manning et al., 2017; Swanson et al., 2017), and T2 relaxation-based myelin water imaging MWI (Prasloski et al., 2012; Lee et al., 2018) are likely less affected by fiber orientation”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
What the sources say
- Supportedcites Ganzetti et al., 2014 source
In the Discussion section on myelin-related information, the paper reports that T1-w/T2-w scores were more uniform than fractional anisotropy (FA) across white-matter structures. It attributes some FA variability to crossing fibers with different orientations, supporting the hedged claim that the ratio measure is less affected by fiber orientation than FA. The cited paper does not address the other techniques listed in the sentence, which have separate citations. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites Uddin et al., 2018 source
- Not checked — no full text of the sourcecites Manning et al., 2017 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- It may state two separate claims as one. 5
- Probably not a substantial claim. 3
Every source the paper cites for this claim was checked and supports it.
In the paper
“changes in AD can induce spurious alterations in RD and vice versa in voxels containing crossing fibers (Wheeler-Kingshott and Cercignani, 2009)”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > General Discussion
What the sources say
- Supportedcites Wheeler-Kingshott and Cercignani, 2009 source
The Abstract states that simulations of crossing-fiber voxels show a change in radial diffusivity can cause a fictitious change in axial diffusivity, and vice versa. The Discussion likewise describes changes to both fitted measures in its crossing-fiber model. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Modeling individual fibers at the sub-voxel level like this could lead to more sensitive measurements and more detailed understandings about tissue degeneration in various disorders (Finkelstein et al., 2021).”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
What the sources say
- Supportedcites Finkelstein et al., 2021 source
The Introduction describes fixel-based analysis as modeling individual fibers at the sub-voxel level, providing a more comprehensive understanding of fiber changes, and being used in several neurological disorders. The Conclusions say it may provide a sensitive biomarker for axonal degeneration, although the study’s sensitivity comparison was limited to an HIV cohort. (LLM, conf=0.90)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“recent fixel-based analysis approaches have been proposed to characterize a specific fiber population within a voxel (i.e., a “fixel”) (Raffelt et al., 2017).”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
What the sources say
- Supportedcites Raffelt et al., 2017 source
The Methods section (‘Fixel-based morphometry’; page unavailable) proposes a measure for each fixel, defined by its orientation and voxel location. The Conclusion (page unavailable) describes the resulting framework as fibre-specific and able to handle multiple fibre bundles within a voxel, supporting the citing sentence’s characterization. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As a result, MD and Trace values are theoretically more robust to multiple fiber populations and/or complex fiber geometries, and are likely the best DTI indicators of how tissues are constraining diffusion within a voxel.”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“NODDI can estimate neurite density in dendrites and axons, as well as orientation dispersion (i.e., fanning of neurites), which are factors that contribute to, but are distinct from DTI-based FA measures.”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
What the sources say
- Not checked — no full text of the sourcecites Zhang et al., 2012 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it suggests that strong biophysical interpretations and conclusions should not be drawn using FA, AD or RD measurements alone”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > General Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“Orientation dispersion estimates the angular variability between neurites and provides a better measure than FA in regions with fanning or crossing fibers.”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Potential Alternatives to Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity
What the sources say
- Not checked — no full text of the sourcecites Zhang et al., 2012 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
FA, AD, and RD are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease.
“Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease.”
The paper relies on this without support.
Many diffusion imaging end-users continue to apply and interpret FA, AD, and RD as standalone biomarkers of white matter microstructure, and this has not become common knowledge among them.
“based on the continued application and interpretation of these metrics in the broader biomedical/neuroscience literature, it appears that this has perhaps not yet become common knowledge among diffusion imaging end-users.”
The paper relies on this without support.
The conventional interpretation that higher FA values generally reflect greater white matter density is widely held.
“the conventional thinking was that all else being equal, higher FA values generally reflected greater white matter density”
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Demonstrating the Problem (Pitfall) > Thought Experiment #1: Interpreting Fractional Anisotropy Differences or Changes (Increases and Decreases)
“Bold arrow represents a relatively large increase (λ1 in part A)”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Demonstrating the Problem (Pitfall) > Thought Experiment #1: Interpreting Fractional Anisotropy Differences or Changes (Increases and Decreases)
“thin arrows represent a relatively small increase (λ1 and λ2 in part A)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Demonstrating the Problem (Pitfall) > Thought Experiment #2: Interpreting Fractional Anisotropy Equivalence or Stability
“if a multiple sclerosis (MS) lesion or traumatic brain injury damages all of the underlying fiber bundles within a particular region equally (e.g., increased membrane permeability and decreased myelination leading to an equal reduction in λ1, λ2, and λ3), FA will appear unchanged”
§ Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure > Demonstrating the Problem (Pitfall) > Thought Experiment #1: Interpreting Fractional Anisotropy Differences or Changes (Increases and Decreases)
“all three fibers experience the same amount of tissue damage, such that all three eigenvalues (λ1, λ2, and λ3) are increased proportionally”
Citations
Cites
The basis of anisotropic water diffusion in the nervous system—A technical review.
Beaulieu, C. (2002) · NMR in Biomedicine · doi:10.1002/nbm.782 · Cited by 4,628 · cited 3×
“Additionally, there have been several excellent in-depth reviews published on the biophysical interpretations of diffusion MRI signals (Beaulieu, 2002; Jelescu and Budde, 2017; Jelescu et al., 2020).”
BackgroundMethodBasser, P. J., & Pierpaoli, C. (1996) · Journal of Magnetic Resonance, Series B · doi:10.1006/jmrb.1996.0086 · Cited by 4,306 · cited 2×
“…of diffusion-encoding directions ( ≥ 6 orthogonal directions) (Alexander et al., 2007), is very easy to calculate (based on the common tensor model) (Basser and Pierpaoli, 1996), yields high test-retest and even inter-site/cross-scanner reliability (Vollmar et al., 2010; Luque Laguna et al., 2020),…”
BackgroundProbabilistic diffusion tractography with multiple fibre orientations: What can we gain?
Behrens, T. E. J., Berg, H. J., Jbabdi, S., Rushworth, M. F. S., & Woolrich, M. W. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2006.09.018 · Cited by 3,471 · cited 2×
“…fiber geometries and/or multiple fiber bundles in different orientations (i.e., crossing fibers, kissing fibers, etc.) is now thought to be at least 33% (Behrens et al., 2007), and is more likely somewhere between 60 and 90% (Jeurissen et al., 2013) – with many regions thought to contain as many…”
BackgroundNODDI: Practical in vivo neurite orientation dispersion and density imaging of the human brain
Zhang, H., Schneider, T., Wheeler-Kingshott, C. A., & Alexander, D. C. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.03.072 · Cited by 3,288 · cited 4×
“…to: diffusion kurtosis imaging (DKI) (Jensen et al., 2005; Jensen and Helpern, 2010), neurite orientation dispersion and density imaging (NODDI) (Zhang et al., 2012), tensor-valued diffusion encoding or b-tensor encoding (Szczepankiewicz et al., 2016, 2019), and novel fixel-based analysis…”
BackgroundMethodInfluentialCharacterization and propagation of uncertainty in diffusion-weighted MR imaging
Behrens, T. E. J., Woolrich, M. W., Jenkinson, M., Johansen‐Berg, H., Nunes, R. G., Clare, S., Matthews, P. M., Brady, J. M., & Smith, S. M. (2003) · Magnetic Resonance in Medicine · doi:10.1002/mrm.10609 · Cited by 3,038 · cited 2×
“…aspects of tissue microstructure, (2) non-invasively map the brain’s white matter pathways using deterministic (Mori et al., 1999) and/or probabilistic (Behrens et al., 2003) tractography approaches (Maier-Hein et al., 2017; Jeurissen et al., 2019), and (3) indirectly measure brain function (Le…”
BackgroundDiffusion tensor imaging of the brain
Alexander, A. L., Lee, J. E., Lazar, M., & Field, A. S. (2007) · Neurotherapeutics · doi:10.1016/j.nurt.2007.05.011 · Cited by 2,747
Jensen, J. H., Helpern, J. A., Ramani, A., Lu, H., & Kaczynski, K. (2005) · Magnetic Resonance in Medicine · doi:10.1002/mrm.20508 · Cited by 2,488 · cited 3×
“For example, DKI data acquired using conventional hardware and reasonable scan times can resolve crossing fibers significantly better than conventional DTI (Glenn et al., 2016), and certain DKI metrics such as kurtosis fractional anisotropy (KFA) and quantitative kurtosis tensor measures (e.g., radial tensor kurtosis) a…”
BackgroundWhite matter integrity, fiber count, and other fallacies: The do's and don'ts of diffusion MRI
Jones, D. K., Knösche, T. R., & Turner, R. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2012.06.081 · Cited by 2,402 · cited 2×
“Indeed, the complex interactions between these factors and the resulting inability to ascribe apparent diffusion changes to any particular cause, is why (Jones et al., 2013) and others have advocated for researchers to exercise caution when interpreting DTI data and avoid drawing conclusions about microstructural or t…”
BackgroundTractography-based connectomes are dominated by false-positive connections
Maier-Hein, K. H., Neher, P., Houde, J.-C., Côté, M.-A., Garyfallidis, E., Zhong, J., Chamberland, M., Yeh, F.-C., Lin, Y.-C., Ji, Q., et al. (2016) · doi:10.1101/084137 · Cited by 1,376
MRI quantification of non-gaussian water diffusion by kurtosis analysis
Jensen, J. H., & Helpern, J. A. (2010) · NMR in Biomedicine · doi:10.1002/nbm.1518 · Cited by 1,251 · cited 3×
“For example, DKI data acquired using conventional hardware and reasonable scan times can resolve crossing fibers significantly better than conventional DTI (Glenn et al., 2016), and certain DKI metrics such as kurtosis fractional anisotropy (KFA) and quantitative kurtosis tensor measures (e.g., radial tensor kurtosis) a…”
Background
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Sorted by citations
Key, M. N., & Szabo‐Reed, A. N. (2023) · Nutrients · doi:10.3390/nu15112495 · Cited by 90
“A region with a high preference for a particular orientation will have a high FA value, indicating highly organized fibers, a sign of intact white matter tracts [32].”
BackgroundGong, Z., Bilgel, M., Kiely, M., Triebswetter, C., Ferrucci, L., Resnick, S. M., Spencer, R. G. S., & Bouhrara, M. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.12968 · Cited by 76
“53,54 Therefore, the association between myelin content and cognition has not been directly established.”
An ALE meta-analytic review of musical expertise
Criscuolo, A., Pando‐Naude, V., Bonetti, L., Vuust, P., & Brattico, E. (2022) · Scientific Reports · doi:10.1038/s41598-022-14959-4 · Cited by 76
Hinojosa, C. A., George, G. C., & Ben‐Zion, Z. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02558-w · Cited by 60
“The pattern of diffusivity can be computed using scalar measures such as fractional anisotropy (FA), whereby lower FA values illustrate a reduced axonal packing density [42].”
Gimbel, B. A., Anthony, M. E., Ernst, A. M., Roediger, D. J., de Water, E., Eckerle, J. K., Boys, C. J., Radke, J. P., Mueller, B. A., Fuglestad, A. J., et al. (2022) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-022-09470-w · Cited by 39
“, NODDI) that allows for greater specificity with regard to white matter microstructure compared to traditional diffusion tensor imaging metrics such as FA and MD [54, 67].”
BackgroundMicrostructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19
Silva, L. S., da Costa, B. A., Aventurato, Í. K., João, R. B., de Campos, B. M., de Brito, M. R., Bechelli, J. F., Silva, L. C. S., dos Santos, A. F., Alvim, M. K. M., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-52005-7 · Cited by 41
“However, the significance and interpretation of higher values of AD in the absence of alterations of other diffusivities requires extreme caution, due to the complexity of biophysical properties of these metrics 71 .”
BackgroundEarly life cold and heat exposure impacts white matter development in children
Granés, L., Essers, E., Ballester, J., Petricola, S., Tiemeier, H. W., Iñiguez, C., Soriano‐Mas, C., & Guxens, M. (2024) · Nature Climate Change · doi:10.1038/s41558-024-02027-w · Cited by 37
“Second, MD could be a more robust measure when inferring the underlying tissue characteristics of white matter as compared with FA 40 .”
Human brain changes after first psilocybin use
Lyons, T., Spriggs, M., Kerkelä, L., Rosas, F. E., Roseman, L., Mediano, P. A. M., Timmermann, C., Oestreich, L., Pagni, B. A., Zeifman, R. J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71962-3 · Cited by 30
“However, interpretation of the axial diffusivity changes is complex, not least due to crossing fi ber-related confounds 43 .”
Lin, C., Frigerio, I., Bol, J. G. J. M., Bouwman, M. M. A., Wesseling, A. J., Dahl, M. J., Rozemüller, A. J. M., van der Werf, Y. D., Pouwels, P. J. W., van de Berg, W. D. J., et al. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00400-5 · Cited by 30
Frontostriatal and limbic contributions to cognitive decline in Parkinson's disease
Brown, G., Hakun, J. G., Lewis, M. M., Jesus, S. D., Du, G., Eslinger, P. J., Kong, L., & Huang, X. (2022) · Journal of Neuroimaging · doi:10.1111/jon.13045 · Cited by 28
Khan, A. F., & Iturria‐Medina, Y. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03073-w · Cited by 31
“Linking these biomarkers, which are often non-speci fi c to pathophysiology [191, 192], to mechanistic pathways requires information about features such as gene expression and Fig.”
BackgroundMarrie, R. A., Patel, R., Figley, C. R., Kornelsen, J., Bolton, J. M., Graff, L. A., Mazerolle, E. L., Helmick, C. A., Uddin, M. N., Figley, T. D., et al. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.910014 · Cited by 26
“Choice of Diffusion Metric It is increasingly recognized that a large proportion of white matter fiber tracts have complex architecture including crossing fibers such that variations in DTI measures do not necessarily reflect variations in structural integrity of myelin or axons (55, 56).”
BackgroundSelf-citationLitwin, T., Rędzia-Ogrodnik, B., Antos, A., Przybyłkowski, A. M., Członkowska, A., & Bembenek, J. P. (2024) · Brain Sciences · doi:10.3390/brainsci14070727 · Cited by 27
“FA quantifies the variability of particle movements in space and correlates with tissue structure coherence [30,31].”
BackgroundMethodInfluentialPušnik, L., Serša, I., Umek, N., Cvetko, E., & Snoj, Ž. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1070227 · Cited by 20
“We hypothesize that the fibers crossing between the fascicles contributed to high fascicular coefficients of variation within the same fascicle and explain why no difference was observed (Figley et al., 2022).”
BackgroundLiu, Y., Jiang, Y., Du, W., Gao, B., Gao, J., Hu, S., Song, Q., Wang, W., & Miao, Y. (2024) · Scientific Reports · doi:10.1038/s41598-023-50768-z · Cited by 20
“This might be due to FA is a relative measure, the quantitative information might be inaccurate in the presence of crossing fibers 44 .”
BackgroundThanaraju, A., Marzuki, A. A., Chan, J. K., Wong, K. Y., Phon-Amnuaisuk, P., Vafa, S., Chew, J., Chia, Y. C., & Jenkins, M. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105716 · Cited by 21
Self-citationThe impact of resective epilepsy surgery on the brain network: evidence from post-surgical imaging
Sainburg, L. E., Englot, D. J., & Morgan, V. L. (2025) · Brain · doi:10.1093/brain/awaf026 · Cited by 19
“57 Functionally, multiple FDG-PET studies have found increases in glucose metabolism after TLE surgery distant from the resection site, 16,24-26 which may indicate compensation for the activity of the resected area.”
Individual variation in the chimpanzee arcuate fasciculus predicts vocal and gestural communication
Hecht, E. E., Vijayakumar, S., Becker, Y., & Hopkins, W. D. (2025) · Nature Communications · doi:10.1038/s41467-025-58784-5 · Cited by 12
“…whether individual variation in AG behavior was associated with AF volume, asymmetry, and fractional anisotropy (FA), a scalar measure of white matterthat can re fl ect myelination and/or tract coherence, although it is not a comprehensive index of all aspects of white matter microstructure 30 .”
Whole-brain white matter variation across childhood environments
Carozza, S., Kletenik, I., Astle, D. E., Schwamm, L. H., & Dhand, A. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2409985122 · Cited by 20
“Second, we employed metrics derived from a tractography method that is robust to crossing fibers ( 44 , 45 ), which has been considered a confounding factor in FA analyses ( 46 ).”
Marchi, N. A., Daneault, V., André, C., Martineau‐Dussault, M., Baril, A., Thompson, C., Montplaisir, J. Y., Gilbert, D., Lorrain, D., Boré, A., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13833 · Cited by 16
“27 However,conventionaldiffusiontensorimaging(DTI)measures have limitations, such as partial volume effects, which may be particularly important in the AD continuum where atrophy leads to ex vacuo increases of cerebrospinal fluid and free water (FW) in brain tissue.”
BackgroundLeptin bioavailability and markers of brain atrophy and vascular injury in the middle age
Charisis, S., Short, M. I., Bernal, R., Kautz, T. F., Trevino, H., Mathews, J. J., Velarde, A. G., Muhammad, J. A. S., Luckey, A. M., Aslam, A., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13879 · Cited by 15
“…density, lower membrane permeability, greater myelination, etc.), due to the presence of crossing fibers throughout the majority of cerebral WM. 58 Notably, PSMD performs even better than traditional MD by leveraging skeletonization to focus the analysis of MD on the main fiber tracts,…”
BackgroundInfluentialAlzheimer's and vascular disease classification using regional texture biomarkers in FLAIR MRI.
Chan, K., Fischer, C. E., Maralani, P., Black, S., Moody, A., & Khademi, A. (2023) · NeuroImage: Clinical · doi:10.1016/j.nicl.2023.103385 · Cited by 14
“Recent studies on dMRI imaging show FA values are highly variable and conclusions about tissue integrity should be made with caution (Figley et al., 2022).”
BackgroundFaiyaz, A., Doyley, M. M., Schifitto, G., & Uddin, M. N. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1168833 · Cited by 20
“Diffusion tensor imaging (DTI), a widely used dMRI approach, has been shown to be sensitive to pathological changes in the brain (5).”
BackgroundSelf-citationMahmoodi, A. L., Landers, M. J. F., Rutten, G.-J. M., & Brouwers, H. B. (2023) · Cancers · doi:10.3390/cancers15143631 · Cited by 14
Structural connectivity changes in focal epilepsy: Beyond the epileptogenic zone
Barrios‐Martinez, J., Almast, A., Lin, I., Youssef, A., Aung, T., Fernandes-Cabral, D. T., Yeh, F.-C. F., Chang, Y., Mettenburg, J., Modo, M., et al. (2024) · Epilepsia · doi:10.1111/epi.18175 · Cited by 20
Advanced MRI Methods for Diagnosis and Monitoring of Multiple Sclerosis ( MS )
Elahi, R., Taremi, S., Najafi, A., Karimi, H., Asadollahzadeh, E., Sajedi, S. A., Rad, H. S., & Sahraian, M. A. (2025) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.29817 · Cited by 17
“Current evidence increasingly suggests that FA, along with AD and RD, should not be interpreted as isolated biomarkers of WM integrity [97].”
Heijmans, M., Wolters, A. F., Temel, Y., et al. (2022) · Journal of Parkinson s Disease · doi:10.3233/jpd-223349 · Cited by 13
“However, due to the presence of many crossing fibers in the white matter, FA can also increase as a result of disproportionate degradation of one or more of these fiber bundles, even despite an actual decrease in local fiber density and myelination [10, 37].”
BackgroundAge of onset of obsessive-compulsive disorder differentially affects white matter microstructure
Vriend, C., de Joode, N. D., Pouwels, P., Liu, F., Otaduy, M., Pastorello, B., Robertson, F. C., Ipser, J., Lee, S., Hezel, D. M., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02390-8 · Cited by 13
Feng, Y., Chandio, B. Q., Villalón‐Reina, J. E., Thomopoulos, S. I., Nir, T. M., Benavidez, S. M., Laltoo, E., Chattopadhyay, T., Joshi, H., Venkatasubramanian, G., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14371 · Cited by 16
Structural connectivity of an interoception network in schizophreniaPreprint
Yao, B., Gu, P., Lasagna, C. A., Peltier, S., Taylor, S. F., Tso, I. F., & Thakkar, K. N. (2022) · PsyArXiv (OSF Preprints) · doi:10.1016/j.pscychresns.2023.111636 · Cited by 11
Donald, K. A., Hendrikse, C. J., Roos, A., Wedderburn, C. J., Subramoney, S., Ringshaw, J. E., Bradford, L. E., Hoffman, N., Burd, T., Narr, K. L., et al. (2024) · NeuroImage Clinical · doi:10.1016/j.nicl.2024.103572 · Cited by 12
“…restriction of water diffusion in white matter (i.e., fiber packing density, axon diameter, directional organization, myelination, and membrane permeability; Beaulieu, 2002), caution should be taken when interpreting higher FA as indicating higher microstructural integrity (Figley et al., 2022).”
BackgroundUddin, M. N., Singh, M. V., Faiyaz, A., Szczepankiewicz, F., Nilsson, M., Boodoo, Z. D., Sutton, K. R., Tivarus, M. E., Zhong, J., Wang, L., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-80372-8 · Cited by 13
“Utilizing micrometer-scale displacement of tissue water, diffusion MRI (dMRI) can noninvasively detect microstructural abnormalities in the brain 15–18 .”
Self-citationExercise habits and mental health: Exploring the significance of multimodal imaging markers
Yao, Z., Hsieh, S., & Yang, M. (2023) · Progress in brain research · doi:10.1016/bs.pbr.2023.11.001 · Cited by 12
Jochems, A. C. C., Maniega, S. M., Clancy, Ú., Arteaga, C., García, D. J., Chappell, F. M., Hewins, W., Locherty, R., Backhouse, E. V., Barclay, G., et al. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.032259 · Cited by 11
“…at the microstructural level from FA, because its interpretation is limited in areas containing complex white matter fiber geometries or multiple crossing fibers, 53 we demonstrate that areas of WMH regression follow a different trajectory over time than other white matter areas for FA, MD, and T1.”
Ghaderi, S., Mohammadi, S., & Fatehi, F. (2024) · World Neurosurgery · doi:10.1016/j.wneu.2024.07.037 · Cited by 11
Plank, J. R., Gozdas, E., Dai, E., McGhee, C., Raman, M. M., & Green, T. (2024) · Human Brain Mapping · doi:10.1002/hbm.70087 · Cited by 11
Porcu, M., Cocco, L., Cau, R., Suri, J. S., Mannelli, L., Manchia, M., Puig, J., Yang, Q., & Saba, L. (2023) · Brain Topography · doi:10.1007/s10548-023-01020-4 · Cited by 11
“The DTI metrics analyzed in our research (FA, MD, RD and AD) reflect different aspects of WM properties (Winston 2012; Winklewski et al. 2018; Martinez-Heras et al. 2021; Figley et al. 2022).”
InfluentialSelf-citationZhao, H., Rong, B., Gao, G., Zhou, M., Huang, J., Tu, N., Bu, L., Xiao, L., & Wang, G. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1364786 · Cited by 10
Fislage, M., Winzeck, S., Woodrow, R., Lammers‐Lietz, F., Stamatakis, E. A., Correia, M., Preller, J., Feinkohl, I., Hendrikse, J., Pischon, T., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13749 · Cited by 11
Papini, M. G., Avila, A. N., Fitzgerald, M., & Hellewell, S. C. (2024) · Journal of Neurotrauma · doi:10.1089/neu.2024.0039 · Cited by 10
“105,109,114 History of concussion or repetitive had injury was found to affect both blood and dMRI biomarkers of WM. Henry et al. found elevated FA in the corticospinal tract in athletes with a history of ‡ 3 concussions with concurrent changes to MD within the corpus callosum.”
Kucikova, L., Xiong, X., Reinecke, P., Madden, J., Jackson, E., Tappin, O., Huang, W., Dounavi, M., & Su, L. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102510 · Cited by 10
Early life adversity and white matter microstructural organization—a systematic review
Mitchell, O., Roddy, D. W., & Connaughton, M. (2025) · Brain Imaging and Behavior · doi:10.1007/s11682-025-01007-8 · Cited by 11
“These issues can result in incorrectly identified tracts, partial volume errors, and inaccurate measurements (Figley et al., 2022; Keihaninejad et al., 2012).”
Lewis, L., Corcoran, M., Cho, K. I. K., Kwak, Y., Hayes, R. A., Larsen, B., & Jalbrzikowski, M. (2023) · Schizophrenia · doi:10.1038/s41537-023-00411-7 · Cited by 9
Mueller, C., Nenert, R. E., Catiul, C., Pilkington, J., Szaflarski, J. P., & Amara, A. W. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149016 · Cited by 9
Gunatilake, N., Boyes, A., Elwyn, R., Brunet, A., Hermens, D. F., & Driver, C. (2025) · Adolescent Research Review · doi:10.1007/s40894-025-00263-5 · Cited by 13
“White matter integrity is influenced by a number of pathophysiological mechanisms and disruptions to white matter organization can arise from any of these mechanisms (Figley et al., 2022; Lagopoulos et al., 2013).”
Gudberg, C., Stevelink, R., Douaud, G., Wulff, K., Lazari, A., Fleming, M. K., & Johansen‐Berg, H. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.745014 · Cited by 10
“While specific biological interpretation of diffusion metrics can be challenging, particularly in regions of crossing fibers (Figley et al., 2022), our findings suggest a consistent picture of altered white matter microstructure across widely distributed regions.”
BackgroundThe role of brain white matter in depression resilience and response to sleep interventions
Bresser, T., Leerssen, J., Hölsken, S., Groote, I. R., Foster‐Dingley, J. C., van den Heuvel, M. P., & Someren, E. J. W. V. (2023) · Brain Communications · doi:10.1093/braincomms/fcad210 · Cited by 8
“More sophisticated diffusion analysis methods are becoming available.(18,60) Improved reproducibility, better inference and increased sensitivity and specificity, especially in regions with crossing fibres, may be expected from these more sophisticated methods and by using multiple modalities.”
InfluentialAsturias, A., Knoblauch, T., Rodriguez, A., Vanier, C. H., Tohic, C. L., Barrett, B., Eisenberg, M., Gibbert, R., Zimmerman, L., Parikh, S., et al. (2023) · Frontiers in Neuroimaging · doi:10.3389/fnimg.2023.1153115 · Cited by 9
Janowska, J., Gargaś, J., Zajdel, K., Wieteska, M., Lipinski, K. A., Ziemka‐Nałęcz, M., Frontczak‐Baniewicz, M., & Sypecka, J. (2024) · Brain Pathology · doi:10.1111/bpa.13255 · Cited by 10
“One hypothesis is that it may not be associated with the changes in myelination, but fiber density and directional organization changes during brain development [58].”
BackgroundStructural connectivity in recovery after coma: Connectome atlas approach
Pozeg, P., Alemán‐Gómez, Y., Jöhr, J., Muresanu, D. F., Pincherle, A., Ryvlin, P., Hagmann, P., Diserens, K., & Dunet, V. (2023) · NeuroImage Clinical · doi:10.1016/j.nicl.2023.103358 · Cited by 10
“(Figley et al., 2022) this drawback can be improved with modern diffusion techniques that are more robust to crossing fibers.”
BackgroundAssessing quantitative MRI techniques using multimodal comparisons
Carter, F., Anwander, A., Johnson, M., Goucha, T., Adamson, H., Friederici, A., Lutti, A., Gauthier, C., Weiskopf, N., Bazin, P., et al. (2022) · bioRxiv · doi:10.1371/journal.pone.0327828 · Cited by 5
“The relatively low correlation in WM is also likely to be partially driven by the mismatch between the tensor-based simplification of WM architecture as FA, which best represents a single fibre population, and the reality that most regions include multiple fibre populations [76].”
Schrempft, S., Trofimova, O., Künzi, M., Ramponi, C., Lutti, A., Kherif, F., Latypova, A., Vollenweider, P., Marques-Vidal, P. M., Preisig, M., et al. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.1231-23.2024 · Cited by 8
The Impact of Insufficient Sleep on White Matter Development in Late Childhood and Early Adolescence
Santos, J. P. L., Soehner, A. M., Ladouceur, C. D., & Versace, A. (2024) · Journal of Adolescent Health · doi:10.1016/j.jadohealth.2024.10.007 · Cited by 9
Schellekens, M. M. I., Li, H., Boot, E. M., Verhoeven, J. I., Ekker, M. S., Meijer, F. J. A., Kessels, R. P. C., de Leeuw, F., & Tuladhar, A. M. (2024) · NeuroImage Clinical · doi:10.1016/j.nicl.2024.103711 · Cited by 9
“This may be due to the degeneration of one or more fiber bundles in crossing fibers, resulting in a paradoxical increase in FA T compared to controls (Figley et al., 2021).”
Lewandowska, P., Bajada, C., Mysak, Y., Domagalik, A., Kossowski, B., Baumbach, C., Kaczmarek-Majer, K., Degórska, A., Skotak, K., Sitnik-Warchulska, K., et al. (2025) · Human Brain Mapping · doi:10.1002/hbm.70306 · Cited by 5
“Other direction-specific metrics (e.g., axial and radial diffusivity) were not included, as their interpretation can be more ambiguous in whole-brain averages across heterogeneous tissue types and regions with complex fiber architecture (Figley et al. 2022).”
Buthmann, J. L., Uy, J. P., Miller, J. G., Yuan, J. P., Coury, S. M., Ho, T. C., & Gotlib, I. H. (2024) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2024.101368 · Cited by 7
“…one metric of white matter tract structural organization (i.e., FA); scientists have called for the analysis of multiple measures before drawing strong conclusions about tract organization (Figley et al., 2022), and it is important that our findings be replicated and extended in future studies.”
BackgroundRetzler, C., Hallam, G., Johnson, S. J., & Retzler, J. (2023) · Research on Child and Adolescent Psychopathology · doi:10.1007/s10802-023-01065-w · Cited by 7
“The factors identified here can provide a starting point for less exploratory approaches in future studies, and be used in combination with other brain imaging metrics as suggested by Figley et al. (2022).”
MethodZhao, X., You, M., Ren, W., Ji, L., Liu, Y., & Lu, M. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1467578 · Cited by 7
Plank, J. R., Morgan, C., Dell’Acqua, F., Sundram, F., Hoeh, N. R., Muthukumaraswamy, S. D., & Lin, J. C. (2025) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2025.05.002 · Cited by 10
Characterisation of the neonatal brain using myelin-sensitive magnetisation transfer imaging
Blesa, M., Vaher, K., York, E. N., Galdi, P., Sullivan, G., Stoye, D. Q., Hall, J., Corrigan, A. E., Quigley, A. J., Waldman, A. D., et al. (2023) · Imaging Neuroscience · doi:10.1162/imag_a_00017 · Cited by 8
White matter brain age as a biomarker of cerebrovascular burden in the ageing brain
Du, J., Pan, Y., Jiang, J., Lam, B. C. P., Thalamuthu, A., Chen, R., Tsang, I. W.-H., Sachdev, P. S., & Wen, W. X. (2024) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-024-01758-3 · Cited by 9
“While some diffusion weighted imaging (DWI) measures such as fractional anisotropy (FA) and mean diffusivity (MD) can be used to examine the WM microstructural integrity, they typically capture distinct physiological properties [4].”
Brain health measurement: a scoping review
Lee, A. H. Y., Shah, S., Atha, K., Indoe, P., Mahmoud, N., Niblett, G., Pradhan, V., Roberts, N. W., Malouf, R. S., & Topiwala, A. (2024) · BMJ Open · doi:10.1136/bmjopen-2023-080334 · Cited by 10
“24 Another drawback of using MRI as a key method of measuring brain health is its significant cost.”
MethodKwiatkowski, A., Weidler, C., Habel, U., Coverdale, N. S., Hirad, A. A., Manning, K. Y., Rauscher, A., Bazarian, J. J., Cook, D. J., Li, D. K. B., et al. (2024) · Human Brain Mapping · doi:10.1002/hbm.26811 · Cited by 8
“Figley et al. (2022) have highlighted that in the presence of crossing fibers, which is the case in most WM voxels, FA can remain stable even with significant alterations in the underlying tissue composition.”
Lewis, C. J., Chipman, S. I., Johnston, J. M., Acosta, M. T., Toro, C., & Tifft, C. J. (2025) · Journal of Neurology · doi:10.1007/s00415-025-13091-3 · Cited by 6
Genç, B., Aslan, K., Özçağlayan, A., & İncesu, L. (2023) · Magnetic Resonance in Medical Sciences · doi:10.2463/mrms.mp.2023-0054 · Cited by 7
Sullivan‐Toole, H., Jobson, K. R., Hoffman, L. J., Stewart, L. C., Olson, I. R., & Olino, T. M. (2023) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2023.101307 · Cited by 7
“The FA metric is influenced by a number of factors (Beaulieu, 2002; Curran et al., 2016); however, greater FA is generally interpreted as representing greater structural coherence of white matter tracts (but see Figley et al., 2022 for a more thorough discussion).”
BackgroundAsymmetries and hemispheric interaction in the auditory system of elderly people
Angenstein, N. (2024) · Frontiers in Neuroimaging · doi:10.3389/fnimg.2023.1320989 · Cited by 6
Spatola, G., Triebkorn, P., Richieri, R., Baunez, C., Farisse, J., Cretol, A., Guedj, E., Jirsa, V., & Régis, J. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e34699 · Cited by 6
“The disadvantage of this approach however is that DTI cannot account for multiple crossing fibres within a voxel, which may lead to overlooking or wrong interpretation of changes [20,21].”
BackgroundYi, X., Wang, Y., Shen, L., Fu, Y. H. H., Xiao, Q., Zhang, J., Ding, J., Jiang, F., Zhang, Z., Grecucci, A., et al. (2025) · Brain Imaging and Behavior · doi:10.1007/s11682-025-01046-1 · Cited by 6
“Although fractional anisotropy is the most commonly used metric in DTI studies, other DTI parameters including radial diffusivity (RD) and axial diffusivity (AD) may also provide meaningful diffusivity information of WM fiber tract integrity and efficiency (Figley et al., 2021 ).”
InfluentialGimbel, B. A., Roediger, D. J., Ernst, A. M., Anthony, M. E., de Water, E., Rockhold, M. N., Mueller, B. A., Mattson, S. N., Jones, K. L., Riley, E. P., et al. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1172010 · Cited by 6
“Using novel diffusion modeling approaches may identify potential white matter microstructural abnormalities with greater specificity (Sherbaf et al., 2019; Figley et al., 2021).”
BackgroundLim, L. L., Talozzi, L., & Howells, H. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-05759-3 · Cited by 8
“Finally, given the presence of crossing fibres, we caution against over-interpreting the conventional DTI-based metrics (FA, AD and RD values) as standalone biomarkers of WM microstructure [97].”
BackgroundExplaining recovery from coma with multimodal neuroimaging
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APOE4 poses opposite effects of plasma LDL on white matter integrity in older adults
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Aging Brain from a Lifespan Perspective
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“25 It has also been reported that MD could be more closely related to neurite density than FA, AD, or RD measures.”
D’Antonio, F., Teghil, A., Boccia, M., Gabrielli, G. B., Giulietti, G., Conti, D., Suppa, A., Fabbrini, A., Fiorelli, M., Caramia, F., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-65536-w · Cited by 5
“For instance, a selective loss of unidirectional fibers in a brain area with crossing fibers can lead to an increase in FA, while the loss of fibers in a white matter region characterized by only one direction (such as the corpus callosum) can result in a decrease in FA 57,58 .”
Gilliam, J. R., Sahu, P. K., Vendemia, J. M. C., & Silfies, S. P. (2024) · PLoS ONE · doi:10.1371/journal.pone.0309344 · Cited by 5
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“28 Based on conventional interpretation, we could infer that higher FA value might reflect increased number of microstructural tissue element, however, due to the presence of crossing fibers, disproportionate atrophy (while preservation of other fiber bundles) could result in increase of FA,…”
Diffusion tensor imaging after COVID-19 infection: A systematic review
Nelson, B. K., Farah, L. N., Saint, S. A., Song, C., Field, T. S., Sossi, V., Stoessl, A. J., Wellington, C. L., Honer, W. G., Lang, D. J., et al. (2025) · NeuroImage · doi:10.1016/j.neuroimage.2025.121150 · Cited by 6
“…are derived based on the principal direction of diffusion in a voxel and in the case of crossing fibres within a voxel, disproportionate degeneration of fibre bundles in one direction can lead to increased anisotropy even in the presence of damage to the white matter tracts (Figley, et al., 2022).”
Coexisting depression and frailty as an accelerated aging phenotype of late-life depression
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Nostadt, A., Schlaffke, L., Merz, C. J., Wolf, O. T., Nitsche, M. A., Tegenthoff, M., & Lissek, S. (2024) · BMC Psychology · doi:10.1186/s40359-024-01800-y · Cited by 5
“Higher FA values suggest better connectivity (connectivity with more directed diffusion) and in addition, facilitate communication between brain areas important for learning and memory [26, 50].”
BackgroundMethod9-HODE associates with thalamic atrophy and predicts white matter damage in multiple sclerosis
Fung, W. H., van Lingen, M. R., Broos, J. Y., Lam, K., van Dam, M., Fung, W. K., Noteboom, S., Koubiyr, I., de Vries, H. E., Jasperse, B., et al. (2024) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2024.105946 · Cited by 6
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Mirmosayyeb, O., Panah, M. Y., Vaheb, S., Ghoshouni, H., Mahmoudi, F., Kord, R., Kord, A., Zabeti, A., & Shaygannejad, V. (2025) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2025.106261 · Cited by 7
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“Composite measures also capture the multidimensionality of brain morphology and may therefore be more sensitive to abnormalities therein than any of their components alone 45,46 .”
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Longitudinal Identification of Pre‐Lesional Tissue in Multiple Sclerosis With Advanced Diffusion MRI
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Quantitative diffusion imaging and genotype‐by‐sex interactions in a rat model of Alexander disease
Stowe, N. A., Singh, A. P., Barnett, B. R., Yi, S. Y., Frautschi, P. C., Messing, A., Hagemann, T. L., & Yu, J. J. (2023) · Magnetic Resonance in Medicine · doi:10.1002/mrm.29917 · Cited by 4
“23 With NODDI, however, that we specifically see decreased neurite density and orientation dispersion of neurites is consistent both with previous histological analyses of our AxD rat model 10 and with characteristic microstructural Tabular summary of the significant effects of the Alexander…”
ResultFreire, I., Lopes, T., Afonso, S., & Pereira, D. J. (2024) · Neuroradiology · doi:10.1007/s00234-024-03362-7 · Cited by 6
Dewan, M. V., Jungilligens, J., Kobus, S., Diezel, M., Dathe, A.-K., Schweiger, B., Hüning, B. M., Felderhoff‐Müser, U., & Bruns, N. (2024) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2024.06.009 · Cited by 5
Feng, Y., Chandio, B. Q., Villalón‐Reina, J. E., Benavidez, S. M., Chattopadhyay, T., Chehrzadeh, S., Laltoo, E., Thomopoulos, S. I., Joshi, H., Venkatasubramanian, G., et al. (2024) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) · doi:10.1109/embc53108.2024.10781681 · Cited by 4
“As crossing fibers are widespread in the brain [43], [44], both micro-and macro-structural abnormalities detected by DNT in one WM tract could still be due, partly or fully, to differences in another fiber population, even when accounting for bundle geometry.”
Bettcher, B. M., Lopez‐Paniagua, D., Wang, Y., McConnell, B. V., Coughlan, C. M., Carlisle, T. C., Thaker, A. A., Lippitt, W., Filley, C. M., Pelak, V. S., et al. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100834 · Cited by 3
McMaster, E. M., Newlin, N. R., Cho, C. Y., Rudravaram, G., Saunders, A. M., Krishnan, A. R., Remedios, L. W., Kim, M. E., Xu, H., Schilling, K. G., et al. (2025) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2025.110539 · Cited by 3
“The effect of spatial sampling on image-based brain map approximations can be observed in the microstructure [9].”
Metadata
- Authors
- Figley, C. R., Uddin, M. N., Wong, K., Kornelsen, J., Puig, J., & Figley, T. D.
- Affiliations
- Health Sciences Centre (CA)
- University of Rochester Medicine (US)
- University of Manitoba (CA)
- Corresponding author
- Figley, Chase R.
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-01-14
- Volume
- 15
- Pages
- 799576-799576
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC8795606
- OpenAlex
- W4205639396
- Semantic Scholar
- be9d91e96b10025ed794c12fd9c9656efe11d15a
- Cited by
- 253
- References
- 54
- Citations by year
- 2026: 66 · 2025: 68 · 2024: 76 · 2023: 33 · 2022: 10
- FWCI
- 24.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Health Sciences Centre Foundation
- Research Manitoba
- Natural Sciences and Engineering Research Council of Canada
- 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 › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- fractional anisotropy, axial diffusivity, radial diffusivity, white matter microstructure, diffusion MRI, crossing fibers, MRI biomarkers
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