Reconstructing the human brain's wiring diagram from axons up

Sarah R Heilbronner; R Clay Reid; Tanya K Casta; Franco Pestilli

doi:10.1016/j.tins.2025.11.001

Reconstructing the human brain's wiring diagram from axons up

Trends Neurosci. 2025 Dec 1:S0166-2236(25)00238-3. doi: 10.1016/j.tins.2025.11.001. Online ahead of print.

Authors

Sarah R Heilbronner¹, R Clay Reid², Tanya K Casta³, Franco Pestilli⁴

Affiliations

¹ Departments of Neurosurgery and Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Electrical and Computer Engineering and Neuroengineering Initiative, Rice University, Houston, TX 77005, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: sarah.heilbronner@bcm.edu.
² Allen Institute for Brain Science, Seattle, WA 98109, USA.
³ Departments of Neurosurgery and Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Psychology, Department of Neuroscience, Center for Perceptual Systems, Center for Learning and Memory, University of Texas at Austin, Austin, TX 78712, USA.

PMID: 41330839
PMCID: PMC12695016 (available on 2026-12-01)
DOI: 10.1016/j.tins.2025.11.001

Abstract

The human brain's long-range axonal connections are the scaffolding for communication across functionally distinct areas. Yet knowledge of the human brain's wiring diagram remains limited, largely due to longstanding technological challenges. Recent innovations in microscopy may now enable mapping human brain connectivity at the mesoscale (groups of neurons and their axons). In this review we describe the challenges of generating the wiring diagrams of the human brain, avenues forward, and reasons why such an effort is so important. We argue for building a human mesoscale connectome via a multimodal, multi-species, axon-centric approach, focusing on where axons begin and end to reconstruct connectivity across spatial resolutions. Finally, we consider the utility of a potential exemplar connectome for both clinical applications and research.

Keywords: connectome; diffusion MRI; neuroanatomy; tract-tracing; tractography.

Publication types

Review

Abstract

Publication types

Grants and funding