Cerebrum Fall 2021

EME RG ING ID EAS I N B R A I N S C I EN C E • FA LL 2021

THE PRESSURE TO PERFORM

FALL 2021 | VOLUME 2, ISSUE 4

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 Prize went 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

SECTIONS 6 10 11 11 12 14 42

Advances • Notable brain science findings Briefly Noted • By the Numbers, Brain in the News Bookshelf • A few brain science books that have recently caught our eye In Memoriam • J. Allan Hobson and Elaine Snell Clinical Corner • A Conversation Worth Having, By Adam P. Stern, M.D. Neuroethics • False Hope and Deep Pockets, By Philip M. Boffey Awards • And the Winner is: Neuroethics Essay Contest

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

COVER ILLUSTRATION: DANIEL HERTZBERG

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FROM THE EDITOR

Batter Up

BY BILL GLOVIN Editor-in-Chief

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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 highprofile 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

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EMERGING IDEAS IN BRAIN SCIENCE

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, Incorporated. DANA is a federally registered trademark owned by the Foundation. © 2020 by The Charles A. Dana Foundation, Incorporated. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher, except in the case of brief quotations embodied in articles.

Letters to the Editor 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.

CONTRIBUTORS

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.

Magic of the Mind > Page 28

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

Brain Trees > Page 34

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 medical writer in Washington, D.C.

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ADVANCES Notable brain-science findings

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IMAGE: SHUTTERSTOCK

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

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cientists in Germany have hit another milestone in learning how tiny, brain-based ORGANOIDS can help in research, this time by prompting some to develop the lightreceptive 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.

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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 change in activity. More study is needed, but the results suggest another avenue for diagnosis and treatment besides medication. l

IMAGE: JAY GOPALAKRISHNAN ET AL./ UNIVERSITY HOSPITAL DÜSSELDORF

BY NICKY PENTTILA

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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

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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.

IMAGE: SOFIA LANDI

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ADVANCES Notable brain-science findings

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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 cofounded 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

IMAGE: SHUTTERSTOCK

n 2019, the Food and Drug Administration approved the first drug specifically designed to ease the symptoms of POSTPARTUM DEPRESSION, based on a series of studies that showed the GABA-receptortargeting 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, 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

IMAGES: AKILI INTERACTIVE

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BRING NEUROSCIENCE TO YOUR COMMUNITY!

Outreach Grants for USA and Canada!

Deadline: November 7

Grants are open to qualified Brain Awareness Week partners in the US and Canada to support outreach activities in celebration of the 2022 campaign.

For details and to apply, visit brainawareness.org/grants/us-canada Dana.org

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BRIEFLY NOTED

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BY THE NUMBERS mental health researchers, Nicholas Balderston and Meaghan Creed, were selected as the winners of the 2021 Klerman and Freedman Prizes.

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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.

2 The year the 0 average life span 6 is expected to 0 reach age 90.

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

1,000

brains have been donated since 2008 to the Veterans Administration, Boston University, and the Concussion Legacy Foundation collaboration for CTE Research.

35,000

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93,000

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

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

Africans are helping the NeuroGapPsychosis project collect and study data to find genetic markers linked to schizophrenia and bipolar disorder.

$56,000

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“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., Ph.D., associate professor in the Department of Psychiatry and Behavioral Sciences at Duke University, from an essay that first appeared in Cell magazine.

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

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> 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

BY THE NUMBERS IMAGES: SHUTTERSTOCK, THE NOUN PROJECT KAFUI DZIRASA PHOTO: LES TODD / DUKE PHOTOGRAPHY BRAIN TREE ILLUSTRATION: ISTOCK

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

BY BRANDON BARRERA 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,

preparing them to fundamentally alter their relationship with the oftenunwanted 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 lesserknown 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 nearconstant 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

IN MEMORIAM 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 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.

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 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.

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CLINICAL CORNER

A Conversation Worth Having

BY ADAM P. STERN, M.D.

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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

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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).

PHOTO: COURTESY OF ADAM STERN

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NEUROETHICS

False Hope and Deep Pockets

BY PHILIP M. BOFFEY

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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

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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, 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

ILLUSTRATION: SHUTTERSTOCK

$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 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 News, wrote recently that the accelerated

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.

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BY CARL SHERMAN ILLUSTRATION BY DANIEL HERTZBERG

Assessing mental health risks for those in the public eye

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NE OF THE MOST MEMORABLE MOMENTS IN LAST SUMMER’S TOKYO Olympics was a star performance that didn’t happen. Shortly after a mistake 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 competitions 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.

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“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.”

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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

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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.

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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

KEVIN LOVE PHOTO: ERIK DROST/WIKIPEDIA CREATIVE COMMONS / SIMONE BILES PHOTO: SHUTTERSTOCK

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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 drugrelated 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 20

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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 highclimax 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/

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“THE WAY THE GENERAL PUBLIC VIEWS ELITE ATHLETES IS THAT THEY HAVE ‘THE LIFE.’ THEY JUST GET TO PLAY SPORTS.”

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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

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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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Research from four labs in different parts of the world led to a major breakthrough—and the 2021 Brain Prize.

Migrain

THE ROAD TO NEW TARGE

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CIENCE LIKES TO PACKAGE ITS SUCCESSES IN NEAT STORIES THAT SHOW a clear progression from this to that. The “bench-to-bedside” story—when biological insights yield targeted treatments—is a long-time favorite. Reality, however, doesn’t always cooperate, and history is littered with basic-science discoveries that seemed important but failed to yield viable treatments.

When they do succeed, it’s cause for celebration—and awards. Migraine research is an example.

Although it is the second most disabling condition in the world, affecting one billion people, migraine had long been relegated to the backwaters of scientific research. Only recently has research bloomed—scientific papers sharply increased from the 1990s onward, with discoveries in basic science driving a new class of drugs that some in the field are calling game changers. This year, the recognition of four migraine researchers with a major neuroscience award has pushed the field into the limelight of science.

The four—Lars Edvinsson of Lund University, Sweden; Peter Goadsby of King’s College London and UCLA; Michael Moskowitz of Harvard Medical School/ Massachusetts General Hospital; and Jes Olesen of the University of Copenhagen and the Danish Headache Center—will accept the Brain Prize from the Crown Prince of Denmark at a ceremony in Copenhagen on October 25.

The prize, worth 10 million Danish krone (about $1.5 million USD), has been awarded yearly since 2011 by Denmark’s Lundbeck Foundation.

The Holy Grail of Scientific Progress?

The 2021 Brain Prize recognizes science that embodies the so-called bench-to-bedside research described above.

That’s a jargony term scientists seem to love that denotes the rare and wonderful occurrence when laboratory research aimed at illuminating fundamental mechanisms (the “bench”) yields insights that lead to drugs that ultimately help millions of sick people (the “bedside”). In the case of migraine research, the leading character is a neuropeptide called calcitonin gene-related peptide (CGRP).

“The winners of The Brain Prize discovered a novel and powerful molecular target and took it from the bench to the bedside,” says Richard B. Lipton, a headache specialist at Montefiore Headache Center, who has been involved in clinical trials of the new drugs. He says therapeutics based on the discoveries are “changing the lives of people with migraine all over the world.” That accomplishment, Lipton says, is worthy of a Nobel.

The drugs are classic receptor blockers. They plug 24

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up the molecular keyhole where CGRP binds to the cell surface or alter CGRP itself so it can’t lock onto its receptor. This seemingly simple switch stops migraine in its tracks—at least for some people, some of the time, to some degree. Even with those caveats, it’s arguably the biggest news in the clinical treatment of migraine in a decade or more. It’s also the first migraine-specific therapy, since most drugs used to treat migraine were developed for other conditions, such as epilepsy. All have their limitations. The approval since 2018 of seven new drugs for migraine—six of them targeting CGRP—changes the landscape, even if the drugs have been slow to catch on.

The biggest victory may be for translational science.

“CGRP demonstrates that if you understand enough about the problem, you can actually make a difference for some patients,” Peter Goadsby says. “A real difference.”

Still, it wasn’t exactly a straight line from there to here.

As so often goes in science, the path included its share of zigs and zags, mixed in with the healthy disagreements that sometimes propel science forward and other times slow it down.

A Penchant for Peptides At the center of the story is an ambitious young Swede with a penchant for peptides. In the 1970s, Lars Edvinsson was mapping the autonomic nerves in cerebral circulation for his Ph.D. thesis at Lund University. In 1976, one year after receiving his doctorate, he discovered what would later be recognized as the first neuropeptide—a short chain of amino acids that neurons use as messenger chemicals.

Edvinsson called it vasoactive intestinal peptide (VIP).

He teased out what VIP does and how it works, showing that when it is released by nerve fibers terminating in the blood vessels around the brain, it causes these vessels to dilate. The finding was “kind of a revolution to the field,” he recalled in a session at the International Headache Congress (IHC) on Sept. 11. It showed that peripheral nerves regulate blood flow around the brain via these

peptide messengers. It set off a race to identify other such compounds, and many more were found.

When CGRP was discovered in 1983 by a team at the University of California San Diego led by Michael Rosenfeld, Edvinsson, who already had his lab set up to study neuropeptides, immediately started investigating it. But not because he was interested in migraine, per se—he was focused on unraveling the biology. The CGRP-headache connection was made a couple of years later.

At an INSERM (the French National Institute of Health and Medical Research) meeting in Paris in 1984, Edvinsson laid out what he had discovered about CGRP and some other peptides of scientific interest, including the research darling at the time, Substance P. It was, in retrospect, a watershed moment in the building of the scientific case for CGRP, and a defining moment for the young scientist’s career. But at the time, it didn’t go over well.

Edvinsson recounted the occasion in a recent Zoom interview: “No one believed it.” His suggestion that CGRP was a more important drug target than Substance P went against the conventional wisdom of the time, which was fueling a flurry of drug-development efforts.

The chairperson of the scientific session in which he delivered it, an esteemed Harvard neurologist who was himself a Substance P advocate, challenged the data and questioned Edvinsson’s conclusions in front of the 1,000 or so attendees. Ironically, the antagonist was none other than Brain Prize co-winner Michael Moskowitz.

A few years before the Paris encounter, Moskowitz had coined the term trigeminovascular system (the trigeminal nerve sends sensations of pain to the brain) and hypothesized that Substance P and other “as yet unidentified peptides” might be important in headache pain. As such, he had conceptualized a role for migraine and drew attention to the system as a target for

“I had a tough time in science because for the first 20 years, no one was interested in CGRP.”

therapeutics. The thinking was based on the very kinds of discoveries that Edvinsson was working toward in his laboratory in Lund.

Recalling those years at the recent IHC session, Edvinsson said: “We showed that CGRP was the only neuropeptide released in patients during migraine and chronic headache, but no one was interested. People were interested in Substance P.” In an interview, he expounded further: "I had a tough time in science because for the first 20 years, no one was interested in CGRP.” There were a few exceptions to the general lack of belief in CGRP, including Brain Prize co-winner Peter Goadsby. As Edvinsson recalls it, “this young fellow from Sydney” approached him at a scientific meeting to talk about the data he had presented. Coffee led to collaboration and a series of experiments over ten years, including audacious human studies that measured CGRP in blood taken directly from patients’ jugular veins during a migraine attack. “When Lars and I started this, people said it was crazy,” Goadsby recalls. “We got a lot of heavy-duty flack.” They kept at it, nonetheless, publishing their work with patients in 1990 and laying the groundwork for CGRP as a therapeutic target.

As history would have it, Substance P turned out to be a 20-year sidetrack that ultimately failed to deliver clinical benefits in migraine. The trial that drove the final nail in the coffin was published in 1999. Only then, Edvinsson says, did science—and industry—start paying attention to CGRP. And things started to blossom.

Game Changers in An Overlooked Field?

Today, two types of drugs are based on the CGRP target: monoclonal antibodies (mAbs) that bind CGRP or its receptor to block its action, and gepants, which are classic small-molecule receptor blockers. Four monoclonal antibodies are approved to prevent migraine; three are given by subcutaneous injection and one by intravenous infusion. Of the two gepants, one is approved for acute treatment and one for both acute and preventive treatment. A third is under review as a preventive.

Lipton, a neurologist at Einstein College of Medicine, says he believes the drugs are game changers for a number of reasons. For starters, he says the joint approval for both acute treatment and prophylaxis represents a “new treatment paradigm.” Gepants may also overcome a problem called medication overuse headache, in which taking pain medicine too frequently paradoxically increases headache frequency. Gepants have the opposite effect when used frequently as acute treatment. In addition, Dana.org

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“To have gone from a laboratory concept to something that is real and that people are prescribing today in the world—I find that pretty exciting.” triptans, the last wave of drugs used for migraine, hold a risk of cardiovascular complications due to their vasoconstrictive action.

“The gepants are safe in cardiovascular disease and make clear that vasoconstriction is not necessary for effective acute treatment,” says Lipton. “This represents an important therapeutic advance and mechanistic insight.”

How exactly the drugs work is a current focus of investigation for Edvinsson. CGRP is known to be a potent vasodilator—it opens blood vessels when activated— but Edvinsson doesn’t believe that’s the mechanism of therapeutic action. “The story that CGRP dilates blood vessels is old news,” he says. His lab’s recent work suggests something far more complex, that the drugs interfere with the way different nerve fibers interact in signaling pathways inside cells. “This is how people think about it today,” he says.

Both Edvinsson and Goadsby have described the profundity of prescribing these drugs for their patients after having been so closely involved in their development.

“The first time I wrote a prescription for a CGRP medicine,” Goadsby said at the IHC session, “I thought, ‘Wow, really?’

To have gone from a laboratory concept to something that is real and that people are prescribing today in the world—I find that pretty exciting.”

Despite the hope and accolades, the drugs’ pick-up among migraine sufferers has been slow, for many reasons. For one, the mAbs require injections; then there’s the hesitancy of insurance companies to pay for them, since the older triptans are available as generics and 26

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therefore less expensive. Many payors require that triptans be tried first and allow the more expensive drugs only if the triptans fail. The choices for migraine treatment are many, even if none work in all—or even most—people.

Many people also find relief in nonpharmacological approaches and lifestyle changes to eliminate migraine triggers.

Migraine Research “Coming of Age” Together, the CGRP findings and the new targets they have uncovered within the trigeminovascular system “take the field out of the 19th century,” Moskowitz says.

That bodes well for sustaining the progress in future generations of research. “It can’t be seen as a sort of mystery disease if you want to attract people into the field,” Moskowitz says. “Success begets success.”

Olesen, who spearheaded a decades-long effort to create an internationally accepted classification system for headache—a Herculean endeavor that has been integral to progress in the field—says that migraine “used to be in the back alley of research.” Despite being “ridiculously underfunded” by the NIH, he says migraine is becoming one of the better understood conditions in neurology. “The field has opened up for basic research, for intelligent basic neuroscience. The progress per dollar is bigger than in any other field. That itself is a big achievement.”

Goadsby sees the recognition of their research as a coming of age for the field, reflecting its transition from "being a pastime of either cranks or people at the margins, to being a topic that is respectable enough for mainstream science to ask biological questions that relate to migraine.” As the current president of the American Headache Society, he is working with the U.S. NINDS (National Institute of Neurological Disorders and Stroke) to set benchmarks for progress in migraine research—an indication, he says, of the maturity of the field.

A roadmap for research might address some unanswered questions. We still don’t know what causes migraine, for example. We don’t know why migraines are more frequent and severe in women—a question Edvinsson’s lab is focused on answering. And a healthy debate continues as to whether the pain and associated symptoms of migraine are vascular or neural at their root—recent evidence points to the latter, against longstanding convention—and how the two interplay. Yet, for once, it seems the medical “mystery disease”—long ignored and stereotyped by society and science alike—is getting seen. l

CGRPTargeted Therapies for Migraine Brand Name and Drug

Treatment, Prevention, or Both

How Administered

Therapy Type

Dosage

AIMOVIG (Erenumab-Aooe)

Prevention

Subcutaneous injection

Monoclonal antibodies (mAb)

One or two shots (70 mg) per month

AJOVY (Fremanezumab)

Prevention

Subcutaneous injection

mAb

One shot (225 mg) per month or three shots (675 mg) every three months

EMGALITY (Galcanezumabgnim)

Prevention

Subcutaneous injection

mAb

Two shots (120 mg each) the first month; one shot per month thereafter

VYEPTI (eptinezumabjjmr)

Prevention

Intravenous infusion

mAb

100 mg IV every three months

NURTEC ODT (rimegepant)

Acute treatment; prevention

Pill form

gepant

One 75 mg pill once every other day

UBRELVY (Ubrogepant)

Acute treatment

Pill form

gepant

50 or 100 milligrams (mg) per day, as needed

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HE RT ZB ER G IEL

N A L TO OPENLY DEM ONSTRATE TH E PRINCIPLES OF SLEIGHT hand before hu OF ndreds of neur opsychiatrists. Yet I fo und myself d oi ng just that at the vi rtual Americ an Neuropsychiatric Ass ociation conf erence in March of 2021 . While simul taneously studying neur obiology at th e University of Pennsylvan ia and perform ing sleight o f h a n d m a gi c sh o w s at ve n u e s in the Philadelp hia area, I was recruited by two rese archers to co llaborate on their talk: “The Neuropsy chiatry of Magic.” In my portion, I exp lained how magicians ta ke advantage of limitations in our p erceptual syst ems, the narrowness of our attention, and the ease with whi ch our mem ories can be manipulat ed.

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After receiving his degree in neurobiology from the University of Pennsylvania, our author decided to pursue a career as a magician, a profession that requires a unique understanding of how the mind works (and the best ways to fool a brain).

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C A R D C H E AT I N G A N D C O N G A M A Spark is Lit My path to performing magic professionally began in San Francisco where, as a ten-year-old, I was bored out of my mind while volunteering at a school fundraiser.

Thankfully, one of the event’s workers—mid-50s, pot belly, salt and pepper handlebar mustache—was a magician.

He had me put my initials on a card of my choice (the five of diamonds) and inserted it into the middle of the deck. Miraculously, it repeatedly rose to the top of the deck with no discernible manipulation. Before this life-altering moment, I had only ever seen magic done on stage from a distance. Watching magic closeup was unimaginably different. With the deck of cards literally inches from my face, there were no barriers, physical, conceptual, or otherwise, between me and the magic. It was a truly visceral, adrenaline-pumping experience—the start of what has become a lifelong obsession.

Soon, I was venturing every weekend to Misdirections Magic Shop, one of the last great brick-and-mortar magic stores in this new age of online magic. The front door’s threshold felt like a portal to another world.

Jokes and pranks on the left, backlit glass display cases on the right, filled with all sorts of magic props: cards, coins, boxes, wands, and more. And behind those cases, which made up the store’s counter, stood Joe Pon, who I was lucky enough to meet the first time I walked into the shop.

Why so lucky? Joe isn’t your typical magic store owner. Rather than go for the easy sale of an expensive prop, he measures a customer’s experience level and steers them to a useful how-to book or video. Furthermore, he has a vast, jack-of-all-trades knowledge of magic. If you have a question, Joe knows the answer, and the few times he doesn’t, he knows exactly where to find it.

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ES A R E T H E P U R E S T F O R M O F D E C E P T I O N , R E Q U I R I N G B O T H M A N

While preparing for this talk—two years in the making due to the pandemic—I started creating videos about magic, sleight of hand, and neuroscience on YouTube.

One of my videos, in which I demonstrate ten levels of sleight of hand, has garnered more than two million views and has allowed me to amass a following of over 80,000 subscribers. (A more recent video is adapted from my portion of the talk.) With the exposure I’ve gained from social media, I’ve managed to stay busy teaching magic to students of all levels and performing for companies like Google, Microsoft, Warner Music, and more.

With magic books and videos, instruction can often feel impersonal. Joe had a strict policy: If you bought it from him, he would provide lifetime support, taking you to the back end of the shop where you huddled over the countertop so he could quietly teach you the ins and outs of the trick, the variations, and the performance theory. It was a special, intellectually intimate moment of connection between you and a vast body of seemingly arcane knowledge, all through the conduit of a man in shorts and a black polo shirt imprinted with the words “Misdirections Magic.”

I went there every single weekend—sometimes Friday, Saturday, and Sunday—lingering until an alarm clock with the sound of a barking dog signaled that it was time for Joe to close.

While most first-time buyers desired the instant gratification of a “special” deck that does the trick for you, I wanted to learn real sleight of hand that could be done with any deck of cards. The first book Joe sold me was Card College Volume 1 by the Swiss magician Roberto Giobbi, the first installment in a five-volume, 1,500-page encyclopedic course on sleight of hand with cards.

The book was both inspiring and frustrating.

Nuanced, technical descriptions accompanied by illustrations of the necessary finger movements allowed for precise communication, but not at a fourth grade reading level. I would often entice a parent to help me make sense of whatever the heck “this combination of actions results in a diagonal motion that forms a break between the packet and the rest of the deck” meant.

But it was bliss. At a time in middle school when many students experience social growing pains, myself included, both Card College and the magic store were an escape. I would often practice upwards of ten hours a day. One afternoon, my dad knocked on my door around 5 p.m. to ask if I’d eaten lunch yet. It was then that I realized I’d been so engrossed in practicing I had forgotten to eat both lunch and breakfast, and I was ravenous. But not quite ravenous enough to put the deck of cards down just yet.

Ultimately, I took a three-year hiatus in my obsession,

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L AND PSYCHOLOGICAL DEXT

brought on by the fact that performing magic for my peers at school had turned me into the “magic kid,” and I didn’t want to be seen as onedimensional. But on a whim, I volunteered to put together a presentation about the history of magic in my junior year of high school. I ended up pouring nearly 100 hours into developing, scripting, and practicing a 45-minute act that wove together magic performance, theory, and history.

Through this experience, I found a gap in my knowledge that reignited my passion. I had never learned the bottom deal, a highly advanced cardcheating maneuver where you apparently deal the top card of the deck, yet imperceptibly take the bottom card instead. This technique—now my personal favorite—served as a gateway to the sleight of hand techniques used by professional card cheats. It was first described in detail in the “bible” of sleight of hand with cards, The Expert at the Card Table, written in 1902 by the mysterious S.W. Erdnase. His name is an anagram. Backwards, it spells E.S. Andrews, yet to this day, no one knows his true identity, which, considering that he was a sleight of hand expert revealing the secrets of his trade to the public, is probably what he wanted.

After a year of diligently practicing the bottom deal, I set my sights on the holy grail of sleight of hand with cards: the legendary center deal. It’s a move so rare that even in the age of social media, most magicians have never seen it demonstrated. At age 12, I was lucky enough to have met Jason England, one of the top sleight of hand experts in the world. He was kind enough to watch video clips I sent him and provided detailed feedback over email. A few thousand hours of my life later, I could put the four aces into the dead center of the deck, deal out a game of poker, and secretly pull an ace from the center every time I dealt to my hand. Then came the second deal, the Greek deal, false shuffles, stacking the deck, and a handful of techniques better left a secret.

Oddly enough, I have no interest in cheating at cards, nor any interest in gambling for that matter.

I’ve been to many casinos in Las Vegas yet have

MY HANDS—UNLESS I CAN FIND SOMETHING TO DISTRACT YO U

AT T H E K E Y M O M E N T S .

E R I T Y. I T ’ S Y O U R E Y E S A G A I N S T PHOTO: TAYLOR WONG

never felt tempted to place a bet. In the words of the American master Ricky Jay, I’m primarily interested in the philosophy of cheating at cards. Nevertheless, and perhaps not surprisingly, my friends never let me touch the deck when we play cards.

The Neuroscience Behind Magic At the University of Pennsylvania, I set my sights on a career as a scientist, unsure of where that might lead.

Early on in my freshman year, I traveled to Washington, D.C., to begin taking lessons from Darwin Ortiz, a magician and sleight of hand expert who has authored some of the most important books on magic. Through studying with him, I began to understand why I was so fascinated by gambling sleight of hand despite my indifference towards actual gambling.

Card cheating and con games are the purest form of deception, requiring both manual and psychological dexterity. It’s your eyes against my hands—unless I can find something to distract you at the key moments. A waitress might “accidentally” stumble while handing you your drink at a private poker game. Take your eyes off the dealer for a heartbeat, and they can switch the entire deck of cards for one that is stacked to give you a strong hand, but to give an accomplice a slightly stronger hand. Cheating at cards is both a feat of sleight of hand skill and social engineering.

It was this realization that sparked my interest in the psychological and philosophical implications of deception. Magic has the unique ability to shine a very bright light on the ways in which we lie to one another and to ourselves.

By my junior year of college, I was taking upperlevel neuroscience classes focused on topics such as learning, memory, neural circuits, neurodegenerative diseases, and more. I noticed parallels between the sleight of hand I was practicing and the “sleight of mind” I was studying in my classes. Magic doesn’t happen on a regal stage or in the agile hands of the performer. By definition, it happens only in the mind of the observer. From a materialist’s perspective, your experience of the world is constrained by how your brain works. While it receives and interprets a range of stimuli from the outside world, your perception, cognition, and memory can be manipulated to fundamentally alter your experience. These processes are central to the deceptive practices that make magic work.

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M AG I C H A S T H E U N I Q U E AB I L IT

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N TO S H I N E A V E RY B R I G H T L I G H T O N T H E WAYS I N W H I C H W E L I E TO O

From Obsession to Occupation While in college, I ventured to the newly opened Smoke and Mirrors Magic Theater in Philadelphia to see another magician’s show. I ended up performing at the venue nearly 40 times before graduating in May of 2020.

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What is Magic?

Arturo de Ascanio, the father of the Spanish school of magic, wrote that, at its core, magic is the difference between an initial condition and a final condition, leaving the viewer with the impression that there is no naturalistic causal link. As an example, let’s analyze that first card trick that I saw when I was ten. Imagine watching a performer who shows an audience the five of diamonds, initialed with a permanent marker by an audience member. The magician slowly inserts the card into the middle of the deck, snaps his fingers, and then reveals that the card has appeared at the top. It can’t be a duplicate—not only have you examined the deck, but the initials ensure that it must be the same card— and yet, it rose to the top.

Now imagine that you walked into the room after the card had been inserted into the middle of the deck. You would see a person on a stage turn over the top card of the deck—the five of diamonds—and then see the audience applaud, much to your surprise. You might think you had walked into a cult of the five of diamonds, and you would experience no magic.

Similarly, imagine that you saw the magician display the five of diamonds and place it into the middle of the deck, but then you left the room. You would never experience the magician revealing that it had risen to the top, so once again, you would experience no magic. In the first example, you missed out on the initial condition (the card in the middle of the deck), and in the second example, you missed out on the final condition (the card on top of the deck). Without experiencing both conditions, the presence or absence of a naturalistic causal link is irrelevant.

Given this definition, a magician’s primary aim is to ensure that you do not suspect, let alone detect, the true causal link at play. In order to do so, the magician must exploit loopholes in the way you process reality.

Thus, all trickery can be described and understood in neuroscientific terms, because it happens only in your mind.

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By filming these performances and analyzing them (as scientifically as one can), I began to hone the craft of performing magic for an audience. Using these videos as audition footage, I was invited to perform at the Hollywood Magic Castle—considered a sort of “mecca” for magicians —and appeared on Penn & Teller: Fool Us! on national television.

Performing magic live is a mixture of all-cylindersfiring focus, exciting and spontaneous interaction, and utterly fulfilling bliss. I realized that if I didn’t give magic a shot as a full-time career, I would regret it for the rest of my life.

Now What?

When the pandemic halted live performances, I began teaching private lessons and performing magic shows virtually over every platform under the sun.

The primary challenge with virtual magic is making the show feel “interactive” rather than like watching a YouTube video. A key is to constantly “spotlight” audience members as they participate in the tricks.

These moments of participation create an opportunity for the same type of spontaneous interaction that makes live performance so engaging.

Looking into the ever-uncertain future, I will continue to hone my sleight of hand skills with cards and occasionally branch out into magic that uses more minimalistic props. I’ve also realized that I don’t want live performance to be the only thing I do. If performers have learned anything from the pandemic, it’s that unpredictability may be the new normal. My goal is to one day have my own, long-running, intimate parlor show at an upscale venue. And, I certainly don’t want to leave my academic roots behind, so I hope to continue collaborating with researchers when possible and to engage in scientific discourse.

When I gaze into the past (though as I’ve learned from magic, our memories are quite unreliable), I can visualize my ten-year-old, bored-out-of-his-mind self at a fundraiser with nothing to do. Thinking back to my first experience witnessing close-up magic, it was the psychological principles at play that set it apart from all magic I’d seen previously. My brain had no explanations or excuses—nowhere to run. And then the trapdoor under reality opened up, dropping me into an exhilarating freefall, bathed in wonder. l

A N OT H E R AND TO OURSELVES.

RISING TO THE TOP

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his short video of that cardrises-to-the-top trick reveals some important principles of deception. In order to illustrate, Daniel Roy will put aside the nebulously defined “magician’s code” of secrecy and explain how the trick works.

Method A: False Shuffle The first time Roy does the trick, he gives the deck a few shuffles. He places the signed 5 of diamonds on top of the deck and gives the cards another shuffle, clearly mixing the top card into the deck. Yet, when he turns the top card over, it’s the 5 of diamonds. Through a complex series of sleight of hand maneuvers, he mimics the actions of a real shuffle, yet retains the positions of certain cards.

Method B: The Pass The second time Roy does the trick, he uses a different method. He places the 5 of diamonds into the middle, then executes a difficult technique known as a pass, where the deck is secretly given a cut, even though it looks like the cards have not changed position. The selected card is revealed to once again be on top.

Method C: The Second Deal For this final repetition, Roy puts the 5 of diamonds on top of the deck. He apparently takes the card and puts it PHOTO: DANIEL ROY

into the middle of the deck. In reality, he performs a second deal, secretly taking the second card (instead of the top card) and putting it into the middle. In a live performance, he would allow an audience member to square up the deck and turn over the top card, revealing that the 5 of diamonds has risen to the top.

Now that we understand the methods behind the trick, let’s examine the psychological principles that underlie the deception.

Principle 1: Conditioning A false shuffle (method A) deceives the eye, but to avoid arousing suspicion, the magician can condition you to accept this shuffle by performing the real shuffle a few times beforehand. You become accustomed to whichever manner of shuffling he uses, making the subsequent false version even more deceptive. This may occur because perception involves the intake of external stimuli and the projection of expectations onto the outside world.

Principle 2: The Critical Interval There’s a problem with methods A and B. After the selected card is placed in the middle, sleight of hand must be performed to bring the card to the top. The time in between card-goes-in-the-middle

and card-appears-on-top is when the audience would naturally suspect sleight of hand to occur. This period is known as the critical interval and is defined as the time between the last sighting of the initial condition and the first sighting of the final condition. The initial condition is the 5 of diamonds going into the middle. The final condition is the 5 of diamonds appearing on top. Ideally, the sleight of hand would be moved out of this interval. That’s exactly what happens in method C: The second deal is performed before the card is put into the middle.

Principle 3: Memory Manipulation In method C, Roy puts the deck on the table and, in a live performance, would let an audience member square the deck. To create the impression that this final moment was “hands off,” he might claim that he won’t touch the deck from now on, or even walk away from the deck, putting distance between himself and the cards. He’s attempting to distort the audience’s experience by narrating a slightly inaccurate version of events—a process known as postevent misinformation. Furthermore, people vastly overestimate their ability to accurately remember past events, which makes memory manipulation techniques more powerful. l Dana.org

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BRAIN TREES f

NEUROSCIENTIST AND ARTIST DANA SIMMONS F I N D S FA M I L I A R PAT T E R N S O F N AT U R E THROUGH THE LENS OF HER MICROSCOPE

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G L O V I N

“Vima” — Purkinje cells are among the most highly branched neurons in the brain, making them resemble trees. In fact, Dana colloquially refers to Purkinje cells as “the microscopic trees inside the brain.” She reflects this in Vima, where she used her micrographs of Purkinje cells to build a burgeoning forest.

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e have billions of neurons floating around in our noggins but—like snowflakes—no two look exactly alike. Dana Simmons, a neuroscientist who studied how autism affects the brain, created the following works of art from the beauty she saw through her use of microscopy.

Purkinje cells are a type of neuron that resides in an area called the cerebellum, a region in the back of the brain that controls movement, posture, and balance. “In this microscopic world, I saw something strikingly familiar—a cell with dozens of branches that made it look like the trees outside my window,” says Simmons. “I found that this branching pattern, which I call the ‘Purkinje Pattern,’ is present all throughout nature on both microscopic and macroscopic scales.”

Simmons, who received her Ph.D. in neurobiology in 2018 from the University of Chicago and created her work as a researcher there, points out that Purkinje cells are unusual neurons because they have many more branches (called dendrites) than typical neurons. These branches collect information from many different inputs.

“The way I got all of the colors is through patching the cell, which means attaching a small glass tube to the cell

body,” she explains. “Think of it like sticking a straw into a tennis ball and then flowing fluorescent dye through the straw. It diffuses through the branches in about 45 minutes.

The dyes indicate the cell’s activity, and they tell us how one neuron communicates with the surrounding neurons.”

Some of her other artwork focuses on the tiny knob-like spines that dot dendrites like leaves on a tree, which are the molecular sites of learning and memory. “We wanted to see how communication between neurons, taking place at these spines, differed in autism,” says Simmons, adding that, in her artwork, she was influenced by her mother (an art teacher) and her grandfather (an art director and painter). Two of her other major influences are Andy Warhol, known for using everyday figures to create Pop art, and Santiago Ramón y Cajal, an early 20th century Spanish scientist who created drawings of cellular neuroanatomy.

“My goal is to inspire curiosity and promote enthusiasm for science,” says Simmons, who is today a health science communicator and recently moved to Washington, D.C. “I’m really excited about the possibilities for analytical people to think more creatively, and for more creative people to start thinking more analytically. We can all learn a lot from each other.” l Dana.org

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“Purkinje 4x2” — Purkinje 4x2 shows four Purkinje cells, twice each: one set where Dana left the microscope’s backlight on, which how her confocal microscope typically operates to capture data from these cells.

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revealed the texture of the brain slice in which her Purkinje cells were embedded, and one set with the backlight removed, which is

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“Manza” — Manza exhibits the characteristic “Y” shape of Purkinje cell dendrites. While individual Purkinje cells do have slightly different shapes, they almost all include a primary dendrite that bifurcates in two secondary branches, which then split even more to generate a broad and extensive dendritic arbor.

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“Molino” — Molino showcases a wheel composed of Purkinje cells. These cells reside in the cerebellum and play a critical role in balance, coordination, and learning new movements. After completing her experiments each day, Dana experimented with the settings on her confocal microscope to manipulate the colors and textures of her micrographs.

This piece includes one neuron replicated several times in different colors.

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“Purkinje Cells 24 Times” — Purkinje Cells 24 Times. One of Dana’s primary artistic inspirations is the pop art of Andy Warhol. Warhol object. Emulating Warhol’s style, such as in this piece, Dana added color to make her neurons pop and showed them in multiples in e

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took known faces and everyday objects and presented them in a new light. To Dana, a Purkinje cell has become an everyday research effort to attract curiosity from onlookers.

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AWARDS

GENERAL INTEREST

Beyond Disinformation: Deep Fakes and False Memory Implantation

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S BRAIN RESEARCH, EMERGING technologies, ethics, policy, and law intersect with increasing regularity, neuroethics continues to gain traction as a scientific discipline. Since 2014, the International Neuroethics Society and the International Youth Neuroscience Association have teamed to hold a Neuroethics Essay Contest for secondary and high school students from around the world. The contest aims to promote interest in neuroethics among students in high school, university, and early career training programs.

Here are excerpts from the winners in three categories: general audience, academic, and high school. The full essays, with citations, may be referenced by linking to the essay title.

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Erin Morrow, Emory University (United States)

OST SOCIAL MEDIA USERS ARE INTIMATELY familiar with labels on their timelines and feeds for content deemed “manipulated media.” Twitter rolled out new policies last year to address photos or videos found to be “significantly and deceptively altered or fabricated.” The first such content to be flagged on this platform showed thenpresidential candidate Joe Biden appearing to state “We can only re-elect Donald Trump.” In reality, this Kansas City speech was deceptively spliced, edited, and thus taken out of context—but by the time this post received its warning label, it had already garnered over five million views.

Yet, misleadingly cropped video is not the only form of deceptive content being popularized. Also within the jurisdiction of this new regulation is an emerging form of media: deep fakes. These artificial intelligencegenerated creations, often in the form of videos that deceptively portray public figures, have emerged within the past decade as a force of disinformation to be reckoned with. Such videos can now manipulate the facial expressions and speech of these figures with minimal distortion.

Deep fakes of public figures have the potential to influence discourse and decision-making in the realms of politics, public health, and more through a powerful cognitive system: memory. Deep fakes can “implant” false memories; that is, they can cause individuals to recall entirely new events that did not actually occur.

Famed memory psychologist Elizabeth Loftus has shown, with others, that certain false memories can be consistently recalled weeks after initial encoding. l

ACADEMIC ESSAY

Continued Access to Invasive Neural Devices: Lessons from the AIDS Epidemic

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By Nathan Luke Higgins, Monash University (Australia)

N 1987, AS AIDS BEGAN TO TAKE HOLD IN THE US, the compound azidothymidine (AZT) was entered into phase I clinical trials. At the time, a positive HIV diagnosis was a life sentence. So, when participants receiving AZT started to improve, many argued that AZT be made immediately available to all HIV-positive patients. This classic case was the origin of the debate around “expanded access,” or whether there is a moral obligation for researchers to make experimental compounds available to extremely vulnerable patients.

As the AIDS epidemic reached its nadir in the 1990s, desperation for anti-retroviral drugs safer and more effective than AZT drove pharmaceutical companies to conduct trials of novel compounds in nations hard-hit

by AIDS, such as South Africa, Uganda, and Zimbabwe.

These trials, conducted in predominantly low-income nations, raised a separate but related ethical dilemma: Is there a moral obligation, once the trial has ended, to provide continued access to a beneficial medication?

In 2000, the Joint United National Program on HIV/ AIDS issued a guideline that specifically addressed continued access, namely that “any HIV preventative vaccine demonstrated to be safe and effective (…) should be made available to all participants in the trial in which it was tested.” The debate over continued access has since diversified, and has been recognized in international ethical documentation, such as the Declaration of Helsinki, and by the Council for International Organization of Medical Sciences and World Health Organization. In recent years, statements released by pharmaceutical companies suggest convergence on the conditions under which continued access to drugs ought to be offered to participants. l

HIGH SCHOOL

Exploring the Ethical Implications of Neurotheological Studies

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By Rafael Hiu Nok Au (Hong Kong)

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HE KINGDOM OF GOD IS WITHIN YOU.” The renowned biblical saying has been proclaimed by not only prophets, but recently also endorsed by some neuroscientists. As the development of neuroscience increasingly provides more and more scientific explanations for things we think and feel, some neuroscientists propose that spiritual and religious beliefs must have some sort of neuroscientific basis. The notion has evolved into a separate branch of study—neurotheology — where neuroscientists attempt to explain religious experience and behavior in neuroscientific terms.

As an example, a study carried out by Newberg et al. investigated the effects of a type of Islamic prayer, which is described to evoke feelings of “surrender” and “connectedness with God,” on brain activity by measuring changes in cerebral blood flow (CBF) using single-photon emission computed tomography.

Compared to a less intense Islamic prayer, the target sample displayed decreased CBF in the prefrontal cortex and related frontal lobe structures, and increased CBF in the caudate nucleus, insula, thalamus, and globus pallidus. l

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ADVISORY BOARD

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

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

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

This work has considerable ramifications for the understanding of the origin of the signals detected with the current functional brain imaging techniques used in neurologic and psychiatric research.

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

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ADVISORY BOARD

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

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

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

CHARLES F. ZORUMSKI, M.D. Charles Zorumski is the Samuel B. Guze Professor and head of the Department of Psychiatry and Professor of Neuroscience at Washington University School of Medicine in St. Louis. Zorumski is also Psychiatrist-in-Chief at Barnes-Jewish Hospital and founding director of the Taylor Family Institute for Innovative Psychiatric Research.

Zorumski’s laboratory studies synaptic transmission in the hippocampus. Since 1997, he has served on the steering committees of the McDonnell Center for Cellular and Molecular Neurobiology and the McDonnell Center for Systems Neuroscience and was director of the Center for Cellular and Molecular Neurobiology from 2002 to 2013. Zorumski has also served on the editorial boards of JAMA Psychiatry, Neurobiology of Disease, and served on the board of Scientific Counselors for the NIMH Intramural Research Program from 2009 to 2013. Since 2011, he has also served on the scientific advisory board of Sage Therapeutics, a publicly-traded company developing neurosteroids and oxysterols as treatments for neuropsychiatric illnesses.

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

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CEREBRUM STAFF

Bill Glovin Editor-in-Chief Glovin has been a working journalist for more than 30 years. He is executive editor at the Dana Foundation and hosts the Cerebrum Podcast. He has served as editor of Cerebrum since 2012.

Previously, he was senior editor at Rutgers Magazine, managing editor of New Jersey Success, editor for New Jersey Business and a staff writer for The Bergen Record. Glovin graduated from George Washington University with a degree in journalism.

He sometimes escapes from in front of the monitor to enjoy basketball, biking, and guitar.

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

Brandon Barrera Editorial Assistant Barrera is a New York City journalist, born and raised in Queens and living in Manhattan. A public affairs assistant at the Dana Foundation, he is the host of the Dana Foundation’s Communicating Brain Science podcast and writes about books for the magazine.

Before coming to Dana, he helped produce content for Bronx Net, a public access television channel. When not enthralled by all things sci-fi, Barrera is fond of cycling, film, and arguing the finer points of tabletop gaming.

Bruce Hanson Art Director Hanson is responsible for the design and production of Cerebrum. A graduate of Rutgers University’s journalism program, he has worked in a variety of capacities in publishing and media for more than 30 years. In 1991, he founded EGADS, a studio which specializes in graphic design for education, arts and culture, publishing, and technology. When away from his desk, he'll most likely be playing guitar in a live music venue or plotting with his wife about how to book cheap flights to distant destinations.

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Join us as we talk to our Cerebrum neuroscientist authors about their research, personal stories, and how their work has the potential to make a difference in people’s lives.

dana.org/cerebrum-podcast