CerebrumSummer2020

VIRAL Going

Neuroscience adapts to the COVID-19 world

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.

Emotional Intelligence Comes of Age

Page 28

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.

Emotional Intelligence Comes of Age Page 28

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 Racing to Understand Covid-19 and the Brain

Page 16

Brenda Patoine

Neuroscience Adapts to the Covid World Page 10

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.

COVER ILLUSTRATION: WILLIAM HOGAN

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.

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

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 and the Brain, Page 16

4 Evidence eventually 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 experienceexpectant, 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

Front-Burner Issues

BY BILL GLOVIN Executive Editor, Dana Foundation

As 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

EMERGING IDEAS IN BRAIN SCIENCE

Bill Glovin Executive Editor

Seimi

Rurup Assitant Editor

Podcast

Barrera Editorial Assistant

Brandon

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 Foundation, Incorporated. All rights reserved. No part of this publication may be reproduced, 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 publisher, except in the case of brief quotations embodied in articles.

Letters to the Editor

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Letters may be edited for length and clarity. We regret that we cannot answer each one.

ADVANCES

Notable brain science findings

BY NICKY PENTTILA

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 onequarter 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 Covid19’s progress through the country. This method of collection 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, lowincome 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 mathbased 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

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

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 alcoholdependent people. In both trials, patients who received 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

PHOTO: DENNIS CONNORS

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

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

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.

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

> 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.’ Pandemic 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 Suicide?

> 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

BOOKSHELF

A few brain science books that have recently caught our eye

BY BRANDON BARRERA

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

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.

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

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

Jumping the Gun

BY PHILIP M. BOFFEY

From 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

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-inplace mandates, and limits on visits to nursing homes can exacerbate

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.

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

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 ReviewsCovid 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

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.

Neuroscience

BY BRENDA PATOINE

ILLUSTRATION BY DANIEL HERTZBERG

Neuroscience Adapts to the COVID WORLD

THE 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.

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 datagathering 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

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

Walter Koroshetz / NINDS

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.

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

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.

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.

inequities.

Indira Raman / Northwestern

Robert Finkelstein / NINDS

“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

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.

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

Justin MacArthur / Johns Hopkins

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,

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 carbonintensive.

“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

Nita Farahany / Duke

Shannon Agner / Washington University

Racing to Understand

Covid-19 Brain

and the

BY KAYT SUKEL ILLUSTRATION BY DAN PAGE

AA44-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-yearold 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.

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

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— 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 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

Diane Griffin / Johns Hopkins

Dorian McGavern / NINDS

Kenneth Tyler / University of Colorado

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, 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 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

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.”

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 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

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

Sherry Chou / University of Pittsburgh

Richard Smeyne / Thomas Jefferson University

exhibit symptoms such as tremors—the kind of movement disorder seen in Parkinson’s. Smeyne wonders if there might be a link between viral infection and this or other forms of neurodegeneration.

“We know, for example, that the 1918 flu pandemic killed a lot of people,” he says. “But what a lot of people don’t realize is that starting around 1936 to 1943, there was a dramatic increase in the rate of Parkinson’s disease. It’s the only time, I believe, in history, that the average incidence rate (number of newly diagnosed people at a specific time point) jumped from two to three percent in people over the age of 55. There could be a link between flu infection and later issues.”

H1N1, or the swine flu, does not directly infect neurons like its bird counterpart. Yet, studies consistently show that it can lead to a cytokine storm or hyperactive immune response in the brain. When Smeyne and his team gave mice that had recovered from a previous swine flu infection small doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that can mimic Parkinson’s disease, they found that evidence of permanent damage.

“The animals that had been infected showed basically a Parkinsonian-type lesion in the (brain’s) substantia nigra. Those who hadn’t been infected showed no effect,” he says. “It suggests that flus or viruses that cause these cytokine storms could prime the brain for later insult. It’s possible that your brain could sustain damage later from the virus you were infected with today.”

Understanding Covid-19 and the Brain

As more case studies about Covid-19 are published, it is becoming clear that SARS-CoV-2 is a virus with immense

reach. But to date, much of what doctors and scientists have to go on is anecdotal evidence—not hard data. Moving forward, UC neurologist Tyler says, there are many questions that need to be investigated so we can better understand how the novel coronavirus impacts the brain and neurological function.

“It’s hard to do research in the middle of a pandemic— doctors are focused on saving lives,” he says. “But these case studies are showing that we better pay attention. Future studies should look carefully at how this virus enters the host, what kind of cells it infects, how it spreads in the body, and what kind of damage it is doing. That’s going to take time.”

Pathological studies looking at individuals who have perished from Covid-19 have already started. A small pathological study of 18 patients, published as a letter in the New England Journal of Medicine in June, suggests that most damage occurred due to hypoxia, or a lack of oxygen to the brain. Researchers are also relying organoids, so-called “mini-brains,” to see how the virus may affect the different cells in these three-dimensional, self-organization tissue culture models. Using this approach, researchers from Johns Hopkins University discovered that Covid-19 can both infect and spread across neural tissue—but they cannot say with any certainty that the virus can pass through the blood brain barrier to get into the brain in the first place.

While such studies are revealing curious and sometimes contradictory new insights about Covid-19, they are only a first step in a long scientific journey. To more fully understand how this virus affects the nervous system, researchers will need a good animal model and, until a vaccine is developed, a biosafety level 3 laboratory in which to do controlled experiments.

To get into the brain or spinal cord, a virus has to essentially invade all the brain’s peripheral defenses like the bloodbrain barrier as well as the different immune responses.

“One of the biggest challenges is finding an appropriate model—not all viruses affect mice or rats the same way they do humans,” says NINDS scientist McGavern. “A good model system allows us the ability to work out the molecular mechanisms and get a better idea of what the virus is doing, how it’s getting into the body, what cells it infects, and how it’s disrupting those cells.”

Such studies can help illuminate how Covid-19 does neurological damage now—and, potentially, in the future.

Human studies will be vital in developing treatments for the novel coronavirus. Pittsburgh’s Chou and colleagues have already started a multi-center international consortium to look at the links between Covid-19 and stroke.

“The initial phase 1 study is already up and running,” she says. “Its focus is really trying to describe the phenomenon that neurocritical care professionals are seeing. How many people with Covid-19 are having this problem? What does the problem look like, exactly? Once we know that, we can dive

in more deeply to ask how this stroke may happen, as well as the possible mechanisms and risk factors involved.”

But both she and other researchers caution that it will take time to fully understand the nature of Covid-19 and how it affects the central nervous system. While that may sound daunting in the midst of the current pandemic, the good news is such research findings will likely better prepare both scientists and clinicians for the next.

“When you think about the different viruses that have emerged over the last century—AIDS, H1N1, Ebola, West Nile, Zika, just to name a few—the one predictable thing seems to be that new viruses are going to continue to emerge as human pathogens,” says Tyler. “It’s likely that many of them will have an impact on the human nervous system in different ways. The more we can understand the pathogenesis of these viruses, even though they are quite different, the more we can add to our base of knowledge so we can better understand and manage the next virus that comes along, whatever it may be.” l

POXVIRUS VACCINIA VIRUS MUMPS

RABIES VIRUS ORF VIRUS

HERPES VIRUS

RETROVIRUS TIPULA IRIDESCENT VIRUS

ADENO VIRUS TOGAVIRUS

CORONAVIRUS INFLUENZA VIRUS

TOBACCO MOSAIC VIRUS POLYOMA VIRUS POLIOMYELITIS VIRUS BACTERIOPHAGE

Viruses which can infect humans come in a variety of shapes and sizes, and differ in their ability to invade and affect hosts.

THAT FEELING IN YOUR BONES

BY GÉRARD KARSENTY, M.D., Ph.D. ILLUSTRATION BY JAMES O’BRIEN

BONES T

HE STORY BEGINS VERY FAR FROM NEUROSCIENCE. In the early 1990s, as an assistant professor of molecular genetics, I was interested in the molecular basis of bone mineralization. This led me to osteocalcin, a bone-derived hormone found at high concentrations in the skeleton. But there were obstacles to this research. For one, making a knock-out mouse lacking osteocalcin to help determine its functions was anything but easy. More generally, entering a new field made it extremely difficult to find funding, gain acceptance among my peers, and address other real-life issues.

Research by geneticist

Gérard Karsenty at Columbia University

Medical center has revealed that our bones do much more than provide protection and support. A protein called osteocalcin—released as a hormone by the skeleton—has been linked to sugar levels, exercise, and male fertility. More recently, he has shown that osteocalcin triggers a “fight or flight” response to threat.

Eventually, we were able to engineer mice that lacked osteocalcin, and we anticipated that we would find problems with their bones. But their skeletons appeared essentially normal, a result I found intriguing as well as discouraging. Equally intriguing were a number of other issues we found. The mice had unusually fatty abdomens; they had trouble breeding and, unlike typical rodents, never rebelled or tried to bite or escape. The lack of osteocalcin, apparently, had wide-ranging effects on mice’s fat stores, livers, muscles, pancreases, and testes.

Based on such observations, in 1995 I hypothesized that osteocalcin is a hormone that regulates fertility and some aspects of energy metabolism, including fat mass. If so, does this make bone an endocrine organ that directly influences the physiology of other organs, starting with reproductive functions and energy metabolism? At that time, I was not bold enough to follow this hypothesis, and it took me ten years to muster the courage to explore it further.

Evidence eventually 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. The narrative of how these discoveries—much of which controverted accepted scientific dogma—were made over 25 years is anything but linear.

Early Findings

Skeletons do a lot more than just give our bodies their shape. In 2007, we were able to show that through osteocalcin, bones play a crucial role in regulating blood sugar: mice engineered to lack the hormone were essentially diabetic; they were less sensitive to insulin and produced less of it than wildtype mice. When we provided osteocalcin, their insulin sensitivity and blood sugar normalized. When we first presented these findings at a conference, endocrine experts were surprised by the potential implications for the treatment of metabolic diseases, chief among them being type 2 diabetes. Our work also raised provocative questions about the skeleton’s role in fertility. In 2011, we discovered that bones play a crucial role in male reproduction: mice that did not produce osteocalcin had abnormally low levels of testosterone and were sterile, while those producing high levels of osteocalcin had abundant testosterone and bred frequently. (The finding did not appear to be relevant to females.)

Neuroscience came to the fore in our 2013 paper, published in the journal Cell, when we showed that bone plays a direct role in memory and mood. Mice, whose skeletons did not produce osteocalcin as a result of genetic manipulation, were anxious, depressed, and almost completely unable to master a test of spatial memory. When we infused them with the missing hormone, however, their moods improved and their performance on the memory test nearly normalized. We also found that, in pregnant mice,

osteocalcin from the mother’s bones crossed the placenta and helped shape the fetal brain: i.e., bones talk to neurons even before birth.

Human Health Implications

With age, bone mass decreases and memory loss, anxiety, and depression become more common. These may be separate, unfortunate facts about getting old, but they could also be related. Many physicians recommend exercise as a way to prevent agerelated memory loss. Does it help, at least partly, by maintaining bones, which make osteocalcin, which in turn helps preserve memory and mood? In

my view, a higher bone mass means a greater capacity for osteocalcin production. A question before us is: Would it ever be possible to protect memory or treat age-related cognitive decline with a skeletal hormone?

My vision of the skeleton as central to energy usage, reproduction, and memory has persuasive evidence in mice, but the extent to which these results translate to people remains an open question. Most hormones have similar functions in mice and humans. Still, osteocalcin is clearly not the only substance that regulates blood sugar, male fertility, and cognition, and its relative importance may be different in

rodents and people. In mice, our work has shown that no other substance can compensate for a lack of osteocalcin when it comes to these functions. Is the same true for humans?

We now recognize that the body is far more networked and interconnected than most people think. No organ is an island. The skeleton often seems to play a surprising role. If insulin impacts bone, bone should help regulate insulin. If testosterone has an influence on bone mass, the skeleton should act on the testes. And, most fundamentally, just as the brain talks to the skeleton, bone should help regulate the brain. We continue the search to learn how this bidirectional influence works.

Danger Lurks

While identifying multiple functions for a novel hormone is a good start, it raises a new question: the common link between them. Why does osteocalcin regulate these particular physiological functions? And what others might it regulate?

One common link involves the prototypical human reaction to acute danger: the stress or “fight or flight” response, a suite of physiological processes that were studied and

An endocrine mediation of the ASR

When we first presented these findings, endocrine experts were surprised by the potential implications for the treatment of metabolic diseases, chief among them being type 2 diabetes.

analyzed with great insight by the late Bruce McEwen. These processes that make up the acute stress response include increases in heart rate, blood pressure, energy expenditure, respiration, and adrenal secretion of the hormone cortisol.

Many of the physiological processes regulated by osteocalcin are needed to escape danger. Memory, for instance, enables creatures in the wild to remember where predators are and where there is food. The capacity for exertion (i.e., to run) is also needed to escape danger, as is the ability to mobilize glucose, another function of osteocalcin. Thus, the hypothesis that osteocalcin is a hormone essential in situations of acute danger offers the most convincing argument for links between the physiological functions that it regulates. This, of course, does not exclude additional commonalities among such functions.

As for any physiological process, many questions remain regarding the biology of the acute stress response. For one, how does the activity of the sympathetic nervous system surge so quickly in situations of acute danger? This is a crucial issue, given this system’s key role in controlling bodily functions that are not directed consciously, including heartbeat, breathing, and digesting. In theory, the two arms of the nervous system, the sympathetic nervous system and the parasympathetic nervous system (which conserves energy by slowing body functions like heart rate and digestion), are supposed to work in equilibrium: How is osteocalcin involved in this balancing act?

A key question at this point was whether osteocalcin is actually a stress hormone (i.e., is it implicated in the initiation and/or unfolding of the acute stress response)? To qualify, only two

criteria must be met: stress hormone’s circulating levels should rise within minutes in animals facing an acute danger. And such a hormone should regulate, directly or indirectly, the physiological processes, such as those enumerated above, that are recruited to mount an acute stress response.

Concrete Answers

The first observation we made is that in mice, rats, and humans facing danger, circulating osteocalcin levels rise within minutes. How can acute fright quadruple concentration of the hormone so quickly? A chemogenetics approach targeting the fear center of the brain’s bilateral amygdala region provided an answer to this question by showing that, between a stressor and the release of osteocalcin by bone, there was signaling in the brain. A battery of genetic testing, of cell culture assays, and abrogation of neuronal signaling ruled out the possibility that mediators of such signaling are

circulating molecules, implicating a neurotransmitter instead.

In this regard, osteocalcin’s structure illustrates the cleverness of evolution. The hormone is synthesized in osteoblasts (cells that lead to the formation of bone). It is then modified by the enzyme gamma carboxylase and enters the circulation in the carboxylated form, which is inactive, and the uncarboxylated active form. The inactive form can be blocked by the neurotransmitter glutamate, which is present in both brain and bone.

Here’s how they all come together: Under acute stress conditions, signals in the amygdala (and possibly other fear centers in the brain that we have not yet tested) lead to the release of glutamate. This neurotransmitter goes to the bone, where it enters osteoblasts and blocks the inactive form of osteocalcin, so that only the hormonally active form is released into the circulation.

What allows us to call osteocalcin a true stress hormone is that,

furthermore, in its absence (in mice in which osteocalcin has been bred out), typical responses to acute stress are either abolished or severely blunted: These animals show little or no increase in energy expenditure, heart rate, and blood oxygenation. Hence, on genetic grounds, osteocalcin is necessary to trigger the acute stress response.

How, most fundamentally, does osteocalcin work to create an acute stress response? Since it synthesizes the chemical norepinephrine in the brain, we thought that it would do the same in the peripheral nervous system. But it does not. Instead, studies show that osteocalcin sends its signals through a receptor found on neurons, and these signals then travel from the central nervous system to peripheral organs. The net result: The surge in circulating levels of osteocalcin inhibit the recycling of acetylcholine molecules and the electrical activity of certain neurons, reducing activity of the parasympathetic nervous system (the system that slows down responses

such as breathing and heartbeat), and leaving the sympathetic nervous system unopposed and ready to initiate the acute stress response. We cannot rule out the possibility that osteocalcin signaling has other effects as well, such as contributing directly to the increase in energy expenditure in target organs.

Acute Stress Response in the Absence of Adrenal Glands

If osteocalcin is necessary to trigger the acute stress response, the next question is whether it is sufficient to trigger this response. There is ample evidence that, at the time, the acute stress response develops a surge of circulating glucocorticoid hormones— the role of which has not been fully understood. So, in view of the results we had obtained, the elephant in the room was to determine whether adrenal glands are actually necessary to mount an acute stress response.

In a totally unambiguous manner, mice or rats that have had their adrenal glands removed—and thus

cannot synthesize glucocorticoid and mineralocorticoid hormones or epinephrine—develop an absolutely normal acute stress response when exposed to stressors. The same is true in patients with adrenal insufficiency. In other words, the acute stress response does not seem to require the adrenal glands to develop. An added and precious benefit of asking if adrenal glands are necessary to mount an acute stress response was to illuminate the role of osteocalcin in the initiation of the acute stress response.

How could we explain that the acute stress response does not need glucocorticoid hormones? The answer came from general endocrinology. It has been known for decades that glucocorticoid hormones (corticosterone in rodents, cortisol in humans) are powerful inhibitors of osteocalcin expression in osteoblasts. As a result of that, mice and rats whose adrenal glands have been removed have elevated circulating osteocalcin levels at baseline, and these levels

Bruce McEwen, a neuroendocrinologist at Rockefeller University, was a pioneer in studying acute stress response, or the so-called “flight or fight” response.

surge higher under stress than in sham-operated animals. This raises the hypothesis that adrenalectomized animals develop a normal acute stress response simply because they are hyper-osteocalcinemic. We reasoned that if this hypothesis was true, then reducing circulating osteocalcin levels and preventing them from surging in mice that had been adrenalectomized, should prevent the development of an acute stress response when exposed to stressors.

We found that mice with osteocalcin that lack only one allele were not hyperosteocalcinemic and that their circulating osteocalcin levels did not increase when exposed to stressors. When these mice with osteocalcin were adrenalectomized, they were now unable to develop an acute stress response when exposed to stressors, indicating genetically that osteocalcin is not only necessary, it is also sufficient to mount an acute stress response, at least in the case of adrenal insufficiency. From an evolutionary standpoint, this study also

illustrated, one more time, that with the appearance of bone, the way many physiological functions are achieved or regulated had changed.

When it comes to the acute stress response per se, the data cited above raise many questions. Is osteocalcin needed for the development of all stress manifestations, or only for the ones we studied in the mouse? Does osteocalcin act only through regulation of parasympathetic tone, or does it also signal directly in organs whose activity is recruited under stress? What is the molecular identity of the glutamatergic neurons found in bone? Where are their cell bodies? Where do they connect in the brain? Can we use osteocalcin signaling in the parasympathetic nervous system to identify novel functions of the hormone? Finally, why do circulating glucocorticoid levels go up during the acute stress response? Although we have learned a great deal about this mysterious but elusive hormone along this long and winding road, so much more needs to be explored. l

> From Our Podcast with Gérard Karsenty

“Do our bones influence our minds?” “There is no question, absolutely. There are always naysayers who said I prefer the world as it was 50 years ago, and I prefer bone as it was before it became an endocrine organ. But, no, the evidence is overwhelming, and they're overwhelming because they come from so many labs, in so many countries. So, there is no way to stop data right now.”

“Is osteocalcin being studied by other geneticists or neuroscientists? It's interesting in the sense that it's kind of the merging of two, almost completely different, fields. It is a great example of how science works cross-functionally.”

“About 25 to 30 labs in the world are working on osteocalcin in mice and in humans. Neuroscience is part of our project as you see with this article, but we are also delving into new areas of research that are all centered around the notion that the bone may have been invented by evolution, in part, as a survival tool when animals left the sea to go to land. And what we are trying to write now is a new chapter of the physiology of danger through osteocalcin. But the function of bones, the classical function of bones, fits this definition because while you are sitting and listening to me, if the ceiling falls on your head, you will be unhappy, but you will not die, because bone protects your brain.”

Neuroscience came to the fore in our 2013 paper, published in the journal Cell, when we showed that bone plays a direct role in memory and mood.

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.

ILLUSTRATION BY ANNA

GODEASS

EMOTIONS MATTER. They influence how we learn, the decisions we make, the relationships we build and maintain, our everyday performance, and the ways in which we contribute to our world. Inextricably tied to our cognitive faculties and manifested in each of our interactions with ourselves and others, emotions underscore what we feel, how and what we think, and how we behave.

Affective science recognizes two related but distinct aspects within the rich complexity of emotional experience: core affect and emotion. Core affect is the internal perception and evaluation of experiences as positive or negative—feeling pleasant or unpleasant—and the effect on energy— feeling lethargic or energized. Emotion is the subjective response to specific situations, manifested as happiness, sadness, rage, pride, relief, etc.

Emotions are relatively shortterm affective responses, evoked by something real or imagined in our environment, that shift our thoughts, physiology, expressions, and behaviors. Although often used interchangeably, we recognize the difference and relationship between emotions, moods, and feelings. Moods are generally taken to mean “less intense emotions,” and though they may originate in the emotional response to a situation, moods are more sustained and may or may not have an easily identifiable cause.

Feelings are our private experience of emotions. Therefore, our emotions act as signals that guide our response to the world, inform our moods and underlie our feelings, while continuously adapting to meet the changing demands of life as we age. Lastly, the skills we access to deal with emotional experiences are aspects of intelligence—such as the ability to recognize emotion in oneself and

A key ingredient in a positive and healthy relationship is the ability to interpret and understand what the other person is feeling, and to identify, express, and manage one’s own emotions.

others, and to regulate our emotions in the service of our thoughts or actions. Despite the leading role emotions play in our life, as a subject of science they’ve been treated as an understudy; we have a long history of denying their importance in the human condition. Emotions are sometimes stereotyped as a sign of weakness and encouraged to be bottled up and checked at the door of our homes, classrooms, sports arenas, and workplaces. Further, difficulty reaching agreement on reliable, valid, and approachable metrics to meaningfully measure emotions undermine our taking them seriously as a skillset worthy of attention, research, and instruction.

The Evolution of a Field

The identification of emotional intelligence (EI) occurred late when compared to other kinds of intelligence. It wasn’t until 1990 that psychologists Peter Salovey and John Mayer introduced the first formal theory of EI, defined as “the ability to monitor one’s own and others’ feelings and emotions, to discriminate among them, and to use this information to guide one’s thinking and actions.” EI was a synthesis of three burgeoning areas of research, which demonstrated that emotions, when used intelligently, supported reasoning and complex problem-solving.

The first area of research was the rediscovery of Charles Darwin’s functional view of emotion—the idea that emotions are valuable sources of information that both energize behavior and ensure survival. Next was recognition that emotions and moods play essential roles in cognition, judgment, and behavior. For example, cognitive psychologist Gordon Bower at Stanford University demonstrated the link between emotions and thought with the use of hypnosis. First, subjects were made to feel either happy or sad.

Then they were asked to complete three tasks: recall lists of words, write entries in a diary, and remember childhood experiences. Subjects who were made to feel happy recalled more positive memories and words and remembered more pleasant events for their diaries. Likewise, the participants who were made to feel sad recalled more unpleasant memories, words, and events.

The third area of scientific inquiry was a search for “new” intelligences to include a broad array of cognitive abilities rather than a single mental ability, as expressed with IQ. Howard Gardner, a professor from Harvard University, proposed a theory of multiple intelligences that urged educators to place a greater emphasis on abilities beyond the verbal and mathematical, such as intrapersonal and interpersonal skills. Other researchers, including Robert Sternberg, proposed a theory of “successful intelligence” and pushed psychologists to consider creative and practical abilities.

Such research has had a positive impact: Social and behavioral outcomes are now recognized alongside academic development as a primary goal of education in the U.S., as evidenced in the Every Student Succeeds Act [ESSA], 2015. Yet questions still permeate some education circles around the value of so-called “soft skills,” the time schools should spend teaching students about them, and whose job it is to “teach” them.

The reality is: what is valued in our society gets taught. We want our children to be competitive in the global economy. But despite the longstanding evidence of the important role emotions play in being successful personally and professionally, we have been slow to warm to the idea that they represent a skillset that should be integrated into

the curriculum, rather than a frill taking time away from more critical areas of instruction.

As a society, we’re invested in STEM (Science, Technology, Engineering, and Math) education, and our preschoolers are learning Mandarin, while our primary school students are learning how to code. Meanwhile, science and technology companies, who make up an overwhelming proportion of the global economy, report that the skills they are looking for in new employees are those grounded in EI. These include emotion management, perspective-taking, creative problem-solving, and the ability to have difficult conversations, both give and receive feedback, and lead and inspire teams. A recent study by McKinsey and Microsoft found that top managers believe that just 30 to 40 percent of new hires have enough of these skills.

Developing Emotional Intelligence

The development of our EI begins in infancy, through interactions with caregivers, and continues as children are socialized across their school

The Limbic System

Hypothalamus Controls body temperature, hunger, fatigue, sleep

Amygdala

Memory, decision-making, and emotional responses

Hippocampus Memory, navigation

Despite the leading role emotions play in our life, as a subject of science they’ve been treated as an understudy; we have a long history of denying their importance in the human condition.

years alongside parents, peers, and teachers. Further, as language skills develop, our capacity to experience emotions more granularly increases, as does our ability to differentiate our individual interpretations from others in how we make meaning of what is happening in the world around us.

Our brains are experience-expectant, constantly shaped by and shaping who we are through interactions with the world and those within it. From our earliest moments, we write the code for how we think and act with the environmental resources available to us, which include everything from the nutrition we receive to nourish our brains, to the instruction we receive to educate our minds, to the relationships we form with our families and peers. Ongoing research finds that, along with white matter, intense growth in the cortical and subcortical areas of the brain are experience-dependent and that even subtle emotional regulatory interactions can permanently alter young children’s brain activity levels. This process may play a critical role in the establishment and maintenance of

the limbic system.

Emotional intelligence is acquired through informal life experiences (e.g., observing how parents, peers, teachers, and television characters talk about and manage emotions) and formal instruction (e.g., receiving direct instruction to build emotion vocabulary and learn helpful emotion regulation strategies).

Over the last two decades, our team at the Yale Center for Emotional Intelligence created a schoolwide, evidence-based approach for developing EI, which we named “RULER.” RULER is designed to integrate the teaching and learning of emotion skills into the fabric of schools across the process of development, and to improve interactions between and among school leaders, teachers, students, and families. Evidence is accumulating for RULER’s positive impact on academic performance (e.g., grades), social and emotional skills development (e.g., emotion regulation and social competence), well-being, classroom climate (e.g., relationships between and among teachers and

Basal ganglia Control of movements, learning, habit, cognition, and emotion

Thalamus Regulation of sleep, consciousness, and alertness

students), bullying, teacher instructional skills, and teacher stress and burnout. The RULER framework is based on Mayer and Salovey’s (1997) ability model of EI—the capacity to solve problems in the area of emotion. The name itself is an acronym for the five key emotional skills of:

• Recognizing emotions — identifying them in the face, body, and voice of others and in our own thought process and physiology.

• Understanding emotions — knowing the causes and consequences of different emotions, including their influence on thinking and behavior. For example, anger occurs when we perceive something as unfair, whereas disappointment arises as a result of unmet expectations.

• Labeling emotions — having a rich vocabulary to describe a wide range of emotions, including basic ones like joy and sadness and complex ones like shame and jubilance.

• Expressing emotions — communicating emotions effectively to different people across multiple contexts and cultures.

• Regulating emotions — using thought and action strategies to manage emotions (e.g., to prevent anxiety, enhance joy, decrease stress, or increase contentment).

According to the ability model of EI, there are individual differences in each of the skills that can be measured by performance tests. Such tests, as opposed to self-report scales, address the reality that individuals are often inaccurate when making judgments about their abilities, and their emotion skills in particular. Increasing empirical evidence over the last 30 years demonstrates the positive effects of EI—measured as an ability—on our health, relationships, academic

The development of our EI begins in infancy, through interactions with caregivers, and continues as children are socialized across their school years alongside parents, peers, and teachers.

achievement, and success in the workplace.

Beginning in adolescence, EI serves both protective and predictive functions in developmental health. Adolescents with better EI engage in less risky health behaviors, including the usage of alcohol and cigarettes. EI also correlates with less depression and better conduct, and may protect against suicidal behavior.

The benefits of EI continue into young and later adulthood. College students (especially males) with higher EI have lower rates of substance abuse and aggression, and there is ample evidence that adults with higher EI enjoy better physical and mental health.

A key ingredient in a positive and healthy relationship is the ability to interpret and understand what the other person is feeling, and to identify, express, and manage one’s own emotions. Research shows an association between EI and quality relationship formation and maintenance: it supports successful interpersonal functioning by providing individuals with the skills they need to gain perspective, communicate, and regulate effectively. Higher levels are correlated with increased sensitivity in the perception of others, as well as with stronger relationships with family, peers, colleagues, and partners across the lifespan.

There is evidence indicating that EI is associated with academic achievement because it promotes students’ abilities to attend to and regulate their emotions during learning and instruction. Our cognitive capacities to encode, store, and retrieve learning are necessarily dependent on our EI abilities: attention underwrites human information processing; and emotions like anxiety and fear, especially when prolonged and managed poorly, disrupt concentration and interfere with thinking. Chronic stress is a frequent consequence of

poor EI. It can result in the persistent activation of the sympathetic nervous system and the release of stress hormones like cortisol, which over time impacts brain structures associated with executive functioning and memory, diminishing one’s ability to focus and absorb information.

In the workplace, EI continues to provide developmental benefits. Research has linked it to such outcomes as performance quality— particularly in the context of jobs requiring more emotional labor (e.g., displaying specific emotions, as would be expected of teachers and customer service workers)— and leadership ability. EI correlates with leadership emergence, the degree to which someone not in an official leadership position influences colleagues. Other studies have shown promising associations between EI and transformational leadership—the process by which managers motivate and inspire their employees to work toward a common vision. Employees with greater EI also report greater job satisfaction and experience less stress and burnout, and they leave their jobs less frequently than those with lower EI.

Of course, how EI is taught and learned depends on age, but unlike learning other skills such as math and science or English language arts, there is no age at which it is too early or too late to acquire better EI. The parts of the brain needed to develop EI are active from birth until senescence.

EI is a field whose time has come. It is no longer an understudy waiting in the wings for an opportunity to contribute, and we must value EI and give it centerstage attention. But EI takes work, and we can’t expect our future doers and leaders to optimize this skillset if we haven’t given them the opportunity to develop and refine it at home, at school, and in the workplace. l

JOSEPH T. COYLE, M.D.

Joseph T. Coyle is the Eben S. Draper Chair of Psychiatry and Neuroscience at Harvard Medical School. A graduate of the Johns Hopkins School of Medicine in 1969, he was a research fellow at the National Institute of Mental Health with Nobel Laureate, Julius Axelrod. After psychiatric residency at Hopkins, he joined the faculty in 1975. In 1982, he became the director of the Division of Child and Adolescent Psychiatry. From 1991 to 2001, he was chairman of the Department of Psychiatry at Harvard Medical School. His research interests concern the causes of neuropsychiatric disorders. He is the past-president of the Society for Neuroscience (1991), a member of the National Academy of Medicine (1990), a fellow of the American Academy of Arts and Sciences (1993), a fellow of the American Association for the Advancement of Science (2005), and the former editor of JAMA Psychiatry

MARTHA J. FARAH, Ph.D.

Martha J. Farah is the Walter H. Annenberg Professor of Natural Sciences at the Center for Neuroscience & Society, University of Pennsylvania. She is a cognitive neuroscientist who works on problems at the interface of neuroscience and society. Her recent research has focused on socioeconomic status and brain development. Farah grew up in New York City, was educated at MIT and Harvard, and taught at Carnegie-Mellon University before joining the University of Pennsylvania. She is a fellow of the American Academy of Arts and Sciences, a former Guggenheim Fellow and recipient of honors including the National Academy of Science’s Troland Research Award and the Association for Psychological Science’s lifetime achievement award. She is a founding and current board member of the International Society for Neuroethics.

PIERRE MAGISTRETTI, M.D., Ph.D.

Pierre Magistretti is the dean of the Division of Biological and Environmental Science and Engineering at King Abdullah University of Science and Technology and professor emeritus in the Brain Mind Institute, EPFL and Center for Psychiatric Neuroscience, Department of Psychiatry–CHUV/UNIL, Switzerland. Magistretti received his M.D. from the University of Geneva and his Ph.D. from the University of California at San Diego. Magistretti’s research team has made significant contributions in the field of brain energy metabolism. His group has discovered some of the cellular and molecular mechanisms that underlie the coupling between neuronal activity and energy consumption by the brain. This work has considerable ramifications for the understanding of the origin of the signals detected with the current functional brain imaging techniques used in neurologic and psychiatric research.

HELEN S. MAYBERG, M.D.

Helen S. Mayberg is a neurologist renowned for her study of brain circuits in depression and for her pioneering deep brain stimulation research, which has been heralded as one of the first hypothesis-driven treatment strategies for a major mental illness. She is the founding director of Mount Sinai Health System’s The Nash Family Center for Advanced Circuit Therapeutics Mayberg received an M.D. from the University of Southern California, trained at the Neurological Institute of New York at Columbia University, and was a post-doctoral fellow in nuclear medicine at Johns Hopkins Medicine. Immediately prior to joining Mount Sinai, Mayberg was Professor of Psychiatry, Neurology, and Radiology and held the inaugural Dorothy C. Fuqua Chair in Psychiatric Neuroimaging and Therapeutics at Emory University School of Medicine. She is a member of the National Academy of Medicine, The American Academy of Arts and Sciences, and the National Academy of Inventors. She is on the board of the International Society for Neuroethics and won the society’s Steven E. Hyman for Distinguished Service to Neuroethics (2018).

JOHN H. MORRISON, Ph.D.

John H. Morrison is UC Davis Distinguished Professor, director of the California National Primate Research Center (CNPRC), Professor of Neurology in the School of Medicine, and professor in the Center for Neuroscience at UC Davis. Morrison earned his bachelor’s degree and Ph.D. from Johns Hopkins University and completed postdoctoral studies in the laboratory of Dr. Floyd E. Bloom at the Salk Institute for Biological Studies. Morrison’s research program focuses primarily on the neurobiology of aging and neurodegenerative disorders. His laboratory is particularly interested in age-related synaptic alterations that compromise synaptic health, lead to cognitive decline, and potentially leave the brain vulnerable to Alzheimer’s Disease. Morrison is a member of the National Academy of Medicine.

ADVISORY BOARD

RICHARD M. RESTAK, M.D.

Richard Restak is clinical professor of neurology at George Washington Hospital University School of Medicine and Health Sciences, a member of the clinical faculty at St. Elizabeth’s Hospital in Washington, DC, and also maintains a private practice in neurology and neuropsychiatry. A graduate of Georgetown University School of Medicine, Restak has written over 24 books on the human brain and has penned articles for the Washington Post, The New York Times, the Los Angeles Times, and USA Today; and presented commentaries for both Morning Edition and All Things Considered on National Public Radio. He is a past recipient of the Claude Bernard Science Journalism Award, given by the National Society for Medical Research.

HARALD SONTHEIMER, Ph.D.

Harald Sontheimer is I. D. Wilson Chair and professor and founder and executive director of the Virginia Tech School of Neuroscience. He is also Commonwealth Eminent Scholar in cancer research and director of the Center for Glial Biology in Health, Disease & Cancer and the Fralin Biomedical Research Institute. A native of Germany, Sontheimer obtained a master’s degree in evolutionary comparative neuroscience, where he worked on the development of occulomotor reflexes. In 1989, he obtained a doctorate in Biophysics and Cellular & Molecular Neuroscience form the University of Heidelberg. He moved to Yale University for post-doctoral studies and later founded Transmolecular Inc., which was acquired by Morphotec Pharmaceuticals. He is the author of Diseases of the Nervous System (Elsevier, 2015).

STEPHEN WAXMAN, M.D., Ph.D.

Stephen Waxman is the Bridget Flaherty Professor of Neurology, Neurobiology, and Pharmacology at Yale University, and served as chairman of neurology at Yale from 1986 until 2009. His research uses tools from the “molecular revolution” to find new therapies that will promote recovery of function after injury to the brain, spinal cord, and peripheral nerves. A member of the National Academy of Medicine, Waxman has been honored in Great Britain with the Physiological Society’s annual prize, an accolade that he shares with Nobel Prize laureates Andrew Huxley, John Eccles, and Alan Hodgkin. In 2018, Waxman received the Julius Axelrod Prize from the Society for Neuroscience.

CHARLES F. ZORUMSKI, M.D.

Charles Zorumski is the Samuel B. Guze Professor and head of the Department of Psychiatry and Professor of Neuroscience at Washington University School of Medicine in St. Louis. Zorumski is also Psychiatrist-in-Chief at Barnes-Jewish Hospital and founding director of the Taylor Family Institute for Innovative Psychiatric Research. Zorumski’s laboratory studies synaptic transmission in the hippocampus. Since 1997, he has served on the steering committees of the McDonnell Center for Cellular and Molecular Neurobiology and the McDonnell Center for Systems Neuroscience and was director of the Center for Cellular and Molecular Neurobiology from 2002 to 2013. Zorumski has also served on the editorial boards of JAMA Psychiatry, Neurobiology of Disease, and served on the board of Scientific Counselors for the NIMH Intramural Research Program from 2009 to 2013. Since 2011, he has also served on the scientific advisory board of Sage Therapeutics, a publicly-traded company developing neurosteroids and oxysterols as treatments for neuropsychiatric illnesses.

CAROLYN ASBURY, Ph.D.

In-House advisor

Carolyn Asbury has worked in health philanthropy for more than two decades, directing neuroscience-related health programs at the Robert Wood Johnson Foundation and directing the Pew Charitable Trusts’ Health and Human Services Program prior to consulting with the Dana Foundation. Her own research, through the University of Pennsylvania’s Leonard Davis Institute, concerns policies to facilitate development and market availability of drugs and biologics for “orphan” (rare) diseases. She undertook pro bono research and helped to design the Orphan Drug Act; authored “Orphan Drugs: Medical vs Market Value,” and has authored several journal articles and book chapters on these topics. She has served on the boards of several nonprofit health-related organizations, including the National Organization for Rare Disorders, U.S. Pharmacopeia, College of Physicians of Philadelphia, and Treatment Research Institute.

Bill Glovin Executive Editor

Glovin has been a working journalist for more than 30 years. He is executive editor at the Dana Foundation and hosts a regular podcast on brain science. He has served as editor of Cerebrum since 2012. Previously, he was senior editor at Rutgers Magazine, managing editor of New Jersey Success, editor for New Jersey Business and a staff writer for The Bergen Record. Glovin graduated from George Washington University with a degree in journalism. He sometimes escapes from in front of the monitor to enjoy basketball, biking, and guitar.

Seimi Rurup Assistant Editor

Rurup oversees the production of all digital and print content at the Dana Foundation. She previously served as editor of Brain in the News, which was the Foundation’s longest running print publication, and utilizes her background in fine arts to contribute to current publications and social media. She also contributes to the Foundation’s Neuro News section. Rurup graduated from Sarah Lawrence College with a degree in writing. When she is not in the office, she can be found in one of NYC’s many museums, Brooklyn cafés, or at home cooking with friends.

Brandon Barrera Editorial Assistant

Barrera is a New York City journalist, born and raised in Queens, N.Y. Barrera was a contributor to the Dana Foundation blog and Bronx Net. He is currently a public affairs assistant at the Dana Foundation and, when not enthralled by all things sci-fi, is fond of cycling, film, and arguing the finer points of tabletop gaming.