Most Detailed 3D Reconstruction of Human Brain Tissue Ever Produced Yields Surprising Insights

The NIH Brain Research Through Advancing Innovative Neurotechnologies ? (BRAIN) Initiative has expanded scientists’ understanding of the human brain in recent years, offering fascinating insights into the ways that individual cells and complex neural circuits interact dynamically to enable us to think, feel, and act. But neuroscientists still have much more to learn about how our brains are put together at the most fundamental, subcellular level. ?

As a step in that direction, in a new study supported in part by the NIH BRAIN Initiative and reported in the journal Science , researchers have created the most detailed nanoscale resolution map ever produced of a cubic millimeter of brain tissue, about the size of half a grain of rice.

Despite its small size, this fragment of healthy brain contained about 57,000 cells of various types, 230 millimeters of blood vessels, 150 million neural connections, or synapses, and the protective myelin that insulates neurons. To capture it all in vivid detail, the researchers relied on electron microscopy to amass an impressive 1,400 terabytes of imaging data. For perspective, one terabyte of data is enough to store 100,000 photos on your smartphone.

While there are many more details yet to analyze given the sheer quantity of data, this impressively detailed subcellular map has already revealed multiple brain structures that have never been seen before. This includes a class of triangular neurons in deep brain layers being described for the first time. The map also revealed axons, the long extensions of nerve cells that carry electrical impulses, with as many as 50 synapses and other unusual structures, including axons arranged into extensive spiraling patterns that now warrant further study.

The findings come from a team led by Jeff W. Lichtman , Harvard University, Cambridge, MA, and Viren Jain, Google Research, Mountain View, CA. They recognized that fully understanding the human brain requires knowledge of its most basic construction. While the imaging technologies needed to produce this kind of map were available, there were other barriers, including a limited availability of healthy and high-quality human brain tissue samples for study.

Most biopsies of the brain are done to examine or take out abnormal growths of cells or tissues, making them unsuitable for understanding the normal makeup of the brain. In this case, the researchers were able to obtain a tiny sample from the brain tissue removed and destined for disposal during the normal course of surgery for a patient with epilepsy. The researchers first stained the preserved sample to make the cells easier to trace individually before slicing it into 5,000 thin layers for microscopic imaging.

To put those slices back together into a complete 3D reconstruction, the researchers relied on artificial intelligence (AI) models. Because the dataset is too large for any one group to fully analyze, they’ve made it all freely available to the research community in an online resource . They’ve also provided tools for its further analysis and proofreading.

While there is plenty still left to uncover, the findings offer proof-of-principle that it’s possible to visualize the brain at this very detailed level. This is crucial groundwork for new research now supported by the BRAIN Initiative Connectivity Across Scales (BRAIN CONNECTS) program . BRAIN CONNECTS will develop and scale up tools to produce an equally detailed map of a complete mouse brain, which is about 1,000 times larger than the human brain fragment. The researchers now hope their 3D map and others like it will be put to work to understand both normal and disordered brain function more fully.

Reference:

[1] Shapson-Coe A, et al. A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution . Science. DOI: 10.1126/science.adk4858 (2024).

NIH Support: NIH BRAIN Initiative, National Institute of Mental Health