Are Brain Implants the Future of Treatment for Depression and Anxiety?
Sarah, clinical trial participant, at an appointment with Katherine Scangos, MD, PhD, at UCSF’s Langley Porter Psychiatric Institute.
When she woke up after a procedure involving drilling small holes in her skull, a woman suffering from chronic depression reported feeling “euphoric”. The holes were made to fit the wires that connected her brain with a matchbox-sized electrical implant; this would deliver up to 300 short-lived electricity bursts per day to specific parts of her brain.
Over a year later, Sarah, 36, says the brain implant has turned her life around. A sense of alertness and energy have replaced suicidal thoughts and feelings of despair, which had persisted despite antidepressants and electroconvulsive therapy. Sarah is the first person to have received a brain implant to treat depression, a breakthrough that happened during an experimental study published recently in Nature Medicine.
“What we did was use deep-brain stimulation (DBS), a technique used in the treatment of epilepsy,” says Andrew Krystal, professor of psychiatry at University of California, San Francisco (UCSF), and one of the study’s researchers. DBS typically involves implanting electrodes into specific areas of the brain to reduce seizures not controlled with medication or to remove the part of the brain that causes the seizures. Instead of choosing and stimulating a single brain site though, the UCSF team took a different approach.
They first used 10 electrodes to map Sarah’s brain activity, a phase that lasted 10 days, during which they developed a neural biomarker, a specific pattern of brain activity that indicated the onset of depression symptoms (in Sarah, this was detected in her amygdala, an almondlike structure located near the base of the brain). But they also saw that delivering a tiny burst of electricity to the patient’s ventral striatum, an area of the brain that sits in the center, above and behind the ears, dramatically improved these symptoms. What they had to do was outfit Sara’s brain with a DBS-device programmed to propagate small waves of electricity to the ventral striatum only when it discerned the pattern.
“We are not trying to take away normal responses to the world. We are just trying to eliminate this one thing, which is depression, which impedes patients’ ability to function and deal with normal stuff.”
“It was a personalized treatment not only in where to stimulate, but when to stimulate,” Krystal says. Sarah’s depression translated to low amounts of energy, loss of pleasure and interest in life, and feelings of sluggishness. Those symptoms went away when scientists stimulated her ventral capsule area. When the same area was manipulated by electricity when Sarah’s symptoms “were not there” though, she was feeling more energetic, but this sudden flush of energy soon gave way to feelings of overstimulation and anxiety. “This is a very tangible illustration of why it's best to simulate only when you need it,” says Krystal.
We have the tendency to lump together depression symptoms, but, in reality, they are quite diverse; some people feel sad and lethargic, others stay up all night; some overeat, others don’t eat at all. “This happens because people have different underlying dysfunctions in different parts of their brain. Our approach is targeting the specific brain circuit that modulates different kinds of symptoms. Simply, where we stimulate depends on the specific set of problems a person has,” Krystal says. Such tailormade brain stimulation for patients with long-term, drug-resistant depression, which would be easy to use at home, could be transformative, the UCSF researcher concludes.
In the U.S., 12.7 percent of the population is on antidepressants. Almost exactly the same percentage of Australians–12.5–take similar drugs every day. With 13 percent of its population being on antidepressants, Iceland is the world’s highest antidepressant consumer. And quite away from Scandinavia, the Southern European country of Portugal is the world’s third strongest market for corresponding medication.
By 2020, nearly 15.5 million people had been consuming antidepressants for a time period exceeding five years. Between 40 and 60 percent of them saw improvements. “For those people, it was absolutely what they needed, whether that was increased serotonin, or increased norepinephrine or increased dopamine, ” says Frank Anderson, a psychiatrist who has been administering antidepressants in his private practice “for a long time”, and author of Transcending Trauma, a book about resolving complex and dissociative trauma.
Yet the UCSF study brings to the mental health field a specificity it has long lacked. “A lot of the traditional medications only really work on six neurotransmitters, when there are over 100 neurotransmitters in the brain,” Anderson says. Drugs are changing the chemistry of a single system in the brain, but brain stimulation is essentially changing the very architecture of the brain, says James Giordano, professor of neurology and biochemistry at Georgetown University Medical Center in Washington and a neuroethicist. It is a far more elegant approach to treating brain disorders, with the potential to prove a lifesaver for the 40 to 50 percent of patients who see no benefits at all with antidepressants, Giordano says. It is neurofeedback, on steroids, adds Anderson. But it comes with certain risks.
Even if the device generating the brain stimulation sits outside the skull and could be easily used at home, the whole process still involves neurosurgery. While the sophistication and precision of brain surgeries has significantly improved over the last years, says Giordano, they always carry risks, such as an allergic reaction to anesthesia, bleeding in the brain, infection at the wound site, blood clots, even coma. Non-invasive brain stimulation (NIBS), a technology currently being developed by the Defense Advanced Research Projects Agency (DARPA), could potentially tackle this. Patients could wear a cap, helmet, or visor that transmits electrical signals from the brain to a computer system and back, in a brain-computer interface that would not need surgery.
“This could counter the implantation of hardware into the brain and body, around which there is also a lot of public hesitance,” says Giordano, who is working on such techniques at DARPA.
Embedding a chip in your head is one of the finest examples of biohacking, an umbrella word for all the practices aimed at hacking one’s body and brain to enhance performance –a citizen do-it-yourself biology. It is also a word charged enough to set off a public backlash. Large segments of the population will simply refuse to allow that level of invasiveness in their heads, says Laura Cabrera, an associate professor of neuroethics at the Center for Neural Engineering, Department of Engineering Science and Mechanics at Penn State University. Cabrera urges caution when it comes to DBS’s potential.
“We've been using it for Parkinson's for over two decades, hoping that now that they get DBS, patients will get off medications. But people have continued taking their drugs, even increasing them,” she says. What the UCSF found is a proof of concept that DBS worked in one depressed person, but there’s a long way ahead until we can confidently say this finding is generalizable to a large group of patients. Besides, as a society, we are not there yet, says Cabrera. “Most people, at least in my research, say they don't want to have things in their brain,” she says. But what could really go wrong if we biohacked our own brains anyway?
In 2014, a man who had received a deep brain implant for a movement disorder started developing an affection for Johnny Cash’s music when he had previously been an avid country music fan. Many protested that the chip had tampered with his personality. Could sparking the brain with electricity generated by a chip outside it put an end to our individuality, messing with our musical preferences, unique quirks, our deeper sense of ego?
“What we found is that when you stimulate a region, you affect people’s moods, their energies,” says Krystal. You are neither changing their personality nor creating creatures of eternal happiness, he says. “’Being on a phone call would generally be a setting that would normally trigger symptoms of depression in me,’” Krystal reports his patient telling him. ‘I now know bad things happen, but am not affected by them in the same way. They don’t trigger the depression.’” Of the research, Krystal continues: “We are not trying to take away normal responses to the world. We are just trying to eliminate this one thing, which is depression, which impedes patients’ ability to function and deal with normal stuff.”
Yet even change itself shouldn't be seen as threatening, especially if the patient had probably desired it in the first place. “The intent of therapy in psychiatric disorders is to change the personality, because a psychiatric disorder by definition is a disorder of personality,” says Cabrera. A person in therapy wants to restore the lost sense of “normal self”. And as for this restoration altering your original taste in music, Cabrera says we are talking about rarities, extremely scarce phenomena that are possible with medication as well.
Maybe it is the allure of dystopian sci-fi films: people have a tendency to worry about dark forces that will spread malice across the world when the line between human and machine has blurred. Such mind-control through DBS would probably require a decent leap of logic with the tools science has--at least to this day. “This would require an understanding of the parameters of brain stimulation we still don't have,” says Cabrera. Still, brain implants are not fully corrupt-proof.
“Hackers could shut off the device or change the parameters of the patient's neurological function enhancing symptoms or creating harmful side-effects,” says Giordano.
There are risks, but also failsafe ways to tackle them, adds Anderson. “Just like medications are not permanent, we could ensure the implants are used for a specific period of time,” he says. And just like people go in for checkups when they are under medication, they could periodically get their personal brain implants checked to see if they have been altered or not, he continues. “It is what my research group refers to as biosecurity by design,” says Giordano. “It is important that we proactively design systems that cannot be corrupted.”
Two weeks after receiving the implant, Sarah scored 14 out of 54 on the Montgomery-Åsberg Depression Rating Scale, a ten-item questionnaire psychiatrists use to measure the severity of depressive episodes. She had initially scored 36. Today she scores under 10. She would have had to wait between four and eight weeks to see positive results had she taken the antidepressant road, says Krystal.
He and his team have enrolled two other patients in the trials and hope to add nine more. They already have some preliminary evidence that there's another place that works better in the brain of another patient, because that specific patient had been experiencing more anxiety as opposed to despondency. Almost certainly, we will have different biomarkers for different people, and brain stimulation will be tailored to a person’s unique situation, says Krystal. “Each brain is different, just like each face is different.”
Regenerative medicine has come a long way, baby
After a cloned baby sheep, what started as one of the most controversial areas in medicine is now promising to transform it.
The field of regenerative medicine had a shaky start. In 2002, when news spread about the first cloned animal, Dolly the sheep, a raucous debate ensued. Scary headlines and organized opposition groups put pressure on government leaders, who responded by tightening restrictions on this type of research.
Fast forward to today, and regenerative medicine, which focuses on making unhealthy tissues and organs healthy again, is rewriting the code to healing many disorders, though it’s still young enough to be considered nascent. What started as one of the most controversial areas in medicine is now promising to transform it.
Progress in the lab has addressed previous concerns. Back in the early 2000s, some of the most fervent controversy centered around somatic cell nuclear transfer (SCNT), the process used by scientists to produce Dolly. There was fear that this technique could be used in humans, with possibly adverse effects, considering the many medical problems of the animals who had been cloned.
But today, scientists have discovered better approaches with fewer risks. Pioneers in the field are embracing new possibilities for cellular reprogramming, 3D organ printing, AI collaboration, and even growing organs in space. It could bring a new era of personalized medicine for longer, healthier lives - while potentially sparking new controversies.
Engineering tissues from amniotic fluids
Work in regenerative medicine seeks to reverse damage to organs and tissues by culling, modifying and replacing cells in the human body. Scientists in this field reach deep into the mechanisms of diseases and the breakdowns of cells, the little workhorses that perform all life-giving processes. If cells can’t do their jobs, they take whole organs and systems down with them. Regenerative medicine seeks to harness the power of healthy cells derived from stem cells to do the work that can literally restore patients to a state of health—by giving them healthy, functioning tissues and organs.
Modern-day regenerative medicine takes its origin from the 1998 isolation of human embryonic stem cells, first achieved by John Gearhart at Johns Hopkins University. Gearhart isolated the pluripotent cells that can differentiate into virtually every kind of cell in the human body. There was a raging controversy about the use of these cells in research because at that time they came exclusively from early-stage embryos or fetal tissue.
Back then, the highly controversial SCNT cells were the only way to produce genetically matched stem cells to treat patients. Since then, the picture has changed radically because other sources of highly versatile stem cells have been developed. Today, scientists can derive stem cells from amniotic fluid or reprogram patients’ skin cells back to an immature state, so they can differentiate into whatever types of cells the patient needs.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
The ethical debate has been dialed back and, in the last few decades, the field has produced important innovations, spurring the development of whole new FDA processes and categories, says Anthony Atala, a bioengineer and director of the Wake Forest Institute for Regenerative Medicine. Atala and a large team of researchers have pioneered many of the first applications of 3D printed tissues and organs using cells developed from patients or those obtained from amniotic fluid or placentas.
His lab, considered to be the largest devoted to translational regenerative medicine, is currently working with 40 different engineered human tissues. Sixteen of them have been transplanted into patients. That includes skin, bladders, urethras, muscles, kidneys and vaginal organs, to name just a few.
These achievements are made possible by converging disciplines and technologies, such as cell therapies, bioengineering, gene editing, nanotechnology and 3D printing, to create living tissues and organs for human transplants. Atala is currently overseeing clinical trials to test the safety of tissues and organs engineered in the Wake Forest lab, a significant step toward FDA approval.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
“It’s never fast enough,” Atala says. “We want to get new treatments into the clinic faster, but the reality is that you have to dot all your i’s and cross all your t’s—and rightly so, for the sake of patient safety. People want predictions, but you can never predict how much work it will take to go from conceptualization to utilization.”
As a surgeon, he also treats patients and is able to follow transplant recipients. “At the end of the day, the goal is to get these technologies into patients, and working with the patients is a very rewarding experience,” he says. Will the 3D printed organs ever outrun the shortage of donated organs? “That’s the hope,” Atala says, “but this technology won’t eliminate the need for them in our lifetime.”
New methods are out of this world
Jeanne Loring, another pioneer in the field and director of the Center for Regenerative Medicine at Scripps Research Institute in San Diego, says that investment in regenerative medicine is not only paying off, but is leading to truly personalized medicine, one of the holy grails of modern science.
This is because a patient’s own skin cells can be reprogrammed to become replacements for various malfunctioning cells causing incurable diseases, such as diabetes, heart disease, macular degeneration and Parkinson’s. If the cells are obtained from a source other than the patient, they can be rejected by the immune system. This means that patients need lifelong immunosuppression, which isn’t ideal. “With Covid,” says Loring, “I became acutely aware of the dangers of immunosuppression.” Using the patient’s own cells eliminates that problem.
Microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, Loring's own cells have been sent to the ISS for study.
Loring has a special interest in neurons, or brain cells that can be developed by manipulating cells found in the skin. She is looking to eventually treat Parkinson’s disease using them. The manipulated cells produce dopamine, the critical hormone or neurotransmitter lacking in the brains of patients. A company she founded plans to start a Phase I clinical trial using cell therapies for Parkinson’s soon, she says.
This is the culmination of many years of basic research on her part, some of it on her own cells. In 2007, Loring had her own cells reprogrammed, so there’s a cell line that carries her DNA. “They’re just like embryonic stem cells, but personal,” she said.
Loring has another special interest—sending immature cells into space to be studied at the International Space Station. There, microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, her own cells have been sent to the ISS for study. “My colleagues and I have completed four missions at the space station,” she says. “The last cells came down last August. They were my own cells reprogrammed into pluripotent cells in 2009. No one else can say that,” she adds.
Future controversies and tipping points
Although the original SCNT debate has calmed down, more controversies may arise, Loring thinks.
One of them could concern growing synthetic embryos. The embryos are ultimately derived from embryonic stem cells, and it’s not clear to what stage these embryos can or will be grown in an artificial uterus—another recent invention. The science, so far done only in animals, is still new and has not been widely publicized but, eventually, “People will notice the production of synthetic embryos and growing them in an artificial uterus,” Loring says. It’s likely to incite many of the same reactions as the use of embryonic stem cells.
Bernard Siegel, the founder and director of the Regenerative Medicine Foundation and executive director of the newly formed Healthspan Action Coalition (HSAC), believes that stem cell science is rapidly approaching tipping point and changing all of medical science. (For disclosure, I do consulting work for HSAC). Siegel says that regenerative medicine has become a new pillar of medicine that has recently been fast-tracked by new technology.
Artificial intelligence is speeding up discoveries and the convergence of key disciplines, as demonstrated in Atala’s lab, which is creating complex new medical products that replace the body’s natural parts. Just as importantly, those parts are genetically matched and pose no risk of rejection.
These new technologies must be regulated, which can be a challenge, Siegel notes. “Cell therapies represent a challenge to the existing regulatory structure, including payment, reimbursement and infrastructure issues that 20 years ago, didn’t exist.” Now the FDA and other agencies are faced with this revolution, and they’re just beginning to adapt.
Siegel cited the 2021 FDA Modernization Act as a major step. The Act allows drug developers to use alternatives to animal testing in investigating the safety and efficacy of new compounds, loosening the agency’s requirement for extensive animal testing before a new drug can move into clinical trials. The Act is a recognition of the profound effect that cultured human cells are having on research. Being able to test drugs using actual human cells promises to be far safer and more accurate in predicting how they will act in the human body, and could accelerate drug development.
Siegel, a longtime veteran and founding father of several health advocacy organizations, believes this work helped bring cell therapies to people sooner rather than later. His new focus, through the HSAC, is to leverage regenerative medicine into extending not just the lifespan but the worldwide human healthspan, the period of life lived with health and vigor. “When you look at the HSAC as a tree,” asks Siegel, “what are the roots of that tree? Stem cell science and the huge ecosystem it has created.” The study of human aging is another root to the tree that has potential to lengthen healthspans.
The revolutionary science underlying the extension of the healthspan needs to be available to the whole world, Siegel says. “We need to take all these roots and come up with a way to improve the life of all mankind,” he says. “Everyone should be able to take advantage of this promising new world.”
Joy Milne's unusual sense of smell led Dr. Tilo Kunath, a neurobiologist at the Centre for Regenerative Medicine at the University of Edinburgh, and a host of other scientists, to develop a new diagnostic test for Parkinson's.
Forty years ago, Joy Milne, a nurse from Perth, Scotland, noticed a musky odor coming from her husband, Les. At first, Milne thought the smell was a result of bad hygiene and badgered her husband to take longer showers. But when the smell persisted, Milne learned to live with it, not wanting to hurt her husband's feelings.
Twelve years after she first noticed the "woodsy" smell, Les was diagnosed at the age of 44 with Parkinson's Disease, a neurodegenerative condition characterized by lack of dopamine production and loss of movement. Parkinson's Disease currently affects more than 10 million people worldwide.
Milne spent the next several years believing the strange smell was exclusive to her husband. But to her surprise, at a local support group meeting in 2012, she caught the familiar scent once again, hanging over the group like a cloud. Stunned, Milne started to wonder if the smell was the result of Parkinson's Disease itself.
Milne's discovery led her to Dr. Tilo Kunath, a neurobiologist at the Centre for Regenerative Medicine at the University of Edinburgh. Together, Milne, Kunath, and a host of other scientists would use Milne's unusual sense of smell to develop a new diagnostic test, now in development and poised to revolutionize the treatment of Parkinson's Disease.
"Joy was in the audience during a talk I was giving on my work, which has to do with Parkinson's and stem cell biology," Kunath says. "During the patient engagement portion of the talk, she asked me if Parkinson's had a smell to it." Confused, Kunath said he had never heard of this – but for months after his talk he continued to turn the question over in his mind.
Kunath knew from his research that the skin's microbiome changes during different disease processes, releasing metabolites that can give off odors. In the medical literature, diseases like melanoma and Type 2 diabetes have been known to carry a specific scent – but no such connection had been made with Parkinson's. If people could smell Parkinson's, he thought, then it stood to reason that those metabolites could be isolated, identified, and used to potentially diagnose Parkinson's by their presence alone.
First, Kunath and his colleagues decided to test Milne's sense of smell. "I got in touch with Joy again and we designed a protocol to test her sense of smell without her having to be around patients," says Kunath, which could have affected the validity of the test. In his spare time, Kunath collected t-shirt samples from people diagnosed with Parkinson's and from others without the diagnosis and gave them to Milne to smell. In 100 percent of the samples, Milne was able to detect whether a person had Parkinson's based on smell alone. Amazingly, Milne was even able to detect the "Parkinson's scent" in a shirt from the control group – someone who did not have a Parkinson's diagnosis, but would go on to be diagnosed nine months later.
From the initial study, the team discovered that Parkinson's did have a smell, that Milne – inexplicably – could detect it, and that she could detect it long before diagnosis like she had with her husband, Les. But the experiments revealed other things that the team hadn't been expecting.
"One surprising thing we learned from that experiment was that the odor was always located in the back of the shirt – never in the armpit, where we expected the smell to be," Kunath says. "I had a chance meeting with a dermatologist and he said the smell was due to the patient's sebum, which are greasy secretions that are really dense on your upper back. We have sweat glands, instead of sebum, in our armpits." Patients with Parkinson's are also known to have increased sebum production.
With the knowledge that a patient's sebum was the source of the unusual smell, researchers could go on to investigate exactly what metabolites were in the sebum and in what amounts. Kunath, along with his associate, Dr. Perdita Barran, collected and analyzed sebum samples from 64 participants across the United Kingdom. Once the samples were collected, Barran and others analyzed it using a method called gas chromatography mass spectrometry, or GS-MC, which separated, weighed and helped identify the individual compounds present in each sebum sample.
Barran's team can now correctly identify Parkinson's in nine out of 10 patients – a much quicker and more accurate way to diagnose than what clinicians do now.
"The compounds we've identified in the sebum are not unique to people with Parkinson's, but they are differently expressed," says Barran, a professor of mass spectrometry at the University of Manchester. "So this test we're developing now is not a black-and-white, do-you-have-something kind of test, but rather how much of these compounds do you have compared to other people and other compounds." The team identified over a dozen compounds that were present in the sebum of Parkinson's patients in much larger amounts than the control group.
Using only the GC-MS and a sebum swab test, Barran's team can now correctly identify Parkinson's in nine out of 10 patients – a much quicker and more accurate way to diagnose than what clinicians do now.
"At the moment, a clinical diagnosis is based on the patient's physical symptoms," Barran says, and determining whether a patient has Parkinson's is often a long and drawn-out process of elimination. "Doctors might say that a group of symptoms looks like Parkinson's, but there are other reasons people might have those symptoms, and it might take another year before they're certain," Barran says. "Some of those symptoms are just signs of aging, and other symptoms like tremor are present in recovering alcoholics or people with other kinds of dementia." People under the age of 40 with Parkinson's symptoms, who present with stiff arms, are often misdiagnosed with carpal tunnel syndrome, she adds.
Additionally, by the time physical symptoms are present, Parkinson's patients have already lost a substantial amount of dopamine receptors – about sixty percent -- in the brain's basal ganglia. Getting a diagnosis before physical symptoms appear would mean earlier interventions that could prevent dopamine loss and preserve regular movement, Barran says.
"Early diagnosis is good if it means there's a chance of early intervention," says Barran. "It stops the process of dopamine loss, which means that motor symptoms potentially will not happen, or the onset of symptoms will be substantially delayed." Barran's team is in the processing of streamlining the sebum test so that definitive results will be ready in just two minutes.
"What we're doing right now will be a very inexpensive test, a rapid-screen test, and that will encourage people to self-sample and test at home," says Barran. In addition to diagnosing Parkinson's, she says, this test could also be potentially useful to determine if medications were at a therapeutic dose in people who have the disease, since the odor is strongest in people whose symptoms are least controlled by medication.
"When symptoms are under control, the odor is lower," Barran says. "Potentially this would allow patients and clinicians to see whether their symptoms are being managed properly with medication, or perhaps if they're being overmedicated." Hypothetically, patients could also use the test to determine if interventions like diet and exercise are effective at keeping Parkinson's controlled.
"We hope within the next two to five years we will have a test available."
Barran is now running another clinical trial – one that determines whether they can diagnose at an earlier stage and whether they can identify a difference in sebum samples between different forms of Parkinson's or diseases that have Parkinson's-like symptoms, such as Lewy Body Dementia.
"Within the next one to two years, we hope to be running a trial in the Manchester area for those people who do not have motor symptoms but are at risk for developing dementia due to symptoms like loss of smell and sleep difficulty," Barran had said in 2019. "If we can establish that, we can roll out a test that determines if you have Parkinson's or not with those first pre-motor symptoms, and then at what stage. We hope within the next two to five years we will have a test available."
In a 2022 study, published in the American Chemical Society, researchers used mass spectrometry to analyze sebum from skin swabs for the presence of the specific molecules. They found that some specific molecules are present only in people who have Parkinson’s. Now they hope that the same method can be used in regular diagnostic labs. The test, many years in the making, is inching its way to the clinic.
"We would likely first give this test to people who are at risk due to a genetic predisposition, or who are at risk based on prodomal symptoms, like people who suffer from a REM sleep disorder who have a 50 to 70 percent chance of developing Parkinson's within a ten year period," Barran says. "Those would be people who would benefit from early therapeutic intervention. For the normal population, it isn't beneficial at the moment to know until we have therapeutic interventions that can be useful."
Milne's husband, Les, passed away from complications of Parkinson's Disease in 2015. But thanks to him and the dedication of his wife, Joy, science may have found a way to someday prolong the lives of others with this devastating disease. Sometimes she can smell people who have Parkinson’s while in the supermarket or walking down the street but has been told by medical ethicists she cannot tell them, Milne said in an interview with the Guardian. But once the test becomes available in the clinics, it will do the job for her.
[Ed. Note: A older version of this hit article originally ran on September 3, 2019.]