Google and Harvard unveiled the world's most comprehensive high-resolution 3D brain map


Whorl axon - Single spiral axon that produces multiple florets and synapses in the soma and dendritic axes of neurons (Google / Harvard)
Whorl axon - Single spiral axon that produces multiple florets and synapses in the soma and dendritic axes of neurons (Google / Harvard)
 

A team of scientists from the prestigious Harvard University and the tech giant Google has just created an incredible and fascinating brain map color-coded of nearly 4,000 incoming axons that connect to a single neuron.


The mapped region encompasses the various layers and cell types of the cerebral cortex, a region of brain tissue associated with higher-level cognition such as thinking, planning, and language. According to Google, it is the largest brain map with this level of detail to date, and it is freely available online.


To make the map, the researchers cut the tissue into 5,300 sections, each 30 nanometers thick, and photographed them with a scanning electron microscope at 4-nanometer resolution. The resulting 225 million images were computationally aligned and stitched back into a 3D digital representation of the region.


Also, as detailed by engineers specialized in artificial intelligence, machine learning algorithms segmented individual cells and classified synapses, axons, dendrites, cells, and other structures, and humans verified their work. The research team also posted a pre-printed document on the map on the scientific preprint site bioArxiv.


In 2020, Google and the Howard Hughes Medical Institute's Janelia Research Campus made headlines when they similarly mapped a part of a fruit fly's brain. That map, at the time the largest so far, covered some 25,000 neurons and 20 million synapses. Besides targeting the human brain, remarkable in itself. The new map unveiled these days, includes tens of thousands of neurons and 130 million synapses. It occupies 1.4 petabytes of disk space.


By comparison, more than three decades of satellite images of Earth from NASA's Landsat program require 1.3 petabytes of storage. Collections of brain images at the smallest scales are like a world in a grain of sand, Clay Reid of the Allen Institute told Nature, citing William Blake in reference to an earlier map of the mouse brain.


The brain map combines about 225 million photos


All of that, however, is only one-millionth of the human brain. In other words, an equally detailed map of the entire amazing organ is still years away. Still, the work shows how fast the field is moving. A map of this scale and detail would have been unimaginable a few decades ago.


In collaboration with the Lichtman Laboratory at Harvard University, the research team now published the data set H01, a representation of 1.4 petabytes of a small sample of human brain tissue, together with the companion paper, A connectomic study of a petascale fragment of the human cerebral cortex. Sample H01 was imaged at 4 nm resolution by serial section electron microscopy, reconstructed and annotated using automated computational techniques, and analyzed to obtain preliminary information on the structure of the human cortex.


The dataset comprises imaging data covering approximately one cubic millimeter of brain tissue and includes tens of thousands of reconstructed neurons, millions of neuron fragments, 130 million annotated synapses, 104 revised cells, and many additional subcellular structures and annotations, all easily accessible with the Neuroglancer H01 browser interfaces the largest sample of brain tissue ever imaged and reconstructed with this level of detail, in any species, and the first large-scale study of synaptic connectivity in the human cortex that encompasses multiple cell types in all layers of the cortex. The main goals of this project are to produce a novel resource for studying the brain. human resources and improve and scale the underlying connectomics technologies.


What is the human cortex?


The cerebral cortex is the most recently evolved thin surface layer of the brain found in vertebrate animals, showing the greatest variation in size between different mammals (it is especially large in humans). Each part of the cerebral cortex has six layers, with different types of nerve cells (eg, spiny stellate) in each layer. The cerebral cortex plays a crucial role in most higher-level cognitive functions, such as thinking, memory, planning, perception, language, and attention. Although there have been some advances in understanding the macroscopic organization of this complicated tissue, its organization at the level of individual nerve cells and their interconnected synapses is largely unknown.


How they mapped the brain?


The study of the cellular circuits of the brain is known as connectomics. Getting the human connectome, or the whole brain wiring diagram is nonsense similar to the human genome. And like the human genome, at first, it seemed like an impossible feat.


The only complete connectomes are for simple creatures: the nematode worm (C. elegans) and the larva of a marine creature called C. intestinalis. There is a very good reason for this. Until recently, the mapping process was time-consuming and expensive.


Researchers mapping C. elegans in the 1980s used a film camera attached to an electron microscope to image slices of the worm, then reconstructed the neurons and synaptic connections by hand, like a tremendously difficult three-dimensional puzzle. C. elegans has only 302 neurons and roughly 7,000 synapses, but the draft of its connectome took 15 years, and a final draft took another 20. Clearly, this approach would not scale.


What has changed in these years? In short, automation. These days, the images themselves are, of course, digital. A process known as focused ion beam milling reduces each tissue cut by a few nanometers at a time. After a layer is vaporized, an electron microscope takes pictures of the newly exposed layer. The ion beam then cuts through the image layer and the next, until all that remains of the tissue slice is a nano-resolution digital copy. It's a long way from the Kodachrome days.


But perhaps the most dramatic improvement is what happens after scientists complete that pile of images.


Instead of assembling them by hand, the algorithms take over. Your first job is to order the cuts with images. Then they do the impossible until the last decade. They align the images exactly, tracing the path of the cells and the synapses between them, and thus build a 3D model. Humans still review the results, but they no longer do the hardest thing. Even proofreading can be refined. Renowned neuroscientist and advocate of connectomics Sebastian Seung, for example, created a game called Eyewire, where thousands of volunteers check structures.


It's really beautiful to look at, Jeff Lichtman of Harvard, whose lab collaborated with Google on the new map, told Nature in 2019. The programs can track neurons faster than the computer can produce imaging data, he said. “We cannot keep up with them. That's a great place to be.


Seunge explained that people are his connectome. Rebuild the connections and rebuild the mind itself: memories, experience and personality, he said in a 2010 TED talk.


But connectomics has not been without controversy over the years. Not everyone believes that mapping the connectome at this level of detail is necessary for a deep understanding of the brain . And, especially in the field's earlier and more artisan past, researchers worried that the scale of resources required simply won't yield comparatively valuable - or timely results.


" I don't need to know the precise details of the wiring of each cell and each synapse in each of those brains, " said scientist Anthony Movshon in 2019. "What I need to know, instead, is the organizational principles that tie them together." These, Movshon believes, can probably be inferred from observations at lower resolutions.


Also, a static snapshot of the brain's physical connections does not necessarily explain how those connections are used in practice.


" A connectome is necessary, but not sufficient," some scientists have said over the years. In fact, it may be in the combination of brain maps, including higher-level functional maps that track signals flowing through neural networks in response to stimuli , that the inner workings of the brain are illuminated in the sharpest detail. .


Still, the C. elegans connectome has proven to be a cornerstone of neuroscience over the years. And the increasing speed of mapping is beginning to suggest goals that once seemed impractical may actually be within reach for decades to come.


Seung believes that when he started out, he estimated that it would take a person a million years to manually trace all the connections in a cubic millimeter of human crust . The entire brain, he further inferred, would take the order of a billion years. This is why automation and algorithms have been so crucial to the field.


Gerry Rubin, an American biologist specializing in genomes and genetics, said he and his team have monitored a 1000-fold increase in mapping speed since they began work on the fruit fly connectome in 2008. The complete connectome, The first part of which was completed last year, could arrive in 2022.


Other groups are working on other animals, such as octopuses, and say that comparing how different forms of intelligence are connected can be a particularly rich terrain for discovery.


The complete connectome of a mouse, a project that is already underway, may follow the fruit fly by the end of the decade. Rubin estimates that going from mouse to human would take another million times the speed of mapping. But he points to the trillion-fold increase in DNA sequencing speed since 1973 to show that such dramatic technical improvements are unprecedented.


The genome can also be a suitable comparison in another way. Even after sequencing the first human genome, it has taken many years to scale genomics to the point where we can more fully realize its potential. Perhaps the same is true of connectomics.


Even when technology opens new doors, it can take time to understand and make use of all it has to offer.


" I think people were impatient for what connectomes would provide, " said Joshua Vogelstein, co-founder of the Open Connetome Project, last year. “The amount of time that elapses between the planting of good technology and the actual scientific practice using that technology is usually about 15 years. Now 15 years have passed and we can start doing science. "


Advocates hope that brain maps will provide new insights into how the brain works, from thinking to emotions to memory, and how to better diagnose and treat brain disorders. Others, including Google no doubt, hope to get insights that can lead to more efficient computing (the brain is amazing in this respect) and powerful artificial intelligence.


It's not known exactly what scientists will find as they, neuron by synapse, map the inner workings of our minds , but they seem to be waiting for some big breakthroughs.

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