Cerebrum Fall 2021

The fall issue of Cerebrum magazine explores the parallels between magic and brain science, performance pressure and its link to mental illness, new migraine treatments from this year's Brain Prize winners, and a sampling of brain art inspired by autism.




FEATURES 16 The Pressure to Perform

Are those who perform before the public—hundreds, thousands, even millions of spectators at a time—at heightened risk of mental illness? It’s complicated. By Carl Sherman 22 Migraine: The Road to New Targeted Drugs The 2021 Brain Prizewent to four individuals whose independent research led to useful treatments for a disorder affecting a billion people. By Brenda Patoine 28 Magic of the Mind After receiving his degree in neurobiology, our author decided to pursue a career as a magician, a profession that requires a unique understanding of how the mind works. By Daniel Roy

34 Brain Trees

A sampling of work by Dana Simmons, Ph.D., a neuroscientist who created works of art from the beauty she saw through the use of microscopy to study autism. By Bill Glovin


Advances • Notable brain science findings Briefly Noted • By the Numbers, Brain in the News


11 Bookshelf • A few brain science books that have recently caught our eye 11 In Memoriam • J. Allan Hobson and Elaine Snell 12 Clinical Corner • A Conversation Worth Having, By Adam P. Stern, M.D. 14 Neuroethics • False Hope and Deep Pockets, By Philip M. Boffey 42 Awards • And the Winner is: Neuroethics Essay Contest

4 From the Editor | 5 Contributors | 44 Advisory Board | 46 Cerebrum Staff






Batter Up

BY BILL GLOVIN Editor-in-Chief


I t’s been a while, but I still clearly remember the stress and anxiety that came along with pitching for my high school team in Fair Lawn, New Jersey. Leading up to high school, I had always played third base when I wasn’t pitching—a position I much preferred. But because I had an effective curve ball and threw strikes, the coaches insisted I pitch. I came to hate the spotlight and the idea that so much of the game’s outcome depended on my performance. As time went on, baseball felt more like a chore and something I played because the world around me expected it, and I was glad to finally leave the pressure behind me. That’s the reason why basketball star Kevin Love’s admission about coping with stress and depression was so relatable to me and countless others. His admission on a mostly taboo subject seemed to finally open the floodgates to a frank discussion about the pressures performers face in a way that hadn’t been addressed before. Performers came forward from almost all walks of life to say the issue was much more than about stage fright, and to empathize and say “thank you” for the courage in speaking up. Love’s struggles especially resonated with high- profile performers, many of whom opened up about their need to justify multimillion-dollar contracts, the pressure to keep people around them employed, and the need to meet the expectations of fans, the media, and even entire countries—as was the case with Simone Biles and the recent Tokyo Summer Olympics. And so, many questions ensued: Why do some performers struggle and not others? Can their stress and anxiety be prevented or treated? What happens in the brain to cause such calamity? We hope our cover story provides some of the answers. Another story we are proud to present is one about the evolution of a new class of drugs for migraine, a problem for an estimated one billion people and one that’s categorized as second on the list of brain disorders affecting people worldwide. Our story traces the path that four individuals took in various labs around the world to win the most recent Brain Prize. Much like the many Covid-19 stories we’ve run, it is science working to humanity’s benefit. We also are also fortunate to have Daniel Roy tell his story of how his passion for magic coincided with him receiving a degree in neurobiology, and how brain science helps inform his work as a professional magician. Finally, we showcase the art of Dana Sutton, a neuroscientist who was inspired to create works of art after using microscopy to conduct her research on autism spectrum disorder. All in all, a power-packed issue, which we hope you enjoy. 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 10 Rockefeller Plaza, 16 Floor New York, NY 10020 or cerebrum@dana.org Letters may be edited for length and clarity. We regret that we cannot answer each one.



The Pressure to Perform > Page 16

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.

Migraine: The Road to New Targeted Drugs > Page 22

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.

DANIEL ROY , a professional magician, received a B.S. degree in neurobiology from the University of Pennsylvania. He has appeared at the Hollywood Magic Castle and the Chicago Magic Lounge, and his audiences have included Fortune 500 Companies, Hollywood actors, and members of the U.S. Congress. In 2019, he became one of the youngest magicians ever to receive the

Magic of the Mind > Page 28

Milbourne Christopher award for Close-Up Magician of the Year.

DANA SIMMONS holds a Ph.D. in neurobiology from the University of Chicago, where she researched autism spectrum disorder and its connection to the cerebellum. While performing experiments in the lab, Simmons found that neurons called Purkinje cells looked like microscopic trees and began creating digital art that represents the tiny trees of the brain. Dana now works as a

Brain Trees > Page 34

medical writer in Washington, D.C.



ADVANCES Notable brain-science findings


P eople with COVID-19 infections have reported symptoms including brain fog, loss of sense of taste and smell, seizures, and both mild and severe strokes. Researchers in the UK were able to take advantage of the huge data collected in the UK Biobank to determine what Covid is doing in our brains. They invited back 782 people who had already banked brain scans to be MRI-scanned again; roughly half the volunteers had been infected during the intervening time and half had not. Most of the people infected had moderate or mild symptoms; only 15 people had needed to be hospitalized. The researchers found that the amount of gray matter shrunk between scans in people who had had Covid, especially in brain areas that involved smell, taste, cognitive function, and memory formation. Their results are correlations—so suggestive but not direct proof. A second UK-based study , using online data collection (a clinically validated web quiz) also found a correlation between Covid infection and cognitive deficits that persisted even after people had cleared the infection. l


S cientists in Germany have hit another time by prompting some to develop the light- receptive tissues that make up eyes. The “optic cup” structures took about 30 days to form and firmed up by 60 days, the same time frames as in natural human development. These cups, which arose in about three-quarters of the 314 organoids created, contained lens and corneal types of tissue. They connected to other parts of the organoid and formed electrically active networks that responded to light. Some potential uses for this type of organoid are observation—learning more about the stages of growth during development and what might go wrong—and drug testing. A hallmark of ADHD (attention-deficit/ hyperactivity disorder) is trouble staying focused. Researchers in Switzerland wondered if giving a signal to a person at the moment their focus starts to slip, measured by the amplitude of their alpha brainwaves recorded by EEG on the scalp, could help them train their brains to stay on track on unrelated tasks later. They gave 47 volunteers neurofeedback in the form of a “Space Race” video game; players could see the rocket move forward when they were in the zone and stop when they passed out of their in-focus threshold. After one half-hour session, people with ADHD did improve on a test of focus, and their brains showed a consistent milestone in learning how tiny, brain-based ORGANOIDS can help in research, this change in activity. More study is needed, but the results suggest another avenue for diagnosis and treatment besides medication. l


S taying cognitively active as we get older might help stave off DEMENTIA for as much as five years, suggests a longitudinal study of 1,903 people over age 80. All the volunteers started the study with few symptoms of dementia, but over the next two decades, 457 people developed enough symptoms to be diagnosed with Alzheimer’s. Those who reported that they often read magazines, newspapers, or books; wrote letters; and played games like board games, cards, and puzzles tended to stay sharp longer. Interestingly, the results did not see a link between years of formal education (considered a common measure of early-life cognitive activity) and age of onset of dementia. Also, researchers reported that whether people stayed “cognitively active” or not did not depend on their level of symptoms; the early stages of dementia did not appear to drive people to stop their activities. l W hen we see a very familiar face (like a grandmother), and have that visceral FLASH OF RECOGNITION , what is happening in our brains? It appears that a single area in the temporal pole region, at least in monkeys, triggers this sensation. Researchers in New York found one type of neuron in the region that responded to faces the monkeys had seen and been in the presence of much more strongly—and superfast— compared with those they had not seen before or those they had only seen on video screens. The scientists say that this reaction is the first evidence of a “hybrid” brain cell, one that shows aspects of both sensory cells (fast, reliable response to visual stimuli) and memory cells (responding only to stimuli the brain has seen before). l

An area (red/yellow) in the brain’s temporal pole specializes in familiar face recognition.




ADVANCES Notable brain-science findings

I n 2019, the Food and Drug POSTPARTUM DEPRESSION , based on a series of studies that showed the GABA-receptor- targeting drug was much faster-acting than current treatments (3 days vs. 6-8 weeks for therapy or standard antidepressants). It was not clear then how long the effects would last; the studies followed their volunteer subjects for only 30 days. A new report from UNC Hospitals in Chapel Hill, NC, suggests that the effects are, indeed, long-lasting, but also acknowledges that there are steep barriers to entry for people in need: The drug, brexanolone, is expensive and must be administered intravenously over a few days in a hospital setting. Now, Administration approved the first drug specifically designed to ease the symptoms of an experimental drug people can take by mouth, targeting the same GABA receptors, has shown promise in randomized clinical trials. Mothers taking zuranolone daily for two weeks showed fewer depressive symptoms than those taking a placebo and also started seeing results in three days. This study followed their volunteers for 45 days. l

T he question of whether video games have a positive or negative impact on children with attention deficit/ hyperactivity disorder (ADHD) has long been an area of contention among researchers and clinicians. In recent months, the Food and Drug Administration made history by granting approval for EndeavorRX, a video game to be prescribed as a treatment for kids between the ages of 8 and 12 who suffer from ADHD. Akili Interactive—the

company that created the game, was co- founded by Adam Gazzaley, who is the company’s chief scientific adviser and a professor of neurology, physiology, and psychiatry at the University of California, San Francisco. l




Outreach Grants for USA and Canada! Deadline: November 7

For details and to apply, visit brainawareness.org/grants/us-canada Grants are open to qualified Brain Awareness Week partners in the US and Canada to support outreach activities in celebration of the 2022 campaign.




“ B Y T H E N U M B E R S

2 mental health

“I have tried to live in a a world that does not

see color but have only succeeded in living in a world

that does not see me.” — Kafui Dzirasa , M.D.,

researchers, Nicholas Balderston and Meaghan Creed, were selected as the winners of the 2021 Klerman and Freedman Prizes.

BRAIN IN THE NEWS Links to brain-related articles we recommend > New York Times: When It Comes to People Like My Daughter, One Size Does Not Fit All > NBC News: Deep brain stimulation may ease opioid addiction when other treatments fail > Scientific American: Caffeine Boosts Bees’ Focus and Helps Them Learn > New York Times: Tapping Into the Brain to Help a Paralyzed Man Speak > Quanta Magazine: How Computationally Complex is a Single Neuron > New York Times: Cupid in Quarantine: What Brain Science Can teach Us About Love > Washington Post: FDA-approved gaming is already here, pointing to its therapeutic potential > The Star-Ledger: There’s no vaccine for opioid use disorder > Science Focus: The mind-blowing science behind how our brains shape reality > New York Times: I Can’t Stop Wondering What’s Going on Inside My Cat’s Head > University of Cambridge: The Pict Warrior Fighting Her Inner Demons > Washington Post: The mystery of 9/11 first responders and dementia > Orchid: Identify Your Healthiest Embryo > Science: A cautionary tale of eugenics Ph.D., associate professor in the Department of Psychiatry and Behavioral Sciences at Duke University, from an essay that first appeared in Cell magazine.

ONE HUNDRED FOUR of 818 first responders to 9/11 show signs of cognitive impairment. 15 components make up

the MIND diet, which has shown to reduce a person’s risk of developing Alzheimer’s disease and helps maintain cognition in older adults.


brains have been donated since 2008 to the Veterans

Administration, Boston University, and the Concussion Legacy Foundation collaboration for CTE Research.

The year the average life span is expected to reach age 90.

2 0 6 0

Africans are helping the NeuroGap- Psychosis project collect and study data to find genetic markers linked to schizophrenia and bipolar disorder. 35,000

$56,000 is the amount Biogen plans to charge for its new Alzheimer’s drug, Aduhelm.

overdose deaths occurred as a result of the pandemic in 2020, a 30 percent increase over the previous year.



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

preparing them to fundamentally alter their relationship with the often- unwanted discomfort and unease of anxiety. Using the latest research and her own experience, Suzuki guides readers through the neural and biological processes of anxiety, emphasizing why learning to listen to (and not ignore) our sources of worry and discomfort trains us for dwelling comfortably on the knife’s edge of good anxiety—a reliable source of motivation and heightened focus we can tap into to increase productivity and quality of life. A compelling guidebook, Good Anxiety is poised to complement the moment. Committed: Dispatches from a Psychiatrist in Training by Adam Stern (Houghton Mifflin Harcourt) An incoming psychiatry resident at Harvard Medical School, Adam Stern found himself training alongside brilliant minds with prestigious pedigrees from the halls of Yale, Duke, and, of course,

Harvard. As a graduate of the lesser- known State University of New York’s Medical University in Syracuse, Stern was quickly subsumed by a lack of confidence in his own abilities. In his memoir Committed , Stern, now an assistant professor of psychiatry at Harvard Medical School and a practicing psychiatrist, chronicles his and his fellow 14 residents’ arduous trek to completing their Harvard residency training, capturing the intensity, whimsy, and near- constant struggle with self-doubt. Stern emphasizes the trainees’ growth as doctors and as people, vividly detailing the four years of the program and making sure to include some of the most challenging and rewarding patient portraits found within the psychiatric wards. While these patients’ stories of struggling with manic depression, schizophrenia, and anorexia nervosa are included in the work, the spotlight remains on the residents. A memoir that reads like a medical trainee journal infused with the essence of Grey’s Anatomy (the TV drama), Committed is a vibrant and realistic glimpse into the life of a resident psychiatrist. l


Good Anxiety: Harnessing the Power of the Most Misunderstood Emotion by Wendy Suzuki (Atria Books) A recent September

figure from the US Census Bureau’s Household Pulse Survey shows that 28 percent, or more than one in four, of U.S. adults reported experiencing anxiety indicators— symptoms such as uncontrollable worry, nervousness, or feeling on edge—in the previous week. In the face of this age of anxiety, New York University neuroscientist and author of Healthy Brain, Happy Life Wendy Suzuki suggests approaching anxiety with a paradigm-shifting (if seemingly counter-intuitive) idea: anxiety, mind you, is actually beneficial and crucial for motivating optimal living. In Good Anxiety, Suzuki provides readers with tools that go beyond effectively managing anxiety,


J. Allan Hobson, M.D. , a psychiatrist and pioneering sleep researcher who disputed Freud’s view that dreams held hidden psychological meaning. — A Dana Alliance

Elaine Snell , a contributor to the Dana Foundation over the last 25 years beginning in 1997 when she spearheaded press efforts to inform the public, media, and neuroscience

for Brain Initiatives member, Hobson was a professor of psychiatry at Harvard Medical School and director of the Laboratory of Neurophysiology at the Massachusetts Mental Health Center. Over a career that spanned more than four decades, his own research and that of others showed that sleep is crucial to normal cognitive and emotional function, including learning and memory. In more than 20 books—among them The Dreaming Brain (1988); Dreaming as Delirium : How the Brain Goes Out of its Mind (1999), and Dream Self (2021), a memoir—he popularized his research and that of others, including the findings that sleep begins in utero and is essential for tissue growth and repair throughout life.

community of the launch of the European Dana Alliance for the Brain (EDAB). — Snell’s skill in science communication contributed to many Dana Foundation and EDAB efforts, including the success of our Brain Awareness Week campaign throughout Europe. She helped develop more than 150 programs for public debate and dialogue on issues in contemporary science at Dana Centre at the London Science Museum. With Foundation support, Snell ran the press office at FENS Forum since their first meeting in 1998. From 2012 to 2015, she served as chief operating officer of the British Neuroscience Association and subsequently served in the same capacity for the International Neuroethics Society.




A Conversation Worth Having

life-altering, exist in my own inner world without disclosing it to at least those people who explicitly asked. “Thank you for your concern. I am doing well now,” I might reply. Still, when I wasn’t engaged in a session with a patient, my mind was almost entirely consumed with the worry that my cancer might return. As my worst fears predicted, the cancer was soon found beyond the kidney in my lungs, lymph nodes, and even my other kidney. I’ve had five different procedures and endured three different systemic immunotherapies that have thankfully slowed the disease. My ordeal has helped me gain new appreciation for the patient experience, especially where life and death are concerned. I see the flaws in the system and the torturous path patients have to walk just to find their way through the maze that is modern medical care. The marvels in healthcare today have kept me alive, but the everyday logistics of being a patient is much harder than most doctors realize. I have gained more insight into the patient experience as a man living with serious illness than I ever did as the doctor, even after years of deliberate training in just that. To help process what I’ve been through, I began writing about my experience at the intersection of being a doctor and a patient. One of my essays got the attention of a literary agent. Eventually I used my new perspective to reflect back upon my own psychiatric training in a book called Committed . Writing that memoir helped me to better understand the origins of my own life and that of my patients in empathic dividends that continue to enhance my practice. I still don’t bring up my illness with patients unless it directly affects their care—or if the patient brings it up. There’s still some value in the old lessons to self-disclose with a patient only when it may offer a window into something of value for them. That said, when patients ask about my health now, I am more open and honest about my experience. I think they find that genuine openness— unexpected as it may seem from a psychiatrist—to be refreshing and engaging in a way that was once missing. Thankfully, in recent months, I’ve been able to truthfully offer up that “I am doing well now” and then delve into wondering what it must be like to have a doctor dealing with his own imperfect humanity. I usually find that it’s a conversation worth having. l ADAM P. STERN is the director of psychiatry at Beth Israel Deaconess Medical Center’s Berenson-Allen Center for Noninvasive Brain Stimulation, and an assistant professor of psychiatry at Harvard Medical School. He is the author of Committed: Dispatches from a Psychiatrist in Training (Clarion-Mariner, 2021).

BY ADAM P. STERN, M.D. I N MY TRAINING AS A PSYCHIATRIST, I WAS TAUGHT THAT self-disclosure should be considered in the context of the patient’s well-being. There were occasional circumstances when talking about one’s own life could be seen as a useful therapeutic tool if it was a path toward better insight on the part of the patient, or even a stronger alliance between doctor and patient. Beyond that, speaking about one’s own personal life was traditionally thought to be unproductive and potentially harmful. Who knew what thoughts or unconscious reactions a patient might have to their doctor spontaneously recounting their weekend plans or home life stressors? For the first several years out of training, I followed this principle with a certain dogmatic faith. When I got married and had my first child, I put a framed picture of them in my office just out of sight from where the patient might see it. I kept my social media platforms private to avoid the awkward interaction of having to reject patient requests for virtual “friendship.” This approach ran into some difficulty, though, in January of 2018 when I was unexpectedly diagnosed with an aggressive Stage III kidney cancer. Within a week of the diagnosis, I was on the operating table to have a 10 cm malignant mass removed along with my entire left kidney, and a recovery at home followed over the next several weeks. My colleagues at work were able to reschedule patients and find adequate coverage, but it didn’t feel right to me that none of the people I cared for knew the reason their treatment was being affected. It felt as though a large asteroid had crashed into my home, but no one outside of my family really knew about it. I was spending every moment of every day picking up the pieces of my world and wondering what my future held, while my patients were left to let to their imaginations fill in the blanks during my nearly two-month absence. When I did return, I was about 25 pounds lighter, and patients noticed. Some of them complimented my weight loss, and I didn’t know how to respond. Others told me they hoped everything was alright and that they worried about me while I was out. There were no easy responses to these questions, and I usually defaulted to a stance of appreciative non-denial. It didn’t feel right to have something so intense, and






False Hope and Deep Pockets

Aduhelm. At least six affiliates of Blue Cross and Blue Shield have said they will not cover the costs because the drug is still experimental or because clinical benefit has not been established, according to the Boston Globe . The most worrisome issues concern the drug's price tag. Biogen wants to charge $56,000 a year for the drug, which by some measures does not look all that exorbitant. As I wrote in a column on price gouging published May 13, 2019,

BY PHILIP M. BOFFEY T HE FIRST NEW DRUG TO TREAT ALZHEIMER’S disease in nearly two decades was initially hailed as an important advance but quickly became notorious for its exorbitant pricing and for raising a slew of ethical concerns. The drug, which will be sold under the brand name Aduhelm, was developed by Biogen, an American multinational company based in Cambridge, Mass. It was approved by the Food and Drug Administration (FDA) under a controversial “accelerated approval” process despite a nearly unanimous recommendation against approval by an advisory committee of experts. Three members of the panel quit in protest. The evidence supporting Aduhelm’s safety and effectiveness is astonishingly skimpy. Of two phase 3 clinical trials conducted by the company, only one showed hints that Aduhelm might slow cognitive decline slightly, while the other showed no benefit. After additional analysis, Biogen concluded that in one of the trials a high dose appeared to slow decline—but only by a fraction of a point on an 18-point rating scale. On the downside, some 30 to 40 percent of the patients receiving the high dose suffered brain swelling or bleeding. Despite that skimpy resume, the FDA decided to approve the drug under its accelerated approval program which allows it to rely on a surrogate endpoint that is “reasonably likely” to predict a clinical benefit. The biomarker it relied on was the presence of amyloid beta plaques in the brain. Experts on both sides of this controversy agree that Aduhelm substantially reduced the presence of plaques. But they disagree on whether that matters. Although such plaques are often associated with Alzheimer’s, there is no evidence that reducing the amount of plaque will slow the disease. Peter Bach, a leading expert on drug pricing, notes that multiple comparative clinical trials have cast doubt on the theory that reducing the build-up of plaque will attenuate the progression of Alzheimer’s. That leads him to suspect, he said in an email, that “the one allegedly somewhat positive study of Aduhelm was very likely to be a false positive finding.” Both the Cleveland Clinic and Mount Sinai’s Health System in New York City have decided not to administer

drugs to treat multiple sclerosis had soared to $60,000 a year, drugs to treat

brain cancer had reached $30,000 a month ($360,000 a year), and a drug to treat nerve destruction from a very rare disease was priced at an astronomical $450,000 a year. That is not an indication that Aduhelm is reasonably priced. Rather, it is evidence that the whole drug-pricing system in this country is out of whack. Biogen’s $56,000-a-year for the drug alone is not the total cost. The doctors whose offices administer the drug intravenously once a month get paid for their services, posing a huge conflict of interest when they decide who to treat and for how long. Other associated costs, such as diagnostic tests to determine whether a patient has a lot of plaques and monitoring tests to determine how a patient is progressing could add tens of thousands of dollars a year to a patient’s annual bill. Those costs will fall heavily on Medicare, which is supported by the American taxpayer, on those with private insurance, whose costs are borne by individuals or their employers; and on the uninsured, who may find the costs prohibitive. Even many insured patients may not be able to afford their copayments. Estimates by the Kaiser Family Foundation suggest that the costs to Medicare and the patients who use the drug could reach anywhere from $29 billion to $57 billion a year. Given the underwhelming evidence and all the uncertainties, how should Aduhelm be priced? The Institute for Clinical and Economic Review (ICER) calculated that a fair annual price for this drug, which it deems likely to become one of the top-selling drugs in the history of the US, would lie between $2,500 and



$8,300, a far cry from the $56,000 the company is seeking. The institute charged that the FDA “has failed in its responsibility to protect patients and families from unproven treatments with known harms.” It estimated that Biogen could rake in “well in excess of $50 billion per year” while waiting for evidence to confirm that patients were actually benefiting. The FDA’s approval process itself was rife with ethical conflicts . In one highly improper move, a top FDA official held an off-the-record meeting with a key Biogen executive in 2019, apparently violating long-standing rules and practices designed to keep the approval process transparent and unbiased. The revelation by the medical news site STAT caused such an uproar that the acting head of the agency felt obliged to ask the inspector general of the Department of Health and Human Services to investigate the circumstances that led to the drug’s approval. That inquiry is not yet complete, but the emerging evidence suggests an overly cozy relationship between the regulators and the industry. On September 1, two House committees launched a joint investigation into the appropriateness of the FDA’s handling of Alduhelm. This sorry saga has left me wondering whether the accelerated approval process itself might be considered an unethical approach to regulating a drug whose clinical value is so uncertain and

approval process often gives companies a “commercial end run” around FDA regulation. The companies are required to do further controlled studies to verify the drug’s clinical benefit. If the results are negative, the FDA may withdraw its approval, but it does not have to and often fails to. The agency gave Biogen nine years, until 2030, to complete follow-up studies on Aduhelm. So, the company will continue to earn tens of billions a year on a drug whose clinical value might never be proven. The approval of Aduhelm was welcomed by the Alzheimer’s Association, an advocacy group for patients and their families, which complained only about the high price tag because it would make it unaffordable for many patients. However, the association has its own ethical issues ; it receives funding from the drug industry and from Biogen itself. One top geriatrician considers the association “a big promoter, almost a marketer, for Biogen.” Experts have proposed several ways to force down exorbitant drug prices. These include revising the formula that determines what Medicare pays for drugs, allowing the national insurance program to negotiate lower drug prices, and tying prices in this country to the lower prices charged abroad. One intriguing idea is to have the Centers for Medicare and Medicaid Services initiate a process that could require companies and prescribing physicians, as a condition for reimbursement, to provide continuing data on their patients that could be compared with a comparable group of patients that did not receive Aduhelm. That could provide useful information even if Biogen’s required clinical trials are never completed. Another potentially important reform, suggested by Peter Bach, would limit manufacturers to a ten percent profit over the cost of manufacturing and distributing the drug, thus providing a reasonable return without allowing companies to charge what the market will bear based on hope and wishful thinking. None of these proposals may come to pass or, if enacted, prove effective. But surely, they are worth a try. Desperate patients deserve access to the best available treatments, but the price has to be affordable for patients and the American healthcare system. 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.

whose ability to slow mental decline will be hard to measure. Once the drug is on the market, it will be difficult—if not impossible—to recruit enough patients for the follow-up trial that is supposed to document definitively whether Aduhelm really works. Few patients are likely to volunteer for a trial in which they might well get a placebo when they can probably get Aduhelm prescribed directly by a physician. Elisabeth Rosenthal, M.D., who is editor-in-chief of Kaiser Health New s, wrote recently that the accelerated




Assessing mental

health risks for those in the public eye


NE OF THE MOST MEMORABLE MOMENTS IN LAST SUMMER’S TOKYO Olympicswas a star performance that didn’t happen. Shortly after amistake in executing a difficult maneuver had cost her a medal—and threatened serious injury—gymnastic phenomenon Simone Biles announced that she was withdrawing from key compe- titions for mental health reasons. Despite returning several days later to take medals in some subsequent events, Biles was derided as a quitter by some. But upon the whole, the response was respect for her courage in protecting herself, and in going public with her mental health concerns.




Stage Fright and Other Sorrows Performers of all sorts are unquestionably subject to special challenges. Anxiety surrounding the performance itself—“stage fright”—is the most obvious. This has been most studied in musicians. Various studies have suggested that between 15 and 70 percent of professional musicians report performance anxiety. “These statistics are probably on the low end—every musician gets a little nervous before every performance,” says Kageyama. “It’s a matter of degree, whether they feel their nerves are derailing their performance, or a useful adjunct.” Attempting to control anxiety can itself be a problem. A 2015 survey of 447 players conducted by the International Society of Symphony Orchestra Musicians found that 70 percent had used beta blockers, cardiac drugs that blunt the physiological response to anxiety. In extreme cases, performance anxiety can end a career. “A lot of musicians are talented enough but can’t make it performance-wise,” says psychiatrist David Shapiro , of Weill Cornell Medical College. “Anxiety leads to avoidance, and they miss gigs or are repeatedly unable to get to jobs on time.” Severe stage fright crippled singer-songwriter Carly Simon’s career, kept singer Adele from touring, and drove Vladimir Horowitz, one of the great classical pianists of the last century, off the concert stage for decades. Fear of public failure is at the heart of performance anxiety, and its severity can depend on the nature of the performance (e.g., solo vs. orchestral) and the size of “YOU WOULD BE AMAZED AT HOW FREEING IT IS JUST TO TALK TO SOMEBODY AND TELL THEM THE TRUTH ABOUT WHAT YOU’RE GOING THROUGH.”

Her example was not isolated. Two months earlier, second-seed Naomi Osaka withdrew from the French Open tennis tournament, citing the debilitating effects of stress and her struggles with depression. In recent years, public disclosures have made it clear that mental health problems are by no means uncommon among celebrity entertainers as well, a star cast that includes actors Jon Hamm, Kim Basinger, and Alec Baldwin, and singers such as Bruce Springsteen and Lady Gaga. Are those who perform before the public—hundreds, thousands, even millions of spectators at a time—at heightened risk of mental illness? It’s complicated. The mental health of athletes has received the most attention: There are international societies for sports psychiatry and sports psychology , and data for mental health conditions are far more abundant than for other fields. It is possible that problems are underreported due to concerns about image or remaining on the team. But among present and elite athletes, it appears that the prevalence of depression, anxiety, and other mental maladies is the same or just slightly higher than in the general population. “The mental health [of athletes] is comparable to the public at large,” psychiatrist Carla Edwards of McMaster University summarizes. “But athlete-specific factors could place them at higher risk in some circumstances. “[Mental health difficulty] can eke its way into sports in lot of different ways,” says Edwards, president of the International Society for Sports Psychiatry. “Athletes can enter sports with pre-existing problems; or [problems] can develop as result of sport-related issues—such as pressure or maltreatment; arise independently; or be exacerbated by sports. A lot of athletes, conversely, need to keep sports incorporated into their lives for their mental health.” Many of the same stresses are common to other endeavors in the glare of the spotlight. “Performance is performance is performance,” says Julliard psychologist Noa Kageyama . “The details may vary, but the basic principles are the same. All [performers] experience the same sorts of challenges.” There may be differences between groups, however. Less robust data suggest that professional musicians suffer more than their share of depression and anxiety symptoms. A recent Norwegian study , for example, found that 18 percent of musicians within Norway reported significant psychological distress, compared to 8 percent of workers in other fields.


the audience. But while a violinist may feel peak stress when picking up his or her bow before a packed concert hall, many musicians “are not that nervous in front of an audience of strangers, as opposed to teachers, fellow musicians, or friends and family members” whose negative evaluation would carry a special sting, says Kageyama. Some anxiety in the heat of athletic competition is inevitable (“I don’t think you’re human if you don’t get nervous,” according to hockey great Sidney Crosby), but stage fright per se tends to be less problematic in sports, says Edwards. “Athletes on a high-performance pathway from an early age are exposed to larger and larger crowds... When they’re in their element and know that they’re good at it, the anxiety is not there. “Even for some athletes with social anxiety—they hate to go to parties—performing in front of 10,000 people is not an issue. They don’t worry about it at all.” In any case, the performance itself is only part of the story, and not necessarily the biggest part. A more substantial threat to mental health may come outside the arena and off the stage. “The way the general public views elite athletes is that they have ‘the life.’ They just get to play sports,” says Edwards. “They don’t understand that’s the tip of the iceberg, and in the submerged part is all of the other things that contribute to challenges and pressures.” It starts early. Elite athletes and musicians frequently excel from their first years, and training and performance may dominate and destabilize their childhood, disrupting family relationships and schooling. Young performers can be subject to pressure from parents and others who identify too closely with and exploit their success—the “achievement by proxy distortion.” Stage mothers (and fathers) have their equivalent in the worlds of sport and music. The lives that many star entertainers, elite athletes, and virtuoso musicians lead entail years of sustained stresses and pressures, which can include frequent travel and irregular hours, disturbed sleep, and rigorous training or practice schedules. Invasion of privacy comes with the territory, and personal relationships may be strained. “Celebrity can be a mental health risk factor if the person is not psychologically healthy enough before becoming a celebrity,” says Beverly Hills psychiatrist Carole Lieberman , who has worked with actors and other performers and as a consultant in the entertainment industry. Those in the public eye have always had to deal with

audience catcalls and bad press. But the internet puts such assaults on steroids: You’re performing—and living—before an often vociferous public of millions, not thousands. “Social media amplifies the effect of criticism,” says psychologist Michael Hollander of McLean Hospital and Harvard. Failure in competition, or personal disclosures (like Biles’s and Osaka’s concerns about their mental health) can unleash a barrage of vicious commentary that reverberates for weeks or months. “You’re a victim of these comments, and you can’t fight back,” says Hollander. “I think the impact of that shouldn’t be undersold.” In the pandemic, performers faced the same mental health challenges as everyone, with an extra burden all their own. “[Covid] cut off access to training,” says Edwards, speaking of the 2021 Olympics. “Athletes always measure themselves against their former selves—they expect to perform as well or better. If they aren’t able to train as much as before, it plants seeds of doubt.” Connection to their programs, teammates, and coaches normally girds athletes’ mental health, she says. Those who were forced to train in isolation lost those supports. For musicians and entertainers, as well as athletes, the inability to do their thing in front of live audiences, for months on end, has been emotionally taxing, Kageyama says. Now that concert and other venues are reopening, “it’s been difficult for many to get back into performing. Musicians fear being out of rhythm, out of practice. ‘Getting back on the horse’ has been a source of additional stress and anxiety.” While star performers may turn to alcohol and drugs to cope with the pressures of their lives, relieve physical




evident,” he says. Neuroplasticity—the ability of nerve cells to form and change connections—increases in some areas and declines in others. Reduced growth factor in hippocampal and cortical regions may inhibit working memory. The release of the excitatory neurotransmitter glutamate is critical to how the brain adapts, but at high levels can have a detrimental effect. “With too great intensity, or prolonged intensity over time, [stress] can contribute to pathophysiologic changes in brain processing, even to the development of the behaviors and emotions we call depression,” Sanacora says. A number of alterations typical in the depressed brain—e.g., reduced hippocampal and prefrontal cortex volume and synaptic density, increase in inflammatory markers—can be related to the effects of chronic stress. On the immediate level, stress can invade performance, posing physical risks: A 2021 meta-analysis of 18 papers suggested that stress —both surrounding competition and in other aspects of their lives—along with anxiety and, to a lesser extent, depression, increased the risk of injury to athletes including football players, gymnasts, runners, soccer players, and swimmers. The effect on performance quality is more evasive: studies of its association with anxiety , for example, are inconsistent. “Athletes talk about their optimal zone of functioning; chronic stress makes it hard to get there, which can undermine their confidence,” says Edwards. For musicians, “the most distressing effect of anxiety is a loss of accuracy—intonation, rhythm, quality of sound,” says Kageyama. “Not as noticeable to an audience as to the performer himself is a tendency to play much more cautiously—not taking risks. Instead of going for high- climax moments, everything is a little more muted; there’s a drastic difference in expressiveness.” What happens in the performer’s brain, and how stress and anxiety might disrupt it, are far from clear. But it is evident that the skilled movements of sport and artistic performance demand an intricate choreography of events connecting diverse brain regions. Kathleen Cullen , whose research has focused on “how we move through the world in the face of gravity,” says that in executing complex actions while maintaining balance—as demanded by sports such as gymnastics and basketball and artistic pursuits such as dance—“the brain is computing the sensory input it expects and then comparing it with the sensory feedback it actually receives, combining information from multiple systems.” The vestibular system [a kind of gyroscope/

pain, or improve performance, the extent of misuse is unclear. “It is hard to know whether entertainers have more substance abuse than others,” says Lieberman, “but the fact that their overdoses and partying make headlines gives us the impression that they do.” (Witness the very public meltdowns of stars like Britney Spears and tragic deaths of singers Amy Winehouse and Prince.) There is limited evidence that athletes are more prone to substance problems than the general population, and several studies suggest that celebrities in general are at increased risk of addiction. One analysis of drug- related deaths among famous people found more than half involved entertainers, with athletes the next best represented. Performance and the Brain From a neurobiological perspective, the performer’s life is a study in stress. “Our current stress system developed 10-20,000 years ago. It evolved to escape the Smilodon (extinct saber-tooth cat), not to worry about how we would look in front of 40 million people,” says Gerard Sanacora , professor of psychiatry and director of the Yale Depression Program. “An athlete [or other performer] isn’t going to die from putting in a poor performance and getting booed, but the brain perceives it as a threat.” The dual nature of stress is on full display. “There’s a spectrum from adaptive to toxic, but it’s all the same system,” he says. “When appropriate to changes in the environment, the stress response is positive; it increases cognitive functioning and carries over into enhanced psychomotor, physical activities.” Musicians and athletes know that enhanced arousal is a vital ingredient for vigorous, skilled performance. “But past that, the downside of the curve becomes



accelerometer based on signals from the inner ear] “tells with great precision how the head is moving through space. The proprioceptive system [which tallies input from muscles throughout the body] tells you how limbs are positioned, relative to the body,” says Cullen, professor of biomedical engineering, neuroscience, and otolaryngology at Johns Hopkins University, These signals come through the spinal cord and converge in the cerebellum, “where the brain computes its prediction based on an internal model of sensory flow…. when there’s a difference between proprioceptive and vestibular input and what the brain expects, there’s an error signal, which the athlete can then correct on the fly.” The cerebellum also receives signals from the ventral striatum, bringing in higher-level cognitive functions. All this happens within milliseconds, she says. More generally, the brain’s comparison of an internal model deeply entrenched by the motor learning of endless practice, and the sensory input of the act itself, underlies highly skilled performance. To pitch a cut fastball in baseball with pinpoint precision or execute flawless vibrato on the violin, “you certainly need an intimate relationship in terms of movement and expected feedback,” she says. How things go wrong is an ongoing area of research, Cullen says. But given the complex orchestration of brain processes, it’s no small surprise that overarousal creates “THE WAY THE GENERAL PUBLIC VIEWS ELITE ATHLETES IS THAT THEY HAVE ‘THE LIFE.’ THEY JUST GET TO PLAY SPORTS.”

problems. “What skilled athletes and musicians do are voluntary movements. Cortical areas such as the medial prefrontal cortex encode higher levels of representation and the importance of certain motor behaviors. When the stakes are higher, you pay more attention; but if the stress level gets too high, it can get counterproductive, interfering with the volitional component of movement and flipping you into a reflex, reactive mode. You lose focus on where you are; anxiety becomes a distraction from what you’re trying to do.” A Silver Lining? The dark side of performers’ lives may enlighten the public at large about mental health and illness. “Fifteen years ago, people didn’t talk about this,” says Katrina Gay , chief development officer at National Association for the Mentally Ill. “When athletes and elite influencers share their journey, it encourages people in their own struggles with mood disorders and anxiety. It encourages them to seek help.” The willingness of an admired figure like Simone Biles to make substantial sacrifices for her mental well-being inspires others to do likewise, says Gay. “I’ve noticed more people willing to take a time-out, a mental health break from their own work.” The power of example may be particularly important for groups reluctant to seek help for mental health problems, such as men and racial minorities . A 2020 paper in Academic Psychiatry cited the example of wrestler/action movie star Dwayne “The Rock” Johnson, who has talked openly and tweeted about his depression. “You are not alone,” he told his millions of followers. Kevin Love, a five-time National Basketball Association All-Star, also inspired countless performers and others when he began advocating for mental health awareness after suffering a panic attack during a game in November 2017. His powerful essay for the Players Tribune in 2020 about living with anxiety and depression has helped remove the stigma about seeking treatment that has long plagued high-profile performers. “Talk to somebody. You would be amazed at how freeing it is just to talk to somebody and tell them the truth about what you’re going through. And listen, I’m not trying to sell you some fairy-tale version of mental health. It took me years and years—hell, it genuinely took 29 years for me to realize what I needed. I needed medication. I needed therapy. I still need those things now, and I probably always will.” l



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