Posted on by Lawrence Tabak, D.D.S., Ph.D.
When NIH launched The BRAIN Initiative® a decade ago, one of many ambitious goals was to develop innovative technologies for profiling single cells to create an open-access reference atlas cataloguing the human brain’s many parts. The ultimate goal wasn’t to produce a single, static reference map, but rather to capture a dynamic view of how the brain’s many cells of varied types are wired to work together in the healthy brain and how this picture may shift in those with neurological and mental health disorders.
So I’m now thrilled to report the publication of an impressive collection of work from hundreds of scientists in the BRAIN Initiative Cell Census Network (BICCN), detailed in more than 20 papers in Science, Science Advances, and Science Translational Medicine.1 Among many revelations, this unprecedented, international effort has characterized more than 3,000 human brain cell types. To put this into some perspective, consider that the human lung contains 61 cell types.2 The work has also begun to uncover normal variation in the brains of individual people, some of the features that distinguish various disease states, and distinctions among key parts of the human brain and those of our closely related primate cousins.
Of course, it’s not possible to do justice to this remarkable body of work or its many implications in the space of a single blog post. But to give you an idea of what’s been accomplished, some of these studies detail the primary effort to produce a comprehensive brain atlas, including defining the brain’s many cell types along with their underlying gene activity and the chemical modifications that turn gene activity up or down.3,4,5
Other studies in this collection take a deep dive into more specific brain areas. For instance, to capture normal variations among people, a team including Nelson Johansen, University of California, Davis, profiled cells in the neocortex—the outermost portion of the brain that’s responsible for many complex human behaviors.6 Overall, the work revealed a highly consistent cellular makeup from one person to the next. But it also highlighted considerable variation in gene activity, some of which could be explained by differences in age, sex and health. However, much of the observed variation remains unexplained, opening the door to more investigations to understand the meaning behind such brain differences and their role in making each of us who we are.
Yang Li, now at Washington University in St. Louis, and his colleagues analyzed 1.1 million cells from 42 distinct brain areas in samples from three adults.4 They explored various cell types with potentially important roles in neuropsychiatric disorders and were able to pinpoint specific cell types, genes and genetic switches that may contribute to the development of certain traits and disorders, including bipolar disorder, depression and schizophrenia.
Yet another report by Nikolas Jorstad, Allen Institute, Seattle, and colleagues delves into essential questions about what makes us human as compared to other primates like chimpanzees.7 Their comparisons of gene activity at the single-cell level in a specific area of the brain show that humans and other primates have largely the same brain cell types, but genes are activated differently in specific cell types in humans as compared to other primates. Those differentially expressed genes in humans often were found in portions of the genome that show evidence of rapid change over evolutionary time, suggesting that they play important roles in human brain function in ways that have yet to be fully explained.
All the data represented in this work has been made publicly accessible online for further study. Meanwhile, the effort to build a more finely detailed picture of even more brain cell types and, with it, a more complete understanding of human brain circuitry and how it can go awry continues in the BRAIN Initiative Cell Atlas Network (BICAN). As impressive as this latest installment is—in our quest to understand the human brain, brain disorders, and their treatment—we have much to look forward to in the years ahead.
A list of all the papers part of the brain atlas research is available here: https://www.science.org/collections/brain-cell-census.
 M Maroso. A quest into the human brain. Science DOI: 10.1126/science.adl0913 (2023).
 L Sikkema, et al. An integrated cell atlas of the lung in health and disease. Nature Medicine DOI: 10.1038/s41591-023-02327-2 (2023).
 K Siletti, et al. Transcriptomic diversity of cell types across the adult human brain. Science DOI: 10.1126/science.add7046 (2023).
 Y Li, et al. A comparative atlas of single-cell chromatin accessibility in the human brain. Science DOI: 10.1126/science.adf7044 (2023).
 W Tian, et al. Single-cell DNA methylation and 3D genome architecture in the human brain. Science DOI: 10.1126/science.adf5357 (2023).
 N Johansen, et al. Interindividual variation in human cortical cell type abundance and expression. Science DOI: 10.1126/science.adf2359 (2023).
 NL Jorstad, et al. Comparative transcriptomics reveals human-specific cortical features. Science DOI: 10.1126/science.ade9516 (2023).
As I sit down to write this blog, the COVID-19 pandemic continues to have a widespread impact, and we’re all trying to figure out our “new normal.” For some, figuring out the new normal has been especially difficult, and that’s something for all of us to consider during September, which is National Suicide Prevention Awareness Month. It’s such an important time to share what we know about suicide prevention and consider how we can further this knowledge to those in need.
At NIH’s National Institute of Mental Health (NIMH), we’ve been asking ourselves: What have we learned about suicide risk and prevention during the pandemic? And how should our research evolve to reflect a rapidly changing world?
Over the last few years, people have been concerned about the pandemic’s impact on suicide rates. So far, data suggest that the overall suicide rate in the U.S. has remained steady. But there is concerning evidence that the pandemic has disproportionately affected suicide risk in historically underserved communities.
For example, data suggest that people in minority racial and ethnic groups experienced greater increases in suicidal thoughts during the pandemic . Additional data indicate that suicide rates may be rising among some young adult racial and ethnic minority groups .
Structural racism and other social and environmental factors are major drivers of mental health disparities, and NIMH continues to invest in research to understand how these social determinants of health influence suicide risk. This research includes investigations into the effects of long-term and daily discrimination.
To mitigate these effects, it is critical that we identify specific underlying mechanisms so that we can develop targeted interventions. To this end, NIMH is supporting research in underserved communities to identify suicide risk and the protective factors and effective strategies for reducing this risk (e.g., RFA-MH-22-140, RFA-MH-21-188, RFA-MH-21-187). There are important lessons to be learned that we can’t afford to miss.
Building Solid Foundations
The pandemic also underscored the urgent need to support youth mental health. Indeed, in December 2021, U.S. Surgeon General Dr. Vivek Murthy issued the Advisory on Protecting Youth Mental Health, calling attention to increasing rates of depression and suicidal behaviors among young people. Crucially, the advisory highlighted the need to “recognize that mental health is an essential part of overall health.”
At NIMH, we know that establishing a foundation for good mental health early on can support a person’s overall health and well-being over a lifetime. In light of this, we are investing in research to identify effective prevention efforts that can help set kids on positive mental health trajectories early in life.
Additionally, by re-analyzing research investments already made, we are looking to see whether these early prevention efforts have meaningful impacts on later suicide risk and mental health outcomes. These findings may help to improve a range of systems—such as schools, social services, and health care—to better support kids’ mental health needs.
Improving and Expanding Access
The pandemic has also shown us that telehealth can be an effective means of delivering and increasing access to mental health care. The NIMH has supported research examining telehealth as a tool for improving suicide prevention services, including the use of digital tools that can help extend provider reach and support individuals at risk for suicide.
At the same time, NIMH is investing in work to understand the most effective ways to help providers use evidence-based approaches to prevent suicide. This research helps inform federal partners and others about the best ways to support policies and practices that help prevent suicide deaths.
In July, the Substance Abuse and Mental Health Services Administration (SAMHSA) launched the 988 Suicide & Crisis Lifeline, a three-digit suicide prevention and mental health crisis number. This service builds on the existing National Suicide Prevention Lifeline, allowing anyone to call or text 988 to connect with trained counselors and mental health services. Research supported by NIMH helped build the case for such lifelines, and now we’re calling for research aimed at identifying the best ways to help people use this evolving crisis support system.
With these and many other efforts, we are hopeful that people who are at risk for suicidal thoughts and behaviors will be able to access the evidence-based support and services they need. This National Suicide Prevention Awareness Month, I’d like to issue a call to action: Help raise awareness by sharing resources on how to recognize the warning signs for suicide and how to get help. By working together, we can prevent suicide and save lives.
 Racial and ethnic disparities in the prevalence of stress and worry, mental health conditions, and increased substance use among adults during the COVID-19 pandemic – United States, April and May 2020. McKnight-Eily LR, Okoro CA, Strine TW, Verlenden J, Hollis ND, Njai R, Mitchell EW, Board A, Puddy R, Thomas C. MMWR Morb Mortal Wkly Rep. 2021 Feb 5;70(5):162-166.
 One Year In: COVID-19 and Mental Health. National Institute of Mental Health Director’s Message. April 9, 2021.
988 Suicide & Crisis Lifeline (Substance Abuse and Mental Health Services Administration, Rockville, MD)
Help for Mental Illnesses (National Institute of Mental Health/NIH)
Suicide Prevention (NIMH)
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 16th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Posted on by Dr. Francis Collins
For many people struggling with depression, antidepressants and talk therapy can help to provide relief. But for some, the treatments don’t help nearly enough. I’m happy to share some early groundbreaking research in alleviating treatment-resistant depression in a whole new way: implanting a pacemaker-like device capable of delivering therapeutic electrical impulses deep into the brain, aiming for the spot where they can reset the depression circuit.
What’s so groundbreaking about the latest approach—so far, performed in just one patient—is that the electrodes didn’t simply deliver constant electrical stimulation. The system could recognize the specific pattern of brain activity associated with the patient’s depressive symptoms and deliver electrical impulses to the brain circuit where it could provide the most relief.
While much more study is needed, this precision approach to deep brain stimulation (DBS) therapy offered immediate improvement to the patient, a 36-year-old woman who’d suffered from treatment-resistant major depressive disorder since childhood. Her improvement has lasted now for more than a year.
This precision approach to DBS has its origins in clinical research supported through NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. A team, led by Edward Chang, a neurosurgeon at the University of California San Francisco’s (UCSF) Epilepsy Center, discovered while performing DBS that the low mood in some patients with epilepsy before surgery was associated with stronger activity in a “subnetwork” deep within the brain’s neural circuitry. The subnetwork involved crosstalk between the brain’s amygdala, which mediates fear and other emotions, and the hippocampus, which aids in memory.
Researchers led by Andrew Krystal, UCSF, Weill Institute for Neurosciences, attempted in the latest work to translate this valuable lead into improved care for depression. Their results were published recently in the journal Nature Medicine .
Krystal and colleagues, including Chang and Katherine Scangos, who is the first author of the new study, began by mapping patterns of brain activity in the patient that was associated with the onset of her low moods. They then customized an FDA-approved DBS device to respond only when it recognized those specific patterns. Called NeuroPace® RNS®, the device includes a small neurostimulator and measures about 6 by 3 centimeters, allowing it to be fully implanted inside a person’s skull. There, it continuously monitors brain activity and can deliver electrical stimulation via two leads, as shown in the image above .
Researchers found they could detect and predict high symptom severity best in the amygdala, as previously reported. The next question was where the electrical stimulation would best relieve those troubling brain patterns and associated symptoms. They discovered that stimulation in the brain’s ventral capsule/ventral striatum, part of the brain’s circuitry for decision-making and reward-related behavior, led to the most consistent and sustained improvements. Based on these findings, the team devised an on-demand and immediate DBS therapy that was unique to the patient’s condition.
It will be important to learn whether this precision approach to DBS is broadly effective for managing treatment-resistant depression and perhaps other psychiatric conditions. It will take much more study and time before such an approach to treating depression can become more widely available. Also, it is not yet clear just how much it would cost. But these remarkable new findings certainly point the way toward a promising new approach that will hopefully one day bring another treatment option for those in need of relief from severe depression.
 Closed-loop neuromodulation in an individual with treatment-resistant depression. Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, Liu TX, Rao VR, Sellers KK, Dawes HE, Starr PA, Krystal AD, Chang EF. Nat Med. 2021 Oct;27(10):1696-1700
 The NeuroPace® RNS® System for responsive neurostimulation, NIH BRAIN Initiative.
Depression (National Institute of Mental Health/NIH)
Deep Brain Stimulation for Parkinson’s Disease and other Movement Disorders (National Institute of Neurological Disorders and Stroke/NIH)
Andrew Krystal (University of California San Francisco)
Katherine Scangos (UCSF)
Edward Chang (UCSF)
NIH Support: National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
One of life’s greatest mysteries is the brain’s ability to encode something as complex as human behavior. In an effort to begin to unravel this mystery, neuroscientists often zoom in to record the activities of individual neurons. Sometimes they expand their view to look at a specific region of the brain. But if they zoom out farther, neuroscientists can observe many thousands of neurons across the entire brain firing at once to produce electrical oscillations that somehow translate into behaviors as distinct as a smile and a frown. The complexity is truly daunting.
Rainbo Hultman, University of Iowa Carver College of Medicine, Iowa City, realized years ago that by zooming out and finding a way to map all those emergent signals, she could help to change the study of brain function fundamentally. She also realized doing so offered her an opportunity to chip away at cracking the complicated code of the electrical oscillations that translate into such complex behaviors. To pursue her work in this emerging area of “electrical connectomics,” Hultman recently received a 2020 NIH Director’s New Innovator Award to study the most common human neurological disorder: migraine headaches.
A few years ago, Hultman made some impressive progress in electrical connectomics as a post-doctoral researcher in the lab of Kafui Dzirasa at Duke University, Durham, NC. Hultman and her colleagues refined a way to use electrodes to collect electrical field potentials across an unprecedented seven separate mouse brain regions at once. Using machine learning to help make sense of all the data, they uncovered a dynamic, yet reproducible, electrical brain network encoding depression .
What’s more, they found that the specific features of this brain-wide network could predict which mice subjected to chronic stress would develop signs of major depressive disorder. As Hultman noted, when measured and mapped in this way, the broad patterns of electrical brain activity, or “Electome factors,” could indicate which mice were vulnerable to stress and which were more resilient.
Moving on to her latest area of research, Hultman is especially intrigued by the fact that people who endure regular migraine attacks often pass through a characteristic sequence of symptoms. These symptoms can include a painful headache on one side of the head; visual disturbances; sensitivity to light, odors, or sound; mood changes; nausea; trouble speaking; and sometimes even paralysis. By studying the broad electrical patterns and networks associated with migraine in mice—simultaneously capturing electrical recordings from 14 brain regions on a millisecond timescale—she wants to understand how brain circuits are linked and work together in ways that produce the complex sequences of migraine symptoms.
More broadly, Hultman wants to understand how migraine and many other disorders affecting the brain lead to a state of heightened sensory sensitivity and how that emerges from integrated neural circuits in the brain. In her studies of migraine, the researcher suspects she might observe some of the same patterns seen earlier in depression. In fact, her team is setting up its experiments to ensure it can identify any brain network features that are shared across important disease states.
By the way, I happen to be one of many people who suffer from migraines, although fortunately not very often in my case. The visual aura of flashing jagged images that starts in the center of my visual field and then gradually moves to the periphery over about 20 minutes is pretty dramatic—a free light show! I’ve wondered what the electrical component of that must be like. But, even with treatment, the headache that follows can be pretty intense.
Hultman also has seen in her own life and family how debilitating migraines can be. Her goal isn’t just to map these neural networks, but to use them to identify where to target future therapeutics. Ultimately, she hopes her work will pave the way for more precise approaches for treating migraine and other brain disorders that are based on the emergent electrical characteristics of each individual’s brain activity. It’s a fascinating proposition, and I certainly look forward to where this research leads and what it may reveal about the fundamentals of how our brains encode complex behaviors and emotions.
 Brain-wide electrical spatiotemporal dynamics encode depression vulnerability. Hultman R, Ulrich K, Sachs BD, Blount C, Carlson DE, Ndubuizu N, Bagot RC, Parise EM, Vu MT, Gallagher NM, Wang J, Silva AJ, Deisseroth K, Mague SD, Caron MG, Nestler EJ, Carin L, Dzirasa K. Cell. 2018 Mar 22;173(1):166-180.e14.
Migraine Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Laboratory for Brain-Network Based Molecular Medicine (University of Iowa, Iowa City)
Hultman Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health
Posted on by Dr. Francis Collins
More than 400,000 Americans have now lost their lives to COVID-19. But thousands of others who’ve gotten sick and survived COVID-19 are finding that a full recovery can be surprisingly elusive. Weeks and months after seemingly recovering from even mild cases of COVID-19, many battle a wide range of health problems.
Indeed, new results from the largest global study of this emerging “Long COVID syndrome” highlight just how real and pressing this public health concern really is. The study, reported recently as a pre-print on medRxiv, is based on survey results from more than 3,700 self-described COVID “Long Haulers” in 56 countries . They show nearly half couldn’t work full time six months after unexpectedly developing prolonged symptoms of COVID-19. A small percentage of respondents, thankfully, seemed to have bounced back from brief bouts of Long COVID, though time will tell whether they have fully recovered.
These findings are the second installment from the online Body Politic COVID-19 Support Group and its Patient-Led Research for COVID-19, which consists of citizen scientists with a wide range of expertise in the arts and sciences who are struggling with the prolonged effects of COVID-19 themselves. In an earlier survey, this group provided a first-draft description of Long COVID syndrome, based on the self-reported experiences of 640 respondents.
In the new survey-based study led by Athena Akrami, with Patient-Led Research for COVID-19 and University College London, England, the goal was to characterize the experiences of many more people with Long COVID syndrome. They now define the syndrome as a collection of symptoms lasting for more than 28 days.
This second survey emphasizes the course and severity of more than 200 symptoms over time, including those affecting the heart, lungs, gastrointestinal system, muscles, and joints. It took a particularly in-depth look at neurological and neuropsychiatric symptoms, along with the ability of COVID-19 survivors to return to work and participate in other aspects of everyday life.
The 3,762 individuals who responded to the survey were predominately white females, between the ages of 30 and 60, who lived in the United States. As in the previous survey, the study included adults with symptoms consistent with COVID-19, whether or not the infection had been confirmed by a viral or antibody test. That is a potential weakness of the study, as some of these individuals may have had some other inciting illness. But many of the study’s participants developed symptoms early on in the pandemic, when testing was much more limited than it is now.
More than half never sought hospital care. Only 8 percent said that they’d been admitted to the hospital for COVID-19. And yet, 2,464 respondents reported COVID-19 symptoms lasting six months or longer. Most of the remaining respondents also continued to have symptoms, although they had not yet reached the six-month mark.
Among the most common symptoms were fatigue, worsening of symptoms after physical or mental activity, shortness of breath, trouble sleeping, and “brain fog,” or difficulty thinking clearly. The majority—88 percent—said they coped with some form of cognitive dysfunction or memory loss that to varying degrees affected their everyday lives. That includes the ability to make decisions, have conversations, follow instructions, and drive.
Those who had prolonged symptoms of COVID-19 for more than six months reported contending with about 14 symptoms on average. Most also reported that they’d had a relapse of symptoms, seemingly triggered by exercise, mental activity, or just everyday stress. When surveyed, nearly half of respondents said they’d had to reduce their hours at work due to the severity of their symptoms. Another 22 percent weren’t working at all due to their Long COVID.
The findings show that—even in those people who don’t require hospitalization for severe COVID-19—the condition’s prolonged symptoms are having a major impact on lives and livelihoods, both here and around the world. While the number of people affected isn’t yet known, if even a small proportion of the vast numbers of people infected with COVID-19 develop Long COVID syndrome, it represents a significant public health concern.
Another recent study from China further documents the tendency of COVID-19-related symptoms to linger past the usual recovery time for a respiratory virus . The study, published in Lancet, showed that six months after the onset of illness, more than 75 percent of people hospitalized with COVID-19 in Wuhan between January and May 2020 continued to report at least one symptom. Fatigue, muscle weakness, sleep difficulties, anxiety, and depression all were common. More than half of individuals also had significant persistent lung abnormalities, which were more common in those who’d been more severely ill.
It’s essential for us to learn all we can about how SARS-CoV-2, which is the coronavirus that causes COVID-19, leads to such widespread symptoms. It’s also essential that we develop ways to better treat or prevent these symptoms. The NIH held a workshop last month to summarize what is known and fill in key gaps in our knowledge about Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). In December, Congress authorized funding for continued research on PASC, including an appropriation of funds for NIH to support continued study of these prolonged health consequences.
As these efforts and others proceed in the coming months, the hope is that we’ll gain much more insight and get some answers soon. And, if you’ve had or are currently experiencing symptoms of COVID-19, there’s still time to share your data by participating in the Patient-Led Research for COVID-19’s second survey.
 Characterizing Long COVID in an international cohort: 7 months of symptoms and their impact. David HE et al. Medrxiv. 27 December 27 2020.
 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Huang C, Huang L, et al. Lancet. 2021 Jan 16;397(10270):220-232.
COVID-19 Research (NIH)
Posted on by Dr. Francis Collins
Sheltering at home for more than two months has made many of us acutely aware of just how much we miss getting out and interacting with other human beings. For some, the coronavirus disease 2019 (COVID-19) pandemic has also triggered a more selfless need: to be a good neighbor to the most vulnerable among us and help them stay well, both mentally and physically, during this trying time.
The term “good neighbor” definitely applies to Pablo Vidal-Ribas Belil, a postdoctoral fellow at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Though Vidal-Ribas has his hands full caring for his 4-year-old son in their condo, which is located near NIH’s main campus in Bethesda, MD, he wasn’t too busy to notice that some of his neighbors were in need of help.
Vidal-Ribas extended a helping hand to pick up groceries and prescriptions for the older woman downstairs, as well as several more of his elderly neighbors. He and other concerned neighbors also began enlisting more volunteers to join a neighborhood coronavirus task force. There are now up to 30 volunteers and sometimes hold virtual meetings.
To try to reach everyone in the more than 950-unit Parkside Condominium community, the group coordinated its activities with the help of the management office. They also issued flyers and email messages via the neighborhood list serv, offering to assist people at greatest risk for COVID-19, including seniors and those with compromised immune systems or other serious conditions, by shopping for essential items and dropping the items off at their doors.
The personal interest and care of Vidal-Ribas also comes with medical expertise: he’s a clinical psychologist by training. Vidal-Ribas, who is originally from Barcelona, Spain, came to the United States four years ago to work with an NIH lab that specializes in the study of depression and related conditions in young people. Last year, Vidal-Ribas moved to NICHD as a Social and Behavioral Sciences Branch Fellow, where he now works with Stephen Gilman. There, he explores prenatal and early developmental factors that contribute to attempts at suicide later in life.
His expertise as a psychologist has come in handy. Vidal-Ribas has found that many of the individuals requesting help with grocery items or prescriptions also want to talk. So, the team’s efforts go a long way toward providing not only basic necessities, but also much-needed social and emotional support.
In recognition of this need, the group has expanded to offer virtual chats and other community activities, such as physically distanced games, conversations, or story times. One talented young volunteer has even offered to give music concerts remotely by request. Folks know they can call on Vidal-Ribas and some of the most active task force volunteers at any time.
Vidal-Ribas reports that they’ve taken great care to follow the latest guidelines from the Centers for Disease Control and Prevention on how to protect yourself and others from COVID-19 to ensure that those volunteering their time do so safely. He and other volunteers typically buy for multiple neighbors at once while they do their own personal shopping to reduce the number of outings. They then leave the bags with groceries or prescriptions at their neighbors’ doors with no direct contact. As far as he knows, none of his vulnerable neighbors have come down with COVID-19.
Vidal-Ribas says he’s prepared to continue his volunteer outreach for as long as it takes. And, even when the threat of COVID-19 subsides, he’ll keep on lending a hand to his neighbors. It’s one of the ways he stays connected to his community and grounded within himself during this difficult time. By sharing his story, he hopes it will inspire others to do what they can to help others in need to stay safe and well.
Coronavirus (COVID-19) (NIH)
Social and Behavioral Sciences Branch Fellows (National Institute of Child Health and Human Development/NIH)
Stephen Gilman ((National Institute of Child Health and Human Development/NIH)
Posted on by Dr. Francis Collins
The coronavirus 2019 (COVD-19) pandemic has brought into sharp focus many of the troubling things that we already knew about health disparities in the United States but have failed to address. With the bright light now shining on this important issue, it is time to talk about the role research can play in reducing the disproportionate burden of COVID-19, as well as improving the health of all people in our great nation.
In recent weeks, we’ve seen a growing list of disturbing statistics about how blacks, Hispanics, tribal communities, and some other racial, ethnic, and disadvantaged socioeconomic groups are bearing the brunt of COVID-19. One of the latest studies comes from a research team that analyzed county-by-county data gathered about a month ago. Their findings? The 22 percent of U.S. counties that are disproportionately black accounted for 52 percent of our nation’s COVID-19 cases and 58 percent of COVID-19 deaths. In a paper awaiting peer review, the team, led by Emory University, Atlanta, and amfAR, the Foundation for AIDS Research, Washington, DC., noted that neither the size of the county nor whether it was urban or rural mattered .
Recently, I had an opportunity to discuss the disparate burden of COVID-19 with Dr. Eliseo Pérez-Stable, Director of NIH’s National Institute on Minority Health and Health Disparities (NIMHD). Besides leading an institute, Dr. Pérez-Stable is a widely recognized researcher who studies various factors that contribute to health disparities. Our conversation took place via videoconferencing, with him linking in from his home in Washington, D.C., and me from my home in nearby Maryland. Here’s a condensed transcript of our chat:
Collins: Eliseo, you and I recently had a chance to have a pretty intense discussion with the Congressional Black Caucus about health disparities and the COVID-19 pandemic. So, could you start off with a little bit about what populations are being hit hardest?
Pérez-Stable: Collecting data about disease incidence and mortality on the basis of race and ethnicity and other important demographic factors, like socioeconomic status, had really been absent in this pandemic until recently.
Part of that I think is entirely understandable. Hospitals were pressed with a surge of very sick patients, and there was a certain amount of fear and panic in the community. So, people were not completing all these forms that usually get turned in to the health departments and then forwarded to the CDC. If you go back in history, similar things happened in the early 1980s with the HIV epidemic. We weren’t collecting data on race and other sociodemographic variables initially. But, with time, we did complete these data and a picture emerged.
With the COVID-19 pandemic, obviously, the outcomes are much faster, with over 60,000 deaths in just a matter of three months. And we started to see reports, initially out of Connecticut, Milwaukee, Chicago, and New Orleans, that African Americans were dying at a disproportionate rate.
Now, the initial—and I think still the most likely—explanation for this higher mortality relates to two factors. The first is a higher rate of co-morbidities. We know that if you have cardiovascular disease, more than mild obesity, or diabetes, you’re more likely to get severe COVID-19 and potentially die from it. So, we could have just said, “Aha! It’s obvious why this population, and others with higher rates of co-morbidities might be expected to have higher rates of severe disease and higher mortality.”
But there is a second factor that relates to getting infected, for which we have much-less clear data. There was recently a map in The Washington Post showing the distribution of the rate of COVID-19 infections in Washington, D.C., by ward. The highest rates are in the wards that are east of the Anacostia River, which are about 90 percent African American. So, there is an appearance of a correlation between the proportion of African Americans in the community and the rate of Covid-19 infection. Now why could that be?
Collins: Yes, what explains that?
Pérez-Stable: Well, I think crowding is part of it, certainly in this neighborhood. A second option would be multiple families living under one roof.
Collins: So, you can’t exactly practice physical distancing very well in that situation.
Pérez-Stable: Absolutely. You and I can go into our respective rooms, probably have our respective bathrooms, and socially and physically isolate from the rest of the household if need be. Many people can’t do that. They have three generations in one small apartment, all using one bathroom, maybe two bedrooms for six or eight people.
So, we do face different conditions by which one casual infection can lead to much more community transmission. But much information still needs to be ascertained and there does seem to be some regional variance. For example, in Chicago, Milwaukee, and Atlanta, the reports, at least initially, are worse than they are in Connecticut or Florida. Also, New York City, which has been the epicenter of the U.S. for this pandemic, has an increased rate of infections and mortality among Latino-Hispanic populations as well. So, it isn’t isolated to an African-American issue.
Collins: What about access to healthcare?
Pérez-Stable: Again, we can postulate based on a little bit of anecdote and a little bit of data. I’m a general internist by background, and I can see the enormous impact this pandemic has had on healthcare settings.
First, elective ambulatory visits and elective admissions to the hospital have been postponed, delayed, or cancelled. About 90 percent of ambulatory care is occurring through telemedicine or telephone connections, so in-person visits are occurring only for really urgent matters or suspected COVID-19.
If you have health insurance and can use systems, you can probably, through telephone triage with a nurse, get either approval or nonapproval for being tested [for COVID-19], drive to a place, get tested by someone wearing protective equipment, and never actually have to visit with anyone. And you’ll get your result now back as soon as one day, depending on the system. Now, if you’re insured, but don’t really know how to use systems, navigating all these things can be a huge challenge. So, that could be a factor.
People are also afraid to come to clinic, they’re afraid to show up at the emergency room, because they’re afraid to get infected. So, they’re worried about going in, unless they get very sick. And when they get very sick, they may be coming in with more advanced cases [of COVID-19].
So, telephone triage, advice from clinicians on the phone, is critical. We are seeing some doctors base their decisions on whether a person is able to breathe okay on the phone, able to say a whole sentence without catching their breath. These kinds of basic things that we learned in clinical medicine training are coming into play in a big way now, because we just cannot provide the kind of care, even in the best of circumstances, that people may need.
Of course, uninsured patients will have even more barriers, although everyone in the healthcare system is trying their best to help patients when they need to be helped, rather than depend on insurance triage.
Collins: A big part of trying to keep the disease from spreading has been access to testing so that people, even those with mild symptoms, can find out if they have this virus and, if so, quarantine and enable public health workers to check out their contacts. I’m guessing, from what you said, that testing has been happening a lot less in urban communities that are heavily populated by African Americans and that further propagates the spread of the disease. Am I right?
Pérez-Stable: So far, most testing has been conducted on the basis of symptoms. So, if you have enough symptoms that you may potentially need to be hospitalized, then you get tested. Also, if you’re a healthcare worker who had contact with a COVID-19 patient, you might be tested, or if there’s someone you’ve been very close to that was infected, you may be tested. So, I don’t think so much it’s a matter of disproportionate access to testing by one group or another, as much as that the overall triage and selection criteria for testing have been rather narrow. Up until now, it has not been a simple process to get tested for COVID-19. As we scale up and get better point-of-care tests and much easier access to getting tested, I think you’ll see dissemination across the board.
Collins: It’s interesting we’re talking about this, because this is an area that Congress recently came to NIH and said, “We want you to do something about the testing by encouraging more technology, particularly technology that can be distributed to the point-of-care, and that is out in the community.”
Everyone wants a test that gives you a quick turnaround, an answer within an hour, instead of maybe a day or two. A big part of what NIH is trying to do is to make sure that if we’re going to develop these new testing technologies, they get deployed in places that otherwise might not have much access to testing—maybe by working through the community health centers. So, we’re hoping we might be able to make a contribution there.
Pérez-Stable: The economic factors in this pandemic are also huge. A significant proportion of the population that we’re referring to—the disparity population, the minorities, the poor people—work in service jobs where they’re on the front line. They were the restaurant servers and people in the kitchen, they’re still the bus drivers and the Uber drivers, and those who are working in pharmacies and supermarkets.
On the one hand, they are at higher risk for getting infected because they’re in more contact with people. On the other hand, they’re really dependent on this income to maintain their household. So, if they test positive or get exposed to COVID-19, we really do have a challenge when we ask them to quarantine and not go to work. They’re not in a position where they have sick leave, and they may be putting themselves at risk for being laid off.
Collins: Eliseo, you’ve been studying health disparities pretty much your whole research career. You come from a community where health disparities are a reality, having been born in Cuba and being part of the Latino community. Did you expect that COVID-19 would be this dramatic in the ways in which it has so disproportionately affected certain groups?
Pérez-Stable: I can’t say that I did. My first thought as a physician was to ask: “Is there any reason to think that an infectious agent like COVID-19 would disproportionally infect or impact any population?” My gut answer was “No.” Infectious diseases usually seem to affect all people; sort of equal opportunity invaders. There are some data that would say that influenza and pneumonia are not any worse among African Americans or Latinos than among whites. There are some slight differences in some regions, but not much.
Yet I know this a question that NIH-funded scientists are interested in addressing. We need to make sure that there aren’t any particular susceptibility factors, possibly related to genetics or the lung epithelium, that lead to such different COVID-19 outcomes in different individuals. Clearly, something must be going on, but we don’t know what that is. Maybe one of those factors tracks through race or ethnicity because of what those social constructs represent.
I recently listened to a presentation by Rob Califf, former FDA Commissioner, who spoke about how the pandemic has created a spotlight on our disparities-creating system. I think much of the time this disparities-creating system is in the background; it doesn’t really affect most people’s daily lives. Now, we’re suddenly hit with a bucket of cold water called COVID-19, and we’re saying what is going on and what can we do about it to make a difference. I hope that, once we begin to emerge from this acute crisis, we take the opportunity to address these fundamental issues in our society.
Collins: Indeed. Let’s talk about what you’re doing at NIMHD to support research to try to dig into both the causes of health disparities and the interventions that might help.
Pérez-Stable: Prompted by your motivation, we started talking about how minority health and health disparities research could respond to this pandemic. In the short-term, we thought along the lines of how can we communicate mitigation interventions, such as physical distancing, in a more effective way to our communities? We also asked what we could do to enhance access to healthcare for our populations, both to manage chronic conditions and for diagnosis and treatment of acute COVID-19.
We also considered in the mid- and long-term effects of economic disruption—this surge of unemployment, loss of jobs, loss of insurance, loss of income—on people’s health. Worries include excess use of alcohol and other substances, and worsening of mental and emotional well-being, particularly due to severe depression and chronic mental disorders not being well controlled. Intimate partner violence has already been noted to increase in some countries, including France, Spain, and the United States, that have gone on physical distancing interventions. Similarly, child abuse can be exacerbated under these circumstances. Just think of 24/7 togetherness as a test of how people can hold it together all the time. I think that that can bring out some fragility. So, interventions to address these, that really activate our community networks and community-based organizations, are real strengths. They build on the resilience of the community to highlight how we can get through this difficult period of time.
I feel optimistic that science will bring answers, in the form of both therapies and vaccines. But in the meantime, we have a way to go and we a lot to do.
Collins: You mentioned the promise of vaccines. The NIH is working intensively on this, particularly through a partnership called ACTIV, Accelerating Covid-19 Therapeutic Interventions and Vaccines. We hope that in several more months, we’ll be in a position to begin testing these vaccines on a large scale, after having some assurances about their safety and efficacy. From our conversation, it sounds like we should be trying to get early access to those vaccines to people at highest risk, including those in communities with the heaviest burden. But how will that be received? There hasn’t always been an easy relationship between researchers, particularly government researchers, and the African-American community.
Pérez-Stable: I think we have learned from our historical experiences that mistrust of the system is real. To try to pretend that it isn’t there is a big mistake. Address these concerns upfront, obtain support from thought leaders in the community, and really work hard to be inclusive. In addition to vaccines, we need participation in any clinical trials that are coming up for therapeutics.
We also need research on how optimally to communicate this with all the different segments of the population. This includes not just explaining what it means to be eligible for vaccine trials or therapeutic trials, but also discussing the consequences of, say, getting tested, whether it be a viral or antibody test. What does the information mean for them?
Most people just want to know “Am I clear of the virus or not?” That certainly could be part of the answer, but many may require more nuanced responses. Then there’s behavior. If I’m infected and I recover, am I safe to go back out and do things that other people shouldn’t do? We’d love to be able to inform the population about that. But, as you know, we don’t really have the answers to that just yet.
Collins: Good points. How do we make sure, when we’re trying to reach out to populations that have shouldered such a heavy burden, that we’re actually providing information in a fashion that is readily understood?
Pérez-Stable: One thing to keep in mind is the issue of language. About 5 to 10 percent of U.S. adults don’t speak English well. So, we really have to address the language barrier. I also want to highlight the challenge that some tribal nations are facing. Navajo country has had particular challenges with COVID-19 infections in a setting of minimal medical infrastructure. In fact, there are communities that have to go and get their water for the day at a distant site, so they don’t have modern plumbing. How can we recommend frequent hand washing to someone who doesn’t even have running water at home? These are just a few examples of the diversity of our country that need to be addressed as we deal with this pandemic.
Collins: Eliseo, you’ve given us a lot to think about in an obviously very serious situation. Anything you’d like to add?
Pérez-Stable: In analyzing health outcomes, researchers often think about responses related to a metabolic pathway or to a gene or to a response to a particular drug. But as we use the power of science to understand and contain the COVID-19 pandemic, I’d like to re-emphasize the importance of considering race, ethnicity, socioeconomic status, the built environment, the social environment, and systems. Much of the time these factors may only play secondary roles, but, as in all science related to humans, I think they have to be considered. This experience should be a lesson for us to learn more about that.
Collins: Thank you for those wonderful, inspiring words. It was good to have this conversation, Eliseo, because we are the National Institutes of Health, but that has to be health for everybody. With COVID-19, we have an example where that has not turned out to be the case. We need to do everything we can going forward to identify ways to change that.
 Assessing Differential Impacts of COVID-19 on Black Communities. Millet GA et al. MedRxiv. Preprint posted on May 8, 2020.
Coronavirus (COVID-19) (NIH)
Director’s Corner (National Institute on Minority Health and Disparities/NIH)
COVID-19 and Racial/Ethnic Disparities. Webb Hooper M, Nápoles AM, Pérez-Stable EJ.JAMA. 2020 May 11.
amfAR Study Shows Disproportionate Impact of COVID-19 on Black Americans, amfAR News Release, May 5, 2020.
Posted on by Dr. Francis Collins
These colorful lights might look like a video vignette from one of the spectacular evening light shows taking place this holiday season. But they actually aren’t. These lights are illuminating the way to a much fuller understanding of the mammalian brain.
The video features a new research method called BARseq (Barcoded Anatomy Resolved by Sequencing). Created by a team of NIH-funded researchers led by Anthony Zador, Cold Spring Harbor Laboratory, NY, BARseq enables scientists to map in a matter of weeks the location of thousands of neurons in the mouse brain with greater precision than has ever been possible before.
How does it work? With BARseq, researchers generate uniquely identifying RNA barcodes and then tag one to each individual neuron within brain tissue. As reported recently in the journal Cell, those barcodes allow them to keep track of the location of an individual cell amid millions of neurons . This also enables researchers to map the tangled paths of individual neurons from one region of the mouse brain to the next.
The video shows how the researchers read the barcodes. Each twinkling light is a barcoded neuron within a thin slice of mouse brain tissue. The changing colors from frame to frame correspond to one of the four letters, or chemical bases, in RNA (A=purple, G=blue, U=yellow, and C=white). A neuron that flashes blue, purple, yellow, white is tagged with a barcode that reads GAUC, while yellow, white, white, white is UCCC.
By sequencing and reading the barcodes to distinguish among seemingly identical cells, the researchers mapped the connections of more than 3,500 neurons in a mouse’s auditory cortex, a part of the brain involved in hearing. In fact, they report they’re now able to map tens of thousands of individual neurons in a mouse in a matter of weeks.
What makes BARseq even better than the team’s previous mapping approach, called MAPseq, is its ability to read the barcodes at their original location in the brain tissue . As a result, they can produce maps with much finer resolution. It’s also possible to maintain other important information about each mapped neuron’s identity and function, including the expression of its genes.
Zador reports that they’re continuing to use BARseq to produce maps of other essential areas of the mouse brain with more detail than had previously been possible. Ultimately, these maps will provide a firm foundation for better understanding of human thought, consciousness, and decision-making, along with how such mental processes get altered in conditions such as autism spectrum disorder, schizophrenia, and depression.
Here’s wishing everyone a safe and happy holiday season. It’s been a fantastic year in science, and I look forward to bringing you more cool NIH-supported research in 2020!
 High-Throughput Mapping of Long-Range Neuronal Projection Using In Situ Sequencing. Chen X, Sun YC, Zhan H, Kebschull JM, Fischer S, Matho K, Huang ZJ, Gillis J, Zador AM. Cell. 2019 Oct 17;179(3):772-786.e19.
 High-Throughput Mapping of Single-Neuron Projections by Sequencing of Barcoded RNA. Kebschull JM, Garcia da Silva P, Reid AP, Peikon ID, Albeanu DF, Zador AM. Neuron. 2016 Sep 7;91(5):975-987.
Zador Lab (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Drug Abuse; National Cancer Institute