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Mapping the Mind: New Technologies Allow 3D Imaging of Whole Human Brain Hemispheres at Subcellular Resolution

A groundbreaking new study published in Science details a technological pipeline that allows researchers to process, label, and image entire hemispheres of human brains at unprecedented resolution and speed. This advancement opens doors to a deeper understanding of the human brain in both health and disease.

Mapping the Mind: New Technologies Allow 3D Imaging of Whole Human Brain Hemispheres at Subcellular Resolution

Observing the intricate workings of the human brain in its entirety, from large-scale structures down to the smallest cellular components, has long been a dream for neuroscientists. Now, that dream is becoming a reality. In a landmark study published in Science, a team of researchers at MIT unveils a revolutionary technology pipeline that allows for the detailed imaging of complete human brain hemispheres at subcellular resolution. This innovative approach enabled the team to meticulously process, label, and generate high-resolution images of full brain hemispheres from two donors – one with Alzheimer’s disease and one without.

“We performed holistic imaging of human brain tissues at multiple resolutions, from single synapses to whole brain hemispheres, and we have made that data available,” explains Kwanghun Chung, the study’s senior author and associate professor in MIT’s departments of Chemical Engineering and Brain and Cognitive Sciences.

This technology pipeline really enables us to analyze the human brain at multiple scales. Potentially this pipeline can be used for fully mapping human brains.

While this study doesn’t present a complete map of the entire brain, it lays the groundwork for achieving this goal. The integrated suite of three technologies demonstrates the potential for mapping every cell, circuit, and protein in the brain. The study showcases the pipeline’s capabilities through stunning visuals: sweeping landscapes of neuronal networks, detailed depictions of individual cells, and intricate views of subcellular structures. The researchers also provide a comparative analysis of a specific region within the Alzheimer’s and non-Alzheimer’s hemispheres.

Chung emphasizes the significance of imaging whole hemispheres at such high resolution for understanding both healthy and diseased brains. This approach allows scientists to investigate complex questions within the same brain, eliminating the variability encountered when comparing different brains. Crucially, the technology doesn’t damage the tissue; instead, it preserves it for years, allowing for repeated labeling and analysis of different cells or molecules.

“We need to be able to see all these different functional components — cells, their morphology and their connectivity, subcellular architectures, and their individual synaptic connections — ideally within the same brain, considering the high individual variabilities in the human brain and considering the precious nature of human brain samples,” Chung elaborates. “This technology pipeline really enables us to extract all these important features from the same brain in a fully integrated manner.”

The pipeline’s scalability and speed (imaging a prepared hemisphere takes 100 hours) pave the way for creating a diverse brain bank representing various demographics and disease states. This would allow for robust comparisons and more powerful statistical analyses.

This breakthrough is the culmination of three key innovations, each spearheaded by a co-lead author of the study: The Megatome: Developed by Ji Wang, this device slices brain hemispheres into incredibly thin, undamaged sections, preserving crucial anatomical information. mELAST: Juhyuk Park engineered this chemical process to make brain slices clear, durable, and easily labelable, facilitating high-resolution imaging. UNSLICE: Webster Guan created this computational system to seamlessly reconstruct the imaged slices into a complete 3D hemisphere, aligning even the smallest blood vessels and neural axons.

The researchers demonstrate the pipeline’s capabilities through various examples, including the ability to zoom in from large brain structures down to individual synapses. They also showcase the diversity of labeling possible, highlighting different cell types and structures.

The team used this technology to explore Alzheimer’s disease, focusing on the orbitofrontal cortex. They observed significant neuron loss in areas overlapping with amyloid plaques, a hallmark of the disease. While this study doesn’t offer definitive conclusions about Alzheimer’s, it demonstrates the technology’s potential for such research. Importantly, this technology extends beyond the brain and can be applied to other organs, promising a deeper understanding of human organ function and disease mechanisms.

“We envision that this scalable technology platform will advance our understanding of the human organ functions and disease mechanisms to spur the development of new therapies,” the authors conclude. The National Institutes of Health primarily funded this groundbreaking research, The Picower Institute for Learning and Memory, The JPB Foundation, and the NCSOFT Cultural Foundation.

The link to the original article can be accessed here.

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Dr. Ravindra Shinde is the editor-in-chief and the founder of The Science Dev. He is also a research scientist at the University of Twente, the Netherlands. His research interests include computational physics, computational materials, quantum chemistry, and exascale computing. His mission is to disseminate cutting-edge research to the world through succinct and engaging cover stories.

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