A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution
Open accessAbstract
To fully understand how the human brain works, knowledge of its structure at high resolution is needed. Presented here is a computationally intensive reconstruction of the ultrastructure of a cubic millimeter of human temporal cortex that was surgically removed to gain access to an underlying epileptic focus. It contains about 57,000 cells, about 230 millimeters of blood vessels, and about 150 million synapses and comprises 1.4 petabytes. Our analysis showed that glia outnumber neurons 2:1, oligodendrocytes were the most common cell, deep layer excitatory neurons could be classified on the basis of dendritic orientation, and among thousands of weak connections to each neuron, there exist rare powerful axonal inputs of up to 50 synapses. Further studies using this resource may bring valuable insights into the mysteries of the human brain.
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Technologies developed for FlyWire have already been applied to millimetre-scale chunks of mammalian brain, which are more than 50 times larger in volume than a fly brain.
“Technologies developed for FlyWire have already been applied to millimetre-scale chunks of mammalian brain4,5, which are more than 50 times larger in volume than a fly brain.”
From Neuronal wiring diagram of an adult brain (2024) · cites this paper as [5]
The Abstract and Methods (Reconstruction Pipeline; no page supplied) describe a cubic-millimetre reconstruction of human cortex using automated segmentation and proofreading tools. The cited paper does not identify those tools as technologies developed for FlyWire, so it supports the mammalian-brain application but not the claimed provenance. The more-than-50-times comparison follows the citations and is not judged as attributed to this source. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGiven the high density of synapses, dendrites, and cellular processes in cortex, even subtle activity-related dendritic-spine "twitching" may alter the diffusion environment of water molecules.
“Given the high density of synapses (8 108/mm3), dendrites (400 m/mm3), and cellular processes in cortex (Shapson-Coe et al., 2024), even subtle activity-related dendritic-spine “twitching” (Crick, 1982) may alter the diffusion environment of water molecules (Halpain, 2000; Le Bihan, 2007).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Shapson-Coe et al., 2024
The Results (Cellular and Synaptic Organization; page unavailable) document abundant synapses and dendritic processes in the reconstructed cortex. But the paper reports about 150 million synapses in an approximately cubic-millimeter sample, not the cited 8 × 10^8/mm³, and the passages do not give 400 m/mm³ of dendrites. The spine movement and water-diffusion suggestion is attributed to other citations in the sentence, not to Shapson-Coe et al. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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Neuronal wiring diagram of an adult brain
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“Technologies developed for FlyWire have already been applied to millimetre-scale chunks of mammalian brain 4,5 , which are more than 50 times larger in volume than a fly brain.”
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Light-microscopy-based connectomic reconstruction of mammalian brain tissue
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Self-citationCAVE: Connectome Annotation Versioning Engine
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Single-transistor organic electrochemical neurons
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A scalable and modular automated pipeline for stitching of large electron microscopy datasets
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NEURD offers automated proofreading and feature extraction for connectomics
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Neuronal diversity and stereotypy at multiple scales through whole brain morphometry
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Single spikes drive sequential propagation and routing of activity in a cortical network
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Perisomatic ultrastructure efficiently classifies cells in mouse cortex
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Fast imaging of millimeter-scale areas with beam deflection transmission electron microscopy
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Microglia contact cerebral vasculature through gaps between astrocyte endfeet
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Rabies virus-based barcoded neuroanatomy resolved by single-cell RNA and in situ sequencing
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Synchrotron X-ray imaging of soft biological tissues – principles, applications and future prospects
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Differential cortical layer engagement during seizure initiation and spread in humans
Bourdillon, P., Ren, L., Halgren, M., Paulk, A. C., Salami, P., Ulbert, I., Fabó, D., King, J.-R., Sjoberg, K. M., Eskandar, E. N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48746-8 · Cited by 20 · see citing works
Oligodendrocyte precursor cells facilitate neuronal lysosome release
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Enabling electric field model of microscopically realistic brain
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A multisynaptic spiking neuron for simultaneously encoding spatiotemporal dynamics
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Amyotrophic lateral sclerosis represents corticomotoneuronal system failure
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Infrequent strong connections constrain connectomic predictions of neuronal function
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Synaptic-resolution connectomics: towards large brains and connectomic screening
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Nondestructive X-ray tomography of brain tissue ultrastructure
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SmartEM: machine learning-guided electron microscopy
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Ultrastructure of precapillary sphincters and the neurovascular unit
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Flamourakis, G., Dong, Q., Kromm, D., Teurlings, S. M. W., van Haren, J., Allertz, T., Smeenk, H., de Vrij, F. M. S., Tas, R. P., Smith, C., et al. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202409451 · Cited by 15 · see citing works
Enabling global image data sharing in the life sciences
Bajcsy, P., Bhattiprolu, S., Börner, K., Cimini, B. A., Collinson, L., Ellenberg, J., Fiolka, R. P., Giger, M. L., Goscinski, W., Hartley, M., et al. (2025) · Nature Methods · doi:10.1038/s41592-024-02585-z · Cited by 15 · see citing works
TriSAM: Tri-Plane SAM for Zero-Shot Cortical Blood Vessel Segmentation in VEM Images
Wan, J., Li, W., Adhinarta, J. K., Banerjee, A., Sjöstedt, E., Wu, J., Lichtman, J. W., Pfister, H., & Wei, D. (2025) · IEEE Journal of Biomedical and Health Informatics · doi:10.1109/jbhi.2025.3577625 · Cited by 15 · see citing works
Self-citationNeuroinflammation and nutrition in Alzheimer’s disease
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Volume electron microscopy analysis of synapses in primary regions of the human cerebral cortex
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Physical Network Constraints Define the Multiplicative Architecture of the Brain’s ConnectomePreprint
Piazza, B., Barabási, D. L., Menichetti, G., Castro, A. F., & Barabási, A.-Ĺ. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.27.640551 · Cited by 14 · see citing works
A connectomic resource for neural cataloguing and circuit dissection of the larval zebrafish brainPreprint
Petkova, M. D., Januszewski, M., Blakely, T. M., Herrera, K. J., Schuhknecht, G. F. P., Tiller, R., Choi, J., Schalek, R. L., Boulanger-Weill, J., Peleg, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.10.658982 · Cited by 14 · see citing works
Self-citationEngineering clinical translation of OGSE diffusion MRI
Zhu, A., Michael, E. S., Li, H., Sprenger, T., Hua, Y., Lee, S., Yeo, D. T. B., McNab, J. A., Hennel, F., Fieremans, E., et al. (2025) · Magnetic Resonance in Medicine · doi:10.1002/mrm.30510 · Cited by 13 · see citing works
Pietramale, A. N., Bame, X., Doty, M. E., Schwarz, K. E., & Hill, R. (2025) · Nature Communications · doi:10.1038/s41467-025-66708-6 · Cited by 15 · see citing works
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Brain-like hardware, do we need it?
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Unveiling universal aspects of the cellular anatomy of the brain
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Self-citationNext-generation AI for connectomics
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Self-citationImaging the structural connectome with hybrid MRI-microscopy tractography
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Programmable Analog Circuits with Neuromorphic Nanostructured Platinum Films
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Scalable Approximation and Solvers for Ionic Electrodiffusion in Cellular Geometries
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Self-citationFAST-EM array tomography: a workflow for multibeam volume electron microscopy
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Plaza‐Alonso, S., Cano‐Astorga, N., DeFelipe, J., & Alonso‐Nanclares, L. (2025) · eLife · doi:10.7554/elife.96144 · Cited by 10 · see citing works
The Many Lives of an Oligodendrocyte Precursor Cell
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Tracing nerve fibers with volume electron microscopy to quantitatively analyze brain connectivity
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Self-citationBrain-wide mapping of oligodendrocyte organization and oligodendrogenesis across the murine lifespanPreprint
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In vivo human neurite exchange time imaging at 500 mT/m diffusion gradients
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Presynapses are mitophagy pit stops that prevent axon degenerationPreprint
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Self-supervised image restoration in coherent X-ray neuronal microscopyPreprint
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Multiple sclerosis: what have we learned and can we still learn from electron microscopy
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Connectivity Structure and Dynamics of Nonlinear Recurrent Neural Networks
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Global Neuron Shape Reasoning with Point Affinity TransformersPreprint
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The cognitive neuroscience of memory representations
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Long-range axon branching: contributions to brain network plasticity and repair
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Spike transmission failures in axons from cortical neurons in vivo
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Phase separation in the multi-compartment organization of synapses
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Bridging macroscopic and microscopic modeling of electric field by brain stimulation
Wang, B., & Aberra, A. S. (2025) · Brain stimulation · doi:10.1016/j.brs.2025.04.009 · Cited by 6 · see citing works
Mesoscale volumetric fluorescence imaging at nanoscale resolution by photochemical sectioning
Wang, W., Ruan, X., Liu, G., Milkie, D. E., Li, W., Betzig, E., Upadhyayula, S., & Gao, R. (2025) · Microscopy and Microanalysis · doi:10.1093/mam/ozag053.398 · Cited by 6 · see citing works
Extensive soma‐soma plate‐like contact sites (ephapses) connect suprachiasmatic nucleus neurons
Czeisler, M. É., Shan, Y., Schalek, R. L., Berger, D. R., Suissa‐Peleg, A., Takahashi, J. S., & Lichtman, J. W. (2024) · The Journal of Comparative Neurology · doi:10.1002/cne.25624 · Cited by 6 · see citing works
Self-citationLenz, M., Kruse, P., Eichler, A., Straehle, J., Hemeling, H., Stöhr, P., Beck, J., & Vlachos, A. (2024) · Brain Communications · doi:10.1093/braincomms/fcae351 · Cited by 5 · see citing works
Yang, Z., Kim, J., Baenen, C. M., Fulton, S. J., Zhang, G., Chen, X., Aronova, M. A., & Leapman, R. D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.16.613321 · Cited by 6 · see citing works
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SegNeuron: 3D Neuron Instance Segmentation in Any EM Volume with a Generalist Model
Zhang, Y.-C. S. L.-G., Guo, J., Zhai, H., Liu, J., & Han, H. (2024) · Lecture notes in computer science · doi:10.1007/978-3-031-72111-3_55 · Cited by 5 · see citing works
Cracking the cadherin codes that wire the nervous system
Gray, M. T., & Lefebvre, J. L. (2025) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2025.103086 · Cited by 5 · see citing works
PyReconstruct: A fully open-source, collaborative successor to Reconstruct
Chirillo, M. A., Falco, J. N., Musslewhite, M. D., Lindsey, L. F., & Harris, K. M. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2505822122 · Cited by 5 · see citing works
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Myelination potential and injury susceptibility of grey versus white matter human oligodendrocytes
Cui, Q., Mohammadnia, A., Yaqubi, M., Weng, C., Dorion, M., Pernin, F., Hall, J. A., Dudley, R., Stratton, J. A., Kennedy, T. E., et al. (2024) · Brain · doi:10.1093/brain/awae311 · Cited by 5 · see citing works
Bridging complexity through integrative systems neuroscience
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- Authors
- Shapson-Coe, A., Januszewski, M., Berger, D. R., Pope, A., Wu, Y., Blakely, T., Schalek, R. L., Li, P. H., Wang, S., Maitin-Shepard, J., Karlupia, N., Dorkenwald, S., Sjostedt, E., Leavitt, L., Lee, D., Troidl, J., Collman, F., Bailey, L., Fitzmaurice, A., Kar, R., Field, B., Wu, H., Wagner-Carena, J., Aley, D., Lau, J., Lin, Z., Wei, D., Pfister, H., Peleg, A., Jain, V., & Lichtman, J. W.
- Affiliations
- Harvard University (US)
- Google (Switzerland) (CH)
- Google (United States) (US)
- Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
- Allen Institute for Brain Science (US)
- Northeastern University (US)
- Boston College (US)
- Corresponding author
- Shapson-Coe, Alexander
- Januszewski, Michał
- Berger, Daniel R.
- Jain, Viren
- Lichtman, Jeff W.
- ORCID
- Shapson-Coe, Alexander
- Januszewski, Michał
- Berger, Daniel R.
- Pope, Art
- Wu, Yuelong
- Blakely, Tim
- Schalek, Richard L.
- Li, Peter H.
- Wang, Shuohong
- Maitin-Shepard, Jeremy
- Karlupia, Neha
- Dorkenwald, Sven
- Leavitt, Laramie
- Troidl, Jakob
- Collman, Forrest
- Bailey, Luke
- Fitzmaurice, Angerica
- Kar, Rohin
- Field, Benjamin
- Wu, Hank
- Wagner-Carena, Julian
- Aley, David
- Lau, Joanna
- Lin, Zudi
- Wei, Donglai
- Pfister, Hanspeter
- Jain, Viren
- Lichtman, Jeff W.
- Venue
- Science
- Published
- 2024-05-10
- Volume
- 384
- Issue
- 6696
- Pages
- eadk4858-eadk4858
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC11718559
- OpenAlex
- W4396780205
- Cited by
- 361
- References
- 82
- Citations by year
- 2026: 123 · 2025: 151 · 2024: 77 · 2023: 6 · 2022: 3 · 2021: 1
- FWCI
- 67.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (2014862, CREST, 2124179)
- Broad Institute
- National Institutes of Health (NS104653)
- Intelligence Advanced Research Projects Activity (D16PC0005, D16PC00004)
- Stanley Center for Psychiatric Research, Broad Institute
- Interior Business Center
- National Institute of Mental Health (P50MH094271, MH094271, UG3MH123386, RF1MH125932)
- National Institute of Neurological Disorders and Stroke (U24NS109102, UM1NS132250, U19NS104653)
- National Institute of Biomedical Imaging and Bioengineering (U01EB026996)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Cell Image Analysis Techniques
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- human cerebral cortex, temporal cortex, synapses, glia, oligodendrocytes, excitatory neurons, dendrite orientation, epileptogenic focus
- MeSH terms
- Axons, Cerebral Cortex, Dendrites, Humans, Microscopy, Neuroglia, Neurons, Oligodendroglia, Synapses, Temporal Lobe
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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