sleep disorders
Understanding Long-Term COVID-19 Symptoms and Enhancing Recovery
Posted on by Walter J. Koroshetz, M.D., National Institute of Neurological Disorders and Stroke
We are in the third year of the COVID-19 pandemic, and across the world, most restrictions have lifted, and society is trying to get back to “normal.” But for many people—potentially millions globally—there is no getting back to normal just yet.
They are still living with the long-term effects of a COVID-19 infection, known as the post-acute sequelae of SARS-CoV-2 infection (PASC), including Long COVID. These people continue to experience debilitating fatigue, shortness of breath, pain, difficulty sleeping, racing heart rate, exercise intolerance, gastrointestinal and other symptoms, as well as cognitive problems that make it difficult to perform at work or school.
This is a public health issue that is in desperate need of answers. Research is essential to address the many puzzling aspects of Long COVID and guide us to effective responses that protect the nation’s long-term health.
For the past two years, NIH’s National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases (NIAID), and my National Institute of Neurological Disorders and Stroke (NINDS) along with several other NIH institutes and the office of the NIH Director, have been leading NIH’s Researching COVID to Enhance Recovery (RECOVER) initiative, a national research program to understand PASC.
The initiative studies core questions such as why COVID-19 infections can have lingering effects, why new symptoms may develop, and what is the impact of SARS-CoV-2, the virus that causes COVID-19, on other diseases and conditions? Answering these fundamental questions will help to determine the underlying biologic basis of Long COVID. The answers will also help to tell us who is at risk for Long COVID and identify therapies to prevent or treat the condition.
The RECOVER initiative’s wide scope of research is also unprecedented. It is needed because Long COVID is so complex, and history indicates that similar post infectious conditions have defied definitive explanation or effective treatment. Indeed, those experiencing Long COVID report varying symptoms, making it highly unlikely that a single therapy will work for everyone, underscoring the need to pursue multiple therapeutic strategies.
To understand Long COVID fully, hundreds of RECOVER investigators are recruiting more than 17,000 adults (including pregnant people) and more than 18,000 children to take part in cohort studies. Hundreds of enrolling sites have been set up across the country. An autopsy research cohort will also provide further insight into how COVID-19 affects the body’s organs and tissues.
In addition, researchers will analyze electronic health records from millions of people to understand how Long COVID and its symptoms change over time. The RECOVER initiative is also utilizing consistent research protocols across all the study sites. The protocols have been carefully developed with input from patients and advocates, and they are designed to allow for consistent data collection, improve data sharing, and help to accelerate the pace of research.
From the very beginning, people suffering from Long COVID have been our partners in RECOVER. Patients and advocates have contributed important perspectives and provided valuable input into the master protocols and research plans.
Now, with RECOVER underway, individuals with Long COVID, their caregivers, and community members continue to serve a critical role in the Initiative. The National Community Engagement Group (NCEG) has been established to make certain that RECOVER meets the needs of all people affected by Long COVID. The RECOVER Patient and Community Engagement Strategy outlines all the approaches that RECOVER is using to engage with and gather input from individuals impacted by Long COVID.
The NIH recently made more than 40 awards to improve understanding of the underlying biology and pathology of Long COVID. There have already been several important findings published by RECOVER scientists.
For example, in a recent study published in the journal Lancet Digital Health, RECOVER investigators used machine learning to comb through electronic health records to look for signals that may predict whether someone has Long COVID [1]. As new findings, tools, and technologies continue to emerge that help advance our knowledge of the condition, the RECOVER Research Review (R3) Seminar Series will provide a forum for researchers and our partners with up-to-date information about Long COVID research.
It is important to note that post-viral conditions are not a new concept. Many, but not all, of the symptoms reported in Long COVID, including fatigue, post-exertional malaise, chronic musculoskeletal pain, sleep disorders, postural orthostatic tachycardia (POTS), and cognitive issues, overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
ME/CFS is a serious disease that can occur following infection and make people profoundly sick for decades. Like Long COVID, ME/CFS is a heterogenous condition that does not affect everybody in the same way, and the knowledge gained through research on Long COVID may also positively impact the understanding, treatment, and prevention of POTS, ME/CFS, and other chronic diseases.
Unlike other post-viral conditions, people who experience Long COVID were all infected by the same virus—albeit different variants—at a similar point in time. This creates a unique opportunity for RECOVER researchers to study post-viral conditions in real-time.
The opportunity enables scientists to study many people simultaneously while they are still infected to monitor their progress and recovery, and to try to understand why some individuals develop ongoing symptoms. A better understanding of the transition from acute to chronic disease may offer an opportunity to intervene, identify who is at risk of the transition, and develop therapies for people who experience symptoms long after the acute infection has resolved.
The RECOVER initiative will soon announce clinical trials, leveraging data from clinicians and patients in which symptom clusters were identified and can be targeted by various interventions. These trials will investigate therapies that are indicated for other non-COVID conditions and novel treatments for Long COVID.
Through extensive collaboration across the multiple NIH institutes and offices that contribute to the RECOVER effort, our hope is critical answers will emerge soon. These answers will help us to recognize the full range of outcomes and needs resulting from PASC and, most important, enable many people to make a full recovery from COVID-19. We are indebted to the over 10,000 subjects who have already enrolled in RECOVER. Their contributions and the hard work of the RECOVER investigators offer hope for the future to the millions still suffering from the pandemic.
Reference:
[1] Identifying who has long COVID in the USA: a machine learning approach using N3C data. Pfaff ER, Girvin AT, Bennett TD, Bhatia A, Brooks IM, Deer RR, Dekermanjian JP, Jolley SE, Kahn MG, Kostka K, McMurry JA, Moffitt R, Walden A, Chute CG, Haendel MA; N3C Consortium. Lancet Digit Health. 2022 Jul;4(7):e532-e541.
Links:
COVID-19 Research (NIH)
Long COVID (NIH)
RECOVER: Researching COVID to Enhance Recovery (NIH)
“NIH builds large nationwide study population of tens of thousands to support research on long-term effects of COVID-19,” NIH News Release, September 15, 2021.
Director’s Messages (National Institute of Neurological Disorders and Stroke/NIH)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 18th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Early Riser or Night Owl? New Study May Help to Explain the Difference
Posted on by Dr. Francis Collins
Credit: Clarisse Ricci, University of California, San Diego
Some people are early risers, wide awake at the crack of dawn. Others are night owls who can’t seem to get to bed until well after midnight and prefer to sleep in. Why is this? An NIH-funded team has some new clues based on evidence showing how a molecular “switch” wired into the biological clocks of extreme early risers leads them to operate on a daily cycle of about 20 hours instead of a full 24-hour, or circadian (Latin for “about a day”), cycle [1].
These new atomic-level details, shared from fruit flies to humans, may help to explain how more subtle clock variations predispose people to follow different sleep patterns. They also may lead to new treatments designed to reset the clock in people struggling with sleep disorders, jet lag, or night-shift work.
This work, published recently in the journal eLIFE, comes from Carrie Partch, University of California, Santa Cruz, and her colleagues at Duke-NUS Medical School in Singapore and the University of California, San Diego. It builds on decades of research into biological clocks, which help to control sleeping and waking, rest and activity, fluid balance, body temperature, cardiac rate, oxygen consumption, and even the secretions of endocrine glands.
These clocks, found in cells and tissues throughout the body, are composed of specialized sets of proteins. They interact in specific ways to regulate transcription of about 15 percent of the genome over a 24-hour period. All this interaction helps to align waking hours and other aspects of our physiology to the 24-hour passage of day and night.
In the latest paper, Partch and her colleagues focused on two core clock components: an enzyme known as casein kinase 1 (CK1) and a protein called PERIOD. Clock-altering mutations in CK1 and PERIOD have been known for many years. In fact, CK1 was discovered in studies of golden hamsters more than 20 years ago after researchers noticed one hamster that routinely woke up much earlier than the others [2,3].
It turns out that the timing of biological clocks is strongly influenced by the rise and fall of the PERIOD protein. This daily oscillation normally takes place over 24 hours, but that’s where CK1 enters the picture. The enzyme adjusts PERIOD levels by chemically modifying the protein at one of two sites, thereby adjusting its stability. When one site is modified, it keeps the protein protected and stable. At the other site, it leaves it unprotected and degradable.
Many of these details had been worked out over the years. But, Partch wanted to drill even deeper to answer an essential question: Why does this process normally take 24 hours, which is remarkably slow biochemically? And, what changes in those whose daily cycle gets cut far short?
To find out, her team performed a series of protein structure and biochemical analyses of the CK1 mutation originally found in hamsters, along with several other clock-altering versions of the enzyme found in organisms ranging from flies to humans. What they’ve discovered is a portion of CK1 acts as a switch. When this switch functions normally, it generates a near-perfect 24-hour cycle by keeping PERIOD’s stability just right. In this case, people easily and correctly align their internal clocks to the daily coming and going of daylight.
If the switch favors a faster breakdown of the protein, the daily cycle grows shorter and less tightly bound to daylight. For these early risers, it’s a constant struggle to adjust to life in a 24-hour world. Though they try to get in sync, these early risers are never able to catch up. Conversely, a switch that favors a slower breakdown will lengthen the clock, predisposing some to be night owls.
Such shifts in clock timing can arise from alterations either to the CK1 enzyme or the PERIOD protein. In fact, people with an inherited sleep disorder called Familial Advanced Sleep Phase Syndrome carry a mutation in the PERIOD protein at one of the places that CK1 modifies. The new work shows that this change makes PERIOD more stable by interfering with the enzyme’s ability to mark the protein for degradation.
One thing that makes the CK1 enzyme so fascinating is that it’s extremely ancient. A nearly identical version of the enzyme to the one in humans and hamsters can be found in single-celled green algae! It’s clear that this enzyme and its function in biological clocks is, evolutionarily speaking, rather special. And at one level, that makes total sense—our planet has operated on a 24-hour clock for the entire span of evolutionary time.
The versions of CK1 that Partch’s team studied here are rare in people. She now plans to study other variations that turn up in humans much more often.
Her discoveries are sure to offer a fascinating view on these internal clocks and, pardon the pun, how they make us all tick. She hopes they’ll lead to new ways to adjust the clock in those with sleep disorders and even the means to reset the clock in people who regularly travel overseas or work the night shift.
Ultimately, Partch would like to tap into the crosstalk between biological clocks and the ability of cells to repair their DNA. She wants to see if clock disruptions have any implications for cancer susceptibility. And yes, now’s a good time to find out the answer.
References:
[1] Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch. Philpott JM, Narasimamurthy R, Ricci CG, Freeberg AM, Hunt SR, Yee LE, Pelofsky RS, Tripathi S, Virshup DM, Partch CL. eLIFE. 2020 Feb 11;9.
[2] A mutation of the circadian system in golden hamsters. Ralph MR, Menaker M. Science. 1988 Sep 2;241(4870):1225-7.
[3] Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS. Science. 2000 Apr 21;288(5465):483-92.
Links:
Circadian Rhythms (National Institute of General Medical Sciences/NIH)
Advanced Sleep Phase Syndrome, Familial (Genetic and Rare Disease Center/NIH)
Partch Lab (University of California, Santa Cruz)
NIH Support: National Institute of General Medical Sciences; Office of the Director
How Sleep Resets the Brain
Posted on by Dr. Francis Collins
Caption: Colorized 3D reconstruction of dendrites. Neurons receive input from other neurons through synapses, most of which are located along the dendrites on tiny projections called spines.
Credit: The Center for Sleep and Consciousness, University of Wisconsin-Madison School of Medicine
People spend about a third of their lives asleep. When we get too little shut-eye, it takes a toll on attention, learning and memory, not to mention our physical health. Virtually all animals with complex brains seem to have this same need for sleep. But exactly what is it about sleep that’s so essential?
Two NIH-funded studies in mice now offer a possible answer. The two research teams used entirely different approaches to reach the same conclusion: the brain’s neural connections grow stronger during waking hours, but scale back during snooze time. This sleep-related phenomenon apparently keeps neural circuits from overloading, ensuring that mice (and, quite likely humans) awaken with brains that are refreshed and ready to tackle new challenges.
LabTV: Curious About Sleep Disorders
Posted on by Dr. Francis Collins
Ketema Paul remembers being wowed at an early age by his cousin’s chemistry set and always feeling drawn to science. This interest followed him to Howard University, Washington, D.C., where he earned an undergraduate degree in biology, and on to Georgia State University, Atlanta for his Ph.D. Now, an associate professor at Atlanta’s Morehouse School of Medicine and the subject of our latest LabTV video, Paul runs his own neuroscience lab studying sleep disorders, which affect at least 60 million Americans as chronic or occasional problems and account for an estimated $16 billion in medical costs each year [1].
Paul’s path to the research bench is an interesting one. The product of a tough neighborhood in Washington, D. C., Paul lost a lot of friends to violence and faced many uncertainties. After college, he moved to Atlanta to try his hand at being a music producer and eventually took a side gig as a disc jockey for the campus radio station at Georgia State. Then one day after his radio show, Paul wandered over to have a look inside a nearby neuroscience lab just for kicks and opened the door on a discussion that would change his life.
