Posted on by Dr. Francis Collins
There’s so much to celebrate about our country this Fourth of July. That includes giving thanks to all those healthcare providers who have put themselves in harm’s way to staff the ERs, hospital wards, and ICUs to care for those afflicted with COVID-19, and also for everyone who worked so diligently to develop, test, and distribute COVID-19 vaccines.
These “shots of hope,” created with rigorous science and in record time, are making it possible for a great many Americans to gather safely once again with family and friends. So, if you’re vaccinated (and I really hope you are—because these vaccines have been proven safe and highly effective), fire up the grill, crank up the music, and get ready to show your true red, white, and blue colors. My wife and I—both fully vaccinated—intend to do just that!
To help get the celebration rolling, I’d like to share a couple minutes of some pretty amazing biological fireworks. While the track of a John Philip Sousa march is added just for fun, what you see in the video above is the result of some very serious neuroscience research that is scientifically, as well as visually, breath taking. Credit for this work goes to an NIH-supported team that includes Ricardo Azevedo and Sunil Gandhi, at the Center for the Neurobiology of Learning and Memory, University of California, Irvine, and their collaborator Damian Wheeler, Translucence Biosystems, Irvine, CA. Azevedo is also an NIH National Research Service Award fellow and a Medical Scientist Training Program trainee with Gandhi.
The team’s video starts off with 3D, colorized renderings of a mouse brain at cellular resolution. About 25 seconds in, the video flashes to a bundle of nerve fibers called the fornix. Thanks to the wonders of fluorescent labeling combined with “tissue-clearing” and other innovative technologies, you can clearly see the round cell bodies of individual neurons, along with the long, arm-like axons that they use to send out signals and connect with other neurons to form signaling circuits. The human brain has nearly 100 trillion of these circuits and, when activated, they process incoming sensory information and provide outputs that lead to our thoughts, words, feelings, and actions.
As shown in the video, the nerve fibers of the fornix provide a major output pathway from the hippocampus, a region of the brain involved in memory. Next, we travel to the brain’s neocortex, the outermost part of the brain that’s responsible for complex behaviors, and then move on to explore an intricate structure called the corticospinal tract, which carries motor commands to the spinal cord. The final stop is the olfactory tubercle —towards the base of the frontal lobe—a key player in odor processing and motivated behaviors.
Azevedo and his colleagues imaged the brain in this video in about 40 minutes using their imaging platform called the Translucence Biosystems’ Mesoscale Imaging System™. This process starts with a tissue-clearing method that eliminates light-scattering lipids, leaving the mouse brain transparent. From there, advanced light-sheet microscopy makes thin optical sections of the tissue, and 3D data processing algorithms reconstruct the image to high resolution.
Using this platform, researchers can take brain-wide snapshots of neuronal activity linked to a specific behavior. They can also use it to trace neural circuits that span various regions of the brain, allowing them to form new hypotheses about the brain’s connectivity and how such connectivity contributes to memory and behavior.
The video that you see here is a special, extended version of the team’s first-place video from the NIH-supported BRAIN Initiative’s 2020 “Show Us Your BRAINS!” imaging contest. Because of the great potential of this next-generation technology, Translucence Biosystems has received Small Business Innovation Research grants from NIH’s National Institute of Mental Health to disseminate its “brain-clearing” imaging technology to the neuroscience community.
As more researchers try out this innovative approach, one can only imagine how much more data will be generated to enhance our understanding of how the brain functions in health and disease. That is what will be truly spectacular for everyone working on new and better ways to help people suffering from Alzheimer’s disease, Parkinson’s disease, schizophrenia, autism, epilepsy, traumatic brain injury, depression, and so many other neurological and psychiatric disorders.
Wishing all of you a happy and healthy July Fourth!
Medical Scientist Training Program (National Institute of General Medical Sciences/NIH)
Translucence Biosystems (Irvine, CA)
Sunil Gandhi (University of California, Irvine)
Ricardo Azevedo (University of California, Irvine)
Video: iDISCO-cleared whole brain from a Thy1-GFP mouse (Translucence Biosystems)
Show Us Your BRAINs! Photo & Video Contest (Brain Initiative/NIH)
NIH Support: National Institute of Mental Health; National Eye Institute
Posted on by Dr. Francis Collins
While primarily a respiratory disease, COVID-19 can also lead to neurological problems. The first of these symptoms might be the loss of smell and taste, while some people also may later battle headaches, debilitating fatigue, and trouble thinking clearly, sometimes referred to as “brain fog.” All of these symptoms have researchers wondering how exactly the coronavirus that causes COVID-19, SARS-CoV-2, affects the human brain.
In search of clues, researchers at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) have now conducted the first in-depth examinations of human brain tissue samples from people who died after contracting COVID-19. Their findings, published in the New England Journal of Medicine, suggest that COVID-19’s many neurological symptoms are likely explained by the body’s widespread inflammatory response to infection and associated blood vessel injury—not by infection of the brain tissue itself .
The NIH team, led by Avindra Nath, used a high-powered magnetic resonance imaging (MRI) scanner (up to 10 times as sensitive as a typical MRI) to examine postmortem brain tissue from 19 patients. They ranged in age from 5 to 73, and some had preexisting conditions, such as diabetes, obesity, and cardiovascular disease.
The team focused on the brain’s olfactory bulb that controls our ability to smell and the brainstem, which regulates breathing and heart rate. Based on earlier evidence, both areas are thought to be highly susceptible to COVID-19.
Indeed, the MRI images revealed in both regions an unusual number of bright spots, a sign of inflammation. They also showed dark spots, which indicate bleeding. A closer look at the bright spots showed that tiny blood vessels in those areas were thinner than normal and, in some cases, leaked blood proteins into the brain. This leakage appeared to trigger an immune reaction that included T cells from the blood and the brain’s scavenging microglia. The dark spots showed a different pattern, with leaky vessels and clots but no evidence of an immune reaction.
While those findings are certainly interesting, perhaps equally noteworthy is what Nath and colleagues didn’t see in those samples. They could find no evidence in the brain tissue samples that SARS-CoV-2 had invaded the brain tissue. In fact, several methods to detect genetic material or proteins from the virus all turned up empty.
The findings are especially intriguing because there has been some suggestion based on studies in mice that SARS-CoV-2 might cross the blood-brain barrier and invade the brain. Indeed, a recent report by NIH-funded researchers in Nature Neuroscience showed that the viral spike protein, when injected into mice, readily entered the brain along with many other organs .
Another recent report in the Journal of Experimental Medicine, which used mouse and human brain tissue, suggests that SARS-CoV-2 may indeed directly infect the central nervous system, including the brain . In autopsies of three people who died from complications of COVID-19, the NIH-supported researchers detected signs of SARS-CoV-2 in neurons in the brain’s cerebral cortex. This work was done using the microscopy-based technique of immunohistochemistry, which uses antibodies to bind to a target, in this case, the virus’s spike protein. Also last month, in a study published in the journal Neurobiology of Disease, another NIH-supported team demonstrated in a series of experiments in cell culture that the SARS-CoV-2 spike protein could cross a 3D model of the blood-brain barrier and infect the endothelial cells that line blood vessels in the brain .
Clearly, more research is needed, and NIH’s National Institute of Neurological Disorders and Stroke has just launched the COVID-19 Neuro Databank/Biobank (NeuroCOVID) to collect more clinical information, primarily about COVID-19-related neurological symptoms, complications, and outcomes. Meanwhile, Nath and colleagues continue to explore how COVID-19 affects the brain and triggers the neurological symptoms often seen in people with COVID-19. As we learn more about the many ways COVID-19 wreaks havoc on the body, understanding the neurological symptoms will be critical in helping people, including the so-called Long Haulers bounce back from this terrible viral infection.
 Microvascular Injury in the Brains of Patients with Covid-19. Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. N Engl J Med. 2020 Dec 30.
 The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. Nat Neurosci. 2020 Dec 16.
 Neuroinvasion of SARS-CoV-2 in human and mouse brain. Song E, Zhang C, Israelow B, et al. J Exp Med (2021) 218 (3): e20202135.
 The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, Razmpour R, Hale JF, Galie PA, Potula R, Andrews AM, Ramirez SH. Neurobiol Dis. 2020 Dec;146:105131.
COVID-19 Research (NIH)
Avindra Nath (National Institute of Neurological Disorders and Stroke/NIH)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Aging; National Institute of General Medical Sciences; National Cancer Institute; National Institute of Mental Health
Posted on by Dr. Francis Collins
As research on Alzheimer’s disease (AD) advances, a desperate need remains for an easy blood test to help diagnose the condition as early as possible. Ideally, such a test could also distinguish AD from other forms of dementia that produce similar symptoms. As published recently in Nature Medicine, an NIH-funded research team has designed a simple blood test that is on course to meet these criteria .
The latest work builds on a large body of work showing that one secret to predicting a person’s cognitive decline and treatment response in AD lies in a protein called tau. Using the powerful, but expensive, approach of PET scan imaging, we know that tau builds up in the brain as Alzheimer’s disease progresses. We also know that some tau spills from the brain into the bloodstream.
The trouble is that the circulating tau protein breaks down far too quickly for a blood test to offer a reliable measure of what’s happening in a person’s brain. A few years ago, researchers discovered a possible solution: test for blood levels of a slightly different and more stable version of the protein called pTau181 . (The “p” in its name comes from the addition of phosphorus in a particular part of the protein’s structure.)
In the latest study, researchers in the lab of Adam Boxer, University of California, San Francisco, followed up further on this compelling lead. Boxer’s team measured pTau181 levels in blood samples from 362 people between the ages of 58 and 70. Those samples included 56 people with an Alzheimer’s diagnosis, along with 47 people with mild cognitive impairment and 69 healthy controls.
The researchers also included another 190 people diagnosed with frontotemporal lobar degeneration (FTLD). It is a relatively rare form of dementia that leads to a gradual decline in behavior, language, and movement, often in connection with a buildup of tau in the brain.
The study found that levels of pTau181 were roughly 3.5-times higher in the blood of people with AD compared to people without AD. Those with mild cognitive impairment due to underlying AD also showed an intermediate increase in blood levels of pTau181.
Importantly, people with FLTD had normal blood levels of pTau181. As a result, the blood test could reliably distinguish between a person with AD and a person with FLTD. That’s important because, while FLTD is a relatively rare condition, its prevalence is similar to AD in people under the age of 65. But both conditions have similar symptoms, making it often challenging to distinguish them.
The findings add to evidence that the new blood test can help in diagnosing AD and in distinguishing it from other neurodegenerative conditions. In fact, it does so with an accuracy that often rivals more expensive PET scans and more invasive cerebrospinal fluid tests, which are now the only reliable ways to measure tau.
There’s still plenty of work to do before this blood test is ready for a doctor’s office. But these initial findings are very promising in helping to simplify the diagnosis of this devastating condition that now affects an estimated 5.5 million Americans .
 Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, Bourakova V, Cobigo Y, Heuer H, Spina S, VandeVrede L, Chai X, Proctor NK, Airey DC, Shcherbinin S, Duggan Evans C, Sims JR, Zetterberg H, Blennow K, Karydas AM, Teunissen CE, Kramer JH, Grinberg LT, Seeley WW, Rosen H, Boeve BF, Miller BL, Rabinovici GD, Dage JL, Rojas JC, Boxer AL; Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators. Nat Med. 2020 Mar 2.
 Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Mielke MM, Hagen CE, Xu J, Chai X, Vemuri P, Lowe VJ, Airey DC, Knopman DS, Roberts RO, Machulda MM, Jack CR Jr, Petersen RC, Dage JL. Alzheimers Dement. 2018 Aug;14(8):989-997.
 Alzheimer’s Disease Fact Sheet. National Institute on Aging, May 22, 2019.
Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)
Adam Boxer (University of California, San Francisco)
NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
Note to my blog readers: the whole world is now facing a major threat from the COVID-19 pandemic. We at NIH are doing everything we can to apply the best and most powerful science to the development of diagnostics, therapeutics, and vaccines, while also implementing public health measures to protect our staff and the patients in our hospital. This crisis is expected to span many weeks, and I will occasionally report on COVID-19 in this blog format. Meanwhile, science continues to progress on many other fronts—and so I will continue to try to bring you stories across a wide range of topics. Perhaps everyone can use a little break now and then from the coronavirus news? Today’s blog takes you into the intricacies of memory.
When recalling the name of an acquaintance, you might replay an earlier introduction, trying to remember the correct combination of first and last names. (Was it Scott James? Or James Scott?) Now, neuroscientists have found that in the split second before you come up with the right answer, your brain’s neurons fire in the same order as when you first learned the information .
This new insight into memory retrieval comes from recording the electrical activity of thousands of neurons in the brains of six people during memory tests of random word pairs, such as “jeep” and “crow.” While similar firing patterns had been described before in mice, the new study is the first to confirm that the human brain stores memories in specific sequences of neural activity that can be replayed again and again.
The new study, published in the journal Science, is the latest insight from neurosurgeon and researcher Kareem Zaghloul at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Zaghloul’s team has for years been involved in an NIH Clinical Center study for patients with drug-resistant epilepsy whose seizures cannot be controlled with drugs.
As part of this work, his surgical team often temporarily places a 4 millimeter-by-4 millimeter array of tiny electrodes on the surface of the brains of the study’s participants. They do this in an effort to pinpoint brain tissues that may be the source of their seizures before performing surgery to remove them. With a patient’s informed consent to take part in additional research, the procedure also has led to a series of insights into what happens in the human brain when we make and later retrieve new memories.
Here’s how it works: The researchers record electrical currents as participants are asked to learn random word pairs presented to them on a computer screen, such as “cake” and “fox,” or “lime” and “camel.” After a period of rest, their brain activity is again recorded as they are given a word and asked to recall the matching word.
Last year, the researchers reported that the split second before a person got the right answer, tiny ripples of electrical activity appeared in two specific areas of the brain . The team also had shown that, when a person correctly recalled a word pair, the brain showed patterns of activity that corresponded to those formed when he or she first learned to make a word association.
The new work takes this a step further. As study participants learned a word pair, the researchers noticed not only the initial rippling wave of electricity, but also that particular neurons in the brain’s cerebral cortex fired repeatedly in a sequential order. In fact, with each new word pair, the researchers observed unique firing patterns among the active neurons.
If the order of neuronal firing was essential for storing new memories, the researchers reasoned that the same would be true for correctly retrieving the information. And, indeed, that’s what they were able to show. For example, when individuals were shown “cake” for a second time, they replayed a very similar firing pattern to the one recorded initially for this word just milliseconds before correctly recalling the paired word “fox.”
The researchers then calculated the average sequence similarity between the firing patterns of learning and retrieval. They found that as a person recalled a word, those patterns gradually became more similar. Just before a correct answer was given, the recorded neurons locked onto the right firing sequence. That didn’t happen when a person gave an incorrect answer.
Further analysis confirmed that the exact order of neural firing was specific to each word pair. The findings show that our memories are encoded as unique sequences that must be replayed for accurate retrieval, though we still don’t understand the molecular mechanisms that undergird this.
Zaghloul reports that there’s still more to learn about how these processes are influenced by other factors such as our attention. It’s not yet known whether the brain replays sequences similarly when retrieving longer-term memories. Along with these intriguing insights into normal learning and memory, the researchers think this line of research will yield important clues as to what changes in people who suffer from memory disorders, with potentially important implications for developing the next generation of treatments.
 Replay of cortical spiking sequences during human memory retrieval. Vaz AP, Wittig JH Jr, Inati SK, Zaghloul KA. Science. 2020 Mar 6;367(6482):1131-1134.
 Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Vaz AP, Inati SK, Brunel N, Zaghloul KA. Science. 2019 Mar 1;363(6430):975-978.
Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Brain Basics (NINDS)
Zaghloul Lab (NINDS)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
Getting plenty of deep, restful sleep is essential for our physical and mental health. Now comes word of yet another way that sleep is good for us: it triggers rhythmic waves of blood and cerebrospinal fluid (CSF) that appear to function much like a washing machine’s rinse cycle, which may help to clear the brain of toxic waste on a regular basis.
The video above uses functional magnetic resonance imaging (fMRI) to take you inside a person’s brain to see this newly discovered rinse cycle in action. First, you see a wave of blood flow (red, yellow) that’s closely tied to an underlying slow-wave of electrical activity (not visible). As the blood recedes, CSF (blue) increases and then drops back again. Then, the cycle—lasting about 20 seconds—starts over again.
The findings, published recently in the journal Science, are the first to suggest that the brain’s well-known ebb and flow of blood and electrical activity during sleep may also trigger cleansing waves of blood and CSF. While the experiments were conducted in healthy adults, further study of this phenomenon may help explain why poor sleep or loss of sleep has previously been associated with the spread of toxic proteins and worsening memory loss in people with Alzheimer’s disease.
In the new study, Laura Lewis, Boston University, MA, and her colleagues at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston. recorded the electrical activity and took fMRI images of the brains of 13 young, healthy adults as they slept. The NIH-funded team also built a computer model to learn more about the fluid dynamics of what goes on in the brain during sleep. And, as it turns out, their sophisticated model predicted exactly what they observed in the brains of living humans: slow waves of electrical activity followed by alternating waves of blood and CSF.
Lewis says her team is now working to come up with even better ways to capture CSF flow in the brain during sleep. Currently, people who volunteer for such experiments have to be able to fall asleep while wearing an electroencephalogram (EEG) cap inside of a noisy MRI machine—no easy feat. The researchers are also recruiting older adults to begin exploring how age-related changes in brain activity during sleep may affect the associated fluid dynamics.
 Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Science. 2019 Nov 1;366(6465):628-631.
Sleep and Memory (National Institute of Mental Health/NIH)
Sleep Deprivation and Deficiency (National Heart, Lung, and Blood Institute/NIH)
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
NIH Support: National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke