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Researchers have developed a fast and practical molecular-scale imaging technique that could let scientists view never-before-seen dynamics of biological processes involved in neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis.

The new technique reveals a sample's chemical makeup, as well as the orientation of molecules making up that sample, information that can be used to understand how molecules are behaving. What's more, it acquires this information in mere seconds, significantly faster than the minutes required by other techniques. The faster speed means it will be possible for the first time to watch disease progression in living animal models at the molecular level. With further development, the technique might also be used to detect early signs of neurodegenerative diseases in people.

Researchers led by Sophie Brasselet of the Institut Fresnel, CNRS, Aix Marseille Université, France, describe the new technique as high-speed polarization. They used artificial lipid membranes to demonstrate the technique's capabilities for enhancing neurological research. The artificial membranes used in the study were made of packed layers of lipids that are similar to those found in the myelin sheath that covers axons to help electrical impulses move quickly and efficiently. When diseases such as Alzheimer's and multiple sclerosis progress, these lipids start to disorganize and the lipid layers lose their adhesion. This ultimately causes the myelin sheath to detach from the axon and leads to malfunctioning neural signals.

"We designed a technique able to image molecular organization in cells and tissues that can ultimately let us see the early stage of this detachment and how lipids are organized within this myelin sheath," said Brasselet. "This could help us understand the progression of diseases by identifying the stage at which lipids start disorganizing, for example, and what molecular changes are occurring during this time. This could allow new targeted drug treatments that work differently than those used now."

The new technique makes use of a nonlinear effect that occurs when light interacts with molecules. The frequency, or wavelength, of the nonlinear signal provides the chemical makeup of a sample based on its molecular vibrations, without the need to add any additional fluorescent labels or chemicals.

The researchers built on an existing approach called stimulated Raman scattering imaging, which enhances the Raman signal by modulating the laser light's intensity, or power. To obtain molecular orientation information from the coherent Raman signal, the researchers used an electro-optical device called a Pockels cell to quickly modulate the laser's polarization rather than its intensity. "We took the concept of intensity modulation used for stimulated Raman scattering and transposed it to polarization modulation using an off-the-shelf device," said Brasselet. "The signal detection for our technique is very similar to what is done with stimulated Raman scattering, except that instead of detecting only the intensity of the light, we detect polarization information that tells us if molecules are highly oriented or totally disorganized."

The key, however, is to acquire orientation information fast enough to capture highly dynamic biological processes on a molecular level. With the new approach, it takes less than a second to acquire lipid orientation information in a large image that contains several cells. This information is then used to construct a sequence of "lipid order" images that shows molecular orientation dynamics at subsecond time scales.

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