Fiber-specific structural properties relate to reading skills in children and adolescents
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eLife Assessment:
This study presents a large sample of participants ranging from 6-18 years investigating the association between white matter measures and reading using a sophisticated analysis. The results show a clear association between intra-axonal volume and single-word reading abilities. In sum, this valuable study complements other large-scale studies by applying sophisticated fixel-based analyses.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Recent studies suggest that the cross-sectional relationship between reading skills and white matter microstructure, as indexed by fractional anisotropy, is not as robust as previously thought. Fixel-based analyses yield fiber-specific micro- and macrostructural measures, overcoming several shortcomings of the traditional diffusion tensor model. We ran a whole-brain analysis investigating whether the product of fiber density and cross-section (FDC) related to single-word reading skills in a large, open, quality-controlled dataset of 983 children and adolescents ages 6–18. We also compared FDC between participants with (n = 102) and without (n = 570) reading disabilities. We found that FDC positively related to reading skills throughout the brain, especially in left temporoparietal and cerebellar white matter, but did not differ between reading proficiency groups. Exploratory analyses revealed that among metrics from other diffusion models – diffusion tensor imaging, diffusion kurtosis imaging, and neurite orientation dispersion and density imaging – only the orientation dispersion and neurite density indexes from NODDI were associated (inversely) with reading skills. The present findings further support the importance of left-hemisphere dorsal temporoparietal white matter tracts in reading. Additionally, these results suggest that future DWI studies of reading and dyslexia should be designed to benefit from advanced diffusion models, include cerebellar coverage, and consider continuous analyses that account for individual differences in reading skill.
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eLife Assessment:
This study presents a large sample of participants ranging from 6-18 years investigating the association between white matter measures and reading using a sophisticated analysis. The results show a clear association between intra-axonal volume and single-word reading abilities. In sum, this valuable study complements other large-scale studies by applying sophisticated fixel-based analyses.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this work, Meisler and Gabrieli investigated whole-brain white matter fixel-based analysis and their relationship with reading skills for the first time. They used data from the Healthy Brain Network including children and adolescents with typical reading, reading disability, or unclassified status, however the main focus was on continuous Test of Word Reading Efficiency (TOWRE) measures.
The authors found that the product of fibre density and cross-section, denoted as FDC, was related to TOWRE scores. In particular, higher FDC in bilateral temporal-parietal and cerebellar white matter were most strongly related to better reading measures, with a slight left lateralization. These two main clusters likely involved sections of the arcuate, superior longitudinal, and middle longitudinal fasciculi that …
Reviewer #1 (Public Review):
In this work, Meisler and Gabrieli investigated whole-brain white matter fixel-based analysis and their relationship with reading skills for the first time. They used data from the Healthy Brain Network including children and adolescents with typical reading, reading disability, or unclassified status, however the main focus was on continuous Test of Word Reading Efficiency (TOWRE) measures.
The authors found that the product of fibre density and cross-section, denoted as FDC, was related to TOWRE scores. In particular, higher FDC in bilateral temporal-parietal and cerebellar white matter were most strongly related to better reading measures, with a slight left lateralization. These two main clusters likely involved sections of the arcuate, superior longitudinal, and middle longitudinal fasciculi that overlap in that region, and the superior cerebellar peduncle.
This represents the first investigation of fixel-based analysis related to measures of reading, and the large sample allowed a whole-brain analysis approach and reaffirmation of the importance of the temporal and cerebellar white matter that support reading. The authors also included a supplementary analysis that will be of interest to researchers in the field, where they also investigated other white matter measures and their relationships with reading, where orientation dispersion index was inversely related to reading skills in the same regions.
This paper opens the door for further exploration using fixel-based analysis approaches to study reading, but more widespread development. Though it was not explored here, it would be interesting to see if tracts derived using this analysis approach can aid in understanding regions with crossing fibres, and disentangle the role of specific white matter pathways that support specific reading skills and other cognitive abilities.
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Reviewer #2 (Public Review):
This is a large-scale pediatric study (Healthy Brain Network biobank, n =983) that examines white matter correlates of reading and reading disability. In contrast to most diffusion studies within the reading domain, the outcome measure is not based on the tensor-model, such as fractional anisotropy, but is based on fixel-based analyses, such as FDC. In contrast to a prior study in largely the same sample (Meisler & Gabrieli, 2022) where FA did not correlate with reading nor discriminated between poor and typical readers, the current study observed positive correlations with reading and FDC (but no group differences). More specifically, higher reading scores cohered with higher FDC, with the strongest effects in left temporoparietal and cerebellar tracts.
The introduction is clearly structured (including a …
Reviewer #2 (Public Review):
This is a large-scale pediatric study (Healthy Brain Network biobank, n =983) that examines white matter correlates of reading and reading disability. In contrast to most diffusion studies within the reading domain, the outcome measure is not based on the tensor-model, such as fractional anisotropy, but is based on fixel-based analyses, such as FDC. In contrast to a prior study in largely the same sample (Meisler & Gabrieli, 2022) where FA did not correlate with reading nor discriminated between poor and typical readers, the current study observed positive correlations with reading and FDC (but no group differences). More specifically, higher reading scores cohered with higher FDC, with the strongest effects in left temporoparietal and cerebellar tracts.
The introduction is clearly structured (including a very informative figure 1) and includes an up-to-date literature review on the link between white matter and reading and on the disadvantages of FA versus measures obtained via non-tensor models.
Although large-scale developmental MRI studies on reading are highly needed, the sample has a few disadvantages. First, most children have a neurodevelopmental and/or psychological disorder, which makes it difficult to generalize findings to a general population. Second, the age range of the sample is very wide. Both white matter and reading measures correlate with age, which makes it difficult to disentangle the effects of age on the relation of white matter and reading. GAM could a good statistical approach to flexibly model age-related variance. However, it is not clear why age-standardized reading scores are used instead of the raw reading data given that age-variance is accounted for in the statistical analyses? Using raw (not age-corrected) measures for both the brain and the behavioral level and control for age in the statistical analyses would have been a more straightforward approach. Finally, given that data are cross-sectional, the study cannot investigate dynamic relations between white matter and reading across development.
One conclusion of this manuscript is that future studies should use advanced diffusion models, which is based on the finding that FDC correlated with reading while FA did not (Meisler & Gabrieli, 2022 NeuroImage). Although largely the same sample was used, analyses in which the link between FA (tensor-model) and FDC (advanced diffusion models ) is investigated were not performed. Furthermore, comparison of the FA-findings in the previous study (Meisler & Gabrieli, 2022) and FDC in the current study is complicated because different diffusion analyses are performed. More specifically, for FA a tract-based value is derived per subject whereas for FDC a whole brain Fixel-based-analyses is used (with post-hoc tract assignment based on an atlas and not per subject). It is not motivated why the tract-based method for FA is no longer used for FDC in the current study.
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