Ahmad Hariri discusses neuroimaging gene mapping with research assistant Vanessa Sochat. Photo credit: Jon Gardiner

Durham, NC - You can draw a map of the brain, and you can draw a map of genes. But what would it take to make a map that connects both?

Ahmad Hariri, who joined Duke this fall as a professor of Psychology and Neuroscience, aims to do just that. With a creative blend of the latest neuroimaging technologies, psychoactive drugs, genomics and good old-fashioned personality tests, he is mapping variations in brain circuitry that may predict variations in behavior.

He'd like to understand the individual differences -- some of them inherited -- that underlie our behaviors. Why does one person react to a stressful situation with a lifetime of depression, anxiety and post-traumatic stress, when another seems none the worse for wear? What might be the structural and biochemical roots of a disease like bipolar disorder?

"I want the work to have the potential to inform medicine and help people -- and even beyond that, to inform policy," says Hariri, 37, who also has academic appointments in the Institute for Genome Sciences & Policy and the Duke Institute for Brain Sciences. "You can't protect people from environmental stressors," he says. "You can't lock people up in padded rooms."

Hariri's new colleagues at Duke, Avshalom Caspi and Terrie Moffitt, have used epidemiological methods to find an apparent genetic predisposition to adult depression in people who were traumatized as children. Hariri's work promises to find the precise mechanisms for why that may be true.

"He has sort of single-handedly launched this new area that he calls imaging genetics," Moffitt 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," she said.

The son of Iranian parents who emigrated to Arkansas when he was a child, Hariri started out in science pursuing the familiar path of evolutionary biology, using fruitflies and other models to try to understand where species come from and why hybrids are sterile. But a graduate seminar in animal communication at the University of Maryland suddenly blew him off course. They were discussing how the new technology of neuroimaging could see a brain processing language, "and I thought, 'this is so cool!'"

After volunteering in a neuroimaging lab at the nearby National Institutes of Health, Hariri switched fields and schools, finishing his PhD at UCLA with Susan Bookheimer. Then it was back to the NIH for a 3-year post-doc. He comes to Duke from the University of Pittsburgh, where he was on faculty for six years.

Neuroimaging has opened up huge new vistas for scientists who can, for example, inject a tracer that they know will concentrate around a particular type of cell and then watch in real time as a brain deals with a task. Being able to see how one brain's structure might differ from another is the beginning of inferring how structural differences may account for why individuals think or behave differently.

"We're not able to profile an individual," Hariri is quick to add. "We can talk in general patterns across a large group of people."

Hariri's earlier work focused largely on the amygdala, a small brain structure that is crucial to the formation of emotional states. It also plays a role in encoding memories that have an emotional component, such as a traumatic event. A damaged amygdala can prevent a person from forming a fear response to something that they should avoid.

To see the amygdala at work, it isn't necessary to actually traumatize a person, you merely have to get them to think about emotions, Hariri says. Under a protocol dubbed "Hariri's Hammer" by his students, a subject lying in an MRI machine is shown a trio of faces with distinct expressions such as fear and anger. The subject is simply asked to match a pair of faces that show the same emotion. They shouldn't be at all stressed by the exercise, but "it gets massive responses in the amygdala."

With FDA-approved drugs that can tweak known signaling systems of the brain, such as serotonin, dopamine, glutamate and acetylcholine, Hariri's team has also been able to watch a brain's response to different biochemistry.

Now Hariri is going down yet another level to look at the underlying genetic differences that may account for the biochemical and structural differences. "We're using as many of the tools as we have available to study behavior," Hariri says. "But we're really just skimming the very surface of this ocean of information."

He calls what he does now "mapping circuitry onto behavior."

Hariri has begun pursuing single-letter variations in the spelling of a particular gene that may account for a ten percent difference in anxiety responses in the amygdala. The hope is that this and other single-letter differences in a person's genetic code may be markers for what shows up in brain scans and behavior.

At Duke, he intends to enroll about 1,200 freshmen in a broad and long-term brain study over the next few years. They'll undergo a battery of behavior, cognitive and clinical assessments, some neuroimaging, and some genotyping. Besides being a convenient testing population, Hariri says he became convinced that the transformative process of college would be a good window into the emotional stress responses of the brain.

"We may be able to get to the risk of diseases and we may be able to find the pathways where we could prevent the disorder from ever occurring," he says. "To shift trajectories before they even begin to manifest, that's the dream."