Topographic organization of the human subcortex unveiled with functional connectivity gradients

Abstract

Brain atlases are fundamental to understanding the topographic organization of the human brain, yet many contemporary human atlases cover only the cerebral cortex, leaving the subcortex a terra incognita. We use functional MRI (fMRI) to map the complex topographic organization of the human subcortex, revealing large-scale connectivity gradients and new areal boundaries. We unveil four scales of subcortical organization that recapitulate well-known anatomical nuclei at the coarsest scale and delineate 27 new bilateral regions at the finest. Ultrahigh field strength fMRI corroborates and extends this organizational structure, enabling the delineation of finer subdivisions of the hippocampus and the amygdala, while task-evoked fMRI reveals a subtle subcortical reorganization in response to changing cognitive demands. A new subcortical atlas is delineated, personalized to represent individual differences and used to uncover reproducible brain–behavior relationships. Linking cortical networks to subcortical regions recapitulates a task-positive to task-negative axis. This new atlas enables holistic connectome mapping and characterization of cortico–subcortical connectivity.

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Fig. 1: Gradientography in the human subcortex.
Fig. 2: Model selection: which gradient magnitude peaks are sufficiently large to warrant boundary delineation?
Fig. 3: A multiscale group-consensus parcellation atlas derived from 3T-rfMRI acquired in 1,080 healthy adults.
Fig. 4: Organization of the human subcortex.
Fig. 5: Parcellation homogeneity.
Fig. 6: Replication of 3T parcellation using 7T-rfMRI.
Fig. 7: Personalization of the scale IV atlas.
Fig. 8: Associations between individual variation in behavioral dimensions and subcortical functional connectivity.

Data availability

Neuroimaging data analyses were undertaken using publicly available human neuroimaging datasets acquired and maintained by the HCP18. These datasets are available for download to anyone agreeing to the Open Access Data Use Terms (https://db.humanconnectome.org/). Access to family structure data and several behavioral measures requires acceptance of the HCP Restricted Data Use Terms (https://www.humanconnectome.org/study/hcp-young-adult/document/restricted-data-usage). The independent validation dataset used to assess the reproducibility of the parcellation homogeneity results is currently not publicly available. The new atlas is openly available in the form of NIFTI (Neuroimaging Informatics Technology Initiative) and CIFTI (Connectivity Informatics Technology Initiative) files. To facilitate mapping of whole-brain connectomes, we have also integrated the new atlas into several well-known cortex-only parcellation atlases and the combined cortex–subcortex atlases are made openly available. Supplementary Table 5 provides details about the atlas formats that can be downloaded from the GitHub repository (https://github.com/yetianmed/subcortex).

Code availability

The Matlab (R2018b) codes to compute Laplacian eigenmaps, gradient magnitudes, diversity curves and other computational analyses undertaken as part of this study are openly available at https://github.com/yetianmed/subcortex. The following additional software packages used for this study are freely and openly available: Diffusion Toolkit (v.0.6.4.1) and TrackVis (v.0.6.1): http://trackvis.org/; NBS (v.1.2): https://www.nitrc.org/projects/nbs/; Icasso (v.1.21): https://research.ics.aalto.fi/ica/icasso/; NeuroMArVL: https://immersive.erc.monash.edu/neuromarvl/; PALM (v.alpha116): https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/PALM/ExchangeabilityBlocks; and fMRIPrep (v.1.5.9): https://fmriprep.org/en/stable/index.html.

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Acknowledgements

We thank M. Glasser (Washington University) for provision of the Wishart filter code. We thank L. Cocchi (QIMR Berghofer Medical Research Institute) for provision of the additional validation dataset. All other data were provided by the HCP, the WU–Minn Consortium (1U54MH091657; Principal Investigators: D. Van Essen and K. Ugurbil) funded by the 16 National Institutes of Health (NIH) institutes and centers that support the NIH Blueprint for Neuroscience Research, and by the McDonnell Center for Systems Neuroscience at Washington University. Y.T. was supported by a NHMRC Project Grant awarded to A.Z. (APP1142801). M.B. and A.Z. were each supported by research fellowships from the NHMRC (APP1136649 and APP1118153, respectively).

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Y.T. and A.Z. conceived the idea and designed the study. Y.T. compiled the data, performed the analyses and prepared the visualizations. Y.T. and A.Z. drafted the manuscript. D.S.M. and M.B. provided critical conceptual input. All authors provided critical feedback and editing of the final manuscript. A.Z. supervised the research.

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Correspondence to Ye Tian or Andrew Zalesky.

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Peer review information Nature Neuroscience thanks Janine Bijsterbosch, Rodrigo Braga and Evan Gordon for their contribution to the peer review of this work.

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Tian, Y., Margulies, D.S., Breakspear, M. et al. Topographic organization of the human subcortex unveiled with functional connectivity gradients. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-00711-6

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