Cerebrum Spring 2021

EMERGING IDEAS IN BRAIN SCIENCE • SPRING 2021

SPACE BI etween the ea- rs What the astronaut experience tells us about the brain

CONTRIBUTORS

Mark Shelhamer, Sc.D. Space Between the Ears Page 12

Mark Shelhamer, Sc.D., is professor in the Department of Otolaryngology— Head & Neck Surgery at the Johns Hopkins School of Medicine, where he started as a postdoctoral fellow in 1990. He has bachelor’s and master’s degrees in electrical engineering from Drexel University, and a doctoral degree in biomedical engineering from MIT. At MIT, he worked on sensorimotor physiology and modeling, including the study of astronaut adaptation to spaceflight. He then moved to Johns Hopkins where he continued the study of sensorimotor adaptation with an emphasis on the vestibular and oculomotor systems and nonlinear dynamics. From 2013 to 2016, he served as chief scientist for the NASA Human Research Program. His research since that time has emphasized multi-system and cross- disciplinary interactions that contribute to personal and mission resilience in spaceflight. Peter Campochiaro, M.D., is the Eccles Professor of Ophthalmology and Neuroscience at the Wilmer Eye Institute , Johns Hopkins University School of Medicine. He is a clinician-scientist whose laboratory research studies ocular neovascularization and excessive vascular leakage, which occurs in age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion. The clinical trial group under Campochiaro provided the first demonstration of the benefits of suppression of VEGF in diabetic macular edema and retinal vein occlusion. He has developed strategies for sustained suppression of VEGF that are currently being tested in clinical trials. Campochiaro trained at the University of Notre Dame, Johns Hopkins School of Medicine, and the University of Virginia. 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 . Carl Sherman has written about neuroscience for the Dana Foundation for ten years. His articles on science, medicine, health, and mental health have appeared in national magazines including Psychology Today , Self , Playboy , and Us . He has been a columnist for GQ and Clinical Psychiatry News , and is the author of four books. He holds a doctorate in English literature and has taught at various universities. When not writing about the mind, the brain, and the interesting things people do with them, he enjoys travel, listening to music, looking at art, and copyediting. He lives and works in New York City.

Peter Campochiaro, M.D. Eye of the Needle Page 20

Kayt Sukel Losing Face Page 26

Carl Sherman The Brain and Covid Page 30

COVER ILLUSTRATION: ZOË VAN DIJK

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SPRING 2021 | VOLUME 2, ISSUE 2

FEATURES 12 Space Between the Ears Our author, former chief scientist for the NASA Human Research Program, examines what spaceflight can teach us about cognitive performance and mental abilities. By Mark Shelhamer, Sc.D. 20 Eye of the Needle A clinician and professor of ophthalmology and neuroscience advises a retired attorney about strategies to treat macular degeneration, a condition that affects 200 million people worldwide. By Peter Campochiaro, M.D. 26 Losing Face Newborns and toddlers, as well as K-12 students, have spent the past year living in a world where mask-wearing is the new normal. Is it affecting their brain development and mental health? By Kayt Sukel 30 The Brain and Covid: Strides and Speculations A little more than a year into the pandemic, scientists around the globe continue to learn how Covid-19 affects the brain and mental health—and how patients can overcome

POINTS OF INTEREST NOTABLE FACTS IN THIS ISSUE 4 A common observation among astronauts refers to a phenomenon known as “space fog” or “space stupids”—a sense of cognitive slowing and the need for increased mental effort to perform routine tasks. Space Between the Ears , Page 12 4 With people living longer and longer, it is estimated that by 2040, there will be 300 million individuals with macular degeneration throughout the world. Eye of the Needle , Page 20 4 There are a lot of things that are really important for human communication. And human faces are definitely one of the most important of them. Losing Face , Page 26 4 The National Institutes of Health is allocating more than $1 billion to research investigating Long Covid in all its multi- organ complexity—causes, manifestations, natural history, and treatments. The Brain and Covid , Page 30 4 Microetching, which consists of creating animated images by precisely controlling light’s reflection off of surfaces, was invented by Dunn and collaborator Brian Edwards, Ph.D. Between Thought and Expression , Page 36

nagging symptoms. By Carl Sherman 36 Between Thought and Expression

A sampling of work by Greg Dunn, who was on his way to a Ph.D. in neuroscience when he realized that bringing the brain's beauty to life was a more suitable role for him than lab work. By Bill Glovin

SECTIONS 5 Briefly Noted • By the Numbers, Brain in the News, In Memoriam 6 Advances • Notable brain science findings 7 Bookshelf • A few brain science books that have recently caught our eye 8 Awards • Brain Prize Winners 9 Clinical Corner • Following Your Instincts, By Angela M. Reiersen, M.D. 10 Neuroethics • Big Data, Big Concerns, By Philip M. Boffey

2 Contributors | 4 From the Editor | 44 Advisory Board | 46 Cerebrum Staff

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FROM THE EDITOR

The Johns Hopkins Connection

BY BILL GLOVIN Editor-in-Chief

EMERGING IDEAS IN BRAIN SCIENCE

I t’s no coincidence that two features in this issue are written by Johns Hopkins School of Medicine neuroscientists. The institution, which has been crucial to the evolution of neuroscience, has helped save countless lives, been crucial to educating many of the nation’s top scientists, and provided Cerebrum with many of it authors and advisers over the years. As a lifelong New Jersey native, I never expected such a personal connection. My first encounter occurred in 1999, when I traveled by train to Baltimore to write a Hopkins Medicine cover story about my cousin Michael’s experience in a pioneering outpatient transplant program to treat leukemia. So, I already had a connection with the institution when I became editor of Cerebrum in 2012 and inherited an advisory board that included Don Price and Kay Jamison—Hopkins’ professors and giants in their fields. My advisers, today, include three who passed through the Hopkins pipeline: Harvard professor Joe Coyle, who joined the Hopkins faculty in 1975 and was a former Distinguished Service Professor of Child Psychiatry; Helen Mayberg, a renowned neurologist at the Icahn School of Medicine at Mount Sinai, once a Hopkins post-doctoral fellow; and Dana’s senior consultant Carolyn Asbury, who also trained there. I also worked closely with another giant, Dana scientific adviser Guy McKhann (now retired), founding director of Hopkins’ Zanvyl Krieger Mind/Brain Institute. Over the years, we’ve published articles by a number of Hopkins professors: the late John Freeman on epilepsy, Ellen Silbergeld on drinking water and the brain, Michael Kim and Christopher Jackson on glioblastoma, Susan Magsamen on neuroaesthetics, and Frank Lin on the link between dementia and hearing loss. Writing for us in this spring issue are two more Hopkins professors, Mark Shelhamer on spaceflight’s connection to cognition and mental health (page 12), and Peter Campochiaro on macular degeneration (page 18). Many of our other Cerebrum authors were trained at Hopkins, including Fred “Rusty” Gage (stem cells), John Ioannidis (research study validity), Michael Miller (heart and the brain), and Paul Worley (memory). And with this issue, we welcome new Dana Foundation President Caroline Montojo, former director of Life Sciences and Brain Initiatives at the Kavli Foundation. Guess where Caroline completed her M.A. and Ph.D. programs? Hopkins loomed again for me in a big way in 2018, when—20 years after his transplant—my cousin Michael developed an even more lethal form of leukemia and was admitted into the program for a second time. I returned to the hospital to shadow Michael again for Hopkins Medicine —and wrote about how the technology and experience had drastically improved for patients. This second transplant bought Michael another two-and-a-half years of life, but all of the improvements in the world couldn’t save him a third time. Michael S. Billig, 64, a professor of cultural anthropology at Franklin & Marshall in Lancaster, PA, passed away in January at the hospital. But thank you Johns Hopkins, for extending Michael’s life and doing what you could to help him, for making the world a better place, and for making Cerebrum a better magazine. We couldn’t have done it without you. l

Bill Glovin Editor-in-Chief Seimi Rurup Assitant Editor

Brandon Barrera Editorial Assistant

Carl Sherman Copy Editor

Carolyn Asbury, Ph.D. Scientific Consultant

Bruce Hanson Art Director

Cerebrum is published by the Charles A. Dana Foundation, Incorpo- rated. 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 publica- tion may be reproduced, stored in a retrieval system, or transmitted in any form by any means, electronic, mechanical, photocopying, record- ing, or otherwise, without the prior written permission of the publisher, except in the case of brief quotations embodied in articles. Letters to the Editor Cerebrum Magazine 505 Fifth Avenue, 6th Floor New York, NY 10017 or cerebrum@dana.org Letters may be edited for length and clarity. We regret that we cannot answer each one.

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BRIEFLY NOTED

B Y T H E N U M B E R S $ 0 How much it costs to become a Brain Awareness Week partner. 30 countries have joined together to participate in a study to trace a possible path from Covid-19 to neurodegen- erative diseases, particularly dementia. 8 75 is the percentage of people predicted to get 1664 the year English physician Thomas Willis published his Anatomy of the Brain , which ushered in the era of modern neuroanatomy. hallmarks of environmental exposures detailed in a study that chart the biological pathways through which pollutants contribute to disease.

BRAIN IN THE NEWS Links to brain-related articles we recommend

> New York Times: What Can Covid-19 Teach Us About the Mysteries of Smell? > New York Times: Alzheimer’s Prediction May Be Found in Writing Tests > Nature: How gut microbes can drive brain disorders > Science Daily: How a single gene alteration may have separated modern humans from predecessors > Star-Ledger: How telehealth strengthened its grip on future of our medical care > New York Times: Can Zapping Our Brains Really Cure Depression? > Washington Post: A brain researcher on what Freud got right > NBC News: Exclusive look at NIH investigation into Covid ‘long haulers’

2 0 5 3 9 0 4

The number of studies and articles listed (as of March) when the word “brain” is searched on PubMed.gov, the website of the National Institutes of Health national library.

IN MEMORIAM

Philip Seeman , M.D., Ph.D., a molecular neuropharmacologist who discovered the importance of the dopamine D2 receptor in 1974, showing that the schizophrenia drugs of that era— which were widely used but poorly

Alzheimer’s disease in an artificial intelligence program that measured writing test results.

understood—targeted this brain receptor — A Dana Alliance for Brain Initiatives member while at the University of Toronto, Seeman’s was made an Officer of the Order of Canada for his research on dopamine receptors and their involvement in diseases such as schizophrenia, Parkinson's, and Huntington’s disease. The company he founded, Clera Inc., developed small-molecule therapies for schizophrenia and other dopamine-related brain diseases. Paul Garfinkel, staff psychiatrist with the Center for Addiction and Mental Health in Canada, said that before Seeman’s research, “our theories about what causes schizophrenia were primitive and blaming. They blamed the mother or the family dynamic. His studies showed there’s a biology to this brain illness that’s nobody’s fault.” l

20,000 neuroscientists are represented by the Feder- ation of European Neuroscience Societies ( FENS ) across 33 countries. Their mission is to advance neuroscience education and research.

Unlike your genome, which you can’t do much about except blame your parents and grandparents, your microbiome is potentially modifiable. And that gives great agency to patients. That’s really exciting.”

— John Cryan , Ph.D., a neuroscientist at University College Cork in Ireland

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ADVANCES Notable brain-science findings

eye movements), some volunteer dreamers were able to follow researcher instructions to solve simple math problems, answer yes-or-no questions, or signal the difference between different sensory stimuli (such as flashing lights vs. spoken sounds). After waking, some remembered what the questions or stimuli were, but in the contexts of the stories they were dreaming, such as hearing the researcher’s voice among others during a surreal party. “INTERACTIVE DREAMING,” if it proves out, could help researchers better study dreams and dreaming without having to rely on morning reporting, by which time most of us have forgotten our dreams. l People going under anesthesia during surgery who listen to soothing talk and music via headphones may wake up feeling less PAIN and asking for less pain medicine. In a blinded randomized controlled study of 385 patients, researchers found that those who had listened to music and positive suggestions such as “everything is going well” reported an average of pain scores 25 percent lower, two hours after their operation, compared with those whose earphones gave them only silence—and 70 percent of the audio-plus group asked for no opiates at all, compared with 39 percent of the silence group. l Female mosquitoes love blood—they suck so strongly they can damage an animal’s capillaries. But blood is complex, a combination of components all with their own taste signatures. It’s not a single TASTE like the simple sugars in nectar; how can the mosquitoes be sure this complicated combination is the thing they crave? Researchers have found a group of neurons in the female mosquito’s syringe-like stylet that activate only when a combination of sugar, salts, and other blood components are present. “We knew that the female stylet was unique, but nobody had ever asked what its neurons like to taste,” says Veronica Jové, who led the study . “These neurons break the rules of traditional [single] taste coding, thought to be conserved from flies to humans.” l

BY NICKY PENTTILA

The idea that doctors might restore motor function in people with SPINAL CORD INJURIES by using stem cells derived from the patient’s own bone marrow got a big boost in April 2021. In a case-study description of a Phase 2 study , 13 people with relatively recent spine injuries caused by falls or other minor trauma had marrow drawn, converted in the lab to stem cells, and then re-inserted intravenously. The trial aimed to confirm that the method was safe for humans, which it appears to be. But in addition, more than half the patients showed significant improvement in key functions such as bowel function, coordination, and ability to walk. l We know that keeping physically active in later life is important for preserving cognitive function, and now we’re learning how it may help adolescents build their cognitive capacities. ADOLESCENCE is one of the brain’s sensitive periods, when week, using wrist activity-trackers, interviews, health exams, and magnetic resonance imaging, researchers found that those who were physically healthier and more active had signs of healthier brains: more gray matter, stronger white-matter connections, better blood flow, and more. l Scientists in four labs (in France, Germany, the Netherlands, and the US) are finding evidence against the common wisdom that it’s pointless to try to communicate with sleeping people. After being trained to signal when they were in a lucid part of dream sleep (by making a series of left-right busy connections strengthen as others are pruned. It can also be a time when children grow more sedentary, spending longer hours at school desks and in front of computers. In a study of 50 12-year-olds over the course of one

In adults, twitches occur for about an hour during rapid eye movement (REM) sleep, while in infants, twitches dominate the sleep cycle, helping shape young brain development. Mark Blumberg, a professor of psychological and brain sciences at the University of Iowa, found that twitches in baby rat pups trigger activity in the spinal cord, sensory and motor areas, and the hippocampus. He talked about his research findings in a presentation at the Society for Neuroscience’s Global Connectome conference in January.

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

mathematical modeling, and the insights these models reveal about the brain. According to Lindsay, the brain will ultimately be understood through mathematical and computational theories, imperfect though they may be. Models of the Mind is a captivating and compelling anthology of why she may be right. Smellosophy: What the Nose Tells the Mind

BY BRANDON BARRERA

So You Want to Be a Neuroscientist? by Ashley Juavinett (Columbia University Press) Does the thought of dedicating your academic and professional career to studying the brain ever cross your mind? Maybe you’re already in the workforce, searching for ways to transition into neuroscience but uncertain of how that road unfurls. An insightful and practical guide,

by A.S. Barwich (Harvard University Press) A nascent investigative arena, the scientific study of smell experienced a breakthrough in 1991 with the discovery of olfactory receptors, rapidly propelling the branch of research into the realm of mainstream neuroscience. Celebrating this influx of new, sophisticated,

So You Want to be a Neuroscientist? is the north star for the aspiring brain scientist in you. Having launched her own career recently, Ashley Juavinett, Ph.D., assistant teaching professor of neurobiology at the University of California, San Diego, writes candidly about what neuroscientists-in-training should expect when venturing forth on their own paths. The book covers the current state of neuroscience and where it might be headed, what graduate school entails and the importance of networking and finding mentors, what to expect from conducting research in a lab, and the many career possibilities open after training. Juavinett leaves no stone unturned, making her book invaluable for students, educators, and everyone in between. Models of the Mind: How Physics,

“smelly” research, cognitive scientist and empirical historian A.S. Barwich, Ph.D., ventures into the laboratorial trenches and reports from the “experimental frontier,” offering a historical and philosophical analysis of odor perception. Despite the remarkable progress made in recent decades, Barwich says, the puzzle of olfaction—understanding what perceptual information odors represent and how the brain comes to understand it—remains unsolved. Deftly using interviews with experts in psychology, chemistry, neuroscience, and perfumery, Barwich probes the biological underpinnings of odor, identifying the uncertainties and knowledge gaps in current thinking about odor perception—and perception overall. Perfumed with an inviting bouquet of philosophy, history, and neuroscience, Smellosophy is Barwich’s charmingly compelling love letter to olfaction.

Engineering and Mathematics Have Shaped Our Understanding of the Brain by Grace Lindsay (Bloomsbury Sigma) Using the precision and elegance of mathematics to understand the brain is part of the work computational neuroscientist and author Grace Lindsay, Ph.D., performs regularly. Scientists in her burgeoning field—

Stories and the Brain: The Neuroscience of Narrative by Paul B. Armstrong (Johns Hopkins University Press) In Stories and the Brain : The Neuroscience of Narrative , professor of English and author Paul B. Armstrong, Ph.D., explains how the brain interacts with the social world and why stories are so important. Expanding on

those unifying mathematics and biology—reduce complex biological processes into painstakingly accurate equations and variables when creating useful, predictive mathematical models. In Models of the Mind , Lindsay charts how physics, engineering, statistics, and computer science have influenced brain science and provide the groundwork for the discipline’s future. The chapters cover the history of the different mathematical tools applied in understanding neuronal mechanisms, memory formation and maintenance, the motor and visual cortexes, decision-making, and more. Mercifully, lay readers can jump in and comfortably enjoy the subject matter as Lindsay shies away from requiring special mathematical knowledge on behalf of readers; she instead features the ideas behind the equations, the reasons why scientists employ

the questions of how our brains are suited to the telling and following of stories, Armstrong investigates the neurobiological underpinnings of narrative, shedding light on what our story- telling abilities reveal about language and the mind. Across four chapters, the book explores the roles between stories and experience, discussing neuroscience and narrative theory, the correlations between neuronal and cortical timing processes to paradoxes of narrative temporality, story plots and their use of patterns of action, and bringing different worlds into relation with each other through the exchange of stories. Stories and the Brain is a well-researched, engaging discussion on what narrative theory and neuroscience stand to gain from continued collaboration. l

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AWARDS

DABI Members Win Brain Prize: Migraine Research Recognized T his year, two of the four winners of the Brain Prize—the world’s most prestigious award for brain research—are Dana Alliance for Brain Initiatives (DABI) members: Michael A. Moskowitz and Jes Olesen . The award, sponsored by the Lundbeck Foundation in Sweden, were all awarded for research on migraine, and provides close to $400,000 in US dollars to each winner. The other two winners are Lars Edvinsson , M.D., Ph.D., professor of internal medicine at Lund University in Sweden, and Peter Goadsby , M.D., Ph.D., director of the NIHR-Wellcome Trust King’s clinical research facility at King’s College in London. Moskowitz, M.D., a professor of neurology at Harvard Medical School, showed “that a migraine attack is triggered when trigeminal nerve fibers release neuropeptides that lead to dilated (opened up) blood vessels of the meninges, inflammation, and pain …. He was the first to propose that

Left to right: Michael A. Moskowitz, Jes Olesen, Lars Edvinsson, and Peter Goadsby

blocking the action of released neuropeptides could be a new approach to treating migraine.” Olesen, M.D., a professor of neurology at the University of Copenhagen, gave migraine patients a gene-related peptide called calcitonin (CGRP), which triggered migraine attacks. He then found that certain drugs—known as antagonists—blocked the peptide and effectively treated migraine. Working collaboratively, Edvinsson and Goadsby showed that CGRP—a particularly potent dilator of blood vessels in the meninges—may be of crucial importance in migraine and the key molecule in primary headache disorders.

This Issue’s Cerebrum Podcast Episodes Mark Shelhamer , Sc.D., former chief scientist for the NASA Human Research Program and a professor at the Johns

Peter Campochiaro , M.D., the Eccles Professor of Ophthalmology and Neuro- science at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, and the author of our feature on macular degeneration, “Eye of the Needle.”

Hopkins School of Medicine, is the author of our cover story, “Space Between the Ears.”

"There's something that astronauts sometimes call space fog or the space stupids… the sense that things that I used to be able to do on earth seamlessly without thinking about them, now, all of a sudden, they're a little bit more challenging for me to do.”

“In general, most patients with the wet form of macular degeneration require injections of these medications every four to six or eight weeks for the remainder of their life.”

FOLLOW ON YOUR FAVORITE PLATFORM

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CLINICAL CORNER

I became ill myself with probable Covid-19... with various fluctuating symptoms—nothing like any viral infection I’d experienced before.

Following Your Instincts

I began monitoring the literature on S1R and, in early 2019, I found an article (from research in the laboratory of Alban Gaultier, Ph.D., at the University of Virginia) that indicated that mice lacking the S1R showed excessive production of cytokines (inflammatory molecules), which increased susceptibility to death when exposed to inflammatory triggers or infections. And mice with functioning S1R showed improved survival under these conditions if given fluvoxamine. This work showed that, in addition to down-regulating the ER stress response, the activated S1R could down-regulate cytokine production during severe infections that cause sepsis. I wondered how this new knowledge might be applied to treat human diseases in the future. Then, in March 2020, the Covid-19 pandemic had begun. I became ill myself with probable Covid-19. It was a strange and long-lasting illness with various fluctuating symptoms—nothing like any viral infection I’d experienced before. While still ill, I read that deterioration in respiratory function around the second week of illness seemed to be due to an excessive inflammatory response to the virus rather than the virus itself. The body’s own response to the virus was doing the damage. I immediately thought back to that study of fluvoxamine from the University of Virginia, and I wondered whether fluvoxamine might be effective in treating Covid-19. I sent off some quick emails to colleagues to see what they thought. That led me to Eric Lenze, M.D., a geriatric psychiatrist with extensive experience running randomized controlled trials (RCTs). I sent Lenze an email on March 25, 2020, explaining my hypothesis. He was convinced we should do an RCT, so we got the trial going as quickly as possible. Since patients were isolating at home, our study staff took medications and study supplies to them using no-contact delivery methods. Patients logged oxygen levels, vital signs, and symptoms electronically, and we checked in with them as needed. None of the 80 patients taking fluvoxamine experienced respiratory deterioration by our study definition, but 8.3 percent of the 72 taking placebo deteriorated. It seemed that this treatment actually worked. If these findings are confirmed in our ongoing larger study , fluvoxamine could have huge potential to reduce hospitalizations and deaths related to Covid-19. Thinking back on all this, it has been a strange journey. As a child psychiatrist, I never expected that I’d team up with a geriatric psychiatrist to run infectious disease treatment trials. And although the connection with Wolfram syndrome is indirect, if I had not become interested in the S1R as a result of Wolfram syndrome research, I might never have thought to use fluvoxamine as a treatment for Covid-19. l

BY ANGELA M. REIERSEN, M.D. S everal years ago, a colleague supervising an annual multidisciplinary research clinic studying Wolfram syndrome in children, adolescents, and young adults asked me to use my experience as a child and adolescent psychiatrist to perform neurological and psychiatric assessments of the study participants. Most participants had experienced diabetes from a young age, progressive vision loss due to optic atrophy, and hearing loss. Adolescents and young adults often showed progressive gait and difficulties with balance. These many problems were tied to a defect in a gene that codes for a protein present in the endoplasmic reticulum (ER), a factory and storage area inside our cells, bounded by a network of folded membranes. This protein is called wolframin. When cells are under stress, particularly if they are unable to properly fold proteins, an ER stress response kicks in to get cellular processes back into balance. If this fails, or if the ER stress response does not shut down properly after cellular processes are back in balance, a self-destruct system can kick in, leading to death of the cells. The wolframin protein helps regulate this process, so cells won’t die unnecessarily; but in Wolfram syndrome, the ER stress response is exaggerated. Many participants and their families had come to know each other from previous visits to our research clinic; some had even kept in touch and formed their own supportive community. As I met with them, I was often impressed by their resilience. Many reported initial difficulty adjusting to their diagnosis, but they learned ways to cope with an uncertain medical future. Some reported history of treatment with a selective serotonin reuptake inhibitor (SSRI) for symptoms of anxiety, obsessive-compulsive disorder, or depression. Over the years, I noticed a possible pattern in their responses to these SSRIs, and I became curious. A search of the literature revealed that SSRIs differ in their action on another ER protein called the sigma-1 receptor (S1R), which— like wolframin—is a regulator of the ER stress response. S1R activators (including SSRIs like fluvoxamine and fluoxetine) can down-regulate the ER stress response, while another SSRI (sertraline) may have opposite actions on the S1R. I wondered whether the differing effects on S1R might explain differences in treatment response, particularly in people with genetic disorders of the ER stress response, such as Wolfram syndrome.

Angela M. Reiersen is an associate professor of psychiatry at Washington University School of Medicine.

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NEUROETHICS

Big Data, Big Concerns BY PHILIP M. BOFFEY A n article in the Winter issue of Cerebrum magazine and a podcast episode with the author laid out a tantalizing vision of the enormous potential of advances in neuroimaging and so-called Big Data technologies to revolutionize the treatment of neurological disease. But the author made only a fleeting mention of the ethical issues raised by these advances. Fortunately, the same author— Vince Calhoun , director of the Center for Translational Research in Neuroimaging and Data Science —co-authored a recent article with two experts from the Netherlands that did explore in-depth the major ethical issues raised by these endeavors. It is a welcome effort to flag potential ethical problems while the field is still in an early stage of development. Calhoun’s Center is well-situated to conduct this work. It is backed by three universities in Atlanta, GA, with complementary strengths and missions. They include Emory University, which has expertise in brain disorders, Georgia Tech, which is strong in data mining, and Georgia State, which is proficient in neuroscience and psychology. Calhoun’s Cerebrum article lays out the promise, achievements, and disappointments of the field so far. On the plus side, the knowledge gained from big data and neuroimaging have provided new insights into the working of the brain. But hopes that the discovery of functional magnetic resonance imaging would lead to a clinical breakthrough in assessing and treating mental illness have not yet materialized. Indeed, Calhoun can’t point to any specific examples where neuroimaging is beginning to help the mentally ill. Progress has been slower than he would have liked. His hope is that within ten years we may have learned enough to update our psychiatric diagnostic criteria and refine the medications we prescribe to treat some mental health disorders. The research has been slow to reach the scale required. Calhoun traced the evolution of the field through eras in which researchers studied small numbers of subjects, typically 5 to 20, then larger groups comprised of hundreds of individuals, then the interactions between networks in the brain both at rest and while performing tasks. Each era added to the knowledge base, but they have not yet led to clinical tools to treat mental health disorders or determine drug delivery strategies. We are now firmly in, what he calls, “the era of big data for

neuroimaging and psychiatry.” Several studies already scan tens of thousands of individuals over time, and powerful “deep learning models” require lots of data and computer power. Previous studies have focused on group results and averages. The current goal is to make predictions for individuals of how their symptoms will progress and how they will respond to medications. Calhoun finds “considerable reason to be optimistic about the not-so-distant future.” The article co-authored by Calhoun that explored the ethical issues was published in the journal Human Brain Mapping last July. It analyzed differing approaches in the European Union and the United States toward the use and dissemination of personal health data. Probably, the most important distinction concerns who should be considered to “own” the data and thus have the major say in how it is handled and disseminated. Researchers and universities often believe that the data “belong” to them, and funding agencies in this country consider institutions the owners of the data. In some cases, the funding agencies dictate that the data be shared. By contrast, recent laws in Europe give more rights to the individuals who participate in studies to determine the extent in which they want their data shared. That puts a greater burden on researchers to protect participants’ privacy and obtain their permission before disseminating personal health data. Depending on the circumstances, research journals may also demand that data on which an article is based be uploaded at the time of publication, making them the effective owner of that data. The chief risk in sharing data is that, if it escapes from the research realm or falls into the wrong hands, it can harm the individual whose data has been shared. For example, some studies collect information about substance use and abuse, diseases such as HIV/AIDS, or procedures such as gender reassignment surgery that can stigmatize an individual in some circles. There are ways to protect the privacy of an individual’s health data without unduly hampering research. The trick is to strike an appropriate balance between risk and benefit. One approach is to “de-identify” data that directly defines an individual, such as name, address and date of birth, as well as information on an individual’s physical and mental health or treatments. All such information is stripped from the dataset and replaced by artificial identifiers that can’t be linked to individuals by third parties, such as insurers, but can be traced back by the host researchers, if need be. More robust protection is provided by “fully anonymized” data, which has all personalized data removed and any path back to the original data deleted, making it extremely hard to trace the data back to an individual. However, even this is not

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The chief risk in sharing data is that, if it escapes from the research realm or falls into the wrong hands, it can harm the individual whose data has been shared.

foolproof. For example, in many cases, a large dataset may include people with rare medical conditions or only small numbers of specific ethnic minorities that machine-learning algorithms could use to identify, within certain error margins, a particular individual. The most frightening possibility to me is that some people may actually want to link the data to an individual. It is not far- fetched to worry that insurers, employers, or law enforcement agencies might want your personal data. Indeed, brain scans have already been used in court as evidence. As recently as February, the journal BioTechniques published an article online entitled “Inside the brain of a killer: the ethics of neuroimaging in a criminal conviction.” A study published in Proceedings of the National Academy of Sciences in March 2017 found that, in a laboratory setting, brain scans were able to distinguish between hard-core criminal intent and simply reckless behavior. But a writer in Science cautioned that the approach was “far from being ready for the courtroom.” Calhoun and his co-authors side more with the rights of individuals than with the researchers and institutions that collect data from them, but they seek a balance that will both protect their privacy and allow important science to advance. They call for the research community to work together with attorneys and ethicists to determine how best to make

important advances in medical research, while protecting the data of human subjects. There is no question that data sharing will entail some level of risk. A leak of sensitive information might prove harmful to an individual. But the authors worry that concerns have outpaced reality. “While we do not intend to minimize the importance of data security,” they write, “there is a certain fear that has emerged regarding data sharing where it has become greater than life.” Instead of being real monsters to worry about, they are more like imaginary “monsters under the bed.” The best path forward, the authors say, is for researchers, through discussions with participants and information provided on consent forms, to let participants decide whether they are willing to have their data shared, and under what circumstances. There may be no direct benefit to them, but those willing to share would be doing science and their fellow citizens a seminal service. l Phil Boffey is former deputy editor of the New York Times Editorial Board and editorial page writer, primarily focusing on the impacts of science and health on society. He was also editor of Science Times and a member of two teams that won Pulitzer Prizes. The views and opinions expressed are those of the author and do not imply endorsement by the Dana Foundation.

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ILLUSTRATION: DANIEL HERTZBERG

S BI etween B

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What can spaceflight teach us about the brain? Our author, Mark Shelhamer, former chief scientist for

the NASA Human Research Program and a professor at the Johns Hopkins School of Medicine, lays out how spaceflight relates to brain function, cognitive performance, and mental abilities. SPACE the ea- rs By Mark Shelhamer, Sc.D. • Illustration by Zoë Van Dijk

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A-

FEW SHORT MONTHS AGO , news programs around the globe showed NASA engineers and scientists celebrating as a robot named Perseverance successfully landed on the surface of Mars. The mission: capture and share images and audio that have never been seen or heard before. As impressed as most observers were of this major milestone, many couldn’t help but wonder when we might be ready to someday send humans. While it seems the stuff of science fiction and almost inconceivable, the answer— according to recent NASA planning —is before the end of the 2030s, less than two decades away. There are still many obstacles to accomplishing such a feat, many of which have to do with overcoming cognitive and mental health challenges that would impact a crew: long-term isolation, eyesight impairment, and psychological effects from the stress of danger and what could amount to life-or-death decisions. For a mission to succeed, high mental and cognitive function would be absolutely critical; astronauts would be called on to perform demanding tasks in a demanding

Name something stressful in your day-to-day routine, and it is likely also present in spaceflight—along with stressors that are unique to the context. Failure is Not an Option , the title of NASA Flight Director Gene Kranz’s memoir in 2000, convincingly sums up the situation. High workload is a common feature of spaceflight. Space programs (national or commercial) do not incur the expense of sending people into space for them to rest and relax. On the contrary, astronauts’ daily schedules (at least in the US program) are planned in great detail, and their progress in keeping on schedule is tracked in real time. And there is much to be done during a mission, from normal spacecraft operations, maintenance, and repairs, to a wide range of science experiments and assessments of new space technology. Much of the science, in fact, is dedicated to understanding the human response and adaptation to spaceflight. Along with the high workload, sleep disruptions and misalignment of circadian rhythms are not uncommon. The

normal light-dark cycle, which ordinarily provides a temporal structure to the day and entrains biological rhythms, is missing. Alarms of various kinds repeatedly awaken astronauts to conduct necessary tasks, and the pervasive sense of danger, lest something go wrong, can also be disruptive. All of these

FINDING THE ANSWERS TO OVERCOMING THOSE OBSTACLES HAS NOT ONLY OFFERED US THE OPPORTUNITY TO ADVANCE SPACEFLIGHT, IT ALSO ALLOWS US TO APPLY WHAT WE LEARN TO HELP PEOPLE HERE ON EARTH.

contribute to fatigue and stress. Such factors may not be unique to spaceflight, but the level of isolation and confinement astronauts experience is certainly unlikely to be found at home. As far as spacecraft go, the International Space Station (ISS) is large, but it is still small compared to the indoor and outdoor spaces we have access to here on Earth. There is no such thing as “going out for a walk,” without a great deal of preparation, special and cumbersome suits, and attendant increased risk. Add to this the fact that, while the view outside may be spectacular, astronauts aren’t tasked to look out the window but rather to work inside, where they see the same people and the same scenery day after day, month after month. The stress of interpersonal relations under such circumstances can be challenging. Then there are factors that are even more specific to space travel. The level of carbon dioxide in a spacecraft is typically much higher than here on Earth, because it is expensive in terms of supplies and energy to reduce it. Elevated CO 2 produces such effects as irritability and headache—not the

environment. Losing 20 IQ points halfway to Mars is not an option. Finding the answers to overcoming those obstacles has not only offered us the opportunity to advance spaceflight, it also allows us to apply what we learn to help people here on Earth. While we haven’t yet seen anything as a dramatic as a clear loss of intellectual capacity in space, there are enough indicators to suggest that we should pay close attention. Stress—an emotional or mental state resulting from tense or overwhelming circumstances—and the body’s response to it, which involves multiple systems, from metabolism to muscles to memory —may be the chief challenge that astronauts face. Spaceflight is full of stressors, many of which can have an impact on brain function, cognitive performance, and mental capacities. Several changes in brain structure and function have been observed [in astronauts after spaceflight]. The full implications of these changes for health and performance are not yet known, but any adverse consequences will be increasingly important as spaceflights become longer and more ambitious (such as a three-year mission to Mars).

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PHOTO: NASA.GOV

Astronauts are asked to perform at a very high level in a very demanding situation, under constant supervision and scrutiny; this doesn’t help with the stress level. Beyond such external factors, the high standards they set for themselves may lead to self-imposed stress. A mission is often the peak of one’s professional career, a position of high visibility in which errors of judgement can have immediate and dire consequences. Astronauts are well-prepared and highly trained to overcome and cope with stressors that would be unbearable for most of us. Nevertheless, they are human. Stress takes a toll, especially over the long run and when downtime for rest and recovery is hard to come by. While we understand a great deal about these stressors individually (even if we do not yet know how to counter them effectively), their combination, over an extended period, could lead to problems that we do not yet foresee. In this regard, human spaceflight is not only an exploration of space itself, but also of human limits and capabilities. Effects of Stress What are the effects of these myriad stressors on brain function and mental performance? We know some, and others might become apparent on more ambitious missions such as a trip to Mars. A common observation among astronauts refers to a phenomenon known as “space fog” or “space stupids”—a sense of cognitive slowing and the need for increased mental effort to perform routine tasks . Disrupted sleep and elevated CO 2 alone, in a demanding setting under intense pressure to perform, could easily produce such cognitive problems. Add all the other spaceflight stressors described above, and it is not hard to imagine having even greater difficulty concentrating and a sense of mental lethargy. Related to this is the phenomenon of “neurasthenia”: a vaguely defined sense of fatigue, lack of motivation, irritability, and related somatic sensations. Strangely, though, objective testing of cognitive function in space does not fully support these subjective observations. In- flight cognitive testing shows variable effects and is hampered by a small number of astronaut subjects and poorly controlled conditions (differences in flight experience, fatigue level, sleep, etc.). A laboratory experiment provides a much better- controlled setting, but it cannot reproduce the reality of space travel that we desire to capture. In fact, what space data we do have show few, if any, significant decrements in objective measures of cognitive function . There are some changes in reaction time, for example, but their significance is uncertain . This is similar to the case in which a terrestrial patient has a complaint but testing yields no anomalous results in the clinic. Is the test

Working in zero gravity means a shift of body fluids and could lead to changes in cognitive function and vision.

types of things that are conducive to working with others in a small space. The radiation level is also elevated—although not as high as it is on the moon or Mars, or in deep space on the journey there. The primary long-term risk from radiation is an increased lifetime likelihood of cancer, but there are possible short-term effects as well. There is some evidence from animal studies that a large acute radiation dose (as might result from a solar flare) could cause a deficit in cognitive function. While this remains to be verified in humans, the prospect of a drop in mental capacity when it is most needed—for example, in mid-journey to Mars—should give one pause. Finally, there is weightlessness itself. It is perhaps odd to think of this as a stressor, when we see astronauts cavorting in zero gravity, free to explore the full three-dimensional scope of their confines. But this freedom comes with challenges. Objects, including people, float away if not held in place. Debris floats and can get into the eyes. There are also physiological consequences of the shift of body fluids to the head, which might lead to changes in cognitive function, and certainly contribute to sinus congestion and alterations in the senses of taste and smell.

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flights. (A Mars mission would be about three years, albeit with a long period of Martian gravity which might halt the progression of such weightlessness-induced problems.) In fact, a number of recent imaging studies have examined the brains of astronauts before and after spaceflight. In some cases, these studies show a slight upward shift of the brain in the skull, and an increase in the size of the ventricles (fluid- filled spaces inside the brain where cerebrospinal fluid is made and stored). Not all of these changes are reversed after returning to Earth. There are also changes in neural gray matter, which increases or decreases depending on the functions carried out by the brain area involved, and alterations in connectivity between regions, indicating neural plasticity and reorganization. Researchers have also observed white matter changes in several areas of the brain, including the cerebellum, which is involved in motor control and vestibular processing. So far, it seems that no permanent or dramatic damage to the neural tissue of the brain has resulted from spaceflight. In fact, many of the changes seen in imaging studies may be appropriately compensatory and adaptive for weightlessness—they are the body’s natural adaptive response to an unusual environment and serve the person well as long as he or she is in space.

inappropriate, or are the self-assessments incorrect? Or, as is more likely, is it the fact that motivated, high-performing individuals can rise to the occasion and perform well on virtually any well-defined task, as long as other distractors can be ignored? In the real world (and especially in space), people rarely have this luxury, which suggests why cognitive testing fails to capture the effects of spaceflight stressors in a realistic way. What Happens to the Brain? One such effect relates to changes in visual function . Astronauts returning from early missions of several months on ISS sometimes reported changes in visual acuity. Given all the demands of spaceflight, and the fact that these astronauts aged several months during their missions at a time in life when normal aging often produces decrements in visual function, it was hard to know what to make of these reports. Eventually, it became clear that there were changes in the structure of the eye—mostly temporary but some apparently long-lasting—that were very troubling. Alterations in visual function in high-performing individuals in a dangerous and demanding environment is something that gets a lot of attention, and a great deal of research has been devoted to characterizing and addressing this concern. What is the cause? It has been recognized for decades that, in weightlessness, there is a shift of fluids (i.e., blood, cerebrospinal fluid, lymph) from the lower to the upper body. This results in puffy faces (easily seen in astronaut photographs), sinus congestion, and blunted sensations of taste and smell. There are also changes in fluid drainage from the head, resulting in a buildup of fluid and, presumably, an (as yet unproven) increase in intracranial pressure. Some of the fluid makes its way down the sheath—the outer covering—of the optic nerve that leads to the eye. Among other things, this flow of fluid slightly distorts the shape of the eyeball, which changes its optical properties and hence visual acuity. There are also indications of damage to the retina , the layer of nerve cells in the eye that senses light and sends signals to the brain and that can detach from the epithelium. In advanced degeneration, the macula may bleed and leak fluid. Yellow deposits appear and vision becomes blurry. So far, these ocular effects have not produced dramatic deficits in astronauts’ ability to perform their duties, but they are worrisome. They began to generate serious concern when they became more consistent in ISS crews who spent several months in space (as opposed to crews of Space Shuttle missions who spent a maximum of 17 days there). Particularly disturbing is the possibility that these eye changes are but the canary in the coal mine: an indication of broader and more substantial neural damage that might result from longer

An astronaut's mental health challenge: seeing the same people day after day, month after month.

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