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  • Review Article
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Structural MRI of brain similarity networks

Nature Reviews Neuroscience volume 26, pages 42–59 (2025)Cite this article

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Abstract

Recent advances in structural MRI analytics now allow the network organization of individual brains to be comprehensively mapped through the use of the biologically principled metric of anatomical similarity. In this Review, we offer an overview of the measurement and meaning of structural MRI similarity, especially in relation to two key assumptions that often underlie its interpretation: (i) that MRI similarity can be representative of architectonic similarity between cortical areas and (ii) that similar areas are more likely to be axonally connected, as predicted by the homophily principle. We first introduce the historical roots and technical foundations of MRI similarity analysis and compare it with the distinct MRI techniques of structural covariance and tractography analysis. We contextualize this empirical work with two generative models of homophilic networks: an economic model of cost-constrained connectional homophily and a heterochronic model of ontogenetically phased cortical maturation. We then review (i) studies of the genetic and transcriptional architecture of MRI similarity in population-averaged and disorder-specific contexts and (ii) developmental studies of normative cohorts and clinical studies of neurodevelopmental and neurodegenerative disorders. Finally, we prioritize knowledge gaps that must be addressed to consolidate structural MRI similarity as an accessible, valid marker of the architecture and connectivity of an individual brain network.

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Fig. 1: Structural MRI similarity estimation.
Fig. 2: Two key assumptions of structural MRI similarity analysis.
Fig. 3: Organizational properties of the neocortex.
Fig. 4: Frameworks of cortical evolution, maturation and organization.
Fig. 5: Two theories of homophilic network development.
Fig. 6: The genetic and transcriptional basis of structural similarity.

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Author notes

  1. These authors contributed equally: Isaac Sebenius, Lena Dorfschmidt.

Authors and Affiliations

  1. Department of Psychiatry, University of Cambridge, Cambridge, UK

    Isaac Sebenius & Edward Bullmore

  2. Department of Computer Science and Technology, University of Cambridge, Cambridge, UK

    Isaac Sebenius & Sarah E. Morgan

  3. Lifespan Brain Institute, The Children’s Hospital of Philadelphia and Penn Medicine, Philadelphia, PA, USA

    Lena Dorfschmidt, Jakob Seidlitz & Aaron Alexander-Bloch

  4. Department of Child and Adolescent Psychiatry and Behavioral Science, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Lena Dorfschmidt, Jakob Seidlitz & Aaron Alexander-Bloch

  5. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    Lena Dorfschmidt, Jakob Seidlitz & Aaron Alexander-Bloch

  6. Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA

    Jakob Seidlitz

  7. School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK

    Sarah E. Morgan

  8. Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, UK

    Edward Bullmore

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Contributions

I.S., L.D. and E.B. researched data for the article. All authors provided substantial contributions to the discussion of content, wrote the article and reviewed/edited the manuscript before submission.

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Correspondence to Isaac Sebenius or Lena Dorfschmidt.

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Competing interests

E.B. receives consultancy fees from Boehringer Ingelheim, Sosei Heptares, SR One and GlaxoSmithKline and receives royalties from Hachette, Elsevier. E.B., A.A.-B. and J.S. are co-founders of, and hold equity in, Centile Bioscience Inc. I.S., L.D. and S.E.M. declare no competing interests.

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Glossary

Anlagen

Anlagen are initial clusters of embryonic cells, or more generally the foundations of future tissue types that will differentiate with development.

Architectome

Architectome is a representation of the cortical patterning of differentiation, myelination or lamination in terms of inter-areal similarity.

Connectivity

Connectivity in the context of cortical anatomy refers primarily to monosynaptic axonal connections between areas, such as demonstrated by tract-tracing studies in animal models and approximated by structural MRI similarity and DTI-based tractography.

Connectome

Connectome is a representation of connections in the brain in terms of neuronal or white matter connections.

Cytoarchitectonic

Cytoarchitectonics is the study of the cellular composition, clustering and layering of neuronal tissue including, but not limited to, the proportion of different cell types and their orientation in space; historically rooted in microscopic histology.

Heterochronic

Heterochronic refers to differences in timing or duration of developmental or evolutionary processes in different brain regions.

Homophily

Homophily means that structurally similar cortical areas are more likely to be connected than dissimilar areas, and that structurally similar areas are also likely to be similar to each other in terms of functional connectivity, gene co-expression and other aspects of similarity. Homophily has several near-synonyms, including assortativity, clustering and local efficiency in the language of graph theory. Heterophily is the opposite of homophily, meaning that structurally dissimilar cortical areas are more likely to be axonally connected.

Isocortex

Isocortex has been subdivided into three cytoarchitectonically distinct zones of eulaminate cortex, or into functionally differentiated zones of unimodal or heteromodal association cortex.

Lamination

Lamination is the property of grey matter tissue being organized into a series of layers defined by cell composition.

Mesocortex

Mesocortex, including the insular and cingulate gyrus, has been further subdivided into more primitive (peri-allocortical, agranular) and more evolved (pro-isocortical, dysgranular) zones of cortex.

Myeloarchitectonic

Myeloarchitectonic is often used to refer to the layering and density of myelinated axonal fibres in microscopic histological studies of the cortex but can also be used to refer to the macroscopic organization of white matter tracts interconnecting cortical areas.

Similarity

Similarity is estimated as the association, usually correlation or divergence, between two areas in terms of the vector or distribution of one or more structural MRI metrics of geometry or tissue composition measured locally in each area.

Structural model

Structural model links cytoarchitectonic class with connectivity by showing that the probability and type of connection between two cortical areas depend on their cortical type; areas of the same type will likely be connected across all layers of cortex, whereas areas of different types have lamina-specific connections.

Topological similarity

Topological similarity refers to the similarity between two nodes in a network based on the similarity of their connectivity profiles (for example, in terms of nodal network properties).

Transcription

Transcription refers to the cellular process of copying the genetic information stored in a segment of DNA into an RNA copy.

Wiring cost

Wiring cost refers to the biological cost of forming and maintaining axonal connections between cortical areas, which is often approximated by the physical distance of the connection.

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Sebenius, I., Dorfschmidt, L., Seidlitz, J. et al. Structural MRI of brain similarity networks. Nat. Rev. Neurosci. 26, 42–59 (2025). https://doi.org/10.1038/s41583-024-00882-2

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