The BigBrainWarp toolbox for integration of BigBrain 3D histology with multimodal neuroimaging

  1. Casey Paquola  Is a corresponding author
  2. Jessica Royer
  3. Lindsay B Lewis
  4. Claude Lepage
  5. Tristan Glatard
  6. Konrad Wagstyl
  7. Jordan DeKraker
  8. Paule-J Toussaint
  9. Sofie L Valk
  10. Louis Collins
  11. Ali R Khan
  12. Katrin Amunts
  13. Alan C Evans
  14. Timo Dickscheid
  15. Boris Bernhardt  Is a corresponding author
  1. McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Canada
  2. Institute of Neuroscience and Medicine (INM-1), Forschungszentrum Jülich, Germany
  3. Department of Computer Science and Software Engineering, Concordia University, Canada
  4. Wellcome Trust Centre for Neuroimaging, University College London, United Kingdom
  5. Brain and Mind Institute, University of Western Ontario, Canada
  6. Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences, Germany
  7. Institute of Neuroscience and Medicine (INM-7), Forschungszentrum Jülich, Germany
  8. Department of Medical Biophysics, Schulich School of Medicine & Dentistry, University of Western Ontario, Canada
7 figures, 3 tables and 1 additional file


Magnification of cytoarchitecture using BigBrain, from (A) whole brain 3D reconstruction (taken on to (B) a histological section at 20 µm resolution (available from to (C) an intracortical staining profile.

The profile represents variations in cellular density and size across cortical depths. Distinctive features of laminar architecture are often observable i.e., a layer IV peak. Note, the presented profile was subjected to smoothing as described in the following section. BigBrainWarp also supports integration of previous research on BigBrain including (D–E) cytoarchitectural and (F–G) morphological models (DeKraker et al., 2019; Paquola et al., 2020a; Paquola et al., 2019; Wagstyl et al., 2020).

Evaluating BigBrain–MRI transformations.

(A) Volume-based transformations. (i) Jacobian determinant of deformation field shown with a sagittal slice and stratified by lobe. Subcortical+ includes the shape priors (as described in Materials and methods) and the+ connotes hippocampus, which is allocortical. Lobe labels were defined based on assignment of CerebrA atlas labels (Manera et al., 2020) to each lobe. (ii) Sagittal slices illustrate the overlap of native ICBM2009b and transformed subcortical+ labels. (iii) Superior view of anatomical fiducials (Lau et al., 2019). (iv) Violin plots show the Dice coefficient of regional overlap (ii) and landmark misregistration (iii) for the BigBrainSym and Xiao et al., approaches. Higher Dice coefficients shown improved registration of subcortical+ regions with Xiao et al., while distributions of landmark misregistration indicate similar performance for alignment of anatomical fiducials. (B) Surface-based transformations. (i) Inflated BigBrain surface projections and ridgeplots illustrate regional variation in the distortions of the mesh invoked by the modified MSMsulc+ curv pipeline. (ii) Eighteen anatomical landmarks shown on the inflated BigBrain surface (above) and inflated fsaverage (below). BigBrain landmarks were transformed to fsaverage using the modified MSMsulc+ curv pipeline. Accuracy of the transformation was calculated on fsaverage as the geodesic distance between landmarks transformed from BigBrain and the native fsaverage landmarks. (iii) Sulcal depth and curvature maps are shown on inflated BigBrain surface. Violin plots show the improved accuracy of the transformation using the modified MSMsulc+ curv pipeline, compared to a standard MSMsulc approach.

Overview of spaces and transformations included within BigBrainWarp.

(A) The flow chart illustrates the extant transformation procedures that are wrapped in by the bigbrainwarp function. (B) Arrows indicate the transformations possible using the bigbrainwarp function. The colours, matched to C, reflect distinct functions called within BigBrainWarp. (C) The combination of input type, input template, and output type determines the function called by BigBrainWarp.

Intrinsic functional connectivity of the iso-to-allocortical axis of the mesiotemporal lobe.

(A) i. BigBrain surface models of the isocortex and hippocampal subfields are projected on a 40 µm resolution coronal slice of BigBrain. (ii–iii) The continuous surface model bridges the inner hippocampal vertices with pial mesiotemporal vertices (entorhinal, parahippocampal or fusiform cortex). Vertices at the medial aspect of the subiculum were identified as bridgeheads and used to bridge between the two surface constructions. Geodesic distance from the nearest bridgehead was used as the iso-to-allocortical axis. (B) Iso-to-allocortical axis values were projected from the surface into the BigBrain volume, then transformed to ICBM2009sym using BigBrainWarp. (C) Intrinsic functional connectivity was calculated between each voxel of the iso-to-allocortical axis and 1000 isocortical parcels. For each parcel, we calculated the product-moment correlation (r) of rsFC strength with iso-to-allocortical axis position. Thus, positive values (red) indicates that rsFC of that isocortical parcel with the mesiotemporal lobe increases along the iso-to-allocortex axis, whereas negative values (blue) indicate decrease in rsFC along the iso-to-allocortex axis.

Concordance of imaging-derived effects with histological gradients.

(A) Four stages of histological gradient construction. (i) Vertex-wise staining intensity profiles (dotted lines) are averaged within parcels (solid lines). Colours represent different parcels. (ii) Pair-wise partial correlation of parcel-average staining intensity profiles produces a cortex-wide matrix of cytoarchitectural similarity. (iii) The correlation matrix is subjected to dimensionality reduction, in this case diffusion map embedding, to extract the eigenvectors of cytoarchitectural variation. (iv) The eigenvectors capture histological gradients (Hist-G) and are projected onto the BigBrain cortical surface for inspection. (B) The t-statistic cortical map illustrates regional variations in the effect of age on Aβ deposition (Lowe et al., 2019), which was calculated vertex-wise on fsaverage5. To allow comparison, histological gradients were transformed to fsaverage5 using BigBrainWarp. Scatterplots show the association of the t-statistic map with the histological gradients. (C) Bar plot shows the Bayesian Information Criterion of univariate and multivariate regression models, using histological gradients to prediction regional variation in effect of age on Aβ deposition. The univariate Hist-G2 regression had the lowest Bayesian Information Criterion, representing the optimal model of those tested.

Prediction of functional network by cytoarchitecture.

(A) Surface-based transformation of 17-network functional atlas to the BigBrain surface, operationalised with BigBrainWarp, allows staining intensity profiles to be stratified by functional network. (B) Ridgeplots show the moment-based parameterisation of staining intensity profiles within each functional network. The confusion matrix illustrates the outcome of mutli-class classification of the functional networks, using the central moment of the staining intensity profiles.

Appendix 1—figure 1
Influence of sampling parameters on staining intensity profiles.

(A) Line plots show how the shape of an exemplar profile is changed by various sampling parameters. Far left is the raw profile constructed with 50 surfaces. Centre left are raw profiles constructed with 50–100 surfaces. Centre right are profiles (constructed with 50 surfaces) and subjected to varied levels of depth-wise smoothing. Far right are profiles (constructed with 50 surfaces and subjected to 10 iterations of depthwise smoothing) with varied levels of surface-wise smoothing. (B) Influence of sampling parameters was evaluated based on spatial autocorrelation and number of peaks. (i–ii) The spatial autocorrelation was defined by the number of steps between two vertices on the mesh, as depicted for an example vertex in (i). Then, we calculated the product-moment correlation between all staining intensity profiles and averaged these values based on the relative distance between vertices. The line plot show a decrease in correlation with increasing distance, attributable to spatial autocorrelation. (iii) The number of peaks was calculated to assess the jaggedness the staining intensity profile. (C) Using the lowest iteration of a sampling parameter as a baseline, we 31 calculated the product-moment correlation of profile features (spatial autocorrelation or number of peaks) with increases in the sampling parameter. In other words, the graph shows the similarity of solutions to the baseline sampling parameters. We found that the surface-wise smoothing impacts the spatial autocorrelation and number of peaks, while the number of surfaces and depthwise smoothing have little-to-no effect on spatial autocorrelation and a small effect on number of peaks. (D) For varying degrees of depth-wise (rows) and surface-wise (columns) smoothing, line plots show spatial autocorrelation and histograms show the distribution of number of peaks across profiles.


Table 1
Surface constructions for BigBrain.
Grey and whiteInitialisation and visualisationLewis et al., 2014
Layer 1/2 and layer 4Boundary conditionsWagstyl et al., 2018a
EquivolumetricStaining intensity profilesWaehnert et al., 2014
Deep learning laminarLaminar thicknessWagstyl et al., 2020
HippocampalInitialisation and visualisationDeKraker et al., 2019
Mesiotemporal confluenceInitialisation and visualisationPaquola et al., 2020a
  1. Note: Initialisation broadly refers to an input for feature generation, for example creation of staining intensity profiles or surface transformations.

Table 2
Input parameters for the bigbrainwarp function.
in_spaceSpace of input dataRequiredbigbrain, bigbrainsym, icbm, fsaverage, fs_LR
out_spaceSpace of output dataRequiredbigbrain, bigbrainsym, icbm, fsaverage, fs_LR
wdPath to working directoryRequired
descPrefix for output filesRequired
in_volFull path to input data, whole brain volume.Requires either in_vol, or in_lh and in_rhPermitted formats: mnc, nii or nii.gz
ih_lhFull path to input data, left hemisphere surfacePermitted formats: label.gii, annot, shape.gii, curv or txt
ih_rhFull path to input data, right hemisphere surface
interpInterpolation methodRequired for in_vol. Optional for txt input. Not permitted for other surface inputs.For in_vol, can be trilinear (default), tricubic, nearest or sinc.For txt, can be linear or nearest
out_typeSpecifies whether output in surface or volume spaceOptional function for bigbrain, bigbrainsym and icbm output. Defaults to the same type as the input.surface, volume
out_resResolution of output volumeOptional where out_type is volume. Default is 1Value provided in mm
out_denDensity of output meshOptional where out_type is surface. Default is 164For fs_LR out_space, 164 or 32
  1. Note: the options are subject to change as the toolbox is expanded. Updates will be posted on

Table 3
BigBrainWarp contents.
DataDefinitionOriginal spaceTransformed spaces
ProfilesStaining intensity profiles, sampled at each vertex and across 50 equivolumetric surfacesBigBrainfsaverage, fs_LR (164 k and 32 k)
WhiteGrey/white matter boundaryBigBrain, fsaverage, fs_LR
SphereSpherical representation of surface meshBigBrain, fsaverage, fs_LR
ConfluenceContinuous surface that includes isocortex and allocortex (hippocampus) from Paquola et al., 2020aBigBrain
Histological gradientsFirst two eigenvectors of cytoarchitectural differentiation derived from BigBrainBigBrainfsaverage, fs_LR (164 k and 32 k), icbm
Microstructural gradientsFirst two eigenvector of microstructural differentiation derived from quantitative in-vivo T1 imagingfsaverageBigBrain,
Functional gradientsFirst three eigenvectors of functional differentiation derived from rs-fMRIfsaverageBigBrain
Seven functional networksSeven functional networks from Yeo et al., 2011fsaverageBigBrain
17 Functional networks17 Functional networks from Yeo et al., 2011fsaverageBigBrain, icbm
Layer thicknessLayer thicknesses estimated from Wagstyl et al., 2020BigBrainfsaverage, fs_LR (164 k and 32 k)
  1. Note: Datasets Are Named According to BIDS and Align with Recommendations From TemplateFlow (Ciric et al., 2021).

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  1. Casey Paquola
  2. Jessica Royer
  3. Lindsay B Lewis
  4. Claude Lepage
  5. Tristan Glatard
  6. Konrad Wagstyl
  7. Jordan DeKraker
  8. Paule-J Toussaint
  9. Sofie L Valk
  10. Louis Collins
  11. Ali R Khan
  12. Katrin Amunts
  13. Alan C Evans
  14. Timo Dickscheid
  15. Boris Bernhardt
The BigBrainWarp toolbox for integration of BigBrain 3D histology with multimodal neuroimaging
eLife 10:e70119.