Interferometric Microscope

Scientists know that there are many ways to watch as individual neurons in a brain fire – sending electrical signals from one to the next, but they all share the same basic problem. No matter if it involves chemical agents, genetic modifications, or electrical probes, each method is in some way more invasive than neuroscientists would like.

That may soon change.  With the use of an interferometric microscope, researchers at Stanford University, Palo Alto, California, have created a noninvasive technology that detects when nerve cells fire based on changes in shape. The method could be used to observe nerve activity in light-accessible parts of the body, such as the eye, which would allow physicians to quantitatively monitor visual function at the cellular level.

As Stanford researchers report, they have developed a way to watch brain cells send electrical signals using only light, a few lenses and other optical elements, and a fast video camera.Stanford University

The key to the new approach, said Daniel Palanker, Ph.D., a professor of ophthalmology and senior author on the new paper, is that when neurons fire electrical signals, they subtly change shape. That nanometer-scale change can be measured using optical techniques.

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Tong Ling, Ph.D. and colleagues in the lab of Dr. Daniel Palanker at Stanford constructed an interferometric microscope equipped with a high-speed camera that collects 50,000 frames per second. This speed is important because the changes in cell shape are subtle, so there’s very little signal compared to noise in the images. With high-speed imaging, the researchers can combine 50 frames together in chunks, averaging out the noise and increasing the strength of the signal. They also designed a novel algorithm that would detect informative regions (i.e. the parts of the cells that move the most) and boost the signal further.

“This nanometer-scale shape change is very difficult to see,” said Dr. Palanker, “but with ultrafast quantitative phase imaging, it actually turns out to be visible.”

So far, Dr. Palanker, Dr. Tong Ling, a postdoctoral fellow and the lead author on the new paper, and colleagues have measured those miniscule shape changes in networks of neuron-like cells in a lab dish. They are now adapting their methods to study neurons in the brains of living animals. If that works out, it could lead to a more natural way to study at least some parts of the brain. “It’s all natural, no chemical markers, no electrodes, nothing. It’s just cells as they are,” said Dr. Palanker.Moving forward, team members, including the grant’s principal investigator, Austin Roorda, Ph.D., University of California, Berkeley, will determine how to use this technique with optical coherence tomography, a type of imaging technology commonly used to visualize the back of the eye.

“Non-invasive, all-optical, neural recording techniques like those being pioneered by Dr. Palanker and his team, are very exciting because, unlike other methods, these can potentially be used in human eyes,” said Dr. Roorda. “These developments give promise for a day when we can study retinal diseases in human on a cellular scale and evaluate the treatments to cure them.”