Illustrations by Arlen Schumer
Illustrations by Arlen Schumer

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Modern Marvel

Neuroscientist and comic-book fan Ahmad Hariri wants to take pictures of the brains of 1,200 Duke undergraduates. Can his ambitious idea help us understand how to defeat depression and mental illness?
Writer: 
Catherine Clabby
February 13, 2013

One morning last semester, a Duke undergrad peeled off from a busy day on campus to hustle to a basement office in the Sociology- Psychology Building, where scientists were waiting to peer into her brain. Within minutes the slim first-year student, chic in a black-and-white shorts set, was sitting before a computer screen in a narrow, beige room. For more than an hour, her fingers clicked answers to hundreds of questions about her tastes, behaviors, quirks, and feelings.

Would you wait six months to receive a gift of $100 or would you settle for $70 today? What if you had to wait a year? Would you settle for $20 now? What about $80?

And not long after that:

Are you a planner or spontaneous?…Like puzzles?…Pay debt?…Temperamental?… Trusting?…Regrets?…Dress well?…Throw things?…Arrive on time?

The student—we’ll call her Ella—had signed up for the Duke Neurogenetics Study, the largest research project of its kind in the world. The project is the brainchild of Ahmad Hariri, a professor of neuroscience and psychology who is trying to unearth the biological basis for many of the vast differences in our personalities. Those differences, he’s convinced, influence not just how we behave, but also our vulnerabilities to mental-health disorders such as depression, anxiety, and addiction.

In his detective work, Hariri combines traditional personality surveys with two of neuroscience’s hottest new tools: genetic sequencing and brain imaging. Already more than 600 students have contributed to what is quickly becoming a mountain of data. In addition to the long survey, volunteers offer a DNA sample, which is sequenced by a private lab, and agree to have their brain imaged as it reacts to evocative experiences.

Before Hariri and his research team are done, they intend to record and analyze the brain activity, genetic variation, and personality traits of more than 1,200 Duke students, giving this study significant statistical muscle. Hariri plans to follow up with many of those volunteers for several years to add information on their evolving behaviors. If all goes as he expects, scientists around the world will have the chance to use the trove of data collected out of the basement lab to connect the dots among genes, brain, and behavior.

Hariri and other Duke faculty members are convinced that patterns revealed through the study could help rewrite fundamental views on what causes some psychological disorders. For decades, experts have viewed mental illnesses such as depression, anxiety, and addiction as distinctive illnesses with unique biological causes. Hariri is among a growing group of neuroscientists who are not so certain that’s the case. If they can help clarify the true basis of mental disorders, better, more targeted approaches to diagnosing and treating those diseases may follow. Hariri imagines a day when someone’s genetic profile might signal a potential problem in how his or her brain handles extreme stress, whether that be the death of a loved one or the brutality of combat. That would enable intervention, and maybe prevention, before trouble strikes.

Every brain and every experience is different, and if science can perfect the tools to understand those differences, Hariri says, “we could really have an impact on public health.”

Ahmad Hariri has a favorite photograph. It’s that famed 1987 Annie Leibovitz portrait of basketball great Wilt Chamberlain standing next to jockey Willie Shoemaker at Santa Monica Beach. At seven feet, one inch, Chamberlain is a human tower in black shorts and a muscle shirt. Next to him, Shoemaker is dignified in red-andblack racing silks, but tiny, a mere four feet, eleven inches tall.

“These are both human beings, but they could not be more different,” says Hariri. “But the reality is that differences in people’s behavior dwarf those physical differences. Differences in how people see and respond to the world are much, much greater.”

A desire to understand what causes those differences at a biological level drove Hariri to start his ambitious neurogenetics study at Duke. But the energetic fortyyear- old didn’t travel a straight path to this quest. Born in Iran, Hariri moved to the U.S. with his family in the late 1970s, shortly before the revolution there imposed theocratic rule. First they landed in Arkansas, where Hariri’s mother, a language and literature scholar, had relatives. In time they migrated farther north, and in 1991, Hariri enrolled at the University of Maryland.

From an early age, the clever immigrant kid felt family pressure to become a doctor, a vocation he did not always feel called to. But the complexity and beauty of biology always grabbed him. He took premed courses at Maryland, but ended up rejecting medical school for a graduate training program using molecular tools to better understand evolutionary biology. When the chance to trudge through the jungles of Malaysia to collect flies required for his experiments did not wow him, Hariri realized that field research would never be his thing. “I’m what you call indoorsy,” he explains.

Credit: Arien Schumer

What really jazzed him, though, was encountering a new imaging tool in an animal-communications seminar. The emerging technology, called functional MRI (fMRI), uses a strong magnetic field to capture changes in blood flow in different regions of the brain. With fMRI, scientists could for the first time observe what parts of the brain turn on and off during tasks, creating a real-time image of a brain in action. “This could serve as a place to ask any number of questions about human nature, human behavior, human health, and illness,” Hariri remembers thinking.

After volunteering at a federal lab using fMRI for research, Hariri enrolled at the University of California at Los Angles, where he studied with Susan Bookheimer, who was using fMRI scans to study autism. He went on to a postgraduate fellowship with the National Institutes of Health, where he used fMRI to make a link between observed brain activity and variations in a gene regulating serotonin, a brain chemical very influential in people’s emotions. For that study, Hariri and his mentor, Daniel Weinberger, showed research subjects stark, close-cropped, black-and-white photos of fearful- and angry-looking people while they lay inside the fMRI ring. People with a particular version of a gene that influences serotonin levels had more activity in their amygdala, the brain structure some scientists call the hub of fear, than did others. In 2002, when they published their results, Hariri and Weinberger were hailed for being the first to show how a gene influences how our brains work.

The findings caught the attention of psychologists Terrie Moffitt and Avshalom Caspi, who had been exploring the influence of genes on behavior at King’s College in London. That same year, Moffitt and Caspi had published research showing that abused children with a particular version of a gene involved in chemical messaging in the brain were more likely to develop antisocial personalities than those without the variant. In 2003, they showed that having the gene variant that Hariri and Weinberger had reported on increased a person’s vulnerability to depression after stressful experiences.

A few years later, when the husbandand- wife team was recruited to join the Duke faculty, they asked the university to bring in someone adept in both fMRI and genetics to help them advance their work in those areas. Specifically, they wanted Hariri, who by then was on the faculty at the University of Pittsburgh.

“This work requires so much specialty knowledge. You’ve got to be good at genetics and brain imaging, which are both difficult to learn,” says Moffitt, the Knut Schmidt Nielsen Professor of psychology and neuroscience. “Ahmad is right out front.” (Caspi is the Edward M. Arnett Professor of psychology and neuroscience.)

These days Hariri, who joined Duke’s faculty in 2009, chases more complicated targets than he did at the NIH. Our three-pound brains hold billions of neurons, many of them connected to precise circuits. The ways those neural networks receive and process information in different regions of the brain allow us to learn, love, strategize, flee danger, and process pretty much every human experience. Differences in the function of those circuits may help explain some of every person’s distinctive personality traits.

For many years, the prevailing idea has been that depression, anxiety, and addiction were different diseases with distinct neurological causes. If the behaviors differed, the reasoning went, the underlying biology must diverge, too. So researchers hunted for separate genetic seeds for those roots, knowing an influential gene could guide better drug therapy or give psychologists and psychiatrists better diagnostic tools.

But Moffitt, Caspi, Hariri, and others are beginning to wonder whether that prevailing mental-health paradigm should be busted open. They are observing similarities in genetic profiles and in brain function across disease categories. “My science tells me that people who have depression and anxiety are very similar to one another. People with violent behavior and addiction are very similar to one another,” Moffitt says. “How they act depends on how they were raised and what their opportunities are. One person may go into gambling, another into alcoholism. Underlying at the brain level, they are probably the same.”

That’s all the more reason to look at a lot of brains.

After Ella dutifully answered all of the personality survey questions, Annchen Knodt, a research analyst in Hariri’s lab, asked if she was ready to walk to Duke Hospital to get her brain scanned. In minutes the women had stepped through a side door of the Sociology-Psychology Building and zipped up the few stone stairs to the Davison Building.

Walking down one hall after another in the teeming human hive that is Duke Medical Center at midday, Knodt briefed Ella on what was ahead. “Besides staying still, the most important thing is that you have to stay awake,” she said. “We don’t want to see what your brain looks like when you are asleep. We want to see how it responds to tasks.”

 Credit: Arien Schumer

Duke students get several things in return for taking that walk with Knodt or another member of Hariri’s research team. The study, funded mostly by the university, pays each student $120. Many participants report that the personality survey makes them reflect on parts of themselves they hadn’t considered before. And they obtain a reward widely available only in the early twenty-first century: In exchange for two milliliters of spit deposited into a plastic test tube, they receive a detailed analysis of their DNA from the private genetics company 23andMe. In addition to giving participants private access to the secrets of their DNA, the company adds the results— scrubbed of any identifying information— to its own research databases.

Knodt told Ella she should expect to see both matching and guessing tasks flash on a screen during her fMRI scan. In one task, she would guess whether a hidden number was lower or higher than the number five. In another, she would choose an image that matches another visible on the screen. Just use your first and middle finger to point to the answer on the screen, Knodt advised, promising to coach her through the exercises.

At the Duke Brain Imaging and Analysis Center, technician Luke Pool motioned Ella to walk though a metal detector to make sure she wasn’t bringing anything magnetic into the fMRI chamber. Then he walked her into a dimly lit room and helped her settle on a flat bed that slides into the big ring that houses the fMRI magnet. Knodt watched Ella through a window in the control room.

“Are you okay, Ella?” Knodt asked over an intercom. Ella, who had appeared calm and relaxed from the moment she entered the basement lab, assured her that she was.

In the control room, black-and-white images popped up on Pool’s screen, revealing three views of Ella’s brain, a ridged mass of gray and white seeming to float in the faint outline of her cranium. Knodt stared at another screen, which showed a close-up view of Ella’s right eye. She would watch to make sure it stayed open—a number of students fall asleep during the scan, despite the loud clanging of the machine. “We’re going to start the tasks,” Knodt reported.

The test proceeded as Knodt had described, with a few surprises. For one thing, the number matching tests proved harder than the simple practice screens Ella had run through on a desktop computer earlier. The program is designed to ensure students fail at least some of the time so that the fMRI picks up both positive and negative reactions. Periodically, the screen flashed with black-and-white photographs of faces, the same sort that Hariri and his NIH mentor used in the serotonin experiment. Some photographs showed neutral expressions, but many of the faces revealed extreme anger, surprise, or fear. Although Ella probably didn’t realize it, those photographs caused portions of her brain to light up with activity, giving Hariri a visual roadmap of how her brain processes emotion.

She saw the technician's screen. "Is that my brain?" she asked. "Can I take a picture?"

Hariri, a tall guy who wears crisp sports jackets with jeans on campus, has a reputation for being an enthusiastic and creative teacher. When the material gets tough in a lecture, he likes to lighten things up, driving home complex science with inspired goofiness. Sometimes he calls on Batman to help. In some DC Comics, he’ll tell his students, the caped crusader squares off against a villain named Amygdala, a giant, raging mass of muscle who slams, stomps, and storms through cities. Only Batman can still the menace.

Hariri has had his own confrontations with Amygdala—or, at least, the real-life version, an almond-shaped structure found deep inside the brain. The amygdala processes information from the five senses and is particularly good at sounding alarms, shooting off signals when we sense danger. “This ancient structure in the brain exists in every animal with a backbone. It’s been there for eons to protect you from harm in your environment. It helps you learn what is important, avoid threat, seek reward—in other words, position you so that you live to fight another day,” Hariri says.

Much of Hariri’s work explores the interactions between the amygdala and the prefrontal cortex, which handles higherlevel functions such as planning, decisionmaking, and social behaviors. (As many parents might guess, it’s a part of the brain that is still developing in teenagers.) One of its roles is to tamp down the alarm function of the amygdala and plan a measured response from its signals.

But in real life, the prefrontal cortex isn’t as successful as Batman. It can’t always quiet the amygdala, and in some people the alarm function keeps ringing even when there’s no apparent threat. “Most, if not all, disorders of mood and anxiety are [associated with] ineffective prefrontal regulation of the amygdala,” says Hariri. That’s one reason for the scary faces in Ella’s test. He wants to see whether those kinds of amygdala problems show up in our genes—and what other ways they influence our behavior.

Credit: Arien Schumer

One of Hariri’s graduate students, Yuliya Nikolova, already has used data from the study to make such a connection. Nikolova observed that a student’s propensity to binge drink might hinge on a three-way interaction among stress, the amygdala, and what are called reward circuits in the brain. Reward circuits evolved to reinforce actions that ensure a species’ survival, like eating or having sex, but other things, like drinking alcohol or using drugs, can trigger them. The study found that students with particularly active reward circuits were more likely to report binge drinking in times of stress—but only if they also had relatively weak threat signals from the amygdala. The research suggests that an amygdala on high alarm may be enough to keep someone from acting on their rewardseeking impulses.

Hariri anticipates some critique of the database he’s building one Duke brain at a time. He is quick to point out the obvious limitations of studying a population of Duke undergraduates, with their higherthan- average intelligence and socioeconomic status. But he says the stresses of college life, the diversity of Duke’s student body, and the sheer size of the study are enough to yield plenty of variation.

“There is this knee-jerk reflex that, oh, this is not representative,” he says. “That’s nonsense. They’re not aliens. We’re not studying Martians.”

Besides, he’s not looking for what distinguishes Duke students. He is hunting for commonalities in the brain activity, genetics, and behavior shared by some. Identifying such patterns could provide a shortcut to spotting and treating mentalhealth issues in many others. Although an fMRI scan may be able to spot an overalert amygdala, brain-imaging technology is too expensive and unwieldy to be an effective diagnostic tool. But what if a simple genetic screen could identify people with such a trait—people who might be vulnerable to struggles with anxiety or depression? Such a test could help parents and health-care providers step in and try to prevent a slide into mental illness.

Although Ella probably didn't realize it, those photographs caused portions of her brain to light up with activity, giving Hariri a visual roadmap of how her brain processes emotion.

Hariri suspects those telltale genetic differences aren’t likely to be the rare, exotic mutations that medicine once hoped would explain such diseases. The key, he says, will be to understand how tiny, relatively common genetic variations called polymorphisms lead to a range of behaviors.

“You won’t simply put someone in a [diagnostic] category and then think of them only as that,” he says. “You can consider very core processes or symptoms and how you can address those symptoms. That could change the focus on treatment to some extent.”

Take, for example, something as universal as bouncing back from a disappointment. Most people who confront failure at an important goal are able to move on, but a few are not. They dwell on and repeat their mistakes, deepening their frustration and stress and, in some cases, leading to outright depression. Duke psychologist Tim Strauman is seeing evidence that a genetic variant Hariri first brought to his attention may explain why this group struggles with failure. He and his team have developed an intervention to help people protect themselves from that sort of spiral.

“Ahmad is a big thinker and a game changer,” says Strauman, a professor of psychology and neuroscience who helped recruit Hariri to Duke. “This could change how we understand the influence of genetic processes on behavior.”

Ella did well during her fMRI screening. Her one eye visible in Knodt’s screen seemed to start to close on a couple of occasions, but she did not fall sound asleep. She tackled the tasks that played out on the screen. After Pool helped her down from the fMRI bed, she entered the control room squinting a bit, preparing to take one more short survey and gather her things. Then she saw the technician’s screen. “Is that my brain?” she asked.

Ella explained that she signed up for the study after seeing a flier in a campus restroom stall that asked Do You Have a Brain? She does, of course, and a good one at that. The money DNS was paying was an inviting reason to sign up as a research subject, but like many DNS volunteers, she was driven partly by curiosity. She wanted to catch a glimpse of what she knew so well, yet didn’t know at all.

“Can I take a picture?” she asked softly, reaching for her smart phone.

Ella landed the portrait and much more. In a few weeks, she received an email message from 23andMe notifying her that she could access her DNA screen results. When she dug into her free account, she learned that she might have a slightly higher chance of developing Parkinson’s or Alzheimer’s later in life.

The news didn’t shake her. “This is what I’m born with,” she says. “There are things I can’t change.”

Of course that is true, she cannot change her brain. But as Ella left Duke Medical Center after her scan and reentered the bustle of West Quad, an intriguing possibility remained. She—and hundreds of her peers—may just change neuroscience.

Clabby is a journalist and the senior editor of E.O. Wilson’s Life on Earth, the E.O. Wilson Biodiversity Foundation’s digital biology textbook.