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Taking Brain Imaging Even Deeper

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Thanks to yet another amazing advance made possible by the NIH-led supported the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, I can now take you on a 3D fly-through of all six layers of the part of the mammalian brain that processes external signals into vision. This unprecedented view is made possible by three-photon microscopy, a low-energy imaging approach that is allowing researchers to peer deeply within the brains of living creatures without damaging or killing their brain cells.

The basic idea of multi-photon microscopy is this: for fluorescence microscopy to work, you want to deliver a specific energy level of photons (usually with a laser) to excite a fluorescent molecule, so that it will emit light at a slightly lower energy (longer wavelength) and be visualized as a burst of colored light in the microscope. That’s how fluorescence works. Green fluorescent protein (GFP) is one of many proteins that can be engineered into cells or mice to make that possible.

But for that version of the approach to work on tissue, the excited photons need to penetrate deeply, and that’s not possible for such high energy photons. So two-photon strategies were developed, where it takes the sum of the energy of two simultaneous photons to hit the target in order to activate the fluorophore.

That approach has made a big difference, but for deep tissue penetration the photons are still too high in energy. Enter the three-photon version! Now the even lower energy of the photons makes tissue more optically transparent, though for activation of the fluorescent protein, three photons have to hit it simultaneously. But that’s part of the beauty of the system—the visual “noise” also goes down.

This particular video shows what takes place in the visual cortex of mice when objects pass before their eyes. As the objects appear, specific neurons (green) are activated to process the incoming information. Nearby, and slightly obscuring the view, are the blood vessels (pink, violet) that nourish the brain. At 33 seconds into the video, you can see the neurons’ myelin sheaths (pink) branching into the white matter of the brain’s subplate, which plays a key role in organizing the visual cortex during development.

This video comes from a recent paper in Nature Communications by a team from Massachusetts Institute of Technology, Cambridge [1]. To obtain this pioneering view of the brain, Mriganka Sur, Murat Yildirim, and their colleagues built an innovative microscope that emits three low-energy photons. After carefully optimizing the system, they were able to peer more than 1,000 microns (0.05 inches) deep into the visual cortex of a live, alert mouse, far surpassing the imaging capacity of standard one-photon microscopy (100 microns) and two-photon microscopy (400-500 microns).

This improved imaging depth allowed the team to plumb all six layers of the visual cortex (two-photon microscopy tops out at about three layers), as well as to record in real time the brain’s visual processing activities. Helping the researchers to achieve this feat was the availability of a genetically engineered mouse model in which the cells of the visual cortex are color labelled to distinguish blood vessels from neurons, and to show when neurons are active.

During their in-depth imaging experiments, the MIT researchers found that each of the visual cortex’s six layers exhibited different responses to incoming visual information. One of the team’s most fascinating discoveries is that neurons residing on the subplate are actually quite active in adult animals. It had been assumed that these subplate neurons were active only during development. Their role in mature animals is now an open question for further study.

Sur often likens the work in his neuroscience lab to astronomers and their perpetual quest to see further into the cosmos—but his goal is to see ever deeper into the brain. His group, along with many other researchers supported by the BRAIN Initiative, are indeed proving themselves to be biological explorers of the first order.

Reference:

[1] Functional imaging of visual cortical layers and subplate in awake mice with optimized three-photon microscopy. Yildirim M, Sugihara H, So PTC, Sur M. Nat Commun. 2019 Jan 11;10(1):177.

Links:

Sur Lab (Massachusetts Institute of Technology, Cambridge)

The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Eye Institute; National Institute of Neurological Disorders and Stroke; National Institute of Biomedical Imaging and Bioengineering


Study Suggests Light Exercise Helps Memory

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Fitness group doing tai chi in park

Credit: iStock/Wavebreakmedia

How much exercise does it take to boost your memory skills? Possibly a lot less than you’d think, according to the results of a new study that examined the impact of light exercise on memory.

In their study of 36 healthy young adults, researchers found surprisingly immediate improvements in memory after just 10 minutes of low-intensity pedaling on a stationary bike [1]. Further testing by the international research team reported that the quick, light workout—which they liken in intensity to a short yoga or tai chi session—was associated with heightened activity in the brain’s hippocampus. That’s noteworthy because the hippocampus is known for its involvement in remembering facts and events.


Brain in Motion

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Credit: Itamar Terem, Stanford University, Palo Alto, CA, and Samantha Holdsworth, University of Auckland, New Zealand

Though our thoughts can wander one moment and race rapidly forward the next, the brain itself is often considered to be motionless inside the skull. But that’s actually not correct. When the heart beats, the pumping force reverberates throughout the body and gently pulsates the brain. What’s been tricky is capturing these pulsations with existing brain imaging technologies.

Recently, NIH-funded researchers developed a video-based approach to magnetic resonance imaging (MRI) that can record these subtle movements [1]. Their method, called phase-based amplified MRI (aMRI), magnifies those tiny movements, making them more visible and quantifiable. The latest aMRI method, developed by a team including Itamar Terem at Stanford University, Palo Alto, CA, and Mehmet Kurt at Stevens Institute of Technology, Hoboken, NJ. It builds upon an earlier method developed by Samantha Holdsworth at New Zealand’s University of Auckland and Stanford’s Mahdi Salmani Rahimi [2].


Wearable Scanner Tracks Brain Activity While Body Moves

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Credit: Wellcome Centre for Human Neuroimaging, University College London.

In recent years, researchers fueled by the BRAIN Initiative and many other NIH-supported efforts have made remarkable progress in mapping the human brain in all its amazing complexity. Now, a powerful new imaging technology promises to further transform our understanding [1]. This wearable scanner, for the first time, enables researchers to track neural activity in people in real-time as they do ordinary things—be it drinking tea, typing on a keyboard, talking to a friend, or even playing paddle ball.

This new so-called magnetoencephalography (MEG) brain scanner, which looks like a futuristic cross between a helmet and a hockey mask, is equipped with specialized “quantum” sensors. When placed directly on the scalp surface, these new MEG scanners can detect weak magnetic fields generated by electrical activity in the brain. While current brain scanners weigh in at nearly 1,000 pounds and require people to come to a special facility and remain absolutely still, the new system weighs less than 2 pounds and is capable of generating 3D images even when a person is making motions.


Finding Brain Circuits Tied to Alertness

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Everybody knows that it’s important to stay alert behind the wheel or while out walking on the bike path. But our ability to react appropriately to sudden dangers is influenced by whether we feel momentarily tired, distracted, or anxious. How is it that the brain can transition through such different states of consciousness while performing the same routine task, even as its basic structure and internal wiring remain unchanged?

A team of NIH-funded researchers may have found an important clue in zebrafish, a popular organism for studying how the brain works. Using a powerful new method that allowed them to find and track brain circuits tied to alertness, the researchers discovered that this mental state doesn’t work like an on/off switch. Rather, alertness involves several distinct brain circuits working together to bring the brain to attention. As shown in the video above that was taken at cellular resolution, different types of neurons (green) secrete different kinds of chemical messengers across the zebrafish brain to affect the transition to alertness. The messengers shown are: serotonin (red), acetylcholine (blue-green), and dopamine and norepinephrine (yellow).

What’s also fascinating is the researchers found that many of the same neuronal cell types and brain circuits are essential to alertness in zebrafish and mice, despite the two organisms being only distantly related. That suggests these circuits are conserved through evolution as an early fight-or-flight survival behavior essential to life, and they are therefore likely to be important for controlling alertness in people too. If correct, it would tell us where to look in the brain to learn about alertness not only while doing routine stuff but possibly for understanding dysfunctional brain states, ranging from depression to post-traumatic stress disorder (PTSD).


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