Most detailed ever map of the human brain in 3D

This is some of the best science of the month! A team from Harvard led by Jeff Lichtman “has co-created with Google researchers the largest synaptic-resolution, 3D reconstruction of a piece of human brain to date, showing in vivid detail each cell and its web of neural connections in a piece of human temporal cortex about half the size of a rice grain“.

The story begins with Dr. Jeff Lichtman a professor of molecular and cellular biology at Harvard University, whose lab received a small brain sample a decade ago. This tissue sample was only 1 cubic millimeter but it contained 57,000 cells and 230 millimeters of blood vessels and 150 million million synapses, all amounting to 1,400 terabytes of data.

Excitatory neurons colored by their depth from the surface of the brain. Blue neurons are those closest to the surface, and fuschia marks the innermost layer. The sample is approximately 3 millimeters wide. (Image credit: Google Research & Lichtman Lab (Harvard University). Renderings by D. Berger (Harvard University))

Using all of this data Harvard in collaboration with Google researchers have just accomplished something enormous. They have compiled a 3D reconstruction of this piece of human brain. Using specially developed techniques and algorithms they analysed the data and generated as the researchers say, “a 3D reconstruction of nearly every cell and process in the aligned volume.”

The reconstruction has been named H01, and it has revealed details about the human brain that were previously not visible to us. For example in the sample, and to the team’s surprise, non-neuronal cells called glia outnumbered neurons 2:1. Furthermore, the most common cell type was oligodendrocytes (cells that help coat axons in myelin that protects them). While most neurons had many weaker connections, the study discovered rare, supercharged pathways with up to 50 synapses between axons. Additionally, they found a few axons forming strangely elaborate, swirling patterns.

An image from the reconstruction showing excitatory, or pyramidal, neurons, colored according to size. (Google Research & Lichtman Lab/Harvard University. Renderings by D. Berger/Harvard University)

The following statement explains this scientific feat:

The feat, published in Science, is the latest in a nearly 10-year collaboration with scientists at Google Research, who combine Lichtman’s electron microscopy imaging with AI algorithms to color-code and reconstruct the extremely complex wiring of mammal brains. The paper’s three co-first authors are former Harvard postdoctoral researcher Alexander Shapson-Coe; Michał Januszewski of Google Research, and Harvard postdoctoral researcher Daniel Berger.

The collaboration’s ultimate goal, supported by the National Institutes of Health BRAIN Initiative, is to create a high-resolution map of a whole mouse brain’s neural wiring, which would entail about 1,000 times the amount of data they just produced from the 1-cubic-millimeter fragment of human cortex.

This shows Synapse distributions. A: Volumetric density of excitatory synapses. B: Volumetric density of inhibitory synapses. C: Percentage of excitatory synapses in different layers (lowest values are purple; highest values are yellow). D: Representative pyramidal neuron, with excitatory (orange) and inhibitory (blue) synapses shown. E: Representative interneuron. (Shapson-Coe et al., Science, 2024)

The distribution of cells, blood vessels, and myelin in the sample. (Shapson-Coe et al., Science, 2024)

“The word ‘fragment’ is ironic,” Lichtman said. “A terabyte is, for most people, gigantic, yet a fragment of a human brain – just a miniscule, teeny-weeny little bit of human brain – is still thousands of terabytes.”

The latest map in Science contains never-before-seen details of brain structure, including a rare but powerful set of axons connected by up to 50 synapses. The team also noted oddities in the tissue, such as a small number of axons that formed extensive whorls. Since their sample was taken from a patient with epilepsy, they’re unsure if such unusual formations are pathological or simply rare.

Lichtman’s field is “connectomics,” which, analogous to genomics, seeks to create comprehensive catalogues of brain structure, down to individual cells and wiring. Such completed maps would light the way toward new insights into brain function and disease, about which scientists still know very little.

Google’s state-of-the-art AI algorithms allow for reconstruction and mapping of brain tissue in three dimensions. The team has also developed a suite of publicly available tools researchers can use to examine and annotate the connectome.

“Given the enormous investment put into this project, it was important to present the results in a way that anybody else can now go and benefit from them,” said Google Research collaborator Viren Jain.

Next the team will tackle the mouse hippocampal formation, which is important to neuroscience for its role in memory and neurological disease.

“If we get to a point where doing a whole mouse brain becomes routine, you could think about doing it in say, animal models of autism,” Lichtman explained The Harvard Gazette.

“There is this level of understanding about brains that presently doesn’t exist. We know about the outward manifestations of behavior. We know about some of the molecules that are perturbed. But in between the wiring diagrams, until now, there was no way to see them. Now, there is a way.”

The research has been published in Science, and the data and reconstruction of H01 have been made freely available on a dedicated website.

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