Fibre-specific laterality of white matter in left and right language dominant people

  1. Helena Verhelst
  2. Thijs Dhollander
  3. Robin Gerrits
  4. Guy Vingerhoets

  • Curated by eLife

    eLife logo

    Summary: The paper tackles an important aspect of neuroanatomical and language research concerning the lateralization differences related to functional lateralization of language. No clear cut results are currently available nowadays and methodological limitations of previous approaches are here addressed with a new angle in the tractography analysis. This is certainly of interest, the methodology is sound and the results deserve to be published. However, as you will see all the reviews highlighted that the novelty of this work both in terms of the methodology and results is somewhat limited, in addition to concerns about the nature of the task used. This makes it seem better suited to a more specialized readership.

Reviewed by

Read the full article See related articles

Discuss this preprint

Start a discussion What are Sciety discussions?

Listed in

Log in to save this article

Abstract

Despite the typical symmetrical appearance of the human brain, several functional and structural asymmetries have been reported. Language is the most commonly described lateralised cognitive function, relying relatively more on the left hemisphere in over 90% of the population. This is in line with white matter studies which have revealed leftwards lateralisation of the arcuate fasciculus, a white matter tract that connects important language-related regions. Most research to date examining the structure-function relationship of language lateralisation only included people showing a left language hemisphere dominance. As such, the reported correlations do not allow for inferences of relationships between the directions of functional and structural lateralisation of language.

In this work, we applied a state-of-the-art “fixel-based” analysis approach, which allows to statistically analyse white matter micro- and macrostructure on a fibre-specific level. To study lateralisation using this framework, we defined a bespoke fibre-specific laterality index which allowed us to examine whole-brain white matter asymmetries in samples of participants with left and right language dominance (LLD and RLD respectively). Both groups showed similar extensive and intricate patterns of significant white matter lateralisation. Few group differences were found between both groups, with a similar leftwards lateralisation of the arcuate fasciculus, regardless of functional language lateralisation of the participants. A significant group difference of lateralisation was detected in the forceps minor, with a leftwards lateralisation in LLD and rightwards lateralisation for the RLD group.

In conclusion, we showed that fixel-based analysis of fibre-specific lateralisation indices is an effective approach to study white matter asymmetries. Our results suggest that the lateralisation of language functioning and the arcuate fasciculus are driven by independent biases. The exact relationship between forceps minor asymmetry and language dominance could be an interesting subject of future studies.

Article activity feed

  1. eLife

    Reviewer #3:

    Verhelst and colleagues presented an interesting work about fibre-specific laterality of white matter in left and right language dominant people. A new fixel-based approach was used. Two main results were reported. First, extensive areas of significant lateralization were found in white matter, and second, a cluster of fixels in the forceps minor showed significant differences between people with the left and right language dominance, but no differences were found in other white matter tracts, including the arcuate fasciculus, which is sometimes considered to be relevant to the language lateralization.

    The authors suggest that the lateralization of language functioning and the arcuate fasciculus are driven by independent biases, and that the relationship between forceps minor asymmetry and language dominance could be of interest.

    1. Arguments against traditional fiber tractography and DTI-derived metrics. I agree with the authors that it is a great advantage of the fixel-based approach to investigate fiber-specific effects. But some arguments in the current paper seem to be misleading, and are not very convincing. For example, The authors wrote that "it has been established that streamline counts from fibre tractography do not represent an appropriate metric to quantify white matter connectivity (Jones et al., 2013)." In some rare cases, this could be correct, but I don't know robust evidence that could support this absolute statement. No empirical data was found in either the present paper or the cited paper, and relevant discussions were mainly on the usage of the term e.g., 'streamline count' and data interpretation. It may be still fair to assume a monotonic relationship between 'streamline counts' and the actual white matter connectivity. The authors may want to further clarify this point.

    A similar problem exists for the argument against DTI-derived metrics. It reads like that we should never use DTI-derived metrics in future studies as 'crossing fibers' widely exist in the brain, and that the DTI model could not provide (as) 'reliable and informative results' (as the fixel-based method). My understanding is that these different approaches/metrics could reflect complementary aspects of white matter fibers. I didn't find relevant data or discussions e.g., about the relationship between DTI-derived metrics and the three metrics in the fixel-based analysis (i.e., FD, FC, and FDC). Actually, if the DTI-derived metrics could reflect unique aspects of white matter, the non-significant results in FD, FC and FDC (e.g., in the arcuate fasciculus) could not simply suggest that no differences in every aspect of one white matter tract. Let alone that there are many other metrics that describe regional properties of white matter. Even so, the authors suggested independent biases repeatedly in the text based on the non-significant results in the arcuate fasciculus.

    In addition, it reads strange that, while traditional approaches were simply considered not useful in the Introduction, in the Discussion the consistency with previous results based on these traditional approaches was used to support the current findings. This makes me curious what unique information we could get from the fixel-based approach. Each metric has its own advantages and limitations. I agree that the fixel-based approach could provide great advantage in describing fiber-specific effects. A fair discussion is better for readers to understand the results.

    1. Arguments against traditional laterality index. The authors spent several paragraphs to support their proposed log-ratio laterality index. Their main point against the traditional laterality index is that the traditional index lacks additivity property. While I agree that the log-ratio is a potential approach for laterality studies, it seems that such an additivity property is not necessary for the laterality index. The main reference cited is an old paper from Tornqvist et al., (1985), which focused on relative changes, rather than laterality. In this reference, a relative change index H is considered as additive if and only if H(z/x) = H(y/x)+H(z/y) in a two-stage change: x-->y-->z. But for laterality study, it seems not to be in this case. Only left (i.e., x) and right (i.e., y) quantities are used for characterizing laterality, but without the third quantity (i.e., z). The additivity property seems to be meaningless in the context of laterality calculation. Further clarification is needed.

    In addition, the authors mentioned that the traditional laterality index is 'bounded and therefore lacks the additivity property'. The authors may want to further explain the reasoning behind this statement.

    Finally, although a non-linear relationship between the log-ratio index and the traditional index was showed in the Appendix X, but within the commonly observed range of laterality effect size (i.e., from -0.5 to 0.5 based on the results from this paper), the relationship is almost linear (see Figure 5). Particularly for the most widely used formula (R-L)/((R+L)/2), the results are almost identical to the log-ratio values. Based on this, I guess that if the authors used this traditional laterality index, they would get exactly the same results.

    The traditional laterality index e.g., (R-L)/((R+L)/2) is widely used, which also makes results comparable across studies. This further makes me doubt the necessity of promoting a new laterality index while it does not provide additional information. Back to the beginning, my comments were based on the assumption that the additivity issue is not a problem for laterality studies. The authors may want to clarify.

  2. eLife

    Reviewer #2:

    Verhelst et al. used a multishell tractography (b-value: 700/1200/2800) fixel-based analysis, to map white matter lateralisations relevant for language dominance in a sample of left-handed healthy volunteers (n=23 right hemisphere dominant and n=38 left hemisphere dominant as per fMRI word generation task). The authors show "lateralisation" in the anterior corpus callosum as the main white matter difference between their two groups.

    While this manuscript is methodologically sound, the lack of novel anatomical, cognitive or clinically-relevant conclusions limits its scope (i.e. the arcuate finding is not novel and the callosal finding is not explained in the context of language dominance). The authors raise several interesting points about the common practice in the field (e.g. calculation of lateralisation index, clinical lesion flipping) and challenge them in this manuscript. But without further in-depth discussion, the current results will not be impactful in the field of clinical-anatomical studies.

    Overall, this study is data-driven methodological rather than hypothesis-driven, which leads to a lack of a rationale in the manuscript or a comprehensive embedding in the white matter literature. For example, it has been previously shown that there is no direct linear relationship between the lateralisation of the arcuate fasciculus and handedness or language dominance (e.g. PMID: 32707542, PMID: 32723129, PMID: 29666567, PMID: 27029050, PMID: 29688293 amongst others). The dataset available in this manuscript is of interest, however, and further analysis should be conducted to study the extended white matter network of language in more depth given the ubiquitous findings of alterations mentioned in the results.

    How did the authors determine the fixel clusters as designated white matter tracts (such as the arcuate, uncinate, etc)?

    The authors praise their fixel-based analysis over the use of previous tensor-based models. Some previous studies have also employed advanced tracking algorithms with varying possibilities to map fibre-specific indices or resolve crossing fibres and their uses have been compared (e.g. PMID: 31106944, PMID: 25682261, PMID: 30113753 amongst others). with the advancement of current algorithms many improvements have been achieved which does not categorically negate previous findings, especially when they were shown to be meaningful for cognitive or clinical applications.

    The authors further discuss the "lateralisation" of the forces minor. This terminology I do have an issue with as this is a commissural connection that cannot per se be lateralized. A difference between both hemispheres can, however, possibly be seen in terms of the asymmetry of the callosal projections. This result needs a lot more explanation and warrants an extensive discussion especially in the light of language processes.

    Overall, the anatomical descriptions should be clearer. For example, when the authors mention the "anterior part of the arcuate fasciculus" do they mean the anterior segment or any frontal lobe projections of this pathway?

  3. eLife

    Reviewer #1:

    The paper tackles an important aspect of neuroanatomical and language research concerning the lateralization differences related to functional lateralization of language. No clear cut results are currently available nowadays and methodological limitations of previous approaches are here addressed with a new type of analysis. Despite this new angle in the tractography analysis is of interest, the differences in the tasks that are used to address language lateralization are also as important. This may also explain possible differences in previous studies and also with the current one. This aspect seems to be missed in this work.

    Although the Letter fluency task implies the use of language, this task is commonly considered in neuropsychological assessments as an executive function task. A more appropriate task would have been a Semantic Fluency task or as in previous work (Vernooij et al 2007) a verb generation task. There is a close relationship between executive function and many aspects of language production, there is not doubt about this. But this does not mean they are the same. Actually the Forceps minor has been found to be associated with individual differences in executive functions in language function (Mamiya et al 2018; Farah et al 2020). This is a limitation of the study and should be acknowledged since the results may differ with a more purely linguistic task, limiting the scope of the study and its conclusions in terms of language lateralization. I do believe the data are worth publishing and the methodological approach is novel but the reader should be clearly aware of the limits in terms of the conclusions the authors can draw from the selection of the sample that may correspond to lateralization of executive function for language more than language lateralization per se.

  4. eLife

    Summary: The paper tackles an important aspect of neuroanatomical and language research concerning the lateralization differences related to functional lateralization of language. No clear cut results are currently available nowadays and methodological limitations of previous approaches are here addressed with a new angle in the tractography analysis. This is certainly of interest, the methodology is sound and the results deserve to be published. However, as you will see all the reviews highlighted that the novelty of this work both in terms of the methodology and results is somewhat limited, in addition to concerns about the nature of the task used. This makes it seem better suited to a more specialized readership.

  5. Version published to 10.1101/2020.08.04.236000 on bioRxiv