Bias on the Brain

Brain Studies Seek the Genetic Roots of Our Differences in Personality and Behavior.

Are you someone who revels in the thrill of a roller coaster ride, or do you find yourself cringing at the mere thought of all those twists and turns? Do you obsess over problems and criticisms, or do you step back and consider the bigger picture? Your answers to these questions, along with the many other ways in which you react and respond to events in your life can ultimately be traced back to crackles of activity in your brain. Duke’s Ahmad Hariri wants to understand those brain patterns, where they come from, and ultimately how they make each of us who we are.

“I’m fascinated by how incredibly different people are from each other, not just in the way they look but in the way they respond behaviorally to their worlds, to each other, to the challenges they face and the stress they encounter,” says Hariri, professor of Psychology & Neuroscience and member of the IGSP. “That’s what drives us.”

In an effort to sort all that out, Hariri has embarked on an ambitious effort he calls the Duke Neurogenetics Study. Billed as the largest study of its kind in the world, the effort is designed to establish a database of overlapping behavioral, neural and genetic measures, allowing both exploratory genome-wide studies as well as more careful consideration of the role obvious gene candidates play in defining our personalities and our behaviors. Ultimately, the goal is to trace those differences back to their tangled roots.

Duke students enrolled in the study visit the Hariri lab three times to undergo IQ and memory testing, take a mental health screen, and answer more than 600 questions about themselves. Each participant’s brain is then scanned by magnetic resonance imaging (MRI) to assess brain function and how different parts of the brain are connected to one another. Finally, students offer up a saliva sample that is then sent off to personal genomics company and research collaborator 23andMe for genome analysis.

Fear Factors

Hariri says they have almost 350 undergraduates enrolled thus far, and they hope to reach 500 by this spring semester. Ultimately, they aim to build the database up to 1,000 individuals. “We need a database at least that large to look at gene-gene interactions, gene-environment interactions, and moderators of pathways,” he says.

Most of Hariri’s work to-date has focused on what he refers to as the low-hanging fruit. That includes gene variants in pathways already known to influence brain chemistry: the neurotransmitters serotonin and dopamine, for instance.

In the mid-1990′s, other studies had linked variation in the expression of a serotonin transporter gene to differences in neuroticism and anxiety. Serotonin was also known to influence normal fear.

Hariri was able to show that people with one or two copies of a particular version of serotonin transporter associated with higher serotonin activity had a more active amygdala, the brain’s central processer of fear. He later found that variation in genes related to the neurotransmission of dopamine influence impulsive behavior through their effects on reward centers of the brain.

None of this is to suggest that a person’s genes alone can tell you much about how that person will behave in the real world. A report from Hariri’s lab earlier this year showed that perceived social support can act as a kind of buffer for our genetic predispositions. While the genes we carry may influence the way our amygdala lights up in response to threats, the anxiety we experience depends on whether or not we feel supported by those around us.

“Genes provide the starting point, and that’s it,” Hariri says. “They affect some small bias in the way the brain of an individual processes information.”

Game of Life

That bias in the brain isn’t necessarily good or bad, he says. One version of the serotonin transporter can mean a predisposition toward anxiety and depression. But it can also mean a more sensitive, open and compassionate person. Likewise, a different variant can be associated with a lower risk for anxiety, but also a callous lack of emotion.

The way that differences in amygdala activity play out in the world depends on the activity in still other parts of our brains, including those that regulate our behaviors. Sorting all that out will take a very large sample size, Hariri knows, and that’s exactly what he is after with his neurogenetics study.

“Genes provide the starting point, and that’s it. They affect some small bias in the way the brain of an individual processes information.”
—Ahmad Hariri

Hariri’s approach has been described as a creative blend of the latest neuroimaging techniques, genomics and good old-fashioned personality tests. While Duke colleagues Avshalom Caspi and Terrie Moffitt have relied on longitudinal studies to discover, for example, that the serotonin transporter gene is linked to risk for long-term mood disorders only in those who have also experienced trauma (see “Life Courses” in the September/October 2011 issue of GenomeLIFE), Hariri promises to find the biological underpinnings in the brain that help to explain those findings.

“Ahmad has sort of single-handedly launched this new area that he calls imaging genetics,” Moffitt has said. “Mastering either imaging or genetics is quite enough to ask of a young scientist, but he has somehow managed to master both of them.”

Hariri says his imaging genetics approach holds special promise because patterns of brain activity offer a reasonable approximation for the underlying brain chemistry, which is otherwise very difficult if not impossible to measure. His group is also beginning to come up with ways to combine genes that are related to particular brain signals and consider them jointly. His team recently showed they could account for about 10 percent of the variation in reward-related activity in the brain based on a five-gene profile.

Still, there is a long way to go and Hariri likes to joke that the complexity of the task will ensure his own job security. “We’re not going to stumble on any definitive answers in the foreseeable future,” he says. “We’ll just keep plugging away at it.”

The magnitude of the challenge has only grown with the realization in recent years that none of this is fixed; it is more aptly described as a dynamic interplay.

“Our genes are at the “GO” square on the Monopoly board of life,” Hariri says. “They set the stage for brain chemistry and circuitry, but they are also reshaped as their expression is modified by our experiences. It’s a constant back and forth, and it all comes back to what is happening inside our brains.”

Clinical Indications

Although Hariri got his start in imaging genetics as a postdoctoral researcher in a lab largely focused on schizophrenia, he is clear that his main interests as a biologist and neuroscientist by training aren’t in mental health or disease. That’s why his study focuses on healthy undergraduates as opposed to people representing this or that diagnosis. Nevertheless, the work he does is likely to yield new insights into mental health and psychopathology that will prove clinically useful.

For one thing, a better understanding of the brain pathways underlying behavior could lead to better drugs, he says, noting that the familiar SSRIs (selective serotonin reuptake inhibitors, including Prozac and Paxil) are effective in less than 50 percent of the people who take them.

“Targeting serotonin for depression is not at all dissimilar from using aspirin for a headache,” he says, citing a commonly used analogy. In neither case is there compelling evidence that the drug acts on the source of the problem.

Methods used to profile brain activity and chemistry, perhaps using genomic scans as a proxy, might also help to determine the best course for therapy. Some people surely do need drugs to stabilize them before they can learn strategies to better cope with their emotions. Others might be able to skip the drugs completely.

In some cases, it may even be possible to avert mental illness altogether, by acting on pathways in the brain early. “That’s the dream,” Hariri says. His work suggests that this might sometimes be as simple as instituting programs ensuring adequate social support, especially for young people whose brains are less mature and less able to regulate themselves.

Under Your Skin

Even though participants in his study do get free access to their 23andMe results and he has had his own genome scanned, Hariri cautions that genome testing for behavior or mental illness is not in the cards now.

“In terms of its general value for predicting one’s risk for mental illness or general behavior, it’s no better than having your palms read at this point in time,” he says, while noting that some genetic information provided by 23andMe is already useful in helping individuals understand their relative risk for other types of diseases such as cancer.

He is nonetheless supportive of such services making the information available to those who want it and is convinced that 23andMe’s consumer service will ultimately help to move the science forward. Without their assistance as research collaborators, Hariri would be unable to get the genomic data that his neurogenetics study depends on.

“I was amongst the doubters of 23andMe and other direct-to-consumer companies,” Hariri admits. “I went to the initial meeting not wanting to collaborate, but left with a different perception of what they are doing and of what we can accomplish together. They need scientists to work with them, to help shape and restrain the findings that are reported back to consumers, and to move forward.”

Ultimately, Hariri says the biggest misconception out there when it comes to individual differences is that “they’re only skin deep. Differences in our behavior are as great, if not greater, than those in our physical appearance. More importantly, these individual differences often predict who might succumb to stress and hardship and who will be resilient.”

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