Cerebrum Winter 2021


His Hers & S E X D I F F E R E N C E S I N T H E B R A I N


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 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‘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 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.

Vince Calhoun, Ph.D. The Promise of Big Data Imaging for Mental Health Page 18

Kayt Sukel Psychedelics : Weighing the Healing Power Page 26

Brenda Patoine Your Brain on Food Page 30




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

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

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

2 Contributors | 4 From the Editor | 42 Advisory Board | 44 Cerebrum Staff




A Matter of Opinion

BY BILL GLOVIN Editor-in-Chief


I n 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

Bill Glovin Editor-in-Chief Seimi Rurup Assitant Editor


Brandon Barrera Editorial Assistant

Carl Sherman Copy Editor

Carolyn Asbury, Ph.D. Scientific Consultant

Bruce Hanson Art Director

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Letters may be edited for length and clarity. We regret that we cannot answer each one.



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.

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 > NewYork Times: Hearing Aids Could Use Some Help When we engage kids in sports, we don’t expect them 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. “ 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

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 two- thirds 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-the- counter devices.



ADVANCES Notable brain science findings



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 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 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

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 • 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. 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 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 NIH- funded 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.


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

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 .


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

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

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 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— 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

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 Graff- Radford 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

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 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 with memory , especially when heavy use starts in among high school and middle school students, rates have started back up. At the same time, teenage perception of 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

BY PHILIP M. BOFFEY T roubling 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.


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.

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 low- level 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.





The Sound of Healing

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

BY ABDUL-KAREEM AHMED, M.D. “B ald 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

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. 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. 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

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.


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 real- time 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.

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 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.

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



His H & While the 1990s be Men Are from Mars, Wom addressed behavior, th differences in the ma remain largely a mystery. neuroendocrinologist tells us what we k Sex [ ] BY CATHER I NE S . WOOLLEY, PH . D. I LLUSTRAT ION BY ARMANDO VEVE


Dana.org 13 Hers estseller men Are from Venus he neurobiological sex ale and female brain OUR AUTHOR— an acclaimed t at Northwestern University — know and why we don’t know more. x Differences in the Brain

DIFFERENCES IN THE BRAIN ARE REAL, but they are not what you 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 Sex … structural sex differe actually 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. 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-or- nothing. 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.


rences are quite small, and their interpretation is

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.

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. often based on gender stereotypes with little to no scientific justificatio .



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