Tracing the development and lifespan change of population-level structural asymmetry in the cerebral cortex
Curation statements for this article:-
Curated by eLife
eLife assessment
Roe et al. provide a large-sample analysis of hemispheric lateralisation in brain structure, synthesising local cortical thickness and surface area data from 7 different datasets. The study provides a rich descriptive catalogue of phenomena related to hemispheric anatomical asymmetries. These results are convincing and will prove an important point of reference to neuroscientists who might want to compare their own future results to the ones from this large and varied data set.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
- Neuroscience (eLife)
Abstract
Cortical asymmetry is a ubiquitous feature of brain organization that is subtly altered in some neurodevelopmental disorders, yet we lack knowledge of how its development proceeds across life in health. Achieving consensus on the precise cortical asymmetries in humans is necessary to uncover the developmental timing of asymmetry and the extent to which it arises through genetic and later influences in childhood. Here, we delineate population-level asymmetry in cortical thickness and surface area vertex-wise in seven datasets and chart asymmetry trajectories longitudinally across life (4–89 years; observations = 3937; 70% longitudinal). We find replicable asymmetry interrelationships, heritability maps, and test asymmetry associations in large–scale data. Cortical asymmetry was robust across datasets. Whereas areal asymmetry is predominantly stable across life, thickness asymmetry grows in childhood and peaks in early adulthood. Areal asymmetry is low-moderately heritable (max h 2 SNP ~19%) and correlates phenotypically and genetically in specific regions, indicating coordinated development of asymmetries partly through genes. In contrast, thickness asymmetry is globally interrelated across the cortex in a pattern suggesting highly left-lateralized individuals tend towards left-lateralization also in population-level right-asymmetric regions (and vice versa), and exhibits low or absent heritability. We find less areal asymmetry in the most consistently lateralized region in humans associates with subtly lower cognitive ability, and confirm small handedness and sex effects. Results suggest areal asymmetry is developmentally stable and arises early in life through genetic but mainly subject-specific stochastic effects, whereas childhood developmental growth shapes thickness asymmetry and may lead to directional variability of global thickness lateralization in the population.
Article activity feed
-
-
Author Response
Reviewer #1 (Public Review):
In the current work, the authors aimed to investigate the genetic and non-genetic factors that impact structural asymmetry.
A major strength is the number of data samples included in the study to assess brain structural asymmetry. A consequence of the inclusion of many samples is then also the sample size.
We thank the reviewer for their supportive and insightful comments that have helped improve our paper.
Comment #1: Given that the authors also work with longitudinal data, it would be nice to be able to appreciate the individual effects across time points, this is now a little unclear.
Our lifespan analysis incorporated both single and repeat measures over time in the trajectory estimation, and hence these will be an intermediate estimate of cross-sectional and longitudinal …
Author Response
Reviewer #1 (Public Review):
In the current work, the authors aimed to investigate the genetic and non-genetic factors that impact structural asymmetry.
A major strength is the number of data samples included in the study to assess brain structural asymmetry. A consequence of the inclusion of many samples is then also the sample size.
We thank the reviewer for their supportive and insightful comments that have helped improve our paper.
Comment #1: Given that the authors also work with longitudinal data, it would be nice to be able to appreciate the individual effects across time points, this is now a little unclear.
Our lifespan analysis incorporated both single and repeat measures over time in the trajectory estimation, and hence these will be an intermediate estimate of cross-sectional and longitudinal trajectories. We have clarified this in the Methods (see 1). A comprehensive analysis of the individual-specific asymmetry change effects in the current paper is thus hindered by many properties of the data, including that many participants contribute a single measure, that participants vary in their number of repeat-measures (1-6 timepoints), that the number of repeat-measures is dependent on age, and that the degree of asymmetry change differs between cortical metrics, clusters, and along the age variable. Most importantly, the average degree of asymmetry change is small; Fig. 3 indicates thickness asymmetry typically corresponds to a ~0.1 - 0.2mm difference, such that changes therein will be smaller and thus likely unclear at the individual level. Nevertheless, we have modified the average plots in Figures 2 and 3 to allow better visualization of the individual hemispheric measures across timepoints, as well as an appreciation of the density of our longitudinal data.
1 – (line 646) “GAMMs incorporate both single and repeat measures over time to capture nonlinearity of the mean level trajectories across persons, resulting in population estimates that are intermediate between cross-sectional and longitudinal trajectories”
Comment #2: A possible less well-developed approach is the genetic basis, as this was stated as the main question, here the investigations are not that deep and may only touch upon the question.
We agree the previous formulation of our Abstract did convey this impression, and have thus made the following important amendment:
(Abstract) “Cortical asymmetry is a ubiquitous feature of brain organization that is subtly altered in some neurodevelopmental disorders, yet we lack knowledge of how its development proceeds across life in health. Achieving consensus on the precise cortical asymmetries in humans is necessary to uncover the developmental timing of asymmetry and extent to which it arises through genetic or later influences in childhood.”
Our paper aims to serve as a critical reference for the normative childhood development and lifespan change of cortical asymmetry. We performed heritability analyses as they are informative regarding development and shed light on the timing of influences shaping cortical asymmetry (also possibly prior to age ~4 at which our sample starts). Similarly, genetic correlation analysis sheds light on whether the replicable interregional correlations are underpinned by genetic differences, indicative of coordinated genetic development of asymmetries. We apologize the rationale behind these analyses was not well-specified, and have clarified this (see response #4). Thus, we respectfully disagree the genetic aspect represented the main research question, but rather lends support to our developmental perspective.
Given the density of analyses already included and that these are well-specified within the context of our overarching question, we do not see how adding more genetic analyses will be beneficial for our paper. However, we agree with the Reviewer’s subsequent comment (#8) that the genetic correlations in HCP data should also have been reported, and now incorporate these (see response #8).
Comment #3: Moreover, the association with cognition, handedness, sex, and ICV is somewhat interesting yet seems also a bit minimal to fully grasp its implications.
In the asymmetry field it has been commonplace to assume these factors are strongly related to asymmetry, particularly sex. Here, despite optimizing the delineation of asymmetries, associations with factors purportedly related to it were all very small. We believe this is an important message that may help reorient the field away from entrenched views; unless we show it is not the case, researchers may think the effects of these factors are larger than they are. Further, because questions pertaining to sex and handedness differences will certainly arise for many, we chose to address them by quantifying the average effects in big data, because our lifespan trajectory analysis was not well-suited to assessing e.g. sex differences in asymmetry trajectories (i.e. 3-way non-linear interactions; sexagehemisphere). We have strengthened the reasoning for this analysis in the Introduction (see 1):
1 – (line 118) “Therefore, as a final step, we reasoned that combining an optimal delineation of population-level cortical asymmetries with big data would optimize detection and quantification of the effects of factors commonly assumed important for asymmetry, namely general cognitive ability, handedness and sex.”
Contrary to approaches that often place emphasis on p-values (e.g. pheWAS), our targeted approach using variables long considered important for asymmetry enabled transparent reporting of the effect sizes and directions. We hope the Reviewer agrees we have taken care in this regard, and are careful to communicate the found effects are small. The small effects seem typical of structural brain associations in big data, as may be expected when relating complex phenotypes to any single structural measure. For these reasons, we opt not to extend the analysis beyond our initial targeted approach, arguing instead that the size of the effects is reason enough to report them.
Despite being small, however, we argue they are not negligible (see 2-4). Of note, though it may appear so in Fig. 7, the p-value for the cognitive association was far from just surviving Bonferroni correction (it would survive >13,000 comparisons at our alpha level [⍺=.01], whereas we corrected for our 136). Note we did not accept a 5% false positive rate. We have clarified this in the Results (see 5):
2 – (line 485) “Other factors commonly espoused to be important for asymmetry were associated with only small average effects in adults. For example, we found one region – SMG/perisylvian – wherein higher leftward areal asymmetry related to subtly higher cognitive ability. Since interhemispheric anatomy here is likely related to brain torque 2,3, this may agree with work suggesting torque relates to cognitive outcomes 4,5. Interestingly, that ~94% of humans exhibit leftward asymmetry in this region (Figure 1G) suggests tightly regulated genetic-developmental programs control its lateralized direction in humans (see Figure 6). This result may therefore suggest disruptions in areal lateralization early in life are associated with cognitive deficits detectable in later life as small effects in big data 6. While speculative, this may also agree with evidence that differences in general cognitive ability that show high lifespan stability 6 relate primarily to areal phenotypes formed early in life 7–9.”
3 – (line 461) “We also found areal asymmetry in anterior insula is, to our knowledge, the most heritable asymmetry yet reported with genomic methods 10–14, with common SNPs explaining ~19% variance. This is notably higher than in our recent report (< 5%) 14, illustrating a benefit of our approach. As we reported recently 14, we confirm asymmetry here associates with handedness.”
4 - (line 495) “Consistent with our recent analysis in UKB 14, we confirmed leftward areal asymmetry of anterior insula, and leftward somatosensory thickness asymmetry is subtly reduced in left-handers. Sha et al. 14 reported shared genetic influences upon handedness and asymmetry in anterior insula and other more focal regions. Anterior insula lies within a left-lateralized functional language network 15, and its structural asymmetry may relate to language lateralization 16–18 in which left-handers show increased atypicality 19–21. Since asymmetry here emerges early in utero 22 and is by far the most heritable (Figure 6), we agree with others 16 that this ontogenetically foundational region of cortex may be fruitful for understanding genetic-developmental mechanisms influencing laterality 23,24. Less leftward somatosensory thickness asymmetry in left-handers also echoes our recent report 14 and fits a scenario whereby thickness asymmetries may be partly shaped through use-dependent plasticity and detectable through group-level hemispheric specializations of function. Still, the small effects show cortical asymmetry cannot predict individual handedness. Associations with other factors typically assumed important were similarly small, and mostly compatible with the ENIGMA report 25 and elsewhere 26,27. 5 - (line 3221) ”Although small, we note this association was far from only just surviving correction at our predefined alpha level (⍺ = .01; corrected for 136 tests; Methods).”
6 - (line 348) “we … uncover novel and confirm previously-reported associations with factors purportedly related to asymmetry – all with small effects”
Thus, in quantifying effects we could not include in our lifespan analysis we preempt the questions likely to arise for many researchers, provide a sobering account of the effect sizes of factors typically assumed important for asymmetry, and find results that fit the developmental framework we lay out in the paper. We therefore opt to keep these together with the lifespan and heritability results in the current paper.
Comment #4: To some extent, the aim of the study could still be written with more clarity. However, the authors have in part achieved their aims - assuming it is found a consensus on the brain asymmetry patterns in humans as is stated in the abstract.
Alongside the amendment to the Abstract that better clarifies our aims (response #2), we have restated the aims in the Introduction:
1 - (line 121) Here, we first aimed to delineate population-level cortical areal and thickness asymmetries using vertex-wise analyses and their overlap in 7 international datasets. With a view to gaining insight into cortical asymmetry development, we then aimed to trace a series of lifespan and genetic analyses. Specifically, we chart the developmental and lifespan trajectories of cortical asymmetry for the first time longitudinally across the lifespan. Next, we examine phenotypic interregional asymmetry correlations, under the assumption correlations indicate coordinated development of left-right asymmetries through genes or lifespan influences. To shed light on the extent to which differences in asymmetry are genetic, we test heritability of asymmetry using genome-wide single nucleotide polymorphism (SNP) and extended twin data, and examine whether or not phenotypic associations are underpinned by genetic correlations suggestive of coordinated development through genes. Finally, we screen our set of robust, population-level asymmetries for association with general cognitive ability and factors purportedly related to asymmetry in UK Biobank (UKB). 28
Comment #5: Overall the results support the conclusions, yet the strong interpretation of early life factors in particular is not empirically investigated as far as I gather.
The reviewer is correct that we do not have data on neonates to directly support interpretations of prenatal factors. We have therefore tempered strong interpretations pertaining to prenatal accounts accordingly, have added text at the start of the Discussion to address this (see 1), and qualified all discussion of prenatal factors:
1 – (line 366) “Tracing their lifespan development, we show the trajectories of areal asymmetry primarily suggest this form of asymmetry is developmentally stable at least from age ~4, maintained throughout life, and formed early on – possibly in utero 13,29,30 (while we cannot extrapolate to ages before our sample begins, we note this agrees with findings in neonates 29,30). One interpretation of lifespan stability combined with low heritability may be stochastic early-life developmental influences determine individual differences in areal asymmetry more than later developmental change, but work linking prenatal and childhood trajectories is needed to affirm this”
2 – (Abstract) “Results suggest areal asymmetry is developmentally stable and arises early in life through genetic but mainly subject-specific stochastic effects”
We have also added argumentation regarding a just-published study suggesting the average pattern of neonatal areal asymmetry is largely similar to adults 1. In addition, we reiterate what our data can and cannot say about the developmental timing of asymmetry in several places in the Discussion (see 3 & 5). In other places, we have removed reference to prenatal factors (see 4). Still, while we agree we previously used the terms “prenatal” and “early life factors” interchangeably, we note the latter often encompasses periods of early childhood covered here and is not necessarily restricted to factors present at birth 2,3. Thus, we have amended the Discussion to qualify the age-range the interpretation pertains to (see 5), and then retain the conclusion as follows (see 6).
3 - (line 383) “For areal asymmetry, adult-like patterns of lateralization were strongly established before age ~4, indicating areal asymmetry traces back further and does not primarily emerge through later cortical expansion 33. Rather, the lifespan trajectories predominantly show stability from childhood to old age, as asymmetry was maintained through periods of developmental expansion and aging-related change that were region-specific and bilateral. This may align with evidence indicating areal asymmetry may be primarily determined in utero 29,30, including evidence suggesting little change in areal asymmetry from birth to 2 years 29,33,34, and little difference between maps derived from neonates and adults 29,30. It may also fit with the principle that the primary microstructural basis of cortical area 8 – the number of and spacing between cortical minicolumns – is determined in prenatal life 8,9, and agree with work suggesting asymmetry at this microstructural level may underly hemispheric differences in surface area 35. The developmental trajectories agree with studies indicating areal asymmetry is established and strongly directional early in life 29,36. That change in surface area later in development follows embryonic gene expression gradients may also agree with a prenatal account for areal asymmetry 9”
4 - (line 439) “The strongest relationships all pertained to asymmetries that were proximal in cortex but opposite in direction. Several of these were underpinned by high asymmetry-asymmetry SNP-based genetic correlations, illustrating some lateralizations in surface area exhibit coordinated genetic development.”
5 - (line 481) “Regardless, these results support a differentiation between early-life (i.e. before age ~4) and later developmental factors in shaping areal and thickness asymmetry, respectively.”
6 - (Conclusion) “Developmental and lifespan trajectories, interregional correlations and heritability analyses converge upon a differentiation between early-life and later-developmental factors underlying the formation of areal and thickness asymmetries, respectively. By revealing hitherto unknown principles of developmental stability and change underlying diverse aspects of cortical asymmetry, we here advance knowledge of normal human brain development.”
Overall this is a nice and thorough work on asymmetry that may inform further work on brain asymmetry, its genetic basis, development, environmentally induced change, and link to behavioural variation.
-
eLife assessment
Roe et al. provide a large-sample analysis of hemispheric lateralisation in brain structure, synthesising local cortical thickness and surface area data from 7 different datasets. The study provides a rich descriptive catalogue of phenomena related to hemispheric anatomical asymmetries. These results are convincing and will prove an important point of reference to neuroscientists who might want to compare their own future results to the ones from this large and varied data set.
-
Reviewer #1 (Public Review):
In the current work, the authors aimed to investigate the genetic and non-genetic factors that impact structural asymmetry.
A major strength is the number of data samples included in the study to assess brain structural asymmetry. A consequence of the inclusion of many samples is then also the sample size. Given that the authors also work with longitudinal data, it would be nice to be able to appreciate the individual effects across time points, this is now a little unclear. A possible less well-developed approach is the genetic basis, as this was stated as the main question, here the investigations are not that deep and may only touch upon the question. Moreover, the association with cognition, handedness, sex, and ICV is somewhat interesting yet seems also a bit minimal to fully grasp its implications.
To …
Reviewer #1 (Public Review):
In the current work, the authors aimed to investigate the genetic and non-genetic factors that impact structural asymmetry.
A major strength is the number of data samples included in the study to assess brain structural asymmetry. A consequence of the inclusion of many samples is then also the sample size. Given that the authors also work with longitudinal data, it would be nice to be able to appreciate the individual effects across time points, this is now a little unclear. A possible less well-developed approach is the genetic basis, as this was stated as the main question, here the investigations are not that deep and may only touch upon the question. Moreover, the association with cognition, handedness, sex, and ICV is somewhat interesting yet seems also a bit minimal to fully grasp its implications.
To some extent, the aim of the study could still be written with more clarity. However, the authors have in part achieved their aims - assuming it is found a consensus on the brain asymmetry patterns in humans as is stated in the abstract. Overall the results support the conclusions, yet the strong interpretation of early life factors in particular is not empirically investigated as far as I gather.
Overall this is a nice and thorough work on asymmetry that may inform further work on brain asymmetry, its genetic basis, development, environmentally induced change, and link to behavioural variation.
-
-
-
-