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| Adrian Wanner is delighted with the exceptional international recognition from the US National Institute of Health (NIH). Photo Credit: Scanderbeg Sauer Photography |
Scientific Frontline: Extended "At a Glance" Summary: Mapping the Brain's Connectome
The Core Concept: Mapping the brain's connectome is the process of creating a comprehensive structural wiring diagram of the brain's billions of neurons and their synaptic connections to understand how information is processed.
Key Distinction/Mechanism: Unlike traditional methodologies that rely on fragile, ultra-thin tissue slices prone to physical handling errors, this advanced approach utilizes thicker tissue sections. It employs a multi-beam scanning transmission electron microscope combined with broadband ion beam polishing—a technique adapted from microchip manufacturing—to iteratively remove nanometer-thin layers. This highly stable process generates superior high-resolution data, allowing artificial intelligence (AI) algorithms to reconstruct 3D neuronal networks far more accurately.
Origin/History: The foundational milestone in connectomics was the manual mapping of the nematode C. elegans (comprising just 302 nerve cells), a rigorous process completed in 1986. Building upon this history, the US National Institutes of Health (NIH) BRAIN Initiative recently awarded a $2.6 million grant to researchers at the Paul Scherrer Institute (PSI) and the Francis Crick Institute to modernize, scale, and automate this process for the mouse brain.
Major Frameworks/Components:
- Artificial Intelligence Integration: Machine learning algorithms employed to automate the 3D reconstruction of nerve cells and synapses, reducing required human input by a factor of 50.
- Multi-Beam Scanning Transmission Electron Microscopy: The deployment of 64 parallel electron beams to rapidly and reliably scan brain tissue sections.
- Broadband Ion Beam Polishing: An automated, iterative procedure that smoothly mills away a few nanometers of the sample at a time for continuous imaging, virtually eliminating physical slicing flaws.
Branch of Science: Neuroscience, Neurobiology, Artificial Intelligence.
Future Application: These automated methodologies are designed to feasibly map the complete connectome of small mammals, such as mice. By accelerating the reconstruction process, the technology brings the mapping of highly complex mammalian brains into a realistic timeframe, setting the stage for future neurological mapping endeavors.
Why It Matters: The brain is one of the most complex structures in nature. Deciphering its exact wiring is essential for explaining how the organ transforms complex environmental stimuli into thoughts, decisions, and actions. Furthermore, this intricate structural knowledge is a fundamental prerequisite for understanding the underlying mechanisms of neurodegenerative conditions, such as Alzheimer’s disease.
PSI researchers are to receive funding from the US National Institutes of Health (NIH) as part of its “BRAIN Initiative”. Their aim is to produce a comprehensive map of a mouse’s brain.
Unlocking the secrets of the brain, especially its architecture and wiring, is one of the big challenges in modern life sciences. That is why the National Institutes of Health (NIH) in the USA, one of the world’s largest research agencies, has included this in its program. As part of the NIH BRAIN Initiative, a Swiss researcher has now been awarded a major grant of up to 2.6 million US dollars. The neurobiologist Adrian Wanner, a group leader at the Paul Scherrer Institute PSI, is the project’s principal investigator. Andreas Schaefer from the Francis Crick Institute in London is also closely involved.
The NIH’s decision to invest such a large sum in a project at a Swiss institute demonstrates the exceptional competitiveness of Swiss researchers and confirms PSI’s position as a center for world-class research. “For a young research group leader to receive such a large grant, especially from another country, is by no means commonplace; it testifies to his great scientific talent and the confidence that the international community has in Switzerland as a research location,” says Gebhard Schertler, Head of the Department of Biology and Chemistry, who is delighted with the good news from the United States. Schaefer adds, “This funding will further strengthen the existing collaboration between our groups and institutes.”
Exploring one of nature’s most complex structures
The brain is one of the most complex structures found in nature. The human brain, for example, contains about 100 billion brain cells and many times that number of connections, called synapses. Scientists believe that in order to explain how the brain processes complex information from the environment and transforms it into thoughts, decisions and actions, it is necessary to know the patterns in which the brain cells are wired. They refer to this wiring diagram of the brain as the connectome. It can be used to extract detailed information showing how different types of cells in the brain are connected; this is fundamental particularly to understanding brain diseases such as Alzheimer’s.
The path to this goal is arduous, as demonstrated by the process of decoding the connectome of the nematode Caenorhabditis elegans which was completed in 1986 after years of research. Even though the roundworm’s brain contains just 302 nerve cells and 5000 synapses, mapping it is nevertheless considered a milestone in brain research. To map the connectome of a brain or brain sample, researchers cut the tissue into tiny slices. These ultra-thin slices, 30 to 40 nanometers thick, are then stained and analyzed in a high-resolution electron microscope. The resulting images can be used to reconstruct the nerve cells and their connections, the synapses, and to identify the different types of cells. In the case of the nematode, it was possible to reconstruct the nerve cells by hand. However, this is no longer feasible for larger brains. Reconstructing the connectome of a fly’s brain, for example, would take some 2000 person-years. In other words, 50 people doing nothing else would have to spend their entire 40-year working lives to accomplish the task.
Using artificial intelligence to decipher the brain
In recent years, however, researchers have succeeded in automating the reconstruction process. Advances in imaging and the use of artificial intelligence (AI) have reduced the human input needed by a factor of 50. “It’s almost crazy how well AI works,” Wanner says happily. His colleagues at Princeton University, for example, recently succeeded in reconstructing the connectome of a fly, almost entirely automatically – it took “only” some 50 person-years to perform the manual corrections by humans. If this process can be automated further, even the connectome of small mammals such as mice will be within reach. This is the reasoning behind the NIH’s BRAIN Initiative strategy and funding.
For now, there is still a catch to the procedure outlined. Ultra-thin slices in the range of 30-40 nanometers are difficult to handle. Mistakes can be made when positioning the slide, individual slices can be lost, they can break or crinkle, or the knife can leave notches. More than 50 percent of the errors in the AI’s analysis algorithms are attributable to flaws in the slicing. This is why, for the moment, the AI’s results still have to be checked by hand. On average, this takes about one working week for a single nerve cell in a mouse’s brain – far too long.
A microchip fabrication process can help
The PSI and Crick team are taking a different approach, one that allows more robust imaging and could therefore be crucial in studying the mouse’s connectome. The initial slices are 250 to 500 nanometers thick, because thicker sections are much easier to handle. A multi-beam scanning transmission electron microscope is then used to record images of these sections. Next, a broadband ion beam removes a layer of the sample just a few nanometers thick, and the entire process is repeated. “We copied this procedure from microchip manufacturers,” explains Wanner. After 25 to 50 polishing steps, the entire section has been analyzed and the computer can generate a high-resolution 3D image from the differences between the individual images.
Fewer slicing errors and the higher resolution provided by broadband ion beam polishing means that the AI algorithms can draw on better information when reconstructing the nerve cells. The sections are scanned not just by a single electron beam, but by 64 parallel beams, which also makes imaging very fast and reliable. Preliminary trials included in the research application to the NIH have already demonstrated that the new method works. The next three years will show whether this can lead to significant savings and speed up research into the mouse connectome. During this time, the PSI-Crick project will be funded by the NIH.
Published in journal: n/a
Source/Credit: Paul Scherrer Institut | Werner Siefer
Reference Number: ns092623_01
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