Cerebrum Summer 2020

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NeuroscienceadaptstotheCOVID-19world VIRAL Going


Gerard Karsenty, M.D., Ph.D. That Feeling in Your Bones Page 22

Gerard Karsenty, M.D., Ph.D., is a professor and chair of the Department of Genetics and Development at Columbia University Medical Center. Karsenty’s laboratory identified the master genes of bone formation and parathyroid gland development, and was the first to demonstrate the existence of a central control of bone mass, to uncover its road map, and to establish that bone is an endocrine organ. He showed that the bone-derived hormone osteocalcin is necessary, in mice and in humans, for glucose homeostasis, male fertility, and cognitive functions. Karsenty was awarded his Ph.D. and M.D. degrees at the Medical School of the University of Paris V. He is a member of the editorial board of Cell Metabolism, Genes and Development and the Journal of Cell Biology . Marc Brackett, Ph.D., is founding director of the Yale Center for Emotional Intelligence and professor in the Child Study Center, Yale School of Medicine at Yale University. Brackett is the lead developer of RULER, a systemic, evidence-based approach to social and emotional learning that has been adopted by over 2,000 public, charter, and private pre-school through high schools across the U.S. and in other countries. He is also co-founder of Oji Life Lab, a corporate learning firm that develops innovative digital learning systems for emotional intelligence. With Facebook, Brackett has developed social resolution tools to help adults and youth resolve online conflict, and InspirED, a center to support high school students. Brackett’s new book is Permission to Feel (Macmillan, 2019). Christina Cipriano, Ph.D., is an assistant professor at the Child Study Center and director of Research at the Yale Center for Emotional Intelligence at the Yale School of Medicine. Cipriano’s research focuses on the systematic examination of social and emotional learning to promote pathways to optimal developmental outcomes for traditionally marginalized student and teacher populations. She received her Ph.D. in applied developmental and educational psychology from Boston College and her Ed.M. from the Harvard Graduate School of Education. Cipriano is a Jack Kent Cooke Scholar and the mother of four beautiful children who inspire her each day to take the moon and make it shine for everyone. Kayt Sukel‘s work has appeared in the Atlantic Monthly , the New Scientist , USA Today , the Washington Post , Parenting , National Geographic Traveler , and the AARP Bulletin . She is a partner at the award-winning family travel website Travel Savvy Mom, and is also a frequent contributor to the Dana Foundation’s science publications. She has written about out-of-body experiences, fMRI orgasms, computer models of schizophrenia, the stigma of single motherhood, and why one should travel to exotic lands with young children. She is the author of Dirty Minds : How Our Brains Influence Love, Sex and Relationships and The Art of Risk : The New Science of Courage, Caution & Chance . Brenda Patoine is a freelance science writer, reporter, and blogger who has been covering neuroscience research for more than 30 years. Her specialty is translating complex scientific findings into writings for the general public that address the question of “what does this mean to me?” She has interviewed hundreds of leading neuroscientists over three decades, including six Nobel Laureates. She founded ScienceWRITE Medical Communications in 1989 and holds a degree in journalism from St. Michael’s College. Other areas of interest are holistic wellness, science and spirituality, and bhakti yoga. Brenda lives in Burlington, V.T., with her cat Shakti.

Marc Brackett, Ph.D. Emotional Intelligence Comes of Age Page 28

Christina Cipriano, Ph.D. Emotional Intelligence Comes of Age Page 28

Kayt Sukel Racing to Understand Covid-19 and the Brain Page 16

Brenda Patoine Neuroscience Adapts to the Covid World Page 10




FEATURES 10 Neuroscience Adapts to the Covid World The impact has been sudden and unprecedented, shifting brain science research priorities, and sending shock waves through academia and the global research community. By Brenda Patoine 16 Racing to Understand Covid-19 and the Brain Scientists hope to uncover why the coronavirus sometimes presents neurological symptoms. But how similar is it to other viruses that can invade the nervous system? By Kayt Sukel 22 That Feeling in Your Bones Geneticist Gérard Karsenty at Columbia University Medical center turned to neuroscience to learn why our bones do much more than provide protection and support. By Gérard Karsenty, M.D., Ph.D. 28 Emotional Intelligence Comes of Age Marc Brackett and Christina Cipriano at the Yale Center for Emotional Intelligence trace the formation of a young field and its growing impact on education and personal development. By Marc Brackett, Ph.D., and Christina Cipriano, Ph.D.

POINTS OF INTEREST NOTABLE FACTS IN THIS ISSUE 4 Sherry Chou, a neurologist at the University of Pittsburgh medical center, has organized an international consortium of 50 medical centers to draw neurological data from care that patients have already received. Jumping the Gun , Page 8 4 Further complicating matters are shifting immigration rules that may force foreign nationals, who make up a significant proportion of U.S. researchers, to leave the country. Neuroscience Adapts to the Covid World , Page 10 4 Is the virus getting into the brain directly? Is it affecting the brain through other means? These are important questions to answer. Racing to Understand Covid-19 suggested that the brain, too, is impacted—and that osteocalcin is a messenger, sent by bone to regulate crucial processes all over the body, including how we respond to danger. That Feeling in Your Bones , Page 22 4 Our brains are experience- expectant, constantly evolving and shaping who we are through our interactions with our world and all those within it. Emotional Intelligence Comes of Age , Page 28 and the Brain , Page 16 4 Evidence eventually

SECTIONS 5 Advances Notable brain science findings 6 Briefly Noted By the Numbers, Alzheimer’s Disease, Brain on the Web, The New Normal 7 Bookshelf A few brain science books that have recently caught our eye

8 Neuroethics: Jumping the Gun By Philip M. Boffey

2 Contributors | 4 From the Editor | 26 Advisory Board | 28 Editorial Staff

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Front-Burner Issues

BY BILL GLOVIN Executive Editor, Dana Foundation A s we were trying to decide on what to cover in this issue, the coronavirus was relatively new but already dominating almost every aspect of our lives. All these months later, Covid-19 is still omnipresent. But now, as the world tries to move forward and find answers to the worst global health crisis in modern history, the Black Lives Matter movement and systemic racism has emerged as an issue of vital concern. Given our deadlines, we were unable to address diversity and tolerance in the neuroscience field. We plan to in the future. And while we fear that you may be weary of reading about the coronavirus, it would be odd, and even a bit irresponsible, to ignore it. So, being a publication that focuses on our largest and most complex organ, we offer coverage that has been mostly a sidebar in all of the brain-science reporting dedicated to the pandemic: its potential impact on dementia, stroke, neurodegenerative diseases, mental health, neuroscience as a discipline, and more. Two very talented science writers tackle important issues. First is the enormous impact Covid-19 is having on the field of neuroscience, from education to grants to lab work. Second is a feature on what scientists have already learned about any number of viruses that came before and their effect on the brain. Our neuroethics column examines the dangers associated with the pressure science and the media feel to draw conclusions about the relationship between Covid-19 and the brain. And since it’s impossible to tackle everything, we offer links to notable articles about Covid-19 and the brain that we’ve seen. For readers who are looking to escape for a bit from Covid-19 overload, we offer a feature on osteocalcin, a fascinating, little-known hormone located in bone and that triggers our sense of danger. We are very fortunate to have Gérard Karsenty, a geneticist who is a pioneer in osteocalcin research, explain his path to discovery. We are also fortunate to have Marc Brackett and Christina Cipriano explain the evolution of the relatively new field of emotional intelligence and its impact on education and the business world, based on their research at the Yale Center for Emotional Intelligence. And if you want to dig a little deeper into these topics, you can hear more from some of our authors through our Cerebrum podcasts. Meanwhile, we hope this issue helps enlighten. Stay safe and healthy in these difficult times. l


Bill Glovin Executive Editor

Seimi Rurup Assitant Editor


Brandon Barrera Editorial Assistant

Carl Sherman Copy Editor

Carolyn Asbury, Ph.D. Scientific Consultant

Bruce Hanson Art Director

Cerebrum is published by the Charles A. Dana Foundation, Incorporated. DANA is a federally registered trademark owned by the Foundation. © 2020 by The Charles A. Dana Founda- tion, Incorporated. All rights reserved. No part of this publication may be repro- duced, stored in a retrieval system, or transmitted in any form by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publish- er, except in the case of brief quotations embodied in articles. Letters to the Editor Cerebrum magazine 505 Fifth Avenue, 6th Floor New York, NY 10017 or cerebrum@dana.org Letters may be edited for length and clarity. We regret that we cannot answer each one.


ADVANCES Notable brain science findings


More than one-third of people in the U.S. were showing signs of ANXIETY OR DEPRESSION in April and May, according to estimates by the Census Bureau , compared with one- quarter in 2019. The Bureau and the National Center for Health Statistics are running a weekly “household pulse survey,” collecting data online to quickly track the national mood and other data since the end of April, relatively early in Covid- 19’s progress through the country. This method of collection

our conscious awareness of the pulse, which keeps us from being constantly distracted by our own body sounds, but it could also cause us to miss something superquick, such as a mild shock to the finger, the researchers suggest. They also found that when test volunteers paid conscious attention to their hearts beating, they detected the finger shock even less. l Another potential use for the anesthetic drug KETAMINE is a one-time boost to traditional behavioral therapies to help people abstain from cocaine or alcohol. A chemical derivative of ketamine, esketamine, was approved by the FDA in 2019 as a rapid-acting treatment for severe depression; it is thought to block neural pathways involved in sensory integration, memory, and learning. Researchers wondered if this might open a window to modify memories and sensations that act as strong triggers to people with addictions and lead to relapse. Researchers at Columbia University and the New York State Psychiatric Institute ran separate randomized clinical trials, pairing one dose of the drug (or a placebo) with five weeks of mindfulness-based behavioral training to treat 55 cocaine -dependent people, and with five weeks of motivational enhancement therapy to treat 40 alcohol - dependent people. In both trials, patients who received Researchers have created a simple blood test that can detect ALZHEIMER’S DISEASE (AD). According to a new study , the blood test accurately measures one of the proteins—P-tau181—implicated in AD. Blood P-tau181 indirectly measures tau hyperphosphorylation in the brain, which is one of the hallmarks of the disease, along with the clumpy plaques caused by the protein amyloid β . Prior to this discovery, detecting the proteins and confirming an AD diagnosis was possible only through expensive PET scans, invasive lumbar punctures, or autopsy. l

means the survey only reaches people who have an email address or cell phone number to be contacted; more than 42,000 people responded to the survey in the second week of May. Rates of

anxiety and depression were highest among women, low- income individuals, and younger adults. The young adult numbers are especially worrying as that age group does not seem to be at most risk for the coronavirus; other surveys also have shown an increase in depression, stress, and suicide rates among young adults. l

The brains of young girls and boys fire up in the same ways when they’re doing MATH , according to a study in the Nature journal Science of Learning . Carnegie Mellon University researchers scanned the

brains of 104 kids ages three to ten as they performed basic math tasks and found “one heterogeneous population rather than two categorical groups,” they report. “The findings of widespread gender similarities in boys’ and girls’ brains do not support claims of biological gender differences in childhood.” The results add to the argument that it’s nurture (and societal expectations), not nature, that could explain why there are far fewer teen girls in math-based courses and women in math- based professions. l

We know the brain affects our heart rate—to fight or flee, sit in quiet meditation, or simply keep breathing—but our HEARTBEAT also can affect our perceptions. During the first, strong

beat of the heart’s two-part rhythm, when it pumps blood out to the body, we find it harder to detect a weak electric stimulus to the finger; during the second part, as the blood flows back to the heart, it is easier to detect the stimulus. In a study reported in PNAS, researchers at the Max Planck Institute and the Berlin School of Mind and Brain found that the “P300” component of brain activity is suppressed during the first, outgoing stage. This component is associated with consciousness and decision-making; blocking it suppresses

ketamine were significantly more likely to remain “clean” during the five weeks (48 percent to 11 percent of the placebo group in the cocaine trial), and if they did relapse, it took longer to do so. l

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BY THE NUMBERS 14 million people are projected to be affected by Alzheimer’s disease by 2050. Presently, that number is 5.8 million. 18.6 percent is the increase in antidepressant prescriptions filled in the U.S. from February 16 to March 15. 85 percent of people in a national survey have not heard of the term “aphasia,” a language disorder more common than Parkinson’s, MS, or cerebral palsy. 214 patients, or more than a third in Wuhan, China— where the pandemic started—had neurologic manifestations of the coronavirus. 8,000 steps (roughly four miles) a day helps brain health and may increase your odds of a longer life . ISSUE: Probiotics , which are manufactured mixtures of "good bacteria" that help digest food, have become a growing multibillion-dollar industry. Whether they work was the focus of a recent 60 Minutes segment on the microbiome. During the past 10 years, studies have linked the gut microbiome to a range of complex behaviors, such as mood and emotion, appetite and satiety, and even learning and memory.

Links to brain, mental health, and neuroethics articles we recommend:

> Washington Post: The journey from scientific breakthrough to a life-changing cystic fibrosis drug > Washington Post: She fell more than 30 times. For three years, doctors couldn’t explain why. > Star-Ledger: Living in a ‘toxic’ world raises risk for Alzheimer’s > Scientific American: A Tsunami of Dementia Could Be On Its Way > Tech Crunch: With an ex-Uber exec as its new CEO, digital mental health service Mindstrong raises $100 million > National Geographic: For autistic youths entering adulthood, a new world of challenges awaits > Raleigh News & Observer: Doctors can prescribe a video game for kids with ADHD after landmark FDA decision > The Atlantic: 30 Years Ago, Romania Deprived Thousands of Babies of Human Contact > The American Scientist: The Argument for Music COVID-19 Related > New York Times: Why Am I Having Weird Dreams Lately? > Washington Post: ‘ A minute later, she forgets.’ Pan- demic brings new challenges when a loved one has dementia. > Wired: What Does Covid-19 Do to Your Brain? > NBC News: Her father’s delirium was a first sign of coronavirus. He’s not the only one. > New York Times: Is the Pandemic Sparking Sui- cide? > Associated Press: Pandemic threatens to deepen crisis in mental health care > Star-Ledger: Autism may make it tricky for some to tolerate masks > Scientific American: From Headaches to ‘Covid Toes,’ Corona Virus Symptoms are a Bizarre Mix

The new normal I don’t know anyone right now that’s not having depression-like symptoms. It’s “

hard to keep going when our brains are constantly on fight or flight. It makes people really tired. If you’re having trouble concentrating or getting out of bed, it’s not abnormal. It’s an evolutionary response to a threat. — Luana Marques, psychologist, Harvard Medical School; president, Anxiety and Depression Association of America .


BOOKSHELF A few brain science books that have recently caught our eye

For many medical professionals and community members on the frontlines of the epidemic, naloxone—a short-acting opioid antagonist that “reverses” ODs and saves lives—is the tool coupled with the social movement responsible for shifting the conversation around OD from hushed-tones to the mainstream. In OD: Naloxone and the Politics of Overdose (MIT Press), science historian and professor of science and technology studies, Nancy D. Campbell, follows naloxone’s journey: from its predecessor nalorphine to its synthesis in 1960, and the near-ubiquity it is approaching today. Campbell asks why it took so long for cultural perspectives to accept overdoses as preventable deaths, stressing the necessity of understanding the complex social and material conditions that lie beneath ODs. If meaningful solutions beyond the technological “fixes” that drugs like naloxone proffer are to be realized, Campbell suggests going further than the science of molecular agonists and antagonists. We should not forget the families, witnesses, drug users, former users, advocates, clinicians, and scientists that are part of the social movement; OD is their story. l


What is Health? Allostasis and the Evolution of Human Design by Peter Sterling Systems enduring disruption will make efforts to stabilize and return to normalcy. These error-correcting processes—mechanisms such as shivering or sweating to regulate body temperature—are part of our

physiological regulatory system and are conventionally taught as homeostasis , a feedback-dependent model at the core of modern medical education. But what if a different model of health could shift prescribed therapies for society-wide ailments away from pharmacologically dependent treatments (think obesity, drug addiction, and type 2 diabetes) and offer equitable solutions to societal problems such as climate change? Peter Sterling, Ph.D., a neuroscience professor at the University of Pennsylvania School of Medicine, proposes just that with the concept of allostasis , a model he and Joseph Eyer devised in the 1980s. In What is Health? Allostasis and the Evolution of Human Design (MIT Press), Sterling explains that the allostatic model defines health “as the capacity to respond optimally to fluctuations in demand” and emphasizes “system-level” therapies, such as exercise, that increase the ability for adaptive variation. Sterling dives into the evolutionary history of our dopamine-driven reward system and shows how modern life is inadequately providing the small pulses of “satisfaction” that our biology needs. More importantly, Sterling tacitly admits that his book is meant to offer perspective and aims to elicit critical thinking about current medical practices and societal structure. Sterling’s viewpoint reveals itself to be prescient and, most refreshingly, human. l

The Future of Brain Repair: A Realist’s Guide to Stem Cell Therapy by Jack Price Recovery from stroke can be very different across people—the brain’s plasticity might, after some time, restore some impaired functions to varying degrees. But the brain tissue most deprived of blood flow

is considered lost and irreparable. Will this always be so? Jack Price, Ph.D., professor of developmental neurobiology at King’s College London, asks if stem cell therapies and newer technologies could usher in a new era of brain health. The Future of Brain Repair: A Realist’s Guide to Stem Cell Therapy (MIT Press) considers in detail the growth of stem cell therapies from “tentative ideas” into an ambitious clinical program. Readers can expect to learn why brain repair has stymied neuroscientists and the areas where possible breakthroughs might give birth to real regenerative brain treatment, with Price describing pluripotential stem cells as the potential game-changers. He discusses clinical trials for stem cell therapies for Parkinson’s, stroke, and macular degeneration, and the possibility of new licensed therapies. While stem cell therapy has tugged at the imagination with much hyperbole, Price approaches the science with nuance and empirically tinged optimism. l

OD: Naloxone and the Politics of Overdose by Nancy D. Campbell A 2020 Centers for Disease Control and Prevention report shows that, in 2018, more than 67,300 drug overdose (OD) deaths occurred across the U.S., a four percent decrease from the previous year, and, hopefully, the beginning of a downward trend.

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Jumping the Gun

earlier infections of other strains of coronaviruses and of the strain currently causing Covid-19. The review is notable mostly for how much remains unknown. The paper cites reports of neurological complications, such as loss of smell and taste and headaches, which seem relatively minor, and some potentially far more serious consequences such as strokes, impairment of consciousness, seizures, and encephalopathy. But the mechanisms that may be involved in the various neurological complications that have been seen in association with Covid-19 infection remain uncertain. It remains unknown to what extent the virus damages the nervous system directly or whether the complications are attributable to some secondary mechanism such as an overwhelming immune response , or whether some of the complications are an independent co-occurrence. The researchers called for further studies to understand the pathogenesis of the disease in the central nervous system (CNS). They also deemed longitudinal neurologic and cognitive assessments of individuals after recovery from Covid-19 “crucial” to understand the natural history of the disease in the CNS and to monitor for any long-term neurological sequelae. From severe neurological complications in children to mental health concerns to large observational studies, media has sounded the alarm—despite a lack of scientific data. The journal Science , for example, reported that 25 cases in England of a rare inflammatory condition had raised alarms and that dozens more cases in New York and fewer clusters elsewhere had ratcheted up the concern. Meanwhile, an Italian study published in The Lancet found that eight out of ten children with severe Kawasaki-like disease had antibodies to Covid-19, an

indication that they had been infected with the virus. But we still don’t know whether these severe illnesses in children are caused by the virus, the body’s immune response to the virus, or by some combination of these or other factors. Observational studies published in major journals in Japan, Germany, Iran, and elsewhere have also given conflicting results. One of the largest and most frequently cited, for example, was conducted in Wuhan, China, and published in JAMA Neurology as early as April. It examined a series of 214 consecutive patients hospitalized with laboratory-confirmed Covid-19 at three special care centers in Wuhan. Neurologic complications were seen in 36.4 percent of the patients and 45.5 percent of the severely ill patients, which struck this layman as surprisingly high. But an editorial in the same issue, by scientists at the University of California, San Francisco, concluded that the extent of neurological manifestations has remained unclear and that the Wuhan paper reports “an early view of the incidence and types of neurologic complications and sets the stage for further longitudinal work in the area.” What some are calling “the new normal” tells us that there is little doubt that the pandemic will have lasting mental health effects. An opinion article in Scientific American warned that a “tsunami of dementia” could be on the way because the pandemic can damage the aging brain both directly and indirectly. Respiratory failure increases the risk of dementia due to lack of oxygen to the brain, and hospitalization generally, as well as treatment with ventilators or sedatives, can cause delirium and severe confusion. Moreover, social distancing, shelter-in- place mandates, and limits on visits to nursing homes can exacerbate


F rom scientists and sociologists to psychologists and economists, a worldwide scramble is underway to understand Covid-19 and the brain, but each nugget of information gained seems to be followed by other nuggets that confuse the issue. At this point, lacking any clinical evidence, there is only is a single prospective randomized controlled clinical trial, the gold standard for pinning down causes and consequences. For now, all we have are anecdotal reports, preprints, retrospective observational studies, and media reports of interviews with researchers. In early June, the New York Times reported in amazement about the number of overall scientific papers that have been published, writing that “It is hard to think of another moment in history when so many scientists turned their attention to one subject with such speed.” They reported that the National Library of Medicine ’s database at the start of June contained over 17,000 published papers about the new coronavirus. Most of the papers published about Covid-19 and the brain concerned the viruses’ respiratory effects. But the possible neurological complications, which were observed, have proven especially perplexing. The broadest review of existing knowledge—published online in JAMA Neurology on May 29—illustrates the enormous uncertainties. The authors, all researchers at the Yale School of Medicine, analyzed articles published between 1969 and April 2020 to understand the effects of


MIT Press announced on June 29 that it was launching a new journal called Rapid Reviews-Covid 19 with the explicit purpose of reviewing preprint articles about the pandemic.

been withdrawn by authors or will never appear in a journal. In response to this dilemma, MIT Press announced on June 29 that it was launching a new journal called Rapid Reviews- Covid 19 with the explicit purpose of reviewing preprint articles about the pandemic. The journal will use both artificial intelligence (AI) and an army of volunteer reviewers to parse out the most “important” preprint studies in need of review. This important step needs to mimicked by the media. In publishing or broadcasting summaries of the research or claims in social media accounts, the media needs to make sure the information has been properly vetted and approach the claims with healthy skepticism. The media, which often fails to vet information responsibly due to the pressure of what has become a scramble to satisfy the 24/7 news cycle, needs to do a better job of helping its audience filter out weak research and misleading claims. In an article on the popular website, WebMD, Robert Stevens, M.D., a neurologist at Johns Hopkins School

loneliness that may increase the risk of depression or declines in memory over the long-term. An important research project that caught my eye, and which is now underway, may help shed more light on how to understand, diagnose, and treat Covid-19 and its neurological complications. Sherry Chou, a neurologist at the University of Pittsburgh medical center, has organized an international consortium of 50 medical centers to draw neurological data from care that patients have already received. Her early goal is to determine the prevalence of neurological complications among hospitalized patients and document how they fare. Her longer-term goal is to gather scans, lab tests, and other data to better understand the impact of the virus on the nervous system, including the brain. While the mobilization of the world’s scientific community to understand Covid-19 is unprecedented in history, keep in mind that more than 4,000 papers—known as preprints—have yet to be peer-reviewed. Some have

of Medicine, found neurological complications to be rare from patients infected with the new coronavirus, and he pointed out that “most people are showing up awake and alert and neurologically appear to be normal.” As to why the brain can sometimes be affected, he added that “we are still in the early days of this, and we don’t really know for sure.” Such caution from Stevens and others on the frontlines is the reason we need to be cautious at making definitive pronouncements. Over time, the global research effort ought to provide the answers and help us triumph over this baffling virus. l Phil Boffey is former deputy editor of the New York Times Editorial Board and editorial page writer, primarily focusing on the impacts of science and health on society. He was also editor of Science Times and a member of two teams that won Pulitzer Prizes. The views and opinions expressed are those of the author and do not imply endorsement by the Dana Foundation.

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roscience Adapts to the COVID WORLD BY BRENDA PATOINE ILLUSTRATION BY DANIEL HERTZBERG T HE STORIES FROM THE FRONT LINES OF NEUROSCIENCE RESEARCH IN THE COVID-19 ERA read like a script of a frightening Netflix drama. Entire laboratories shutting down with 48 hours’ notice, researchers scrambling to finish experiments, freeze bio samples, preserve data. Painstakingly bred transgenic animal colonies reluctantly euthanized in university basements. Thousands of clinical trials halted overnight. Then came work-at-home, which for many meant a different kind of drama: balancing academic research with full-time parenting. Add in hiring freezes, funding uncertainties, reopening hurdles, safety protocols, and second-surge concerns, and you’ve got the makings of a principal investigator’s or postdoc’s worst nightmare.

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Young scientists and trainees at crucial points in their careers may be particularly vulnerable, facing derailment in their research paths through no fault of their own.

shuttered. One of the early actions from the NIH—an effort to “plug the hole in the dam,” as Koroshetz put it—was to assure investigators that salaries and stipends covered by federal grants would continue to be paid even as research stopped. The NIH also issued across-the-board extensions for grant applications and assured flexibility for deadlines and timelines, and pledged financial support for shutdown-related delays. How the pandemic will impact the NIH budget moving forward is a big unknown. Robert Finkelstein, Ph.D., director of the extramural research division at NINDS, points to estimates that it would take $9 billion “to make labs whole” after the Covid-19 disruptions—meaning, essentially, re-appropriating the entire NIH 2020 extramural research fund. Where that would leave next year’s research budget is the question on everyone’s minds. “Do we help recoup this year at the expense of next year?” Finkelstein asks. Vulnerable Populations Young scientists and trainees at crucial points in their careers may be particularly vulnerable, facing derailment in their research paths through no fault of their own. Investigators who are at transitional points in their five-year, NIH-funded research grants and who need preliminary results to apply for their next grant are also at risk. Further complicating matters are shifting immigration rules that may force foreign nationals, who make up a significant proportion of U.S. researchers, to leave the country. Childcare and working-parent issues—a perennial concern for women in science—are looming larger than ever in the Covid era of school and childcare closures. In an April commentary in Nature , Alessandra Minello, a social demographer at the University of

Like so many other sectors of society, neuroscience has been hard hit by the coronavirus pandemic. The impact was sudden and unprecedented, bringing virtually all forms of research to a stunned halt and sending shock waves through the global research community. Three months into the laboratory lockdown, as Cerebrum goes to press, scientists are grappling with a radically transformed day-to-day reality, a growing recognition of the lasting impact of Covid-19 on science, and a lot of questions about the way forward. “We’ve lost months of work; there’s no getting around that,” says Walter Koroshetz, M.D., director of the National Institute for Neurological Disorders & Stroke (NINDS) and Dana Alliance

member. Data gathering is mostly halted across the massive research portfolio overseen by the National Institutes of Health (NIH), both internally at institute labs in D.C. and at federally funded laboratories across the country. Clinical research has also been largely at a standstill for the safety of study participants, many of whom have compromised health. Delays in data- gathering lead to delays in results, which means missed deadlines for enrollment goals and other milestones on which further funding is generally based. Domino effects will be felt well past 2020. ‘A Year that Didn’t Happen’ “Everyone is facing a year that didn’t happen, scientifically speaking,” Indira Raman, a neurobiologist at Northwestern University and advisor to NINDS, said in a May 27 meeting of the NINDS Advisory Council that was webcast live . The session was largely focused on how Covid-19 is affecting neuroscience and how to minimize the damage to investigators and their research programs. It wasn’t just experiments that were left in limbo when labs across the country were forced to shut down. Many research staff also wondered how they could continue their work—and continue to be paid—with their labs

Walter Koroshetz / NINDS


she mentors are home with young children, making it impossible to write grants and stay focused. “People are profoundly unproductive in terms of their research,” she says. Hollis Cline, head of neuroscience at Scripps Research Institute, warns that “we are going to lose a cohort of young women scientists who are going to fall through the cracks.” “Childcare,” says Koroshetz, “is the big elephant in the room.” NIH grants don’t cover scientists’ childcare, and there is currently no system for accommodating parenthood in research timelines and applications. Covid sharpens those inequities. Restarting to a New Normal Getting research started again is going to take time and money, with a cost easily in the millions. How to fund that is a big issue, given the financial difficulties many academic medical centers are facing.

Indira Raman / Northwestern

Florence, Italy, wrote of the pandemic’s exacerbation of the “maternal wall” facing female researchers who also wish to have a family. “Academic work— in which career advancement is based on the number and quality of a person’s scientific publications, and their ability to obtain funding for research projects—is basically incompatible with tending to children,” Minello writes. Several female members of the NINDS Advisory Council underscored the outsized impact of parenting on women. Duke University neuroethicist

Nita Farahany says, “People with young kids at home are being disproportionately affected, and caretaking disproportionately falls on women.” Karen Johnston, a stroke researcher at the University of Virginia, says many of the young investigators

Childcare is the big elephant in the room.” NIH grants don’t cover scientists’

childcare, and there is currently no system for accommodating parenthood in research timelines and applications. Covid sharpens those inequities.

Robert Finkelstein / NINDS

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The Covid Pivot As in other areas of science, many neuroscientists are shifting their attention to Covid-19 research. Many of those with clinical training have been recruited to clinical care. Others are carving out creative ways to support coronavirus-related research or care, such as donating unused Personal Protective Equipment (PPE) to medical teams or creating online portals for supporting work in the area, like the Covid-19 Neuro-Arts Field Guide . A group at Columbia University’s Zuckerman Institute set up a 3-D printing shop in their Education Lab, and has been turning out PPE for healthcare workers in New York. Shannon Agner, a pediatric neurologist at Washington University who studies how viruses affect the brain, launched a research program to track the neurodevelopment of babies born to mothers with Covid. In May, NINDS announced supplemental grants available to current grantees for Covid-related research, creating a mechanism for quickly launching research on how the virus affects the brain. The first of these is a NINDS-based web database to track neurological complications of infection with the SARS-COV2 virus, which has been operational since May. “We need to understand what Covid is doing in the brain and the long-term effects of that,” Koroshetz says. Acute Respiratory Distress Syndrome (ARDS), one of the serious complications of Covid-19, is frequently associated with cognitive problems and fatigue in the long term. Among the research questions being asked are: what is causing the prothrombotic, stroke-prone state of the brain during Covid infection, given that both large and small strokes can be a clinical feature of coronavirus infection even before other symptoms

“Clinical, translational, and basic research has been on hold since March. The ramp-up is not going to be sudden, but long,” says Koroshetz. Colonies of research animals will need to be rebuilt, tissue samples thawed and regrown, experiments repeated—all in a socially distanced manner subject to local conditions. “You can’t snap your fingers and be back up and running again.” As of late May, most institutions were putting return-to-work plans into place and trying to figure out how to ease back into laboratory research in a way that protects everyone involved, according to Vicky Whittemore, an NINDS program officer for basic research on epilepsy. Rules may dictate that no more than one person be in the lab at a time, or that labs require partitions. At Johns Hopkins University Hospital, shift work and antigen testing of staff are among the options being

Justin MacArthur / Johns Hopkins

considered, says Hopkins Chief of Neurology Justin MacArthur. A surge of new infections could mandate another shutdown, and people are grappling with how best to prepare for that possibility.

A Johns Hopkins University neurologist

says the institution’s Covid experience “has been a springboard for incredible advancement in telemedicine visits, from just a handful to thousands and thousands.”


manifest; what is the mechanism behind the Covid symptom of anosmia (loss of smell), and does that mean the virus can enter the brain via the olfactory bulb; and what are the neural consequences of the “cytokine storm,” the disordered immune response associated with Covid-19. Silver Linings? Amid the chaos and confusion of science interruptus are a few silver linings that portend long-term benefits of pandemic-forced changes. One example cited by many is the rapid advancement of telemedicine in clinical care and its potential applications to research. In the clinical realm, the switchover to video-based medical visits had been slogging along for years, mostly limited to special populations who were unable to get to a doctor, but it had never really caught on as general practice. With Covid, it became an urgent necessity overnight, as doctor’s offices and hospitals shut their physical doors. Medical groups scrambled to get their systems in place, and barriers to insurance coverage of telehealth fell away. MacArthur, the Johns Hopkins University neurologist,

Nita Farahany / Duke

says the institution’s Covid experience “has been a springboard for incredible advancement in telemedicine visits, from just a handful to thousands and thousands.” While the adoption of telemedicine has catapulted far ahead of where it would be without a pandemic, “teleresearch” has been a little slower to follow, even as the possible applications span all phases of clinical research, from recruitment to e-consent to follow-up. Spurred by the need to sustain research progress during social distancing, researchers are making inroads into each of these areas. In an American Nurses Association webinar on Continuing Clinical Care During Shelter-in-Place, Lesli Skolaris, a stroke neurologist at University of Michigan, says her team has taken clinical trial recruitment “wholly virtual” and says they “may never go back to in-person recruitment.” Jeffrey Cohen, a multiple sclerosis researcher at the Cleveland Clinic, says their research team switched to virtual visits within a week of the Covid shutdown and has shifted some clinical trial assessments to

virtual as well, such as patient reporting or self-administered performance tests. “The old model of research, in which participants have to come to the study site, needs to be reassessed,” Cohen says. One area of need is for scientifically validated assessment protocols tailored for virtual platforms. The pandemic is also shifting the ground for scientific conferences of all sizes, as scores of meetings have been cancelled and others moved online. The 2020 annual meeting of the Federation of European Neuroscience Societies will be a completely virtual affair for the first time ever. So will the meeting of the American Neurological Association (ANA)—a move MacArthur, the current ANA president, predicts “is going to change academic life substantially.” Others say it signals the impending (and overdue) extinction of large in-person meetings that are carbon- intensive. “In every crisis is an opportunity,” Koroshetz says with an eye to the future. “For clinical neuroscience, it’s how to use these newer tools and put them into play over the long-term.” l

Shannon Agner / Washington University

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Racing to Understand Covid-19 Brain and the



A 44-YEAR-OLD MALE PATIENT, with no history of cardiovascular disease, arrived at an emergency room in New York City after experiencing difficulty speaking and moving the right side of his body. The on-call physician quickly determined he had suffered a stroke—a condition that normally affects people who are decades older. In Italy, a 23-year-old man sought care for a complete facial palsy and feelings of “pins and needles” in his legs. Doctors discovered axonal sensory-motor damage suggesting Guillain Barré Syndrome, a rare autoimmune neurological disorder where the immune system, sometimes following an infection, mistakes some of the body’s own peripheral nerve cells as foreign invaders and attacks them. A 58-year- old woman in Detroit was rushed to the hospital with severe cognitive impairment, unable to remember anything beyond her own name. MRI scans showed widespread inflammation across the patient’s brain, leading doctors to diagnose a rare but dangerous neurological condition called acute necrotizing hemorrhagic encephalopathy. A


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At first glance, it may seem that these patients have little in common. Yet all three were also suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, better known as Covid-19. While most individuals infected with this new virus exhibit fever, cough, and respiratory symptoms, doctors across the globe are also documenting patients presenting with a handful of neurological manifestations— leading clinicians and researchers to wonder if Covid-19 also has the ability to invade the human nervous system. “As more people are being tested and diagnosed with this virus, physicians are starting to see more uncommon symptoms and complications, including neurological ones,” says Diane Griffin, M.D., Ph.D., a researcher at Johns Hopkins University’s Bloomberg School of Public Health. “But as Covid-19 is a new virus, we aren’t yet sure why these things are happening. Is the virus getting into the brain directly? Is it affecting the brain through other means? These are important questions to answer.” Viruses and the Nervous System Viruses, simply defined, are submicroscopic infectious agents that can only replicate inside the cells of living hosts. While experts still hotly debate whether these molecules of nucleic acid, protected by a protein shell, should be considered “living,” they are unquestionably insidious in their ability to hijack the inner machinery of cells for their own reproductive purposes, sometimes causing overwhelming damage to their host in the process. Over the last century, the world has seen outbreaks of numerous virus-caused diseases, ranging from polio to influenza to the human immunodeficiency virus (HIV). Some of these have led to devastating pandemics, resulting in millions of deaths. Others, however, only cause mild symptoms, an expected nuisance to deal with each fall and winter. Kenneth Tyler, M.D., chair of the Department of Neurology at the University of Colorado (UC) Anschutz Medical Center, observes there are many viruses that affect the nervous system. Even Diane Griffin / Johns Hopkins

garden variety flu can lead to neurological problems in certain patients—yet, it is important to remember that this remains a rare occurrence. “Millions, perhaps even billions, of individuals are infected with different viruses all the time, and there’s never any issue with the brain,” he says. “Yet, in some cases, we do see encephalitis, or inflammation of the brain due to a particular infection. We are learning there are many reasons why that can occur—

Kenneth Tyler / University of Colorado

and it doesn’t always happen in the same manner or even cause the same type of damage. Some viruses can directly infect different brain cells, both the neurons themselves and glial cells. Others may get to the brain in other ways. It all gets rather complicated rather quickly.”

Taking Different Doors into the Nervous System Dorian McGavern, Ph.D., a senior investigator at the National Institute of Neurological Disorders and Stroke (NINDS), says it is difficult for viruses to gain direct access to the central nervous system (brain and spinal cord). “It’s a relatively closed compartment,” he says. “To get into the brain or spinal cord, a virus has to essentially invade all

Dorian McGavern / NINDS

the brain’s peripheral defenses like the blood-brain barrier as well as the different immune responses. It’s not that easy.” Viruses may enter their hosts through the gastrointestinal tract, the respiratory tract including the nose (and the neurons that reside there), or through the bite of a mosquito or infected animal. The point of entry, and how the virus might spread from that point, likely determine which bodily systems may be most affected. For example, some scientists are hypothesizing that Covid-19 may be targeting blood vessels, which is why we see such widespread damage across different organs. Blood vessel infection would help explain the blood clots seen in some of the young stroke patients, not to


Millions, perhaps even billions, of individuals are infected with different viruses all the time, and there’s never any issue with the brain.

mention inflammatory syndromes observed in the brain. “The blood-brain barrier is made up of blood vessels,” says Griffin. “So, if a virus can replicate in the cells of blood vessels,

compromised by viral infection. The lungs may not be able to supply sufficiently oxygenated blood to the brain, resulting in ischemia and cell death. The failure of those vital systems may also lead to more blood clots. Sherry Chou, M.D., an associate professor of Critical Care Medicine, Neurology, and Neurosurgery at the University of Pittsburgh Medical Center, says anecdotal evidence suggests that Covid-19 patients may be more prone to stroke. “Right now, this is a hunch, based on what physicians are seeing, that needs to be investigated further,” she says. “But, that said, we don’t fully understand what might be behind this phenomenon if it does exist. Could the blood vessels be infected, leading to clots? Could it be the fact that these patients are sick enough that organs start failing which means the clotting system isn’t doing what it is supposed to do and that’s the issue? We just don’t know yet.”

it has a rather direct entrance to the brain. But it could also come into the brain from cells in the blood that are allowed to cross the blood-brain barrier. It could come in through the olfactory neurons in the nose, which project to the rest of the brain. Given the number of direct approaches available, it’s actually amazing that we don’t see viruses causing neurological issues more often.” But it’s just as possible that Covid-19

Sherry Chou / University of Pittsburgh

is not infecting the brain directly, causing neurological impairment

through secondary pathways. One hypothesis that many hold is that damage comes from an overactive immune response to the novel coronavirus, a so-called “cytokine storm.” Proinflammatory cytokines, proteins produced by immune cells to fight off the virus, are released in overwhelming numbers and intensity at an infection site, enter the bloodstream, and produce severe and destructive inflammation in cells and tissues. “Sometimes damage comes from the inflammatory process and immune response—that’s really the culprit,” says Griffin. “The immune system is there to get rid of the virus. But sometimes the kinds of molecules it produces to fight off the virus can be just as detrimental to the cells as the virus is. It’s a bit of a double-edged sword.” Finally, some of the brain-related effects documented with Covid-19 may be the result of other bodily systems being

Damage Now, Damage Later Viruses may also set the brain up for later problems. When Richard Smeyne, Ph.D., a neuroscientist at Thomas Jefferson University who specializes in Parkinson’s disease, viewed a video of a duck infected with bird flu (H5N1), his first thought was, “This bird has Parkinson’s disease.” After studying the brains of infected animals, he discovered the virus had the ability to directly infiltrate and destroy cells in the

Richard Smeyne / Thomas Jefferson University

substantia nigra, the same part of the brain affected by the neurodegenerative disorder. While human beings with H5N1 did not show full-blown Parkinson’s disease, they did often

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