CerebrumWinter2021

His &Hers

SEX DIFFERENCES

Catherine S. Woolley, Ph.D.

His and Hers: Sex Differences in the Brain

Page 12

Catherine S. Woolley, Ph.D., is the William Deering Chair in Biological Sciences and a professor of neurobiology and neurology at Northwestern University. She is a researcher and teacher who has studied hormone actions in the brain for over 30 years. She founded Northwestern’s neuroscience major in 2015 and was named a Charles Deering McCormick Professor of Teaching Excellence in 2018. In 2019, she was elected to the National Academy of Medicine “for pioneering research demonstrating estrogen-driven plasticity of neural circuitry and sex-dependent molecular signaling in brain areas related to cognition, epilepsy, and affective disorders.” Woolley received her Ph.D. in neuroscience from Rockefeller University.

Vince Calhoun, Ph.D.

The Promise of Big Data Imaging for Mental Health

Page 18

Vince D. Calhoun, Ph.D., is founding director of the tri-institutional Center for Translational Research in Neuroimaging and Data Science and a Georgia Research Alliance eminent scholar in brain health and image analysis, where he holds appointments at Georgia State University, Georgia Institute of Technology, and Emory University. He was previously the president of the Mind Research Network and Distinguished Professor of Electrical and Computer Engineering at the University of New Mexico. His work includes the development of flexible methods to analyze neuroimaging data. Calhoun served as the chair for the Organization for Human Brain Mapping from 2018-2019 and is a past chair of the IEEE Machine Learning for Signal Processing Technical Committee.

Kayt Sukel

Psychedelics: Weighing the Healing Power

Page 26

Kayt Sukel‘s work has appeared in the Atlantic Monthly, the New Scientist, USA Today, the Washington Post, Parenting, National Geographic Traveler, and the AARP Bulletin. She is a partner at the award-winning family travel website Travel Savvy Mom, and is also a frequent contributor to the Dana Foundation’s science publications. She has written about out-of-body experiences, fMRI orgasms, computer models of schizophrenia, the stigma of single motherhood, and why one should travel to exotic lands with young children. She is the author of Dirty Minds: How Our Brains Influence Love, Sex and Relationships and The Art of Risk: The New Science of Courage, Caution & Chance

Brenda Patoine

Your Brain on Food Page 30

Brenda Patoine is a freelance science writer, reporter, and blogger who has been covering neuroscience research for more than 30 years. Her specialty is translating complex scientific findings into writings for the general public that address the question of “what does this mean to me?” She has interviewed hundreds of leading neuroscientists over three decades, including six Nobel Laureates. She founded ScienceWRITE Medical Communications in 1989 and holds a degree in journalism from St. Michael’s College. Other areas of interest are holistic wellness, science and spirituality, and bhakti yoga. Brenda lives in Burlington, V.T., with her cat Shakti.

COVER ILLUSTRATION: ARMANDO VEVE

FEATURES

12 His and Hers: Sex Differences in the Brain

The neurobiological sex differences in the male and female brain remain largely a mystery. Our author—an acclaimed neuroendocrinologist at Northwestern University—tells us what we know and why we don’t know more.

By Catherine S. Woolley, Ph.D.

18 The Promise of Big Data Imaging for Mental Health

Knowledge gleaned from big data and advances in neuroimaging have provided new insights into the workings of the brain. Our author, founding director of the Center for Translational Research in Neuroimaging and Data Science, traces the evolution of these two evolving fields.

By Vince Calhoun, Ph.D.

26 Psychedelics: Weighing the Healing Power

New research suggests drugs like psilocybin may help treat neuropsychiatric conditions ranging from depression to opioid addiction. But what do we really know about how psychedelics influence the brain?

By Kayt Sukel

30 Your Brain on Food

Science is increasingly unpacking the ways that diet influences cognitive function and emotional well-being. Growing evidence suggests that the right diet may in fact mitigate some of the ill effects of stress on the brain, while the wrong diet may worsen the effects.

By Brenda Patoine

36 The New Science of Spaces

How can the new field of environmental neuroscience, which is aimed at analyzing the use of physical and social spaces, help architects, urban planners, and policy makers improve psychological and physiological states?

By Seimi Rurup

SECTIONS

5 Briefly Noted • By the Numbers, Brain on the Web

6 Advances • Notable brain science findings

7 Bookshelf • A few brain science books that have recently caught our eye

8 Neuroethics • Marijuana: Young Minds and Other Concerns, By Philip M. Boffey

10 In Memoriam • Duane Alexander, Leslie Ungerleider, Pat Quinn

10 Clinical Corner • The Sound of Healing, By Abdul-Kareem Ahmed, M.D.

35 Talking Neuroscience

• A Sampler of Cerebrum Podcast Episodes

40 Awards • And the Winner Is: Neuroethics Essay Contest

POINTS OF INTEREST

NOTABLE FACTS IN THIS ISSUE

4 One of the most widely cited reasons for studying the brains of both sexes is that the incidence of many neurological and neuropsychiatric disorders varies by sex.

His and Hers: Sex Differences in the Brain, Page 12

4 Have we learned anything about diagnosis or mental illness from the vast trove of neuroimaging data that has been collected over the years?

The Promise of Big Data Imaging for Mental Health, Page 18

4 Despite the continuing legal barriers involved, several unique research centers are actively studying the effects of psychedelic drugs, both from basic science and clinical perspectives.

Psychedelics: Weighing the Healing Power, Page 26

4 Recent evidence suggests polyphenols are involved in cellular signaling pathways that mediate inflammatory processes in the brain.

Your Brain on Food, Page 30

4 Our brains are wired to seek out and remember patterns within our environments, and imageability determines how specific physical elements and their arrangement will capture attention, evoke feelings, and create a lasting impression.

The New Science of Spaces, Page 36

A Matter of Opinion

BY BILL GLOVIN Editor-in-Chief

In April 2014, Cerebrum posted an article titled: “Equal ≠ The Same: Sex Differences in the Human Brain,” by Larry Cahill at the University of California, Irvine. Soon after, six female academicians presented their point of view. “Why Males ≠ Corvettes, Females ≠ Volvos, and Scientific Criticism ≠ Ideology began with: “We welcome this opportunity to correct some of the misapprehensions and mischaracterizations in this account and present a more nuanced view of the relations among sex, brain, and gender.”

This issue’s cover story offers a fresh, updated look at what is still a provocative and debatable topic. One of my advisers, the late pioneering endocrinologist Bruce McEwen, recommended we invite Catherine Woolley at Northwestern, who had long ago stood out in his Rockefeller University lab as a graduate student and who had since gone on to acclaim for groundbreaking research on estrogen-driven plasticity. Her article aptly begins with, “Sex differences in the brain are real, but they are not what you might think.” My hope is that Woolley’s article, and my podcast with her, will help you form your own thoughts.

We are also fortunate to have a leader in the field of big data, Vince Calhoun, take on a topic that has enormous potential to alter neuroscience and mental health: big data neuroimaging. As imaging and computer power continue to evolve, Calhoun—founding director of the tri-institutional Center for Translational Research in Neuroimaging and Data Science in Georgia examines the origins of the field and neuroimaging’s potential to solve issues within neuroscience and mental health. He can also be heard on an episode of our podcast

Other features in this issue include articles on psychedelics to treat depression, the impact of diet on the brain, and the new field of environmental neuroscience. Our neuroethics column tackles some of the dangers of legalized marijuana—especially as those dangers concern developing brains. Our new Clinical Corner column offers a resident’s first-person account of treating a patient with a new noninvasive surgical procedure called focused ultrasound.

These are indeed challenging times for science and medicine. As Covid-19 continues to rage, a rollout of a vaccine cannot come fast enough. Finding ways to slow it down, deal with its aftermath, and defeat it completely will continue to dominate our thoughts. Stay well. l

EMERGING IDEAS IN BRAIN SCIENCE

Bill Glovin Editor-in-Chief

Seimi

Rurup Assitant Editor

Podcast

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

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.

BRAIN IN THE NEWS

Links to brain-related articles we recommend:

> Scientific American: Governments Worldwide Consider Ditching Daylight Saving Time

> New York Times: The Healing Power of Singing

> Wall Street Journal: How to Stop the Negative Chatter in Your Head

> New York Times: When It Comes to Living With Uncertainty, Michael J. Fox Is a Pro

> Washington Post: A pandemic pod could help you get through winter, experts say. Here’s how to form one.

> Consumer Reports: Brain-boosting supplements may have high doses of unapproved Rx medications

> New York Times: Your Brain Is Not for Thinking

> Star-Ledger: Living with long-term effects

> New Scientist: Living electrodes for linking brains to computers tested in rats

> Smithsonian Magazine: The New Science of Our Ancient Bond With Dogs

> Rutgers Magazine: Great Minds

> Washington Post: Atypical forms of dementia are being diagnosed more often in people in their 50s and 60s

> Star-Ledger: A road map to transform the mental health system

> New York Times: Hearing Aids Could Use Some Help

BY THE NUMBERS

4 drugs have been approved by the US Food and Drug Administration for Alzheimer’s disease, though more than 100 have been tested.

30 countries were represented at this year’s International Neuroethics Society virtual meeting, nearly twice as many as the previous meeting in Chicago.

36 advanced degrees in neuroscience were awarded to Black students in 2018 out of a total of 493.

40-50% of Covid-19 patients develop neurological or psychological problems while they are in the hospital.

300,000,000 olfactory receptors are used by a dog, in contrast to 6 million in a human.

2,500 partner events were held in 2019 during Brain Awareness Week, which will be held this year from March 15-21.

10,000 mental health “wellness” apps are available for a broad range of conditions.

When we engage kids in sports, we don’t expect them to grow up to be a pro athlete—we do it for the joy of the game. Science is no different: Kids who discover the joy in science will not necessarily grow up to be a scientist, engineer, or physician, but as a member of a questioning and informed electorate. And we as a society really need that.”

— John A. Pollack, Ph.D., co-director of the  Chronic Pain Research Consortium at Duquesne University and winner of the 2020 Society for Neuroscience Science Educator Award.

ISSUE: Hearing aids, which cost on average $4,700 a pair and are barely covered by Medicare or private insurance, are crucial to one-quarter of Americans in their 60s and nearly twothirds of those over 70 who suffer from hearing loss. The damaging consequences of hearing loss can include social isolation, an increased risk of falls, and much higher rates of dementia. Despite 2017 legislation from Congress that would allow hearing aids to be sold directly to consumers, without a prescription, the Food and Drug Administration had failed the draft legislation to establish safety and effectiveness benchmarks for these over-thecounter devices.

ADVANCES

Notable brain science findings

BY NICKY PENTTILA

When we think of AUGMENTED REALITY (AR) technologies, we usually think of adding, such as glasses that can overlay directions on our field of vision. But augmenting can also mean deleting, such as video editing software that can erase a coffee cup from a Game of Thrones scene or hearing aids that dampen background conversations. Researchers have started investigating using AR to help people on the autism spectrum by using “smart glasses” to delete distracting elements from their visual field so they can focus. In a series of workshops, they came up with the idea for “a mirror-like wall interface filtering out irrelevant visual information from real-time capture of a space.” l

Only about half of people getting treatment for BIPOLAR DISORDER in the US receive both medications and psychotherapy. Researchers analyzed 39 randomized clinical trials, including a total of 3,863 patients, to see if the therapy made a difference in managing symptoms and preventing relapse, and to try and see which therapies worked better. All additional therapies were better than none; cognitive behavioral therapy was found highly effective, as was psychoeducation with “guided practice of illness management skills” in family or group therapy settings (less so in one-on-one). l

EXPOSURE THERAPY is effective in helping people overcome traumatic fears, but what if a person cannot stand even this carefully controlled exposure to what they fear? Researchers are testing a new technique, called “very brief exposure.” In one test, they flashed 16 pairs of images: an image of the fear-object (spiders, in this case) for 30 milliseconds, quickly followed by a “masking” image (rows of ABC’s) for 120 ms. Ten minutes later, they asked the participant to come closer and closer to a live tarantula in a glass aquarium. Participants reported that they did not see the images of the spiders, but their behavior with the spider was less fearful than before the intervention. Such subconscious therapy, if confirmed by other research, could offer a first step for easing the worst fears. l

Some of the same DNA variations seen in people with DEPRESSION are also seen in people with other mental disorders, such as schizophrenia, ADHD, and autism. Researchers wondered if it was possible to “sub-type” people with depression by dividing

We’re a nation living longer and longer. Over the next 30 years, the number of Americans aged 90 and above is expected to triple, according to an NIHfunded research study called 90+ at the University of California, Irvine. The study of 1,600 men and women— beginning in 2003 to determine factors associated with longevity and cognitive function—has been the focus of two 60 Minutes segments six years apart. It has found that:

• Over 40 percent of people aged 90 and older suffer from dementia while almost 80 percent are disabled.  Both are more common in women than men.

• About half of people with dementia over age 90 do not have sufficient neuropathology in their brain to explain their cognitive loss.

• People aged 90 and older with an APOE2 gene are less likely to have clinical Alzheimer’s disease but are much more likely to have Alzheimer’s neuropathology in their brains.

• People who drank moderate amounts of alcohol or coffee lived longer than those who abstained.

• People who were overweight in their 70s lived longer than normal or underweight people did.

them into groups—one group that shares variations linked to schizophrenia and another that shares variations linked to autism, for example. If so, it might be a basis for understanding which depression therapy would be most effective for the different groups. Using the huge UK Biobank database, the researchers found it wasn’t so: The DNA variations shared by schizophrenia and depression were scattered across the entire population of depressed people. l

An experimental drug that has been shown in animals to reverse the cognitive impairments related to Down syndrome and restore memory function months after traumatic brain injury has now been shown to reverse age-related declines in MEMORY and mental flexibility in old mice. The small molecule’s name, ISRIB, spells out what it seems to do: integrated stress response inhibitor. “The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” says Peter Walter, a co-lead on the study l

PHOTO: WILL LANDIN 90 ... AND BEYOND

BOOKSHELF

A few brain science books that have recently caught our eye

BY BRANDON BARRERA

Seven and a Half Lessons About the Brain

by Lisa Feldman Barrett (Houghton Mifflin Harcourt)

Lisa Feldman Barrett, Ph.D., University

Distinguished Professor of Psychology at Northeastern University, presents an intriguing and entertaining collection of short essays on the brain. Filled with anecdotes and distilled neuroscience, it reads like a primer on human nature. In short order, Barrett dispels widely held misconceptions about our brains, setting the record straight with the help of recent research. If you’ve ever attributed some unsavory or impulsive behavior to your “lizard brain,” says Barrett, you’re guilty of referencing guff. Reptiles and non-human mammals have the same kinds of neurons that humans do. The differences that exist are not found in the building blocks (which are the same) but are due to the brains’ developmental stages running for different lengths of time in the different species. In other words, we humans possess differently evolved brains, not more evolved brains with additional parts. Further, our brains are not for thinking—our gray matter is for controlling the body’s needs, masterfully predicting energy requirements before they manifest. Barrett’s essays will familiarize you with the interplay between different brains, the relationship between emotion and reason, and the paradigm-altering power of our collective social reality.

NeuroScience Fiction by Rodrigo Quian Quiroga (BenBella

Books)

A memorable and endlessly scrutable work, Stanley Kubrick’s 2001: A Space Odyssey is regarded by many cinephiles as one of the medium’s crowning achievements. The film’s antagonist, a self-aware supercomputer with a monotone voice and ruthless sense of self-preservation, HAL 9000, has continued to spark the public’s imagination since the film’s release in 1968, a time before the personal computer and self-driving cars. Such is often the case with science fiction, says Rodrigo Quian Quiroga, Ph.D., Research Chair and director of the Center for Systems Neuroscience at the University of Leicester. Sci-fi movies such as Total Recall and The Matrix, he says, rely on cutting-edge breakthroughs in science and, in turn, inspires the discipline. Quiroga’s book explores how science is realizing what for decades only existed in the outlandish realms of futurist writers—implanting a memory, helping a paralyzed person to walk again, reading the mind—

and how these advances are providing insight into some of humanity’s oldest and most profound inquiries. Using ten influential sci-fi movies as springboards to discuss the latest neuroscience, Quiroga examines Minority Report and free will, the illusion of reality and The Matrix, animal consciousness in Planet of the Apes, and machine intelligence in 2001

Unique:

The New Science of Human

Individuality by David J. Linden (Basic Books)

What makes you, you? Is your essence found purely in your genetic material? According to David J. Linden, Ph.D., professor of neuroscience at the Johns Hopkins University School of Medicine, our individuality is forged in the regulation of gene expression, that vital space where experience and genes interact. Linden meticulously outlines the factors that make us singular while commendably keeping things approachable for lay readers. Eager to retire the reductive phrase “nature versus nurture,” Linden suggests understanding individuality as a matter of “heredity interacting with experience, filtered through the inherent randomness of development.” He explains that genes are built to be modified by the full scope of experience—the food you’ve eaten, diseases you’ve had, culture and technology—as early as in the womb. Carefully selected studies, personal stories, and historical accounts keep readers thoroughly engaged as Linden delves into sex and sexuality, gender, intelligence, and culinary proclivities.

Mayo Clinic on

Alzheimer’s Disease

and Other Dementias Edited by Jonathan GraffRadford and Angela M. Lunde (Mayo Clinic Press)

As people worldwide live longer, the World Health Organization (WHO) estimates that the world’s population aged 60 years and older will reach two billion by 2050—that’s more than double the 900 million from 2015. As age-related diseases, Alzheimer's, and other forms of dementia are projected to increase proportionately, making educational resources for caregivers and patients is all the more critical. Organized by neurologists from the Mayo Clinic, this seventh edition is a collection of recommendations for living well with dementia, the latest research on preventative methods, and the newest treatment options for the disease. The content is categorized thematically, inviting readers to engage with the sections most relevant to them and encouraging return visits as needs change. Full-color images of people, illustrations, and charts accompany the stories of people living with dementia and those who care for them, adding a crucial element missing from more clinical texts: humanity. l

Marijuana: Young Minds and Other Concerns

BY PHILIP M. BOFFEY

Troubling ethical issues—especially as they relate to the brains of young people—have been raised by the latest round of marijuana initiatives that won resounding approval from voters in the November elections. While most eyes were focusing on the presidential race between Joe Biden and Donald Trump, or on political races lower on the ballot, four states—Arizona, Montana, New Jersey, and South Dakota—decisively approved the recreational use of marijuana. This brings the total number of states that have done so to 15, plus the District of Columbia.

Most of the issues have been raised in previous legalization battles but have gained heightened importance and some new wrinkles after the latest round of voting. It seems clear that the American public is moving inexorably toward wider use of marijuana, so it is important to keep in mind that while states may make legalized marijuana available to people over the age of 21, federal agencies say the adolescent brain continues to develop until the mid- to late 20s, while some studies show that the frontal lobe in the adolescent brain is still forming at age 30.

Oregon voters approved a particularly sweeping and potentially historic step: the nation’s first measure to decriminalize personal use of small amounts of all drugs, not just marijuana but such “harder” drugs as heroin and cocaine as well. Punishment will be tantamount to a traffic ticket, not a jail sentence. The measure will also greatly expand access to drug treatments and harm reduction services, funded by savings from no longer arresting, incarcerating, and prosecuting people for drug possession, and by marijuana sales taxes.

From an ethical standpoint, it seems far better to treat drug use as a public health problem requiring medical treatment or health services rather than as a justification for locking people up and potentially ruining their lives. Advocates of drug reform hope Oregon’s step will spur similar action in other states and strike a body blow against the so-called “War on Drugs.” Such measures could help reduce the glaring, ethically unjust disparities in the punishment of Black people and other racial minorities for possession of small amounts of drugs.

Government Agencies Weigh In

Any ethical evaluation of marijuana policies should consider the latest scientific understanding of marijuana’s effects on cognitive abilities on adolescents and its potential downstream impacts on education, employment, job performance, and income. The most authoritative governmental sources are the National Institute on Drug Abuse (NIDA) and the Centers for Disease Control and Prevention (CDC), supplemented by a few other federal agencies. Most of the scientific information in this column is gleaned from their websites, buttressed by commentaries from outside experts.

The latest Marijuana Research Report from NIDA was updated in July 2020. A cover letter from Nora Volkow, the agency's director, notes that marijuana is gaining greater acceptance in our society, making it “particularly important” for people to understand what is known about both its adverse health effects and potential therapeutic benefits. Whether the therapeutic benefits outweigh its health risks is still an open question that science has not resolved, the director asserts.

Marijuana is the second most commonly used psychotropic drug in the US, after ethanol (alcohol), and after years of its use tapering downward among high school and middle school students, rates have started back up. At the same time, teenage perception of the risks of marijuana have steadily declined. This is alarming because heavy use of marijuana at an early age can cause harmful changes in the brain, according to a growing number of studies. Some studies have even linked marijuana use to significant declines in IQ and short-lived interference , especially when heavy use starts in adolescence. Those who used marijuana heavily as teenagers and quit using as adults did not recover the lost IQ points, according to NIDA. By contrast, people who only began using marijuana heavily as adults did not lose IQ points.

This is clearly a red flag warning to protect teenagers from excessive use, and policy makers have an ethical duty to keep marijuana out of the hands of teenagers to the extent possible, through such steps as requiring valid identification cards before selling to minors. If nothing else, a vigorous educational campaign in schools and on social media platforms might mitigate the damage.

Whatever harm an individual may personally suffer from marijuana, it seems clearly unethical for users to inflict harm on others. In some homes, children have found and eaten marijuana edibles in overdose quantities. Parents have a moral obligation to protect them. There is some evidence, albeit inconclusive, that marijuana may increase the risk of motor

vehicle accidents, threatening harm to others in the same car or in other vehicles on the road.

And whether smoking marijuana causes lung cancer, as cigarette smoking does, remains an open question. Considerable evidence suggests that students who smoke marijuana have poorer educational outcomes, such as reduced chances of graduating, than their non-smoking peers. But whether marijuana use directly causes these associations remains unanswered.

The “Gateway Drug” Question

Although some studies suggest that marijuana may be a “gateway drug” whose users progress to “harder” substances, most marijuana users do not follow that pathway. A more plausible hypothesis is that people inclined to take drugs start with what’s readily available, such as marijuana, tobacco, or alcohol, and then interact with people who use other drugs that they, too, decide to try. NIDA calls for further research to explore this question.

Heavy users can become dependent on marijuana to function in life, but there are vigorous debates over whether they can be considered “addicted.” The CDC says that about one in six teens who repeatedly use marijuana can become addicted, which means that they may make unsuccessful efforts to quit using marijuana or may give up important activities with friends and family in favor of using marijuana.

Several studies have linked marijuana use to increased risk for psychiatric disorders, including psychosis (schizophrenia), depression, anxiety, and substance-use disorders, but the evidence is mixed and hard to interpret. The strongest evidence links marijuana use and psychiatric disorders in those with preexisting genetic conditions or other vulnerabilities.

A clear-minded article by a British psychiatrist in Cerebrum in early 2015 noted that most people enjoy cannabis (marijuana) in moderation and suffer no ill effects, but he cited studies that cannabis users had an increased risk of psychotic symptoms and full-blown schizophrenia. That judgment was more readily accepted in Europe than in North America, he wrote.

Looking ahead, it is important to recognize that several factors make marijuana more dangerous today than it was 20-30 years ago, especially for young people. The amount of tetrahydrocannabinol (THC) in marijuana, the main ingredient that causes a person to feel high, has increased greatly over the past few decades, from less than 4 percent in the early 1990s to about 15 percent now. Smoking of extracts and resins from the marijuana plant, which have 3 to 5 times more THC than the plant itself, is also increasing.

Vaping of marijuana is on the rise among high school seniors and college students, a dangerous trend because users tend

to vape a higher concentration of THC than they would smoke. Meanwhile, eating food, such as cookies and brownies, infused with marijuana is also on the rise, posing added dangers. A 2019 study of emergency room visits in Colorado found that edibles were more likely than inhaled pot to cause severe intoxication, acute psychiatric symptoms in people with no history of psychiatric illness, and cardiovascular problems.

So-called “marijuana concentrates,” which contain extraordinarily high THC levels and can deliver it to the body quickly, may also be contaminated with toxic substances, raising the risks to unwary users. For adolescents, these concentrates may be throwing important development processes out of balance.

Looking Ahead

President-elect Joe Biden, who during his Senate career was considered a hard-line supporter of punitive anti-drug laws, softened his stance in comments during the campaign. He favors decriminalizing marijuana and expunging the convictions of low-level users so that there would be no permanent criminal record. He would allow states to set their own marijuana policies, but he does not favor federal legalization because he doesn’t believe there have been sufficient studies of its health effects. He favors changing the status of marijuana under federal law from a tightly controlled status that prohibits virtually all uses to a category that would makes it easier to conduct research on marijuana’s health effects.

He has also suggested that people convicted of lowlevel drug offenses should be forced into mandatory rehab programs in lieu of jail. He will need to ensure that whatever compulsion he tries to exert does not infringe on civil liberties.

Some advocacy groups believe Mr. Biden should push for complete legalization of marijuana and removal of virtually all federal controls on its use. For now, his measured approach seems reasonable for a substance about which much remains unknown. And it seems more likely to gain bipartisan political support.

But no matter what direction the political winds blow concerning legalization, the criminal justice system, and the influx of new marketing strategies for new and stronger product, we owe it to our children to study the effects of marijuana on their brain health and step up our efforts to protect them. 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.

Any ethical evaluation of marijuana policies should consider the latest scientific understanding of marijuana’s effects on cognitive abilities on adolescents and its potential downstream impacts on education, employment, job performance, and income.

Duane Alexander, M.D., a former director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

(NICHD) — After leaving NICHD in 2009, Alexander served as an advisor to the director on global maternal and child health issues at the NIH Fogarty International Center. His achievements include the safety and efficacy of amniocentesis for prenatal genetic diagnosis; the prevention of acquired intellectual and developmental disability caused by Haemophilus influenzae type b meningitis, phenylketonuria, and other conditions; the establishment of effective newborn screening programs; and the reduction of Sudden Infant Death Syndrome (SIDS) rates in the US.

Leslie Ungerleider, Ph.D., chief of the Laboratory for Brain and Cognition at the National Institute of Mental Health (NIMH) and a member of the Dana Alliance for Brain Initiatives — At NIMH, Ungerleider was an NIH Distinguished Investigator whose early work with Mortimer Mishkin at NIMH led to the proposal of two functionally dissociated cortical pathways in the primate brain— one of the most impactful and influential concepts in visual neuroscience. Over the years she also helped to illuminate the nature of perception and attention, working in non-human primate models, and in humans using functional brain imaging.

Pat Quinn, a co-founder of the ALS Ice Bucket Challenge, a viral fundraising effort that brought in more than $220 million worldwide for Lou Gehrig’s disease research — Quinn, who was diagnosed with Lou Gehrig’s disease, or amyotrophic lateral sclerosis (ALS), in 2013, a month after his 30th birthday, saw the ice bucket challenge on the social media feed of professional golfer Chris Kennedy, who first dared his wife’s cousin Jeanette Senerchia to take a bucket of ice water, dump it over her head, post a video on social media and ask others to do the same or to make a donation to charity. Senerchia’s husband had ALS. Quinn and co-founder Pete Frates, along with their teams of supporters, helped popularize the challenge.

The Sound of Healing

BY ABDUL-KAREEM AHMED, M.D.

“Bald is beautiful, and it’s better than a rug or a combover,” he said.

“Neurosurgeons prefer bald patients,” I replied from our pre-operative wing, where preparation for focused ultrasound treatment includes a shaved head. The patient, 76-year-old John Williams, had been experiencing tremor of his right hand for the past several years. The chief executive officer of a local door manufacturing company in Maryland, Williams had heard about magnetic resonance imaging-guided focused ultrasound for tremor a few years ago.

“I couldn’t place a golf ball on a tee,” he revealed. Eating, drinking, and writing all became difficult tasks, especially since he is right-handed. Over the years, Williams had learned to make do with his left hand.

He had seen a movement disorder neurologist, who prescribed medications. Essential tremor can affect the hands, feet, face, and voice. Patients find it a challenge to eat, drink, write, or perform other daily functions, and often avoid social outings. Unfortunately, medications did not work for Williams, and his tremor became worse.

He had first considered deep brain stimulation (DBS), a more common neurosurgical treatment that has proven effective in treating his disorder. DBS involves thin electrodes implanted into the brain to modulate a specific portion of the thalamus, the brain’s signal relay station. DBS can be effective and last many years, but Williams thought it was too invasive and was wary of rare complications such as infections, bleeds, or need for revision.

He instead turned to the University of Maryland Medical Center for focused ultrasound treatment, a less invasive, incisionless surgery pioneered by the brothers William and Francis Fry and more recently modernized by Kullervo Hynynen, M.D., and colleagues. Focused ultrasound to treat essential tremor is available at two dozen institutions in the US, and the University of Maryland was an early site for treatment and contributor to clinical trials.

In our multi-center team’s landmark focused ultrasound trial in 2016, patients with essential tremor experienced a 40 percent reduction of symptom severity one year after treatment and a 50 to 60 percent improvement in their

Focused ultrasound to treat essential tremor is available at two dozen institutions in the US, and the University of Maryland was an early site for treatment and contributor to clinical trials.

ability to write, eat, dress themselves, and work. Currently, a new trial we are conducting is directed at bilateral tremor (tremors on both sides), and we are also trialing focused ultrasound to treat symptoms of Parkinson’s disease, to reduce neuropathic pain, and to improve visualization and drug delivery for the treatment of brain tumors.

Focused ultrasound treatment requires that patients first undergo a series of tests for eligibility. A CAT scan reveals if their skull has the required density for treatment. On the day of treatment, a neurosurgeon places a stereotactic frame on the patient’s head. A bag of cooled water sits on their scalp to reduce heating of the skull. The patient lies on the MRI table, where this frame and bag meet a hemispherical array.

In this array, approximately 1,000 sound-emitting elements can be individually steered and converge on a single target where these beams meet within the brain. With this technology, acoustic beams burn a hole the size of a quinoa seed in the thalamus, disrupting a circuit known to underlie essential tremor, all while the patient is awake and under realtime MRI.

Williams decided that the time had come to try it.

“Are you anxious at all?" I asked him.

“Honestly, my wife is more scared than me,” he said, smiling at Carol.

Our staff wheeled him to our focused ultrasound suite. A neurosurgeon specializing in movement disorders placed a stereotactic frame (a square of hard plastic) on his head. This would allow the focused ultrasound workstation to marry his MRI with his prior CAT scan imaging.

We sat him down on the MRI scanner and connected his frame to the hemispherical array with a bag of continuously cooled water in between.

With imaging, we located the left ventral intermediate nucleus, a segment of the thalamus involved in the circuit that underlies tremor, called the dentatorubrothalamic tract. Disrupting this tract, as DBS does, allowed us to affect his right hand.

In sequential steps, our team directed these elements and applied sound. After each treatment, Williams’ tremor was tested to determine the procedure’s effect. He was asked to draw a straight line and then to accurately draw a spiral within boundaries on a sheet. With each dose of sound energy, his attempts became more precise.

“It was a strange experience,” he said.

After an hour—his treatment concluded—an MRI demonstrated successful destruction of the left ventral intermediate nucleus. At the recovery area, his stereotactic frame was removed.

Focused ultrasound has the potential to treat Alzheimer’s, Parkinson’s, and more, and president-elect Joe Biden, author John Grisham, and the Michael J. Fox Foundation have showed their support.

Our nurse handed him a pen and paper. With Carol at his side, Williams adeptly wrote his name. Seeing this, she almost broke down in tears.

“I was not able to do that for many years,” he said. “I’ve been re-training my right hand for eating and shaving now that I can use it again.” A month later, he was using his right hand again.

“It seems miraculous to me,” said Williams. l

Abdul-Kareem Ahmed, M.D., is a neurosurgery resident at the University of Maryland Medical Center.

THE FOCUSED ULTRASOUND FOUNDATION

While the 1990s bestseller Men Are from Mars, Women addressed behavior, the differences in the male remain largely a mystery. neuroendocrinologist tells us what we know

His &Hers

BY CATHERINE S. WOOLLEY, PH.D.

ILLUSTRATION BY ARMANDO VEVE

bestseller

Women Are from Venus the neurobiological sex male and female brain

OUR AUTHOR an acclaimed neuroendocrinologist at Northwestern University— know and why we don’t know more.

Sex Differences in the Brain

Sex … structural sex actuallydifferences

REAL, but they are not what you might think. They’re not about who is better at math, reading a map, or playing chess. They’re not about being sensitive or good at multi-tasking, either. Sex differences in the brain are about medicine and about making sure that the benefits of biomedical research are relevant for everyone, both men and women.

DIFFERENCES IN THE BRAIN ARE

You may be surprised to learn that most animal research is done in males. This is based on an erroneous view that hormonal cycles complicate studies in female research animals, and an assumption that the sexes are essentially the same down at cellular and molecular levels. But these beliefs are starting to change in neuroscience. New research shows that some fundamental molecular pathways in the brain operate differently in males and females, and not just by a little. In some cases, molecular sex differences are all-ornothing.

Recognition that male and female brains differ at a molecular level has the potential to transform biomedical research. Drugs act on molecular pathways. If those pathways differ between the sexes, we need to know how they differ as early as possible in the long (and expensive) process of developing new medicines and treatments for disease.

The Brain’s Sex Differences: Not What You Think

The bulk of public attention to brain sex differences is focused on structural differences and their purported relationship to behavior or cognition. Yet structural sex differences are actually quite small, and their interpretation is often based on gender stereotypes with little to no scientific justification.

Reports of sex differences in the brain often make headlines. For example, a large 2014 study used a type of magnetic resonance imaging called diffusion tensor imaging to show what the authors called “conspicuous and significant” sex differences in brain connectivity; it generated 87 news articles and 162 discussions in blogs in the first month after its publication. Tellingly, most media attention focused on potential behavioral manifestations of the anatomical differences that were reported, even though the researchers did not look at behavior in the study. This may be because the university press release announcing the study suggested that its findings could help provide a neural basis for why men excel at certain tasks, “like cycling or navigating directions, whereas women… are better equipped for multi-tasking and creating solutions that work for a group.”

The urge to link structural sex differences to brain function

seems almost irresistible. This common pattern in reporting led to a suggestion in the New York Times that men devote 6.5 times more gray matter, areas where brain cells are concentrated, to intelligence-related tasks than women do (which is not true, in case that needs to be said). The now infamous 2017 “Google’s Ideological Echo Chamber” memo (whose author was subsequently fired) drew on studies of sex differences to make a case against efforts to achieve gender balance in the technology workforce. The neuroscience of sex differences has also been interpreted incorrectly to promote single-sex education based on purported brain differences between girls and boys that don’t exist.

The proponents of these and other stretches of the imagination have a counterpoint in a vocal group of neuroscientists and scholars who claim that there are no meaningful sex differences in the brain. The latter group’s arguments center on the role of experience in shaping brain structure and connectivity, and the idea that everyone’s brain is a mosaic of male-typical and female-typical characteristics. Indeed, a recent large-scale analysis of brain regional volumes found statistically significant sex differences throughout the brain, but also that these differences are small, with a great deal of overlap between men and women.

Scientists often measure the size of a difference with a statistic called “Cohen’s d.” In the study mentioned above, sex differences in brain regional volume had an average Cohen’s d value of 0.33, which means that men and women actually overlapped by 86.9 percent (ranging from 75.3 percent for the largest differences to 90.8 percent for the smallest ones). So even though there are many sex differences when you compare male averages to female averages, brains don’t fall neatly into two categories based on their physical structure. And even the differences in averages are pretty small.

For perspective, consider the familiar sex difference in height: On average, men are taller than women, but there are also some women who are taller than some men. Here, the comparison has a Cohen’s d value of 2.0, corresponding to only 31.7 percent overlap: The sex difference in height far exceeds any of the sex differences reported in human brain structure.

So, what do structural sex differences in the brain mean for function? The reality is that no one knows. Except in cases of brain disease or injury, or in very rare instances, there is no way to predict what a difference in the size of a certain brain region means for its function. While we can say that a particular part of the brain contributes to functions like memory, language, or even empathy, our understanding of how that brain region contributes to a specific function is still in its infancy. There is no basis to say, for example, whether bigger is better or worse for function. A brain region could vary

in size for any number of reasons, including the number or size of neurons, glial cells, blood vessels, or differences in the amount of extracellular space. The underlying sources of size disparities cannot be resolved from brain scans.

Finally, it is worth noting that for the relatively few brain functions for which there is evidence of a difference between sexes, the neural basis of the difference is unknown. For example, the largest and most reliable cognitive sex difference is in mental rotation of three-dimensional shapes. But this too shows a high degree of overlap between the sexes, 79.9 percent, with a Cohen’s d value of 0.51. Complicating the issue even further, spatial skills like mental rotation are known to improve with practice. This makes it possible that the types of activities boys and men are more likely to engage in, from sports to video games, give them more opportunity to practice spatial skills leading to better scores on spatial tasks.

So, if sex differences in brain structure are so small, so mixed, and so hard to connect to what the brain does, couldn’t we just dispense with the issue of sex when it comes to the brain? Some in the field have suggested that we should. The flaw in these arguments, however, is that structure may be the wrong thing to focus on when it comes to brain sex differences. New research shows robust sex differences at a much deeper level, where no one expected them: in molecular interactions that regulate neural activity.

Out With the Old, In With the New

The billions of neurons in the brain are wired into circuits through trillions of tiny junctions called synapses. At most synapses, neurons communicate when neurotransmitter molecules are released by one neuron and activate receptor molecules on another neuron. The type of neurotransmitter receptor determines whether a synaptic connection is excitatory, stimulating the next cell in line, or inhibitory, silencing a downstream neuron. The effectiveness of each synapse, or its strength, is variable and changes with differences in the amount of neurotransmitter released and/ or its sensitivity to neurotransmitter. This is analogous to adjusting the volume settings for a speaker or a microphone.

Changes in synapse strength are the basis of learning and memory and are involved in disease—in addiction, for example. The molecular machinery that controls synapse strength is finely tuned by a host of molecules, including enzymes, lipids, and small molecules that carry messages from one part of a cell to another. Scientists study these molecular interactions both to better understand the brain and because drugs often work by altering neurotransmission. Each molecule that affects how synapses work is a potential target for new drugs.

In 2012, we discovered a sex-specific molecular mechanism for tuning synapse strength, quite by accident, while studying the action of estrogens in the hippocampus, a part of the brain important in learning and memory, responses to stress, and neurological disorders such as epilepsy. Although estrogens are commonly thought of as reproductive hormones important mainly in females, they are also synthesized in the brain—of both sexes—where they exacerbate seizures and can improve memory

Using female rats, we found that estrogens weaken critical inhibitory synapses in the hippocampus. In the search for a key to this effect, our initial experiments pointed us toward molecules called endocannabinoids, which decrease neurotransmitter release. (Endocannabinoids get their name because they activate receptors also activated by tetrahydrocannabinol, the principal psychoactive component of cannabis.) However, as we probed the connection between brain estrogens and endocannabinoids, our findings didn’t replicate previous results from the scientific literature.

Although confusing at first, we quickly realized that those earlier studies had been done exclusively in males. When we compared males and females directly, we found that the estrogen regulation of inhibitory synapses that was so clear in females was absent in males. That meant that a drug based on the molecular effects of brain estrogens or endocannabinoids could have different effects in each sex.

differences are quiteandsmall,their interpretation is often based on gender stereotypes with little to no scientific justification.

Sure enough, when we tested an inhibitor of fatty acid amide hydrolase (FAAH, an enzyme that breaks down endocannabinoids), it suppressed inhibitory synapses in the hippocampus of females but had no effect on the same synapses in males. This indicated that females, but not males, produce FAAH-sensitive endocannabinoids continuously. As a result, applying the FAAH inhibitor caused endocannabinoids to build up in females, weakening inhibitory synapses in a way that didn’t occur in males.

Endocannabinoids influence diverse aspects of physiology and behavior, including learning and memory, motivational state, appetite, responses to stress, and pain. They are also involved in seizures. Because of these effects, enzymes

that regulate endocannabinoid levels are targets for drug development. Indeed, at the time our study was published, the same FAAH inhibitor that we used had already been tested in human clinical trials, presumably without knowledge that it could affect the brains of males and females differently.

Recognition that molecular mechanisms controlling synapse strength differ between males and females prompted my lab to start using both sexes in all our animal experiments and to compare the sexes in every case. We have found a mixture of sex-based similarities and differences. One important concept emerging from this research is the existence of latent sex differences, in which the same functional outcome in males and females arises through different underlying mechanisms in each sex. This means that sex differences can exist at a molecular level and not at the level of behavior or physiology: There are two routes to the same result. It also means that some sex differences won’t be apparent until the system is perturbed, for example, with a drug that targets one of the molecules that differs between the sexes.

Latent sex differences can also explain apparent inconsistencies in the scientific literature. For example, in contrast to their suppression of inhibitory synapses specifically in females, estrogens strengthen excitatory synapses in the hippocampus of both sexes. Initial studies aimed at understanding the molecular mechanism(s) of this excitatory effect were done in different sexes and came to different conclusions. The group that studied males found that estrogens strengthen excitatory synapses by increasing neurotransmitter sensitivity, whereas our group studied females and found that estrogens strengthen excitatory synapses by increasing neurotransmitter release. Both groups reported that estrogen receptor beta was the critical receptor involved in the different effects they observed.

To resolve the discrepancy, we compared males and females using a technique that can distinguish changes in neurotransmitter release from neurotransmitter sensitivity. This showed that both groups were right: Activating estrogen receptor beta strengthens excitatory synapses in both sexes but through different mechanisms in each sex. The apparent conflict was due to a sex difference. As with FAAH inhibitors, this is especially significant in the context of drug development. Estrogen receptor beta activators are another class of drugs tested in human clinical trials. If results of the animal studies translate to humans, these drugs could have different effects in men and women.

Some latent sex differences have been hiding in plain sight. One is the lasting increase in synaptic strength caused by brief patterns of neural activity called long-term potentiation, or LTP. Discovered in 1973, LTP is thought to underlie the formation of new memories. We found that, although there is no difference

New research shows robust sex differences at a much deeper level, where no one expected them: in molecular interactions that regulateactivity.neural

It may be that the best way to persuade scientists to get serious about sex differences is for non-scientists to demand that they do.

between males and females when LTP is tested under control conditions, LTP in females requires a well-studied enzyme, protein kinase A, whereas in males it does not. This was very surprising because, while LTP has been the subject of intense research with over 10,000 scientific papers published over the last 40-plus years, no one was aware of this profound sex difference in its molecular underpinnings. Apparently, no one had looked.

Molecular sex differences are now found in many areas of interest in neuroscience, including in mechanisms of pain and effects of stress, how an autism-linked gene regulates neurophysiology, and how an intellectual disability-linked gene affects the biochemistry of synapses. Even with this increased awareness, though, what we know now is likely just the tip of the iceberg. The only way to find out which brain mechanisms are similar and different between the sexes is for more scientists to explicitly compare males and females in their studies. While there has been some progress toward this, the majority of animal research still ignores the issue of sex.

Thinking Differently about Sex Differences

One of the most widely cited reasons for studying the brains of both sexes is that the incidence of many neurological and neuropsychiatric disorders varies by sex. For example, autism spectrum disorders are more common in boys than girls, whereas women are more likely to develop major depressive disorder, post-traumatic stress disorder, and anxiety disorders. Schizophrenia tends to develop at an earlier age in men than women, and its symptoms can differ between the sexes. But such differences in prevalence and presentation haven’t persuaded the majority of neuroscientists who investigate molecular mechanisms in the brain to get serious about how sex might affect the outcomes of their studies.

In 2009, more than five times as many neuroscience studies in animals were done using males only as were done using females only. We found a similar imbalance when we analyzed brain studies, specifically in rats and mice, published in five top journals from mid-2011 to mid-2012: 32 percent studied exclusively males, 7 percent exclusively females, and only 4 percent studied both sexes, noting whether there were any differences between them. The rest either used both sexes without saying whether or not there were any differences (29 percent) or failed to mention the sex of the animals studied (28 percent).

This bias toward males prompted the National Institutes of Health, the largest funder of biomedical research in the US, to issue a new policy in 2016 requiring that grant applicants explain how they would consider sex as a biological variable in animal research. At about the same time, many scientific

journals also started requiring researchers to state the sex of animals used in studies they publish. But neither policy requires comparison of the sexes, and researchers often fail to note how many males or females were involved in published studies. By 2017, more scientific papers reported using both sexes, but studies comparing males and females increased only slightly, from four to eight percent.

Why Has the Field Been Slow to Catch On?

One reason neuroscience has been slow to understand the need to compare male versus female research results might be that sex differences in the incidence of human disease, like differences in brain structure, are apparent when considering averages across large populations. This gives the impression that differences between males and females are simply quantitative variations on a common theme: Each sex has or does something, but one sex has or does more of that thing than the other sex. If that were true of all sex differences, then comparison of males and females at a molecular level might not matter much because results from one sex would apply, perhaps with minor differences, equally well to the other. But sex-specific molecular mechanisms and latent sex differences change that calculation.

The existence of latent sex differences makes it clear that molecular mechanisms targeted for drug development can be sex-specific, even in the absence of differences in behavior or disease. It follows that drugs derived from molecular studies in only one sex could be ineffective or have unanticipated consequences in the other.

The next time you hear about a sex difference in the brain, consider whether claims about its implications for brain function have really been tested. And the next time you hear about a new brain study in animals, find out whether the results apply to both sexes. It may be that the best way to persuade scientists to get serious about sex differences is for non-scientists—who, after all, pay the bills for federally funded research—to demand that they do. l

THE PROMISE OF IMAGING FOR

Knowledge gleaned from big data and advances in neuroimaging have provided new insights into the workings of the brain. OUR AUTHOR, founding director of the Center for Translational Research in Neuroimaging and Data Science and a Georgia Research Alliance eminent scholar in brain health and image analysis, traces the evolution of these two evolving fields and how it may have an impact on mental health in the not-too-distant future.

BY VINCE C ALHOUN, Ph

MENTAL HEALTH

H E GREBZTR

LEINADYB

ENTAL AND NEURODEGENERATIVE DISORDERS ARE AMONG

the most costly and common causes of disability in society today. Because the brain is the most complex organ in the human body, diagnosing and treating problems when things go wrong poses enormous challenges. Even before the 1990s was designated the Decade of the Brain, the potential of neuroimaging—the technology that makes it possible to see inside the working brain—was a major focus in psychiatry. Since that time, expectations have been high that neuroimaging would move the needle forward in unraveling the mystery of mental illness.

Living in a time of such national programs as the BRAIN Initiative and Human Connectome Project, we’ve become accustomed to hearing terms such as artificial intelligence, virtual reality, and brain-machine interface. In light of the exponential increase in computational and algorithmic power, one can only assume that we have made great progress via psychiatric neuroimaging. But just how far have we actually come in the last half-century? How close are we to having neuroimaging-based tools that can be used in the clinic? Have we learned anything about diagnosis or mental illness from the vast trove of neuroimaging data that has been collected over the years? I wish I could point to specific examples where the widening use of neuroimaging is beginning to help the mentally ill, but we are just not there yet.

As an undergraduate electrical engineering student at the University of Kansas in 1991, I became enthralled with magnetic resonance imaging (MRI), which makes it possible to see inside the body, noninvasively and safely, using magnetic fields and radio waves. This was the beginning of a career in brain imaging that led me to spend 12 years in a psychiatry department at Johns Hopkins where, I like to joke, I was an engineer “studying the psychiatrists.” In reality, it was a fascinating experience, as I learned the complexity of the problems under study, saw the potential for applying engineering and signal processing principles, and gravitated to the emerging specialty of psychiatric neuroimaging.

It didn’t take me long to realize that the study of psychiatric disorders is extremely difficult, in part, since the assessment of the individual is mainly based on their medical history and symptoms they are experiencing at that moment. And while these assessments can be reliable up to a point, they largely lack biological validity. If someone is feeling depressed, for example, they may be diagnosed with depression. If, however, a few months later they are experiencing hallucinations or

their thoughts are confused, the diagnosis is likely to be schizophrenia or bipolar disorder. There are no objective tests to confirm or rule out any of these disorders. Nor are there cures, although existing treatments may mitigate symptoms. But even determining appropriate treatment can be a formidable challenge, often requiring sequential effort to determine, and the wrong treatment can muddle diagnosis and, in some cases, the wrong medication can make a condition worse.

The Promise of Magnetic Imaging

MRI has been used to visualize the size (i.e., volume) of various brain structures for over 40 years now. And for almost 30 years we have been able to see fluctuations in brain activity using a technique called functional MRI (fMRI), which tracks magnetic signals that reflect changes in blood flow and oxygenation level associated with neuronal activity. The discovery of fMRI raised hopes for a clinical breakthrough in assessment and treatment. Beyond the challenges that lay before them, the psychiatric research community saw the potential that neuroimaging held for helping patients whose lives were disrupted by a malfunctioning brain.

We believed we were on the verge of better understanding how the brain worked, and developing tools and treatments to address what are now understood to be brain disorders, including depression, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Using neuroimaging to identify disrupted brain regions could provide information useful to develop and evaluate new treatments, enable prediction of individual response to such treatments, and help subtype individuals (e.g., schizophrenia and schizoaffective disorder). The obstacles, however, turned out to be more formidable, and progress slower than we would have liked. Our challenges and successes might be best understood through the evolution of five different eras.

Depth 1 Depth 2

FIGURE 1: The above figure shows the potential benefits of more powerful analysis of neuroimaging data. Each dot represents an individual’s brain data, and the dots are color-coded by their diagnosis. The model flexibility increases with increasing depth, and it is clear that this model is better able to separate the disorders with the greatest depth (depth 3, largest panel). Two conclusions we can draw from this are: 1) more complex models separate diagnoses better and highlight the information contained in neuroimaging data, 2) the relationship between diagnoses is complex and there is still a lot of overlap between them. The latter is likely due to imprecision in the diagnostic categories as well as individual differences.

FIGURE 2: The above figure shows us how different brain networks are functioning together. The lines measure the strength of communication among various networks and represent a unique “fingerprint” of our brains. By using such displays, we can evaluate what is called the human functional connectome—and also how mental illness is disrupted.

The “Small N” Era

In the early days of neuroimaging studies, we used a small number of subjects (called “small Ns”). In this era, even though structural and functional MRI studies were initially quite small (e.g., using a "small N" of only 5 to 20 subjects), each promised a potentially revolutionary finding. Initial functional studies had individuals perform a number of carefully designed tasks and tracked how the brain responded to these tasks. But while many studies highlighted specific deficits associated with various mental disorders, differences tended to be relatively small and most studies lacked sufficient controls for the many possible confounds, such as medication or patient movement within the scanner.

Studies that followed often yielded promising findings that pointed toward various brain regions that appeared to be important contributors to brain disorders or symptoms. Many of these findings turned out to be hard to replicate. In some cases, the tasks were difficult for those impacted by mental illness to perform, which made it hard to know if the observed changes were due to the disorder itself or were different simply because the tasks were not being performed. So, the small N problem became a large problem, compounded by the heterogeneity of mental disorders.

To better understand what researchers faced, consider the development of a vaccine for Covid-19, where 30,000 individuals are required for a study. Testing the efficacy and safety of a vaccine is a much simpler problem than treating depression, for example, since the outcome measures are clear (someone gets ill or not). With psychiatric disorders, by contrast, we are simultaneously trying to clarify the diagnosis and understand how the brain is impacted—which regions and what mechanisms are involved.

Despite the challenges, we learned much about how to model neuroimaging data during the small N era, including how to efficiently administer tasks, control for statistical complexities, and compare data. The “dead salmon” paper, which was presented at the Human Brain Mapping conference in 2009, light-heartedly highlighted the already well-known statistical corrections that are needed when studying brain images. The presenters were making an important scientific point regarding the “multiple comparisons problem.” If one does a lot of different statistical tests, some of them will, just by chance, give interesting results. With this, we gained important information about how mental illness impacts the brain. But this was not enough.

The “Large Group” Era

In the next phase of neuroimaging (referred to as the “large group” era), researchers focused on increasing group sizes (typically to hundreds of individuals or more) to increase

confidence that detected effects were not just due to noise and to better characterize the heterogeneity of psychiatric disorders. During this era, we learned with greater confidence which brain regions were activated by tasks, as well as the degree to which regional responses differed in those with mental illness (e.g., auditory oddball or working memory task deficits in schizophrenia).

Likewise, we learned more about how brain structure was impacted by disease (e.g., individuals with schizophrenia consistently show reduced temporal lobe and medial frontal gray matter). Approaches based on meta-analysis offered tools to pool results from many small studies, in order to provide more reliable statistical summaries. During this era, the focus was still very much on isolating specific brain regions, rather than considering the brain as a highly interconnected system.

The “Network” Era

A major shift occurred when our attention turned to brain networks, both at rest and during task performance (referred to as the “network” era). The mathematical tools used to study networks can also be applied to study networks between brain regions. The same approaches Google and Facebook use to leverage the concept of networks to improve search engines and social interactions began to be applied to the brain, which can be thought of as a network of networks. The idea was to identify specific networks of brain regions that are linked to, or correlated with, one another. Among other advantages, this approach enabled us to study the brain even when individuals were resting, rather than performing specified tasks.

By mitigating the formidable challenge of ensuring that everyone was performing the same task the same way, the approach allowed researchers to scale up to much larger numbers, combining data across many imaging centers. In

Using neuroimaging to identify disrupted brain regions could provide information useful to develop and evaluate new treatments, enable prediction of individual response to such treatments, and help subtype individuals (e.g., schizophrenia and schizoaffective disorder).

The same approaches Google and Facebook use to

predict response to antidepressants versus mood stabilizers in adolescents with mood disorders).

addition, fancy new analytical tools that can assess brain activity coming from many regions at once (e.g., multivariate methods and techniques based on graph theory), similar to those used by many software engineering companies, were introduced and are now being used with increasing regularity. But although these approaches have taught us much about how psychiatric disorders impact brain connectivity, they have not yet led to clinical tools. For that we need more precise and individualized information.

The “Prediction” Era

The vast majority of brain imaging researchers focus on describing central tendencies and group results, rather than findings with individual subjects, and the case studies that are reported typically concentrate on explaining the data at hand rather than predicting unseen data from an individual (i.e., Can I use brain imaging to predict a future diagnosis, or to determine if that individual will respond well to a certain medication?). While this may seem like a small distinction, it is quite critical, as the results for these two approaches (studying averages versus studying individuals) often differ. A focus on individual level prediction and forecasting of future trajectories relevant to an individual person is arguably the most important goal if brain imaging is to translate into practical solutions to improve the quality of life and enhance technological development.

Prediction studies typically utilize advanced computational approaches and algorithms that can learn from data (i.e., machine learning). The field has experienced a large growth in studies using machine-learning approaches to make individualized predictions (i.e., informed guesses) of symptoms, cognitive scores, medication response information, and more. Studies of brain function and structure that focus on these estimates have revealed whole brain patterns that show potential to be able to predict and identify mental disorders and to predict treatment response (e.g., using resting fMRI to

Beyond these patterns, they also appear to be predictive of risk for psychiatric disorders. However, we are still only scratching the surface in the prediction era, as these approaches tend to require large amounts of data, and algorithms are still not able to learn well without a good “ground truth” (i.e., If we already know the answer it is not hard to train a computer to recognize it, but with mental illness we are still unsure about even the diagnostic categories). Existing techniques with the data we have are still unable to tell us clearly whether the psychiatric diagnoses accurately reflect the underlying disorder. Thankfully, algorithms are getting smarter, and more data are arriving all the time.

The Era of Big Data

We are now firmly in the era of big data for neuroimaging and psychiatry. The number of large, shared data sets has dramatically increased over the past few years. Several studies, e.g., Aging Brain Cognition and Development and UK Biobank, are scanning tens of thousands of individuals over time (although these are mostly individuals without psychiatric problems, but the assessed measures can be used to study psychiatric issues as a spectrum).

There is interest in considering mental illness as manifested by otherwise everyday human traits that lie outside typical ranges of behavior and process. For example, someone may be anxious about an upcoming deadline, but when anxiety becomes constant and independent of circumstances, it impacts our quality of life and might be considered a psychiatric disorder.

To study mental illness requires vast amounts of data and flexible models that can handle all its complexity. A promising class of powerful models (deep learning models), like those that were used to beat international experts in the game of Go, or that Alexa uses to recognize your commands, have been shown to be very powerful. But they also require a lot of data. The application of deep learning (deep artificial neural networks) to neuroimaging has shown great promise and will likely be a major force in advancing our knowledge and understanding of the data. These approaches require considerable computational resources as the complexity of models and the amount of data continue to grow.

Challenges, Testing, and Discovery

Given that the criteria used to decide who has a mental disorder are largely based on self-reported symptoms and not biologically based, we have a wicked chicken-and-egg problem. Do predictions of mental disorder based on nonbiological characterizations provide useful and actionable

leverage the concept of networks to improve search engines and social interactions began to be applied to the brain, which can be thought of as a network of networks.

information?” The fact is that the brain is incredibly complex; psychiatric illness is complex and multifaceted, including an overlap among existing diagnosis and prediction models that are relatively simple. This creates a perfect storm of difficulty for computational approaches and can lead to a “garbage in—garbage out” problem: We are trying to predict something that is not well defined in the first place. At the same time, the dual challenge of unclear diagnostic categories and the desire to make predictions presents an opportunity.

The use of deep neural network models offers the flexibility to capture relationships that are not yet well understood, including dynamic changes and multimodal contributions. The accelerating pace of algorithmic innovation can only expand this potential, providing tools for 1) predicting existing diagnostic categories, 2) identifying new categories, and 3) combining the two, all based on biological data. The use of hypothesis-based and data-discovery approaches should work together in a “virtuous cycle” in which we learn from new data, update our models accordingly, and learn more by applying these models for finer-tuned analysis.

In many ways, this evolution parallels the development of big data genomics models that have highlighted the polygenic nature of psychiatric disorders by scaling up to deal with extremely large studies. Early larger scale imaging studies also suggest a “polyregional” brain disruption, impacting brain connectivity at a systemic or network level. However, the neuroimaging field has some additional challenges to confront, while also presenting some unique advantages.

Neuroimaging studies require brain scans. Extremely large genomics studies are more easily extended to hundreds of thousands of data sets since these only require saliva or in some cases a blood draw. In contrast, neuroimaging provides greater potential for characterization of mental disorders due to its ability to capture changes over time, as well as a valuable tool for studies focused on intervention or brain stimulation. In addition, neuroimaging changes related to mental disorders tend to be larger and more detectable than those based on genomic studies of these highly polygenic disorders. While it remains to be seen what place neuroimaging and genomics will ultimately occupy in clinical decision-making, it does seem clear that they will be part of the landscape.

Where to Now?

While we have learned a lot, we still have a long way to go before we can fully leverage neuroimaging data to understand psychiatric disorders and help people address their mental health difficulties. In the near-term, predicting medication response is a promising goal, as this bypasses diagnostic

criteria in identifying the best treatment for an individual. For example, one might use fMRI to predict the response to antidepressants versus mood stabilizers or to determine which antidepressant is likely to have the best effect. While this is only a small step, it does have promise as a support to decision-making in the clinic.

Another key question will be how to benefit from large amounts of data while protecting privacy. New data management infrastructure (i.e., neuroinformatics) to support the use of neuroimaging will need to incorporate the ability to safeguard sensitive information. Decentralized or federated approaches may provide a way forward here, combining intermittent neuroimaging with the regular capture of information from a mobile device in a way that preserves privacy and which, for example, has considerable potential to treat disorders such as depression or cognitive decline by detecting mental health patterns. A recent example of this is reflected in some of the Covid-19 tracing apps which are designed with privacy in mind.

While we have not advanced as quickly as we might have hoped in explicating the mysteries of mental illness, there is considerable reason to be optimistic about the not-so-distant future. The brain is an amazing organ, but its complexity, individuality, and role in shaping who we are is also the reason the problems are so challenging. As the author and scholar C.S. Lewis once said: “There are no ordinary people.” Despite such challenges, I remain firmly hopeful and believe we are moving towards the needed solutions. l

While we have learned a lot, we still have a long way to go before we can fully leverage neuroimaging data to understand psychiatric disorders and help people address their mental health difficulties.

Weıghıng the healıng power

BY KAYT SUKEL • ILLUSTRATION BY ZOË VAN DJIK

PSYCHEDELIC DRUGS CONJURE IMAGES OF TIE-DYED TEE SHIRTS, WOODSTOCK, AND VIETNAM WAR protests. While early research into the properties of drugs like psilocybin (magic mushrooms) and lysergic acid diethylamide (LSD) during the middle of the 20th century suggested therapeutic potential for diverse mental health conditions, their role in the 1960s anti-war and counterculture movement made them suspect by law enforcement. Not long after American psychologist Timothy Leary called for people to “turn on, tune in, and drop out,” endorsing the regular use of psychedelic drugs for health and well-being, the federal Controlled Substances Act classified them as highly dangerous Schedule 1 compounds, or drugs with “no currently accepted medical use and a high potential for abuse.”

“Initially, psychedelics showed quite a lot of promise for treating a wide range of mental health conditions—in particular, addiction and post-traumatic stress disorder (PTSD),” says Anil Seth , co-director of the Sackler Centre for Consciousness Science at the University of Sussex in the United Kingdom. “There’s long been a blame game going regarding what led to these drugs being outlawed, mostly focusing on people like Timothy Leary promoting indiscriminate use of what we know are quite powerful drugs. But the end result was that, despite their promise, it became nearly impossible for anyone to do any research at all on them.”

Over the past decade, however, there has been a revival of psychopharmacology and neuroscience research into the effects of psychedelic drugs. In fact, despite continuing legal barriers and funding challenges involved with using these banned drugs in research studies—many researchers wait years for Food and Drug Administration approvals and require funding from non-governmental agencies to move forward—several unique research centers, including the Centre for Psychedelic Research at Imperial College London and Johns Hopkins University’s Center for Psychedelics and Consciousness Research, are now actively studying LSD, psilocybin, and dimethyltryptamine (DMT), from both basic science and clinical perspectives.

“People often come out of a psychedelic experience and say it was one of those most remarkable things they’ve ever experienced—that the experience led to creative insights and improvements in self-identity and mood,” says

Matthew Johnson , a researcher at the Center for Psychedelics and Consciousness Research

“When people consistently say things like that, you start to ask yourself what the heck is going on—you want to understand why.”

Certainly, psychedelic drugs have distinctive psychoactive effects, including visual and other sensory distortions, hallucinations, changes in mood, and alterations in other cognitive processes like working memory and executive function. What’s more, psychedelic “trips” are remarkably subjective experiences. No two people report the same experience on these drugs—nor do single individuals say they have had the same experience during two different exposures. These remarkable experiences, said David Nutt , director of neuropsychopharmacology at Imperial College London, have led scientists to ask fundamental questions about how they work.

“This resurgence really all started with some of us asking a quite simple question; now that neuroscience had advanced to a point where we could take a closer look at the brain,” says Nutt. “What is the nature of the psychedelic state? What are these drugs doing to the brain?”

Disorganized Networks

Robin Carhart-Harris , head of the Centre for Psychedelic Research at Imperial College London, observes that much has been written about the psychedelic experience, especially

since many of these substances, like the naturally occurring peyote and mescaline, have been used in spiritual practices for centuries. But, like Nutt, he believes the biggest mystery remains what psychedelic drugs do in the brain that lead to such powerful perceptual and cognitive effects. Animal work suggests these drugs stimulate serotonin 2A receptors (5-HT2As), resulting in the growth of dendritic branches and an increase in synaptic connections. Neuroimaging work across several laboratories suggests that their use also has a profound “disorganizing” effect on brain networks, including the default mode network, sometimes referred to as the brain’s resting state network.

“There’s something about the 5-HT2A that helps to structure brain activity—and psilocybin disrupts normal patterns of activity in brain networks,” says Nutt. “When we saw it, it all made perfect sense. We could explain hallucinations by a disruption in the coordination of the visual system. We could explain the out-of-body experiences by the disruption of the default mode network. By looking at how these networks were altered, we really could explain almost all of things people report experiencing through these insights into brain function.”

Carhart-Harris says such studies can also offer greater insights into how the brain is organized normally. As these large-scale networks “temporarily disintegrate” in response to the drugs, scientists can learn more about how the brain facilitates normal cognition, including consciousness. Christof Koch , chief scientist of the MindScope Program at the Allen Institute for Brain Sciences, and a leading expert in consciousness, agrees. He hopes to use psychedelics in living brain tissue samples to see changes in the cells.

“New explorations of higher states of consciousness are usually only accessible if your participant has engaged in 20 years of meditation or prayer—and very few people get there,” says Koch. “But psychedelics offer the opportunity to study these changes in the cells reliably at the molecular level. It may help us understand what is required from a neurobiological standpoint to achieve different states of consciousness.”

For his part, Seth hopes to use psychedelics to better understand perception. Sensory distortions are a hallmark response to these drugs, and the extraordinary vividness of such distortions may provide new insights into how the perceptual system works. His work with Carhart-Harris has shown that the disorganization of networks caused by psychedelics has a high degree of randomness—and that information flow decreases between brain regions that normally communicate with one another.

“The take-home, basically, from these studies is that there is a large change in the global properties of brain dynamics which reflect increased disorganization and a lack of structure,” Seth explains. “The brain areas are becoming more random in their activity and speaking to each other less. The more we

can understand about this, the more insights we could gain into what has gone wrong in psychosis or other psychiatric conditions that result in hallucinations or other perceptual defects.”

The study of psychedelics may offer a window into other fascinating phenomena as well. For example, the Johns Hopkins group recently published a study looking at feelings of interacting while using DMT with a compelling presence of another form of consciousness, such as a spiritual entity like God, an angel, a ghost, or even an alien.

“These experiences are rated as extremely significant by those who have them and result in enduring positive effects regarding their attitudes about life and self, mood, and social relationships,” says Ethan Hurwitz , a doctoral student at the University of California San Diego and a member of the Johns Hopkins Center for Psychedelics and Consciousness Research who worked on this study. “The fact that DMT can reliably elicit these kinds of autonomous entity experiences that yield these kinds of positive effects means they could show promise as a potential adjunct to traditional therapies for mood and behavior problems.”

Promise as a Therapeutic

Some of the earliest work on psychedelics, in fact, hinted at their promise for treating depression. Certainly, people often report increased well-being and improved mood after a recreational psychedelic experience—but unlike other euphoriacausing drugs, those feelings can last for days or even weeks after “a trip.” Charles Raison , a psychiatrist at the University of Wisconsin Madison, says, given the personal and societal costs of treatment-resistant depression, it is important to look at psychedelics’ potential as a therapeutic.

“Typical antidepressants don’t work for everyone,” he says. “And psychedelics have these powerful mental health benefits which probably work by very different mechanisms than drugs like selective serotonin reuptake inhibitors (SSRIs).”

Certainly, the basic science work suggests that is the case. Nutt and colleagues demonstrated that psilocybin reduced activity in the subgenual cingulate cortex, a region of the brain implicated in depression.

“This region is one of the driving nodes of depression,” Nutt explains. “And other work has shown that a necessary feature of antidepressant therapies is the ability to switch down activity in this area. When you couple that with the profound changes in the default mode—and there is evidence that overconnectivity in this network leads to depressive ruminations—you see why these drugs may have therapeutic effects.”

Several studies have now shown just that. Recently, the Johns Hopkins group published the first randomized controlled trial of psilocybin-assisted therapy—the drug is administered in

“People often come out of a psychedelic experience and say ever experienced—that the experience led to creative

conjunction with talk therapy—in patients with major depressive disorder. Frederick Barrett , a researcher at the Center for Psychedelics and Consciousness Research, says the study showed an “impressive” positive effect in patients, with more than 70 percent showing a significant response within one month.

“The psychedelic experience is very different than what people experience in waking consciousness,” he explains. “But when people have these experiences, especially when it’s supported by psychotherapy, they may see what is behind their depression and confront those things so they can move forward.”

Johnson, who also worked on the trial, says he sees psilocybin-assisted therapy as a way to “bring psychology back into psychiatry.”

“Everyone is depressed for different reasons,” Johnson says. “And the psychedelic experience can help you get to the heart of your own issues, which when you are guided by a mental health professional, seems to have really strong therapeutic effects.”

Despite such promise, many scientists urge caution. Jeffrey Lieberman , chairman of psychiatry at Columbia University, says that he has concerns that there has not been enough research looking at psychedelics’ safety. There are risks of psychosis in some patients, as well as cardiovascular issues.

“I don’t want to throw cold water on this reemergence because we could certainly use more treatments in depression,” he says. “But there are questions we need to answer: What is their comparative pharmacology (how these drugs compare to other psychedelics or antidepressant medications)? What is their duration of action? What happens when you do multiple dosing? What are the long-term effects to the brain? We don’t know yet.”

Raison wholeheartedly agrees. With two to three percent of individuals in survey studies reporting worse outcomes after taking psychedelics, the answers to these questions matter, and matter greatly.

“The research suggests that there will be a group of people who will not benefit from these agents,” he says. “It’s important we know who they are—who will benefit most and who may actually be harmed from their use—before we start giving it to people who are struggling with their mental health.”

As researchers start to consider the potential of psychedelic treatment beyond depression (some suggest it will have beneficial effects for a host of conditions ranging from drug addiction to PTSD to Alzheimer’s disease), these safety issues will become even more important. And, to add to the mix, Joseph Barnby, a psychopharmacologist at King’s College London, also said he has concerns about the lack of active placebo in both current and future clinical trials.

“In drug trials, you want to be blinded so neither you nor

the study participant knows whether they received the drug, so you are not subject to expectancy effects,” he says. “With psychedelics, you have such a profound shift in the way you experience sensory information, it’s hard to blind people to whether someone has received the drug or not. The effects we see could just be placebo—and, as different trials continue to move forward, that’s something we need to carefully consider.”

Microdosing and the Future

Psychedelics also have strong reputation as a performance enhancer. Many popular musicians, artists, and tech wunderkinds have stated that microdosing—using small doses to avoid large-scale effects—can promote well-being, creativity, and productivity. Certainly, several survey studies have shown that people who microdose report these kinds of positive effects. But while there may be potential there, Carhart-Harris says that full-scale clinical trials are necessary to see whether results hold up.

“There is now a cultural phenomenon around microdosing, particularly in Silicon Valley, but the jury is still out on the evidence,” he says. “There’s been a lot of enthusiastic anecdotal reporting, but the evidence is lacking. Most of what we are seeing in our own lab suggests the effect is driven by positive expectations—it’s a placebo effect. But we need more thorough studies to know.”

That work, as well as the work regarding safety, will hopefully come sooner rather than later. With some states considering legalizing or decriminalizing certain psychedelic substances— Oregon recently became the first state to legalize psilocybin— it’s expected that, as with marijuana, recreational use will likely grow. Barrett says while he is enthusiastic about the clinical potential of these drugs, it’s important for people to know they are not a mental health or performance panacea—and there are significant risks to their use. That’s one of the reasons why he is such a proponent of psychedelic-assisted therapy, as opposed to patients taking these sorts of mind-altering drugs on their own.

“I don’t think anyone should be going to jail for using these drugs. But that doesn’t mean they don’t have powerful effects— and that people won’t get into trouble using them in unsafe conditions,” he says. “I believe the medicalization of these compounds will truly lead to a lot of people being healed if the larger studies replicate and confirm the clinical findings we have now. But people should proceed with caution.”

Seth concurs: “Psychedelics aren’t a magic bullet—and with the boosterism surrounding these drugs at the moment, especially in Silicon Valley, I worry that people might go too far. But, that said, if psychedelics are treated with respect, there is a lot of potential for both basic science and clinical practice. So, there’s a moral, ethical, and scientific obligation to explore these opportunities as far as we can. Let’s follow the evidence and see where it takes us.” l

say it was one of those most remarkable things they’ve creative insights and improvements in self-identity and mood.”

YOUR BRAIN ON

By Brenda Patoine

Illustration by Vanessa Branchi

THE CONSTANT STREAM of “news” and promos touting the next best diet to follow or food to consume to achieve better brain health can make it hard to sort out science-based hope from over-marketed hype. What if all this focus is missing the real culprit of cognitive health: the high-fat, sugar-heavy, overprocessed Western diet?

The question takes on new urgency in the context of a global pandemic in which many people are existing in a state of persistent, heightened pandemic stress. Stress interacts with diet in myriad ways to influence brain function. For starters, it may increase the metabolic demands of the brain, which already commands about 20 percent of the body’s energy in normal adulthood (and up to two-thirds in early childhood). The kind of “uncertainty stress” induced by pandemic unknowns may be particularly taxing, keeping the brain in a constant state of high alert. Growing evidence suggests the right diet may mitigate some of the ill effects of stress, while the wrong one may worsen the effects, especially during sensitive periods of brain development and aging when dietary factors take on heightened import.

Pandemic or not, one thing is abundantly clear: What we eat matters to our brains. Just like physical health, mental and emotional health is intimately tied to the quality of our diet. What that means to you and me, in terms of how, or if, we ought to change our diet to optimize and sustain brain health, is the focus of research around the globe.

No Quick Fixes

“People are after a quick fix,” says Sarah Spencer , who studies how high-fat diets affect the brain as head of neuroendocrinology at RMIT University in Australia. “They want to know, ‘Can I take this pill or eat this bean to fix my brain?’ But it’s a lot more complicated than that. There are no quick fixes.”

Neuroscientist Claire Williams , the head of University of Reading's UK research team that recently published on the acute cognitive benefits of blueberries, concurs: “I don’t think there’s a ‘magic bullet’ that we can take every day of our lives that’s going to ward off declines in cognition from aging.”

Given those caveats, what can we say with confidence about how diet affects brain health, beneficially or detrimentally?

The Anti-Brain Diet

First, the bad news. The typical Western diet is not brainfriendly. Saturated fat and sugar are the big culprits, and they go hand-in-hand with processed foods. The high-fat, highsugar “obesogenic” diet has become a staple of brain studies looking at the detrimental effects of food on cognition and mood in experimental models. These studies find reliable and consistent cognitive impairment after even short periods (for rodents) on such diets.

metabolism—all of these systems

This is clearly established in many reports, says Guillaume Ferreira, a neurobiologist with France’s National Research Institute for Agriculture, Food, and Environment (INRAE) at the University of Bordeaux. “Even after short-term exposure—as little as one week in animals—an obesogenic diet impacts the memory,” he says, citing recent findings from his own laboratory and others. This is the case even in the absence of disease, differential weight gain, or metabolic differences, suggesting that it’s not obesity per se that is detrimental to the brain, but the obesogenic diet.

Sensitive Periods

Ferreira’s team was the first to show that adolescence is a period of vulnerability to diet-induced changes, with findings now replicated widely. “You can see in the literature that high-fat in general is detrimental for brain plasticity and for cognitive processes,” he says. “What we found is that it is even more deleterious during adolescence.”

For Spencer at RMIT, “it does seem that a high-fat, highsugar diet leads to cognitive dysfunction, and that there are periods of vulnerability throughout life.” During the prenatal and perinatal stages, dietary influences can lead to lasting changes in metabolic function, cognition, mood, and even reward processing. In animal models, exposure to a high-fat, high-sugar diet during the first few weeks of life (equivalent to early postnatal in humans) can lead to lasting damage, yet adults on the same diet can endure much longer exposures.

Recent evidence suggests the same thing happens in humans, Spencer says. For example, women who had diets high in junk food during late pregnancy were more likely to have children who subsequently went on to develop obesity. The same is true of children born to mothers who have diabetes during pregnancy.

Better Brains Through Blueberries?

Aging is another period of apparently heightened vulnerability to dietary influences. Barbara Shukitt-Hale, a United States Department of Agriculture research psychologist based at Tufts University, has spent 26 years studying how plant-derived nutrients from berries and other foods benefit the aged brain. In multiple studies, her laboratory has found that feeding older rats a diet supplemented with two percent blueberry extract—equivalent to roughly a half-cup of blueberries daily for a human—reliably and reproducibly improves performance on a battery of

cognitive and motor tests. “You can prevent and even sort of reverse some of the impact of aging,” she says, if the diet is supplemented at the right time and for the right length of time (two months for the rats, or one-twelfth of their lives).

The rats are fed the supplemental blueberries at a critical period where they’re beginning to show age-related cognitive deficits, which normally progress over time. “Blueberries prevented good performers from getting worse but also helped bad performers get better,” Shukitt-Hale says. Her team has also conducted two clinical trials in humans showing similar improvements in cognitive benefits after adding blueberries to the diet.

These results are in line with a burgeoning field of research into so-called phytochemicals, including polyphenols, a large group of plant-derived compounds found in berries, nuts, dark chocolate, and other foods being investigated for brain benefits. “I think that we have some good evidence that eating foods that are high in these phytochemicals can have a positive impact on the brain and cognition,” says Shukitt-Hale.

Polyphenol-rich foods may exert a number of mechanisms at the cellular level to alter the neuronal environment in a beneficial way. Though often referred to as antioxidants, polyphenols’ actions in the brain seems to go far beyond that. “They are antioxidants, but I don’t think they’re just antioxidants. I don’t even think that’s their primary mechanism,” says Shukitt-Hale. “We think the story is much deeper than that.”

Recent evidence suggests polyphenols are involved in cellular signaling pathways that mediate inflammatory processes in the brain. Neuroinflammation is considered a primary culprit in a range of neurodegenerative disorders like Parkinson’s and Alzheimer’s disease, as well as other neurological and psychiatric disorders. Increasing evidence points to inflammatory changes as a primary mechanism by which obesity can lead to cognitive impairment or dementia, which could help explain the observed co-occurrence of dementia with diabetes, a metabolic disorder associated with obesity.

Cognitive Enhancer?

A key finding that has emerged from her own studies and others, Shukitt-Hale says, is that “these foods seem to especially impact learning and memory when the brain is taxed, in the really difficult tasks. If you’re a normal person with no deficits, it seems like these things are helping you when the cognitive load is greatest.” Moreover, she says it seems to help across the lifespan, as evidenced by recent research showing benefits in children, college students, and middle-aged adults.

Williams’ work, for example, is among the first to show short-term acute cognitive benefits of eating blueberries at different ages in humans. “We see small but meaningful cognitive benefits of polyphenol-rich foods in the period of two to six hours post consumption,” Williams says. Her time points are consistent with the peak blood levels of polyphenols. “Importantly, these effects seem to be amplified when performing tasks that are more cognitively demanding, or when participants are more cognitively fatigued.”

Williams stops well short of calling her findings evidence of a quick-fix cognitive enhancer for that upcoming exam or big deadline. “I wouldn’t go so far as to say that we’ve proved it conclusively, but the work is certainly suggestive that having a polyphenol-rich portion (or two) of fruit for breakfast can help cognitive function throughout the day,” she says.

Rescue Attempts

Given what is currently understood about the detrimental effects of high-fat diets and the beneficial effects of others, might it be possible to harness the good ones to help counteract the bad ones?

Ferreira’s team is one group that’s trying. In investigative models, his team is testing various dietary approaches as well as exercise and manipulation of sleep-wake cycles as potential strategies to protect the brain. They recently showed that supplementing animals’ high-fat diet with Omega-3 fatty acids or vitamin A prevented some of the impairment induced by a high-fat diet. “Even if you have an obesogenic

The gut microbiome, the immune system, and systems signal the brain and influence its functions, from sleep and social interactions to the ability and motivation for physical activity. All are impacted by diet.

diet that has very great impact on the brain and memory, you can try to rescue the effect,” he says.

Shukitt-Hale’s lab has investigated a similar rescue approach in rats. They fed animals a blueberry extract along with a high-fat diet and compared them cognitively to animals on the high-fat diet without blueberries or a control group eating regular fare. By the third month, the high-fat, blueberrysupplemented group was no different than the control group that ate regular fare, suggesting a reversal to normal levels.

“The hope is that people will eat these healthy foods instead of something that is not as healthy, but we know that not everyone is going to do that all the time, so it’s interesting that if you include some healthy foods you might mitigate some of the effect of the bad foods,” Shukitt-Hale says. “We’re not advocating people eat crap, and just add a few blueberries and you’ll be fine. That’s not it.”

You Are (More Than) What You Eat

Diet is but one piece of the brain-wellness puzzle, which also includes adequate sleep, hydration, physical activity, and social connectedness. “Diet is important, but it’s not the only element that determines lifelong cognition,” Williams says.

“All of these modifiable behaviors are important for a healthy brain,” says Ruth Barrientos , a neuroscientist at Ohio State University who (with Spencer, Shukitt-Hale and others) recently reviewed the science of diet and cognition. “But in my opinion, diet is one of the cornerstones because it can affect so many systems.” The gut microbiome, the immune system, and metabolism—all of these systems signal the brain and influence its functions, from sleep and social interactions to the ability and motivation for physical activity, she says. All are impacted by diet.

Fernando Gomez-Pinilla , a neurophysiologist and head of UCLA's NeuroLife Lab who studies the role of trophic factors on plasticity, likens it to an orchestra: “you need to have all the components to have the music.” He is interested in how other modalities can contribute synergistically to a healthful diet and has found that exercise can counteract some effects of negative diet and boost the effects of a positive diet. “We need to think beyond diet,” he says. “It’s important to understand that there is a whole package.”

Science Confirms What Mom Said

As the science of dietary influences on cognition matures, what researchers are willing to say with confidence about diet

and the brain turns out to be remarkably old-fashioned.

Shukitt-Hale’s advice? “I like to say just eat a variety of fruits and vegetables because they might be having different effects, and substitute some of these good snacks, if you will, for some of the bad snacks you’re eating,” Based in part on her own research on walnuts, she also advocates eating whole foods vs. isolated compounds of foods. “There’s something about the synergy of the compounds working together.”

Gomez-Pinilla echoes the sentiment that there’s no single miracle ingredient. “Our diets have so many components; we eat many different things every day, some better than others.” It’s the overall impact that matters to brain health, he says, and those effects can be different for each person depending on their genetic makeup and their personal history.

Barrientos concurs: “Nutrients in isolation may not be as effective as when they are interacting with other nutrients in whole foods.” To her, the best advice for a brain-healthy diet boils down to consuming a variety of natural foods that have undergone the fewest alterations.

Williams, whose latest work on blueberries raises the specter of a plant-based, non-drug (and really yummy) cognitive enhancer of sorts, is herself abundantly cautious: “At this stage, I don’t think I’d commit myself to saying anything other than the current dietary advice of eating a balanced diet with a wide variety of fruits and vegetables included,” she says. “A healthy balanced diet and taking regular exercise is what will make the difference for the vast majority of us.”

In other words, do what your mom told you to. Eat smart. l

“I like to say just eat a variety of fruits and vegetables because they might be having different effects, and substitute some of these good snacks, if you will, for some of the bad snacks you’re eating.”

A Sampler of Cerebrum Podcast Episodes

Aselection of some of Bill Glovin’s engaging and memorable interviews with top neuroscientists who discuss their Cerebrum articles, their personal stories, and how their work has the potential to make a difference in people’s lives. Subscribe to Cerebrum here or on your favorite platform.

Catherine Woolley, Ph.D., the William Deering Chair in Biological Science and professor of neurobiology and neurology at Northwestern University and the author of this issue’s cover story on sex differences in the brain.

PREVIOUS EPISODES

Ilina Singh, Ph.D., Professor of Neuroscience & Society and co-director of the Wellcome Center for Ethics and Humanities at the University of Oxford, and author of last issue’s cover story on global neuroscience expansion.

Gregory Bern, M.D., Ph.D., director of the Center for Neuropolicy and Facility for Education & Research in Neuroscience at Emory University, on his Spring 2020 cover story, “Decoding the Canine Mind.”

Jerold Chun, M.D., Ph.D., senior VP of Neuroscience Drug Discovery at Sanford Burnham Prebys, on his January 2019 article, “The Gene Conundrum in Alzheimer’s Disease.”

Thomas R. Insel, M.D., former director of NIMH and co-founder and president of Mindstrong Health, on his November 2018 article, “Building the Thermometer for Mental Health.”

Vince Calhoun, Ph.D., founding director of the Center for Translational Research in Neuroimaging and Data Science and author of this issue's feature on the promise of big data neuroimaging for mental health.

Frank R. Lin, M.D., Ph.D., director of the Cochlear Center for Hearing and Public Health at Johns Hopkins University and author of the Fall 2020 feature on the link between hearing loss and dementia.

Lee Alan Dugatkin, Ph.D., a biologist at the University of Louisville and coauthor of How to Tame a Fox (and Build a Dog), on his Spring 2020 article, “Jump-Starting Evolution.”

Maheen Mausoof Adamson, Ph.D., senior scientific research director for Defense and Veterans Brain Injury Center in Palo Alto, CA, on her November 2019 article, “Rewiring the Brain: Zapping with Precision.”

Michael L. Lipton, M.D., Ph.D., associate director of the Gruss Magnetic Resonance Research Center at Einstein College of Medicine, on his September 2019 article, “Rethinking Youth Sports.”

The New Science of BY SEIMI RURUP

IN MORE NORMAL TIMES, THE WINTER commute from northern New Jersey to Manhattan often involves standing in near-freezing temperatures to wait for the bus, which is often late and almost always out of seats during rush hour. Upon arriving at New York’s Port Authority Bus Terminal, you wait your turn for the escalator and then march alongside fellow commuters toward the doors that empty out into the streets of Times Square.

If you walk east, you’ll reach Bryant Park, a ten-acre respite from the skyscrapers that tower around it. This time of year, a holiday market lines the perimeter, and an ice-skating rink spans the field where people sit in the sun during warmer months. The stress and anxiety of the commute does not disappear completely—you’re still in Midtown, after all—but walking among the London Plane trees throughout the park never fails to take the edge off and add calm to the monotonous trip.

BBryant Park in midtown Manhattan—once known for drug use and considered a no-go area—is a prime example of how creating green space can contribute to relieving stress and anxiety for commuters, residents, and visitors. Since the 1980s, when new management for park restoration and management was established, the park has gradually made improvements. Today, the 9.3-acre park serves as an oasis for people to lounge, take classes, dine, ice skate, shop—and feel safe.

Bryant Park, an enclave once known for drugs and crime, is an example of how environment can be altered to improve psychological and physiological states. While scholars have been studying the psychological aspects of environmental design since the 1970s, environmental neuroscience is a small, but growing, area of research, a field concerned with the way physical environments interact with the brain and behavior, says Justin Hollander, Ph.D., FAICP. Hollander studies how cities and regions manage physical change, along with the cognitive, health, and social dimensions of community well-being. As professor of urban and environmental policy and planning at Tufts University, he and his colleagues convened the First International Conference on Urban Experience and Design last spring, marking a first for researchers, scholars, architects,

A

planners, and designers to come together under this umbrella of science to discuss new ways of assessing urban spaces.

It’s no surprise that living near trees and greenspace is more beneficial to health than living near the grit and congestion of a city, but the extent it plays—especially on attention and memory—is the focus of research by

Marc G. Berman, Ph.D., an associate professor of psychology at the University of Chicago and principal investigator in its Environmental Neuroscience Lab. Berman’s lab has found that if you had ten or more trees per city block, it positively impacts people’s perception by one percent. Researchers have also found a positive association between greenspace around schools and cognitive development in children.

The psychological well-being of a population can be associated, in part, with its proximity to greenspace in both urban and rural settings, according to Berman’s 2019 study in Science Advances. The benefits from interactions with nature—from potted plants and gardens, to public greenspace and wilderness—include increased happiness, positive social interactions, improved manageability of life tasks, and decreases in mental distress. “Cities are centers of prosperity, employment opportunities, access to education, and cultural advancement, all aspects of life that may promote mental health,” he says. “However, they can also be associated with decreased access to nature, especially for individuals living within economically deprived urban areas.”

PHOTOS: SHUTTERSTOCK

IMAGE COURTESY OF MARC BERMAN

fter years of law suits surrounding the fate of a decaying elevated railroad trestle in the Chelsea section of Manhattan, the High Line was renovated into a public park in 2008 and helped transform a neighborhood. Growing evidence suggests that such projects increase happiness, lead to positive social interaction, and decrease mental distresses.

P art of Berman’s study asked participants to rate images of environmental scenes so that the researchers could identify the basic visual cues for what is considered a disorderly environment.

That’s why restorative environments, such as the mountains or the woods, are places that provide a sense of being away (i.e., mental separation), a feeling of extent (i.e., large enough spaces to explore), and compatibility with goals, say researchers. This feature of “compatibility” is thought to be the way a person interacts with his or her environment at a given time. For example, if you work close to an urban park where you can relax over lunch, you are likely to feel restorative benefits on days when you are stressing from a morning’s worth of difficult work issues.

Just as interacting with more natural environments such as trees, water, and grass can positively impact cognition, affect, and overall health, we are prone to feel, think, and act differently when we are in disorderly environments. Berman and colleagues outline disorderly environments as spaces strewn with litter, graffiti, or abandoned buildings, for example. These environments have been linked to “detrimental outcomes” such as perceived powerlessness, distress, depression, and anxiety, and the influential broken windows theory, which links scene-level social disorder cues (e.g., litter, graffiti) to crime and general rule-breaking.

The Impact of Technology

Incorporating eye-tracking technology with their research, Hollander and his colleagues theorize that distinct contexts (e.g., whether you’re walking down a quiet, rural street or in a busy city) can influence cognition and behavior on an unconscious level. Imageability is an important principle in planning and architecture, he points out. Our brains are wired to seek out and remember patterns within our environments, and imageability determines how specific physical elements and their arrangement will capture attention, evoke feelings, and create a lasting impression.

The group recently published a study to demonstrate how the combination of eye-tracking technology and photographs helps to better understand human responses to neighborhood designs in New York City. How we interact with traditional design, how it puts us at ease, and what about it helps us orient ourselves, were some of the questions they sought to answer. “These images depict important public spaces where hundreds of thousands of people regularly congregate or pass through, thus their design attributes really matter,” says Hollander.

Another concern his colleagues in the field are weighing—at least in the short term—is the pandemic’s impact on urban design, as commuting and public access are reconsidered. “Urban spaces are generally designed for cars, and this research can show how to better design places to meet human needs at a biological level, to encourage them to walk and be active,” says Hollander. “Likewise, the design of places impacts people’s well-being and mental health. Understanding this impact and designing cities the right way can ultimately make people happier and healthier.” l

PHOTOS COURTESY OF PLANTUSNYC

This bench placement at Rockaway Beach in New York City is an example of what Hollander calls "a built environment." "People tend not to sit on benches that don’t catch their eye,” he writes. When an outdoor space has no central orienting point, there is a tendency for increased user anxiety in the space. Using eye-tracking technology,

the heatmap of the boardwalk shows that benches grabbed viewers’ attention.

A t Spotify’s corporate headquarters in Manhattan, the greening of a setback creates an environment for employees looking to relieve the stress or simply take an outdoor break with some fresh air.

And the winner

AS 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.

Following are excepts from the winners in three categories: general interest, academic, and high school. The full essays, with citations, may be referenced by clicking on the essay title.

General Interest

God, Politics, and Death: How a New Medicine Raises Age-Old Questions

BY EDDIE JACOBS University of Oxford (United Kingdom)

How would you feel about a new therapy for your chronic pain, which—although far more effective than any available alternative—might also change your religious beliefs? Or a treatment for lymphoma that brings one in three patients into remission, but also made them more likely to vote for your least preferred political party?

These seem like idle hypothetical questions about impossible side effects. After all, this is not how medicine works. But a new mental health treatment, set to be licensed next year, poses just this sort of problem. Psychotherapy assisted by psilocybin, the psychedelic compound in “magic mushrooms,” seems to be remarkably effective in treating a wide range of psychopathologies, but also causes a raft of unusual nonclinical changes not seen elsewhere in medicine. Although its precise therapeutic mechanisms remain unclear, clinically relevant doses of psilocybin can induce powerful mystical experiences more commonly associated with extended periods of fasting, prayer or meditation. Arguably, then, it is unsurprising that it can generate long-lasting changes in patients: studies report increased prosociality and aesthetic appreciation, plus robust shifts in personality, values and attitudes to life, even leading some atheists to find God. What’s more, these experiences appear to be a feature, rather than a bug, of psilocybin-assisted psychotherapy, with the intensity of the mystical experience correlating with the extent of clinical benefit l

winner is...

Academic Obesity, Cognition, and WarningsSociety: from the Sordid History of Eugenics and Scientific Racism

BY SARAH R. ZINN University of Chicago (United States)

Globally, adult obesity rates have nearly tripled since 1975. In the U.S., rates have risen from 15 percent in 1999 to 42 percent in 2018 and one out of every three children aged 2-19 is now being classified as overweight or obese. Indeed, the World Health Organization warns that “obesity is becoming the greatest healthcare burden affecting European society.” In most dominant first-world cultures, the social construction of obesity is of a preventable and catastrophic disease epidemic with a staggering economic burden to society caused by poor personal lifestyle choices. Here, I will outline a different perspective with important scientific and societal implications. Since the attribution of obesity as a poor personal choice, the prioritization of consequences to society, and long-held views of dualism and religious ideology interact to fuel an entrenched stigmatization of fat bodies as an indicator of a “willful” mental weakness and therefore moral failure, researchers exploring the relationship between obesity and cognition must start grappling with the ethical concerns of stereotype confirmation in this vulnerable population. Powerful ethical lessons from science’s history argue that special care, attention to detail, and counterinduction are essential when conducting and interpreting stereotype-confirming research on obesity, neurocognition, and intelligence—care which is vital both for the ethical conduct of science and for the objective pursuit of knowledge. l

High School

Redefining Justice:

Updating Criminal Law to Reflect a New Understanding of the Mind

BY CHERIE FERNANDES The Lawrenceville School (United States)

In the year 2000, 40-year old George Sheppard (a generic name used for narrative purposes) was arrested for possessing child pornography and molesting his 8-year old stepdaughter. He had no previous history of pedophilia, happily married for two years before his sexual impulses abruptly changed. George was fully aware of the immorality of his actions, baffled and appalled by the sudden and sickening changes, but felt unable to control them. He began to visit brothels, accumulated a collection of pornographic material, and, unable to contain his urges, made sexual advancements towards his stepdaughter. When his wife discovered the predatory behavior, he was removed from his home, upon which the behavior only worsened.

While awaiting his day in court, George began to complain of terrible headaches, and a brain scan soon revealed massive tumor in his orbitofrontal cortex, the region of the brain known to control sexual impulses. The tumor was removed, and with it, the pedophilic impulses and lack of self-control. George completed a Sexaholics Anonymous program and was able to return to his family. When deviant sexual impulses returned a year later, another scan revealed that the tumor had as well, and so a second surgery rid George of the tumor and the pedophilic behavior, this time for good. George’s case in particular points to what Stanford neuroscience professor David Eagleman terms “hidden drives and desires [which] lurk undetected behind the neural machinery of socialization”. “When the frontal lobes are compromised,” Eagleman explains, “startling behaviors can emerge.” This disinhibition is also common in patients with frontotemporal dementia, a disease causing the aforementioned lobes to degenerate. The lack of impulse control often causes patients to violate social norms, and commonly landing them in court for the resultant crimes of public nudity, aggression, or shoplifting. The composition of their brains leave them physically incapable of acting differently. l

JOSEPH T. COYLE, M.D.

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

MARTHA J. FARAH, Ph.D.

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

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

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

HELEN S. MAYBERG, M.D.

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

JOHN H. MORRISON, Ph.D.

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

ADVISORY BOARD

RICHARD M. RESTAK, M.D.

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

HARALD SONTHEIMER, Ph.D.

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

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

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

CHARLES F. ZORUMSKI, M.D.

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

CAROLYN ASBURY, Ph.D.

In-House advisor

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

Bill Glovin 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.

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.