Cerebrum Summer 2021

EMERGING IDEAS IN BRAIN SCIENCE • SUMMER 2021 AGEISM STRIKING BACK AGAINST

EXPERIENCE

PLASTICITY

EMPATHY

WISDOM

SUMMER 2021 | VOLUME 2, ISSUE 3

FEATURES 14 Ageism: The Brain Strikes Back! Does the brain improve with age? Our authors, who study successful aging and mental illnesses, address the often debated, complicated question that many of us have long wondered about. By Tanya T. Nguyen, Ph.D., and Dilip V. Jeste, M.D. 22 Interoception: The Secret Ingredient Our authors, who co-direct the Interdisciplinary Affective Science Laboratory at Northeastern University, explain how sensations created inside our bodies connect to the mind and brain. By Lisa Feldman Barrett, Ph.D., and Karen S. Quigley, Ph.D. 30 Narcissism Gets No Respect Why is narcissistic personality disorder, which has been recognized by the American Psychiatric Association since 1980, under-researched

and rarely treated? By Elise Oberliesen 36 Beauty and the Brain

Since 2014, stunning imagery inspired by brain research has launched an annual art exhibition during Brain Awareness Week at the Icahn School of Medicine in NYC. By Bill Glovin

SECTIONS 6

Advances • Notable brain science findings

8 Briefly Noted • By the Numbers, Brain in the News 9 Bookshelf • A few brain science books that have recently caught our eye 10 Clinical Corner • The Value of Vulnerability, By Tom Pisano, M.D., Ph.D. 12 Neuroethics • Keeping a Close Eye on Organoids, By Philip M. Boffey

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

“Big Fat Juicy Brain Tumor” from The Art of the Brain exhibition. For more images from the exhibition, see page 36.

COVER ILLUSTRATION: DAVID PLUNKERT

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FROM THE EDITOR

Am I Losing It?

BY BILL GLOVIN Editor-in-Chief A s we get into our forties and beyond, we realize that we can’t run quite as fast or jump as high as we once did. For many of us, reading glasses are required, and physical ailments that once healed quickly take longer to subside. And we can’t help wondering about our mental faculties. Will we start forgetting where we put our keys? Will we have even more trouble remembering names and dates? Will genetic ties to parents or grandparents with dementia affect us? To find out what happens to our brain as we age, we asked two prominent scientists—Tanya T. Nguyen, Ph.D., and Dilip V. Jeste, M.D., who study aging at the University of California, San Diego—to tell us what the latest research reveals. In our cover story, “Ageism: The Brain Strikes Back,” you may be surprised to learn their thoughts on the findings. Our issue also contains a smorgasbord of other topics that we think are just as engaging. A hot topic receiving a lot of recent attention in the neuroscience field is interoception—a sense that tells us how our body is feeling on the inside. Have a growling stomach, dry mouth, tense muscles, or racing heart? Lisa Barrett, Ph.D., and Karen Quigley, Ph.D., at Northeastern explain the sense that allows us to experience those kinds of bodily sensations. We’ve all come in contact with obnoxious narcissists and wonder how they became so self-absorbed and whether anything can be done about it. One of our features examines narcissism as a personality disorder and gets to the bottom of why this disturbing condition is under-researched and difficult to treat. Another feature depicts a feast-for-the-eyes exhibition that includes striking images of the brain from faculty and students who are members of the Friedman Brain Institute at the Icahn School of Medicine in New York City. Finally, our neuroethics column explores the implications of organoids research while our Clinical Corner is a first-person account from a recent graduate of the Ph.D./M.D. program at Rutgers Medical School. His moving story was first featured on NBC’s Nightly News with Lester Holt , and he agreed to recount his motivations for becoming a doctor and researcher in more detail for our readers. All in all, an issue that we hope has something for everyone. l

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

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CONTRIBUTORS

Agesim: The Brain Strikes Back > Page 14

TANYA T. NGUYEN, M.D. , is an assistant professor of psychiatry at the University of California, San Diego. She is a clinical neuropsychologist with expertise in the assessment and treatment of older adults with neuropsychiatric disorders. Nguyen’s research aims to identify mechanisms of cognitive and biological aging in mental illnesses. Her current work is focused on the relationship between the gut microbiome and brain/behavior. She is the principal investigator of National Institute of Mental Health Career Development Award to investigate the gut microbiota in schizophrenia and how it may contribute to cognitive impairment and accelerated aging in this population. Nguyen received her Ph.D. in clinical psychology from the SDSU/UCSD Joint Doctoral Program in clinical psychology. DILIP V. JESTE, M.D., is senior associate dean for healthy aging and Distinguished Professor of Psychiatry and Neurosciences at University of California, San Diego, His main areas of research include schizophrenia, neuropsychiatric interventions, and successful aging. He has published 14 books, including Wiser (Sounds True, 2020), an exploration of the neurobiology and psychology of wisdom. He is past president of the American Psychiatric Association and editor-in-chief of International Psychogeriatrics . He served as chief of the Units on Movement Disorders and Dementias at the National Institutes of Health, and later won its Mental Health MERIT Award. A member of the National Academy of Medicine, Jeste obtained psychiatry training in Mumbai, India. In the US, he completed his psychiatry residency at Cornell and his neurology residency at George Washington University. LISA FELDMAN BARRETT, PH.D. , is co-director of the Interdisciplinary Affective Science Laboratory at Northeastern University and Massachusetts General Hospital. She is a University Distinguished Professor of Psychology at Northeastern, with appointments at Harvard Medical School and Mass General. She is also Chief Science Officer for the Center for Law, Brain & Behavior at Harvard University. In addition to the books Seven and a Half Lessons About the Brain and How Emotions are Made , Barrett has published over 250 peer- reviewed, scientific papers appearing in Science , Nature Neuroscience , and other top journals in psychology and cognitive neuroscience, as well as six academic volumes published by Guilford Press. She has also given a popular TED talk with over six million views. KAREN S. QUIGLEY, PH.D., is co-director of the Interdisciplinary Affective Science Laboratory at Northeastern University and Massachusetts General Hospital. She is a Professor of Psychology at Northeastern. Her work focuses on individual differences in emotional and affective experience, how humans utilize information from the body in creating emotional experience, and how emotional experiences impact behavior, cognitions, and health. Quigley received her Ph.D. in psychobiology from The Ohio State University and has published more than 100 scientific papers. ELISE OBERLIESEN is a freelance journalist who has written for the Los Angeles Times , the Chicago Tribune , Colorado Daily , AAA HomeandAway Magazine and websites such as AARP.com, nurse.com, and the Colorado Health Foundation. When Oberliesen is not glued to the laptop researching or writing, she spends time lifting weights, skiing, or creating mixed media art. She has two sons and a fur baby called Chester. She earned a B.A. from Michigan State University and now lives in Denver, CO.

Interoception: The Secret Ingredient > Page 22

Narcissism Gets No Respect > Page 30

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ADVANCES Notable brain-science findings

A BRAIN-COMPUTER INTERFACE has helped one man with paralysis to quickly write sentences on a computer screen by picturing himself writing the letters by hand. He had two electrode arrays implanted on the surface of his brain in motor areas; as he imagined writing letters, the electrodes’ signals were fed into a software program that first learned which signal stood for which letter and now can translate it, in close to real- time, to text on a screen. This

BY NICKY PENTTILA

A NEW DRUG intended to slow the cognitive decline caused by Alzheimer’s disease was conditionally approved by the US Food and Drug Administration in June. The drug, Aduhelm, reduces the amount of amyloid- beta plaque in the brains of people diagnosed with mild cognitive impairment, but it is less clear that it actually affects their problems with cognition. Under the FDA’s

accelerated approval process, used when a potential drug would fill a serious “unmet medical need,” the drug’s maker, Biogen, is required to continue its research in Stage 4 clinical trials in hopes that it will eventually show a clinical benefit that is greater than its sometimes-serious side effects. l

translation appears to be far faster than current speech- to-text systems and comes close to the speed of the average person who “thumb types” on their phone. l A team of researchers has restored partial VISION to a man who had a form of blindness in which his light- capturing (photoreceptor) cells had died. They used gene therapy to add light-sensitive (optogenetic) proteins to some of his healthy retinal ganglion cells instead, enabling them to respond to amber light. The man wears goggles that scan their field of view, notice any pixels in which the light changes, and then send a pulse of amber light from that pixel into one of his eyes. After seven months of practice, his brain had learned to convert that signal in a way that helps him see lines on a crosswalk and distinguish when there are two or three glasses on a table. l

Seeking to stifle the body’s natural rejection of foreign material like electrode arrays and other brain implants, researchers in Canada have invented a more brain- like material for IMPLANTS as well as a gentler way of inserting them. Their implants are formed using flexible silicone, which bends and moves much like brain matter. The new scaffolding holding these micro-implants is made of sugars, which dissolve and are washed away soon after insertion. In rats, the implants appeared to be accepted more readily and for longer than methods using soft polymers or hydrogel coatings. l

M ore news that regular physical activity (i.e., EXERCISE and PLAY ) may be good for kids comes from an imaging study of nearly 6,000 nine- and ten-year-olds. Those who were active most days for at least an hour at a time showed brain circuitry that was more efficiently organized, flexible, and robust. The study showed that the more physical activity, the bigger the difference when compared with kids who did not move as much. For kids with higher-than-average body mass indexes, which is associated with harmful effects on the same brain circuits, those who were more physically active seemed to be able to offset the effects. These results are correlations based on large data sets, so very suggestive but not direct proof. l

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ADUHELM PHOTO: BIOGEN; GIRL AND BRAIN INTERFACE IMAGES: SHUTTERSTOCK

A wearable, lightweight headset that measures interact, and sit upright is demonstrated by members of the Center for Human Neuroscience Research at Virginia Tech’s Fralin Biomedical Research Institute: Read Montague (left), professor and director; Chris Huck , a research assistant; and Stephen LaConte , associate professor. The device, developed in Montague’s lab, uses new optically pumped magnetometry technology and quantum sensor chips to measure the strength and originating location of magnetic fields produced by the human brain. l brain activity while research volunteers move around,

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PHOTOS: COURTESY OF THE CENTER FOR HUMAN NEUROSCIENCE RESEARCH, FRALIN BIOMEDICAL RESEARCH INSTITUTE, VIRGINIA TECH

BRIEFLY NOTED

B Y T H E N U M B E R S 1 COUNTRY , Chile, will introduce a “neurorights” bill, making it the first nation to pioneer a regulatory framework which protects human rights from the mani- pulation of brain activity. SIX hours of sleep or more a night

BRAIN IN THE NEWS Links to brain-related articles we recommend > New York Times: Earlier Diabetes Onset Could Raise Dementia Risk > Philadelphia Inquirer: Suicide rate shows decline but maybe not for all groups > New York Times: The Health Benefits of Coffee > Washington Post: FDA approves first drug intended to slow cognitive decline caused by Alzheimer’s disease > New York Times: Many People Have a Vivid ‘Mind’s Eye,’ While Others Have None at All > Brain & Life: Seth Rogen and Lauren Miller Rogen Use Humor to Educate About Alzheimer’s Disease > New York Times: How to Think Outside Your Brain > Scientific American: Electrodes That Stimulate the Brain Reveal the Roots of Conscious Experience > Discover: Psychologists Explain Why You Can’t Remember the Movie You Just Watched

1904 is the year the IQ TEST was introduced, which was in response to the French government’s request for a diagnostic test of children’s intellectual abilities.

is needed for middle-aged people who wish to reduce their chances of developing dementia in their late seventies.

percent of American adults, age 20 to 69, have noise-induced hearing loss . 25

“We have to really temper expecta-

tions and explain to people that this drug is meant for the earliest symptomatic phases. It pains me to say this, but if I have a severe Alzheimer’s patient that can no longer speak or inter-

6,200,000 Americans have Alzheimer’s, a number projected to more than double by 2050, barring breakthroughs in treatment, according to the Alzheimer’s Association .

20,000 virus-containing droplets that can stay in the air for up to ten minutes are produced by a single sneeze .

act much with others and their family member is begging me to give them this drug, I won’t be able to do it.” — Richard Isaacson , M.D., director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian, on the Food and Drug Administration’s controversial decision to approve the first new Alzheimer’s disease drug in 20 years.

participants who drank three to five cups of coffee a day, with or without caffeine, were 15 percent less likely to die early from all causes than were people who shunned coffee.

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BRAIN ILLUSTRATION: ISTOCK; SNEEZE PHOTO: CDC PUBLIC HEALTH IMAGE LIBRARY

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

power of noise on the nervous system, Kraus adroitly gives voice to the power and beauty of sound.

BY BRANDON BARRERA

A Sense of Self: Memory, the Brain, and Who We Are by Veronica O’Keane (W. W. Norton & Company) Having observed and researched mood and psychotic disorders for 37 years, Veronica O’Keane, M.D., professor of psychiatry, developed a fascination with the neural mechanisms that create

Hard to Break: Why Our Brains Make Habits Stick by Russell A. Poldrack (Princeton University Press) It is not uncommon to have a list of good habits and practices that you intend on implementing but can’t quite get to take hold. For many, establishing good sleeping patterns and ending troublesome

experience: sensation, cognition, and emotion. Pull on any one of these threads, O’Keane says, and you will see how emotional and feeling states are intrinsically wired to the formation of memory and the act of remembering. In A Sense of Self , O’Keane takes readers on an exploration of memory, consciously refraining from exceedingly intellectual explanations and instead allowing lived experiences—her own and those of her patients—to lead the way. To be sure, there is no dearth of neuroscientific research; it is instead the case that O’Keane’s approach is personal and full of feeling, much in the way memory operates.

behaviors, such as late-night doomscrolling, can be a real challenge. Neuroscientist Russell A. Poldrack, Ph.D., articulates how these habits—actions and thoughts, from the highly valued to the annoyingly undesired—are formed in the brain, explaining to readers why we get “stuck” and how science can optimize behavioral change. Self- admittedly not an “easy fix” guide, Hard to Break keeps to an evidence-based approach, applying the latest research toward individualized behavioral change. In detail, the book covers dopamine’s complexities and its critical role in modulating plasticity; the different brain systems for habits and planful (goal-directed) behavior; the prefrontal cortex and its relationship to self-control and willpower; and the extreme manifestation of a disease: addiction.

REMEMBER: The Science of Memory and the Art of Forgetting by Lisa Genova (Harmony Books) We remember what is meaningful to us, says Lisa Genova, Ph.D., neuroscientist and best-selling author of Still Alice . Even when we inevitably forget—where you placed your keys, why we walked

Of Sound Mind: How Our Brain Constructs a Meaningful Sonic World by Nina Kraus (MIT Press) Close your eyes for a breath or two and catalog your soundscape. Then, consider

into a room, maybe the color of your house—our brains are functioning normally and within the parameters of its evolutionary history. Genova’s latest work is an approachable and detailed exploration of memory, explaining how memories are made, how we retrieve them, and why forgetting is a normal part of the human experience. Every memory you hold dear lives as a constellation of disparate neurons throughout your brain, physically existing in your head through neural networks of associations. But why are some things easier to remember than others? REMEMBER will help you better understand how emotions, sleep, stress, and meaning affect memory- creation; how to distinguish between normal forgetfulness and forgetfulness caused by dementia, the nuances of your memory’s reliability (see: fallibility); how deliberate, focused attention is paramount to retaining any new information; and what measures can be taken in those instances where forgetting is the goal. l

how swiftly your brain identified and contextualized those ambient sounds. According to neuroscientist and sound researcher Nina Kraus, Ph.D., the brain’s auditory neurons make calculations at one-thousandth of a second, effectively processing stimuli faster than sight, touch, and our other senses. In her latest book, Of Sound Mind , Kraus reveals how our brains make sense of sound, exploring the deep network of interconnectivity between sensing, moving, thinking, and feeling—a view marking a departure from the classical, one-way hierarchical model of auditory processing. We engage with sounds, Kraus says, and conversely, sounds shape our minds. Both an examination of sound as it exists outside of the brain and the biology of sound, Of Sound Mind is heartfelt and rigorous in its exploration of the power of sound. From music’s capacity for healing, methods to enrich sound processing, the impact of speaking multiple languages, and the destructive

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CLINICAL CORNER

The Value of Vulnerability BY TOM PISANO, M.D., Ph.D. W HILE ON THE SKI TEAM A FEW WEEKS INTO MY second semester of college, a failed backflip off a jump resulted in me waking up two days later paralyzed from the chest down. I faced my new reality with feelings of terror, depression, confusion, frustration, and anger as a medical team graciously put up with my sullen mood and answered endless questions. Eventually, I channeled my energy into my inpatient rehabilitation, motivated by defying the odds of never walking again. During a year off, I did a lot of soul-searching, trying to hold off negative thoughts while contemplating the road ahead. Loved ones suggested that I attend a community college close to where I grew up in New Jersey. But I was determined to return to the University of Virginia (UVA), where I had been an engineering major. Further inspiring me were my two younger, teenage brothers who carried me up the stairs to bathe, to the beach to swim, and to hit the ski slopes again. They showed me that I could live a fulfilling life from a wheelchair. I eventually graduated from UVA with a double degree in cognitive science and biology, then took a year off to work with spinal cord injury patients and on exoskeleton research at the James J. Peters VA Medical Center in the Bronx. Those experiences put me on a path to pursue a career in medicine, not just to help people with spinal cord injuries, but people with other diseases as well. Fast-forward 14 years as I embark on a neurology residency after having completed an M.D./Ph.D. program at the New Jersey Medical School in May. Although each patient experience is different, I have found that sharing my own story with patients on an almost daily basis and providing a practical, honest assessment (especially to stubborn, adolescent males who have just been told that they have lost use of about half their body) has made me a better doctor—and helped a variety of patients in their own journey to recovery. Since I use a manual wheelchair, my challenges are obvious to patients, and this can often be used to facilitate empathy and rapport. I met a man in his 40s who was in outpatient rehab several months after having a spinal cord infarction that left him paralyzed from the chest down. Like me, he was forced to also use a manual wheelchair. After his outpatient psychiatry visit, I shared

my story with him. His anxiety about navigating the world in a wheelchair, future relationships, and various other issues came pouring out. But I have found that sharing my experience and showing vulnerability also helps other kinds of patients. A woman in her 60s who was suffering from partial paralysis a few days after a stroke was angry at the world. She responded to questions with short, curt answers, unwilling to disclose what she was thinking or feeling. I again shared my story, telling her about the myriad of emotions I had felt and how, even though our circumstances were different, there is a life after a hospital bed—a life that can be immensely fulfilling if you’re willing to stay positive. Slowly, over the next few days, she started to open up to her family members and caregivers and begin the road to recovery. Although not every medical provider has a re-defining story like mine, most have internal motivations for getting into medicine, be it from personal struggles or via family members’ challenges. Common medical wisdom is to maintain professionalism, and in certain cases, distance is needed to sustain oneself from the many heartbreaks and crushing outcomes a physician can experience. But a delicate balance must be struck between complete detachment and over-sympathizing. This balance requires continuous reassessment to make sure the equilibrium is maintained between the two in order to keep humanity in medicine. I know firsthand that, after a new diagnosis, it takes time for a patient to realign their internal representation with their new external reality. Whether it’s grasping unfamiliar circumstances, expressing feelings, or accepting the isolation that often accompanies an unexpected condition—all factor into the equation. Merely signaling to a patient that you are aware of the difficulties builds a connection and encourages healing. It is human nature to want our experiences validated. Next time you’re given the chance, consider sharing a story that shows your own vulnerability. Whether or not it’s medically related, you just might find those few minutes to be well worth it. l TOM PISANO , 33, recently graduated from the Robert Wood Johnson Medical School and New Jersey Medical School with both a medical degree and doctoral degree in neuroscience. He will spend his intern year at Mount Sinai Morningside-West, followed by a residency at the University of Pennsylvania’s Department of Neurology.

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PHOTO: NICK ROMANENKO / RUTGERS UNIVERSITY

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NEUROETHICS

Keeping a Close Eye on Organoids

or “mini-brains” in a dish, Muotri is more circumspect, describing them as “brain organoids.” The entity, he says, is a miniaturized version of some of the tissue of the brain (containing 2.5 million neurons, the equivalent of a bee brain) that in some aspects behaves like the human brain. As the organoids become more complex, you can see the brain cells oscillate in unison as they start communicating with each other and generate electrical signals that mimic human neural development. Muotri’s other main focus is to study how the brains of Neanderthals differ from the more complex brains of modern humans, or Homo sapiens. He postulates that if we can understand how this complexity arose, we might understand why our human brain is so susceptible to developmental conditions such as autism. Evolutionary biologists have identified 61 genes that are different between us, the Neanderthals, and all other species. Muotri and his colleagues have focused on one of those, called NOVA 1, which regulates hundreds of downstream genes, so “if you’ve messed with that one, there are hundreds of other genes that will change

BY PHILIP M. BOFFEY I was astonished to learn while writing a column on the brain-computer interface in 2019 that patients with amyotrophic lateral sclerosis (ALS), whose brain signals were fed into a computer, could control a complex robotic arm, having it pick up a pitcher and pour water into a glass, just by thinking about it. So you can imagine my surprise when I learned that scientists have achieved comparably difficult tasks—not with signals from a human brain—but simply from a clump of stem calls in a Petri dish. The achievement is clearly described in Alan Alda’s Clear+Vivid podcast featuring Alysson Muotri, a Brazilian citizen who is director of the stem cell program at University of California, San Diego, where much

as well.” He suggests that species carrying an archaic form of that gene may have earlier gestation or maturation times akin to chimpanzees, whereas humans who have a mutated form of that gene take much longer to mature. In a feat I found astonishing, Muotri’s team stuck a probe in a Petri dish to generate signals from an organoid that controlled the movements of a tiny robot. Electrical signals generated in the Petri dish were fed into a computer that told the four-legged robot how to move. The robot had infrared detectors that told when it was getting close to a wall. It sent a signal back to the organoid which then sent a second message to the robot to walk back. Eventually, Muotri anticipates that the organoid will do much of this spontaneously in what might be considered learning. The biggest risk of all these ventures, Muotri says, is that someday an organoid might reach a point of consciousness or

of this pioneering work was performed. The podcast is a useful complement to a more comprehensive report issued on April 8 by the National Academies of Sciences, Engineering, and Medicine. As Alda’s introduction explains, Muotri uses factors that drive skin cells to revert to stem cells and then become brain tissues that self-organize, forming “brain organoids in a dish. Muotri, who has a personal interest because he has a son with autism, hopes to learn how early brain development can change course in conditions like autism and epilepsy—and how our brains differ from those of our evolutionary? cousins, the Neanderthals. Although some people call what he has created “brains”

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self-awareness. His team has ethicists and philosophers watching how the research develops. The National Academies report, entitled “The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance” and partially sponsored by the Dana Foundation, found strong moral arguments in favor of research on these laboratory entities, namely the potential for new knowledge to relieve human suffering and mortality caused by brain disorders, provided that certain ethical protections are in place. The report’s committee also deems it “extremely unlikely that in the foreseeable future” organoids would possess capacities that would be recognized as awareness, consciousness, emotion, or the experience of pain. “Thus, it appears at present that neural organoids have no more moral standing than other in vitro human neural tissues or cultures.” That could change in the future of course, but for now, as one leading researcher told a reporter from Science magazine, the public and funding agencies can be “reassured that nobody is tromping on any ethical boundaries or lines at the moment.” There is always concern that organizations dedicated to advancing science—as the National Academies surely are—will give short shrift to ethical constraints. But the committee seems to have conscientiously kept ethics front and center. By my count, 5 of the 11 committee members were experts in ethical or legal issues. The committee also heard from a wide range of ethicists, religious scholars, and legal experts. There is no doubt that the research is potentially valuable. Each year tens of millions of individuals suffer from neurological and psychiatric disorders for which treatments are often completely lacking or only partially effective. These include neurodegenerative diseases such as Alzheimer’s and Parkinson’s and neurodevelopmental disorders such as autism spectrum disorder, depression, and schizophrenia. The dearth of treatments is due, in large part, to the difficulty of conducting research on an organ containing roughly 86 billion neurons interconnected by trillions of synaptic connections in intricate circuits. Unfortunately, the tools for studying such complex circuits are limited. While research using animal models has advanced understanding, their brains are very different in key respects from the brains of humans, which helps explain why disease treatments that show promise in animals often fail to work in humans. Direct studies of the human brain are seldom feasible for technical, legal, and ethical reasons, so researchers in recent years have developed new models to study

the human brain. The three models evaluated in the Academies’ report are: (1) Human neural organoids , which are tiny three-dimensional aggregates of human neural cells, no more than four millimeters in diameter, grown in the laboratory from stem cells. They are useful research tools because they exhibit some developmental, cellular, and molecular features seen in portions of fetal human brains. (2) Human neural transplants , which insert human stem cells into the brains of nonhuman animals. These transplants enable the study of human neurons, glia, and other brain cells in the context of the behavior of a whole nonhuman animal. (3) Human neural chimeras , which are a special case of transplants in which stem cells are injected into a nonhuman animal very early in embryonic development. They intermingle with the host cells that form the brain. To date, chimeras that develop to fetal stages have only been generated using rodent stem cells put into rodent hosts. But research is advancing rapidly, and it is possible that viable chimeras could one day be generated from human cells injected into the blastocyst of nonhuman primates. The hope is that these new models may yield insights into brain development and function, disease mechanisms, new therapeutic targets, and better screening of potential new treatments. But as the power of the models advances, so do the ethical concerns they raise. These include the blurring of distinctions between human beings and other animals, the welfare and rights of research animals, and consent from the people whose cells are used for this research, among other issues. One paramount concern is that an organoid comprised of human cells might somehow achieve consciousness and experience pain or distress. How to prevent that from happening would require a much broader inquiry with lots of public input, the committee said. It believes that current oversight mechanisms, such as institutional review boards, will suffice for the near-term but that additional oversight may be needed in the future. 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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ILLUSTRATIONS: SHUTTERSTOCK

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Our authors, who study successful aging and mental illnesses at the University of California, San Diego, address the much-debated, complicated question that many of us have long wondered about: Does the brain improve with age?

By Tanya T. Nguyen, Ph.D. and Dilip V. Jeste, M.D.

ILLUSTRATIONS BY DAVID PLUNKERT

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N JAMES HILTON’S 1933 NOVEL LOST HORIZON , SHANGRI-LA WAS A MAGICAL utopia where people lived well beyond 100 years. But now, less than a century later, it seems we are well on our way to making Hilton’s vision a reality. The US Census Bureau reported in 2020 that the average life expectancy has increased from 47 in 1900 to over 80 years today, while the number of people over age 60 exceeds children under 15 for the first time ever. By 2060, the average lifespan will approach 90 years. Astonishingly, more than half of the babies born today will live to age 100 and beyond, which will make Hilton’s seemingly far-fetched vision come to pass.

young people in the workforce. As a result, senior workers are often forced to retire at an arbitrary age, even if they are functioning well. Many are dismissed because they can be replaced by cheaper labor. When they attempt to re-enter the workforce, age, rather than competence, is often the deciding factor. We are also seeing effects of ageism in medicine and psychiatry. Fewer medical students are pursuing geriatric medicine or geriatric psychiatry careers today compared to 15 years ago, due partly to relatively low reimbursement from health insurance and partly to our society’s focus on youth, health, and beauty. So, while the need for healthcare will continue to increase along with the aging population, fewer experts will be available to meet the demand. And if further proof is needed, look no further than an entire anti-aging industry built around prevention and cure—an industry now valued at almost $60 billion globally . Ageism Fact and Fiction But research does not support the perspective that equates aging with gloom and doom. To use a phrase

One might think that people living longer would represent an enormous, thrilling milestone. But unfortunately, aging is rarely perceived that way. The increase in older people—metaphorically termed a “silver tsunami” since the 1980s—has economic implications, including unimaginable healthcare costs. Certain segments of western culture sadly equate aging with such “d” words as degeneration, decline, disability, diseases, dementia, depression, and death. Policy makers and economists are outspoken in their fear that spending money on older people’s care will mean less money for children and younger adults, who represent the future. This attitude—commonly labeled ageism—is analogous to such phenomena as sexism, racism, and bias against certain sexual orientations. Ageism has made many older people feel guilty about living longer and becoming a potential burden. They think—and are encouraged by society to think—that aging is an incurable disease. Ageism also rears its ugly head in more practical ways. It is often said that the longer people put off retirement and keep working, the fewer opportunities there are for

LIVING LONG

THRILLI

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(SAGE) study at the UC San Diego Center for Healthy Aging , where we reported that mental well- being improved in an almost linear fashion from age 20 until the 90s. Young adults in their 20s and 30s suffered the most from depressive symptoms, anxiety, and stress. As the years progressed, most people felt they were aging successfully —a sense of well-being that includes attainment of goals, positive attitudes toward oneself and the future, social connectedness, and adaptation—despite worse physical functioning and social stresses. We saw this phenomenon not only in healthy older adults living in communities but also in those with and being treated for serious mental and medical illnesses, including schizophrenia , AIDS , and cancer . In early 2020, as Covid-19 began to spread worldwide, it quickly became apparent that older adults were vastly more likely than younger adults to develop serious physical complications, to require hospitalization, and to die. Many people also worried about a mental health crisis among the older adults whose social life practically disappeared due to social distancing and isolation. The data , however, suggested the opposite: The mental health of older adults was less adversely affected than that of other adult age groups. In other words, older adults were more resilient and less fearful of dying than younger ones. Of course, when you find that older people are doing better than younger people in anything, an explanation that immediately springs to mind is survivor bias—that is, sicker people die younger, and people who live into old age are a biased sample. While this is certainly true, it is not the only

is inaccurate. Both development and degeneration occur throughout life—from childhood almost until death. Loss of formed synapses in adolescence (via pruning) and the formation of new synapses continue to occur throughout life. It is the balance between the two that leads to maturation of the brain—like a Grand Cru wine evolving from bitterness to perfection. Aging is not simply a physical process—it also entails psychosocial change. And herein lies a paradox: As we grow older, our physical functioning declines, but our mental and social functioning tends to improve. “Successful aging” is not an oxymoron. Sure, with age we slow down physically, and we may have difficulty remembering names and faces, and problems learning new things. Physical capacity and mental speed begin to decline around age 30, and even more noticeably after age 50. But not all mental functions deteriorate. “Crystallized” cognitive skills at age 75 are roughly equivalent to those at age 20. These are the intellectual abilities based on the accumulation of knowledge, facts, skills, and experiences throughout life, such as verbal skills and inductive reasoning. While neurocognitive disorders like dementia become increasingly prevalent with aging, the majority of older people do not develop them. The overall prevalence of dementia (of all types) is just one to three percent at age 65, with the prevalence doubling approximately every six years, to 30 percent by age 85. Other mental illnesses, such as major depression and anxiety disorders, are less common in older than in younger adults. This was part of the findings in our Successful Aging Evaluation

popularized by recent politics, it is a question of facts versus “alternative facts.” There is unquestionably some decline in a number of body structures and functions with age; but this is far from universal. There is considerable heterogeneity within and across older individuals. particularly when it comes to the brain. We generally think of childhood as the period of brain development, and old age of brain degeneration. But this is a simplification, and it

GERWOULD.

ING MILESTONE.

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the production and comprehension of speech, to specific areas of the brain. While it is harder to localize complex behaviors such as compassion and emotional regulation, brain imaging, neuroanatomical, neuropathological, genetic, and other neurobiological studies strongly associate the prefrontal cortex and the limbic striatum with aspects of wisdom. Neuroplasticity of Aging Consider Yoda from Star Wars , Gandalf from The Lord of the Rings , and Albus Dumbledore from Harry Potter —popular mythical icons of wisdom who are in the twilight of their long lives. A number of empirical studies show key components of wisdom to be superior in older adults, compared to their younger counterparts: more prosocial behaviors such as empathy and compassion, better theory of mind , and greater emotional regulation. Elders also demonstrate more self-reflection and insight, tolerance of others’ perspectives and awareness of their own limitations, and a superior ability to facilitate compromise and maintain positive relationships. Put simply: As they age, people tend to become wiser. (Of course, this doesn’t apply to everyone. As Oscar Wilde said wryly, “With age comes wisdom, but sometimes age comes alone.”) More generally, experience—both good and bad—comes with aging and affects people differently, depending on the person and the circumstances. A disaster leads to post-traumatic stress disorder in some, post-traumatic growth in others.

wisdom throughout their texts. Empirical studies in wisdom started in the 1970s, but the field has grown markedly in the last couple of decades: Since 2010, PubMed has added 2,000 papers on wisdom. Still, many scientists dismiss it as a fuzzy construct. Wisdom cannot be defined or measured, so how can one study it, they argue. However, the same logic was used for decades, if not centuries, to ignore consciousness, emotions, cognition, stress, resilience, and well-being. Today, we accept them as scientifically characterized, biologically based entities. Wisdom is a personality trait whose principal components are empathy, compassion, emotional regulation, and self-reflection. It includes qualities that are in notably short supply in today’s highly polarized world: acceptance of uncertainty and of diverse perspectives, and socially focused decision-making. Wisdom is associated with superior well-being, quality of life, and life satisfaction. Indeed, it has a greater impact on mental well-being than objective factors such as physical health and socioeconomic status. The basic conceptualization of wisdom, as described above, has not varied materially across times and cultures, though there are some cultural differences. This suggests that wisdom is largely biologically based and influenced by culture. Since the early 20th century (thanks to the pioneering work of the German neurologist Korbinian Brodmann), we have been able to localize sensory and motor functions, as well as

reason for age-linked improvement in mental health. For example, several long-term studies have shown that mental health improves progressively with aging even in people with serious mental illnesses such as schizophrenia. Recognizing Wisdom In eastern cultures, older people are respected for being wiser. But does wisdom really increase with age? Is this why older adults have better mental well-being? More fundamentally, what is wisdom and how is it related to the brain? The concept of wisdom goes back to the beginning of most religions and philosophies. The word “Homo sapiens” means a wise man (or person). Verses about wisdom are prominent in the Bible and in the Bhagavad Gita of Hinduism. Greek and Eastern philosophers—from Socrates, Aristotle, and Plato to Confucius and Buddha—described

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underlie the brain benefits of an active and stimulated life. People who stay active physically, cognitively, and socially tend to maintain their vocabulary, their ability to recognize events, objects, and people they’ve encountered before, and the motor skills learned during early childhood, such as swimming or bicycling. Their brains are likely to escape the atrophy that occurs in the brains of sedentary, lonely, inactive seniors. Brain imaging and neurophysiology studies have shown that physical exercise as well as mindfulness and meditation increase gray matter volume and white matter brain cells and synaptic connections, respectively, and their activation in the anterior regions that support positive emotions and wisdom. There is a phenomenon called PASA (Posterior-Anterior Shift in Aging) that may help explain why wisdom improves over the life course. Our brains develop in a back-to-front manner; the prefrontal cortex, the last portion to mature, is not fully formed until one’s early 20s. PASA mirrors that sequence: With age, neural activity shifts from the occipital lobes in the back of the brain, which are centers for processing sensory stimuli, to the prefrontal cortex, which is responsible for executive functions. Therefore, while sensory processing may decrease over the years, the brain may recruit higher-order networks in the prefrontal cortex that are associated with wisdom development. Another aspect of the aging process, HAROLD (hemispheric asymmetry reduction in older adults), involves reduced lateralization of the

Though aging is typically associated with a loss of neurons and cognitive decline, the effect is not homogenous across brain regions and domains. One of the most exciting developments in neuroscience during the past two decades is the discovery that our brain continues to evolve into old age through “plasticity,” i.e., strengthening of existing synapses and formation of new ones, in the context of appropriate physical, cognitive, and psychosocial stimulation. Scientists have shown that in old mice (and various other species), physical activity accompanied by psychosocial stimulation can increase the number of synapses as well as neurons in such subcortical brain areas as the dentate gyrus of the hippocampus, and areas around brain ventricles. This neuroplastic response may

BRAIN.

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brain. This means that in younger people, the brain’s right and left hemispheres specialize in somewhat different tasks. Age reduces this asymmetry: Tasks previously managed by a neural circuit housed in a single hemisphere now call on both sides of the brain. Their ability to recruit neuronal networks from both hemispheres for a given mental activity offsets, to an extent, the loss of synapses and neurons in older people. Finally, aging changes the way the brain responds to emotions. This might explain the “positivity effect” of aging , a tendency to favor positive emotions and memories. Older people pay attention to and remember pleasurable and gratifying events better than sad, frightening, regrettable ones, whereas younger individuals retain positive and negative information equally well. It is as if young minds are like Velcro ® for negative experiences,

German neurologist Korbinian Brodmann

(1868–1918) mapped the cerebral cortex, defining 52 distinct regions known as Brodmann areas, based on their cytoarchitectonic (histological) characteristics.

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FIGURE 1: Perceptions of how older people are portrayed in the media Research conducted by the Australian Human Rights Commission revealed that the most common words used to describe older adults in the media are forgetful, slow, frail, vulnerable, burden, grumpy, and sick. The size of each word is directly proportional to the number of mentions of that theme. Responses were based on the question: “Thinking about everything you see and hear in the media (including on TV, online, on the radio, and in newspapers and magazines), how does the media portray older people?”

Evolutionary Value of Human Wisdom of Aging In evolutionary terms, prolonged human longevity would seem to make no sense. Darwin’s theory of evolution is predicated on survival of the fittest, which depends on the ability to procreate. Older people cannot reproduce, so they cannot promote species survival. Among primates, humans are unique in regularly outliving their loss of reproductive capacity by decades. For example, when a person who had menopause or andropause at age 45 lives to age 90, they would have spent the entire second half of their life without fertility. While human life span is increasing, fertility span is not. The average age at menopause or andropause has remained

unchanged (45-50) over millennia. So, how can we explain exceptional human longevity despite unchanged loss of fertility and physical health in old age? Homo sapiens is the only species able to produce offspring years before its brain is fully mature. Biologically, we humans are primed to conceive children with the arrival of puberty around age 12 or 13, while our brains continue to undergo considerable refinement, via processes such as synaptic pruning, until the early 20s. How can adolescents with incompletely developed brains (who are not even legally deemed fully responsible adults), care for their own children and make them fit to survive in potentially risky environments? Here is where data suggests

and older minds like Teflon ® . Older adults more easily dispel feelings of disappointment, regret, and remorse, and worry less about events or issues they cannot change. This may reflect changes in sensitivity of the brain area central to the processing of emotions— the amygdala. In younger people, amygdala activity increases in response to both positive and negative visual images; in their elders, negative images trigger much less activity than positive ones. One caveat must be kept in mind: No age-linked increase in wisdom can continue indefinitely. It ends when neurodegeneration surpasses the aging brain’s ability to compensate. The age when this happens is not fixed and likely varies subject to a number of factors.

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