Researchers will no longer have to choose between studying a single human brain as a patchwork of fragmented images or a distant, pixelated representation of large structures.
A new imaging platform developed by a US team instead seamlessly combines the finer details of brain cells, their connections and contents, with brain-wide maps of entire networks of neurons that support the brain’s overall architecture.
These elements of brain biology exist at vastly different scales, from the nanometer-sized gaps in synapses to centimeter-long brain regions, which until now have required multiple samples from multiple brains to analyze using different technologies on different platforms.
In its first demonstrated use on human tissue, which involved imaging two whole brains, the platform revealed clear changes in the brain of one person with Alzheimer’s disease.
The new platform contains three core elements to slice, process and then image brain tissue with “unprecedented resolution and speed,” according to the research team that developed it, led by Kwanghun Chung, a chemical engineer at the Massachusetts Institute of Technology (MIT). .
First, an innovative device cuts brain tissue into sections. It uses carefully tuned vibrations to prevent wear, cleanly separating the cells as incredibly thin slices without disrupting their connections.
Then, a chemical technique that reversibly transforms tissue sections into a stretchable, expandable tissue hydrogel suitable for antibody tagging and high-resolution imaging of proteins and other internals.
Finally, a computer tool “stitches” the cut tissues back together and maps the connections between individual cells. These ‘projectomes’ of individual brain cells can then be integrated with profiles that capture the molecules expressed in each cell.
“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” to be able to compare whole brains and find individual differences, says Chung.
“This technology pipeline really allows us to pull all these important features from the same brain in a fully integrated way.”
The tissue-twisted hydrogel gently inflates tissue sections so they can be clearly imaged; and a pump steadily saturates the tissues with fluorescent dyes to produce consistent staining across entire organs.
In a dazzling display of the platform’s imaging capabilities, the researchers provide examples where they labeled one entire hemisphere of the brain and then zoomed in to take a snapshot of cell circuits, followed by individual cells and their connections across junctions called synapses.
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As for how the platform reconstructs these connections across multiple tissue sections, the computational tool has an algorithm that compares the blood vessels leaving one layer and entering the adjacent layer, and traces the extensions of adjacent neurons, called axons.
All told, the researchers imaged the entire brains of two generous donors, one with Alzheimer’s disease and one without.
They found the usual pathological hallmarks of Alzheimer’s disease, including the buildup of amyloid plaques and tau tangles, and shriveled brain cells, but their imaging also captured some finer differences.
In the Alzheimer patient, the axons of the brain cells were swollen. Brain cells in areas loaded with tau and amyloid proteins had also lost their protective myelin sheath and withdrawn from their neighbors.
This “supports neuroimaging studies indicating severe damage to orbitofrontal cortex connectivity in the late stages of Alzheimer’s disease,” the team writes in their paper.
However, this gallery represents just one snapshot of just two brains.
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Scientists have recently taken some remarkably detailed images of the human brain, zooming in on a single cubic millimeter of brain tissue – a decade-long effort that ultimately yielded 1.4 petabytes of data.
Imaging how the brain changes as it slowly degenerates in diseases like Alzheimer’s is a slightly more difficult task, because researchers often work with post-mortem brain tissue donated at the end of a person’s life, or rely on traditional scans of the whole brain, such as MRI, in the hope of detecting changes before the disease manifests.
It’s also not yet clear how the platform might adapt to the rapidly evolving field of brain imaging, but the team is optimistic that their system will help drive the development of new therapies and increase the amount of information gleaned from valuable donor tissues is achieved will maximize.
“This pipeline gives us virtually unlimited access to the tissue,” says Chung. “We can always go back and look at something new.”
The research was published in Science.