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For New Insights into Function, a Bigbrain in Very Small Pieces


By Anette Breindl
Science Editor

Scientifically speaking, big data projects are the order of the day. With increasing technological abilities – in computing power, but also in methods to visualize and map biological phenomena – such projects strive for comprehensiveness, most often indicated by an "ome" attached to their field of study: the genome, the transcriptome, the human microbiome.

The newest big data project, published in the June 21, 2013, issue of Science, eschews the "ome" in its name. Instead, is simple, descriptive, and catchy all at once: "Bigbrain," an anatomical map of an entire human brain at a resolution of 20 micrometers.

With that resolution, Bigbrain is 50 times more detailed than the 1-millimeter chunks that are typically acquired with magnetic resonance imaging.

That detail is likely to give new insights into function. As co-author Karl Zilles, from the German Research Center Juelich's Institute of Neuroscience and Medicine, told reporters at a press conference, "Localization of signals in the brain counts. The brain is not how much in this structure where you can probe the structure of function everywhere and you will get more or less the same results. The brain is a highly organized, specially organized structure, and therefore, it is important where you look for data, where you look for molecules for cells and cell types in the brain."

The cortex, for example, is organized in layers that are interconnected with lower brain structures, each other and other cortical areas in a myriad of ways, and in microcolumns that are too small to see at the 1-millimeter resolution that is currently typical. Whether a gene is expressed in layer 4 of the cortex, where information comes in from lower brain areas, or layer 6, which projects back down to those layers, matters for what its effects are.

Several other reference brains exist; for example, the Allen Institute for Brain Science has created anatomical as well as gene expression maps of the adult developing human brain. In April, President Obama announced the BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies), which asks about for $100 million from the National Institutes of Health, the Defense Advanced Research Projects Agency and the National Science Foundation to invent and develop new technologies to better understand brain functioning in health and disease. Organizations such as the Allen Institute and the Kavli Foundation will also support the BRAIN Initiative.

Bigbrain will provide an anatomical scaffold for such data collected by such other methods. Such work could ultimately lead to more specific drugs for neurological disorders. Currently available medications for brain disorders target the neurotransmitter giants – serotonin, dopamine, GABA – that are everywhere in the brain, doing everything.

But drugs such as Merck & Co Inc.'s sleep drug suvorexant, which is currently before the FDA, show that it is possible to find transmitters that are much more specific to certain areas of the brain. (See BioWorld Today, April 16, 2013.)

A more detailed understanding of the brain's anatomy might uncover other possibilities for more targeted interventions, though for now, the work is purely basic science.

In their work, the authors sliced the brain of a 65-year-old female without a known history of psychiatric or neurological disease into roughly 7,500 sections of 20 micrometers. Each section was stained for cell bodies and photographed digitally. The digital images of whole sections were then separated into images of 20 by 20 micrometers length and width to match the thickness of the sections.

That resolution allows scientists to see the largest cells in the nervous system at the single cell level, though it does not quite reach the level of the typical neuron, which is about 10 microns in size.

First author Katrin Amunts told reporters at the press conference, "Of course, we would love to have spatial resolution going down to one micrometer, which has recently [achieved] for the mouse brain."

But, she added, the amount of data that would be needed for such resolution outstrips the capabilities of technology at this point.

"There are simply no computers at this moment," she said, "who would be [able] to process such data."