Prefrontal Connection May be Key in Controlling Anxiety


by Jim Schnabel

November 16, 2009

Natural worriers can relax a little: Neuroscientists are beginning to understand their condition. In particular, recent studies suggest that the prefrontal cortex of the brain normally “gets a grip” on excessive anxiety by moderating the activity of a more primitive region known as the amygdala. When this prefrontal-amygdala connection is weak, excessive anxiety can be the result.

“There’s been an explosion of findings” concerning this connection, says Ahmad Hariri, a neuroscientist at Duke University who is prominently involved in the field.

The latest study was reported in the Sept. 16 issue of the Journal of Neuroscience by Dartmouth College researchers Justin Kim and Paul Whalen. The researchers combined two imaging techniques: functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), which works similarly but can map nerve fiber bundles.

The scientists found that when 20 healthy subjects watched standard test images of “fearful” faces, brain activity increased on the fMRI scans. The increases seemed to map to a nerve-fiber bundle known as the uncinate fasciculus (UF)—a major connection between the temporal lobe, which houses the amygdala, and the frontal cortex.

The researchers also found that the thickness of this fiber tract varied inversely with the subjects’ scores on a standard psychological test of inherent anxiety, known as trait anxiety. “So if the two areas are strongly connected, you tend to show lower levels of [the] trait anxiety, and if the connections aren’t as heavy, you tend to be more anxious,” Whalen says.

The prefrontal cortex is the structure that most clearly differentiates human brains from the brains of other primates. Observations of humans with prefrontal cortex damage suggest that this brain region exerts a relatively sophisticated, moderating influence on the simpler, more impulsive and less flexible structures of the limbic system, which humans share with other mammals.

“The prefrontal cortex is supposed to keep areas like the amygdala in check, and instruct them that, for example, ‘I know that’s a snake, but it’s behind a piece of plexiglass, so we’re good,’” Whalen says. “It’s much like a parent and child. Children are less flexible in their responses to situations than parents, whose job is to instruct them and help them regulate.”

Next steps

The findings add to a growing body of evidence explaining the underlying connections of the brain in anxiety. Previous experiments using fMRI alone, for instance, showed that people with high trait anxiety scores tend to have amygdalas that are less coordinated, or “coupled,” with the prefrontal cortex. In other words, higher amygdala activity corresponds to lower prefrontal activity, and vice versa.

A recent neurogenetics study also concluded that people with a genetic variation affecting the serotonin neurotransmitter system tend to have a thinner UF. “These happen to be the same individuals who show increased amygdala reactivity and decreased coupling between the amygdala and medial prefrontal cortex,” Hariri notes.

A good next step, he says, would be to perform imaging experiments in a relatively large sample of subjects to see whether differences in UF structure can usefully predict the degree of amygdala-prefrontal coupling and trait anxiety.

Whalen also wants to start looking at the UF pathway in people with anxiety-related mental health problems. With Lisa Shin, a researcher at Tufts University, he plans to study people who have post-traumatic stress disorder.

Both Whalen and Hariri note that the amygdala also merits more study in general. Though it is popularly portrayed as the brain’s “fear” region, its fear-related functions are associated with only one portion of the amygdala, known as the lateral nucleus. Other systems within the amygdala appear to be activated by a broader range of situations. “You can show happy faces to subjects and the more dorsal parts of the amygdala are quite interested in them,” Whalen says. “We also know that lesions of the amygdala affect [rats’] ability to learn about tones that predict food.”

Thus, he argues, “biologically relevant learning” is probably a better description of the amygdala’s general function. Hariri notes, too, that the amygdala might only help to signal a “baseline level of arousal,” whereas “other parts of the brain such as the prefrontal cortex use that information and elaborate that information in a way that’s relevant for the specific experience of positive or negative emotion.”

Both researchers attribute the traditional emphasis on the amygdala’s fear-related functions largely to the limitations of laboratory techniques. “We know,” Whalen says, “how to make animal subjects afraid better than we know how to make them happy.”