Zeroing in on the Workings of an Anxious Brain

Nov. 30, 2007
by Jordana Lenon

An anxious temperament can underlie excessive shyness in childhood and is a risk factor for the development of anxiety and affective disorders. University of Wisconsin-Madison researchers Ned Kalin, Steve Shelton and Richard Davidson recently discovered how the primate orbitofrontal cortex, or OFC, mediates fear responses and is linked to the anxious temperament. Their findings appeared Nov. 15 in the journal Biological Psychiatry.

Studies by Kalin’s group in nonhuman primates have long provided information related to the anxious temperament. The team’s earlier studies developed a rhesus monkey model to study threat-induced freezing, which is a trait analogous to human behavioral inhibition. Earlier work by Kalin, Shelton and Davidson demonstrated the involvement of the amygdala in mediating this temperament. Now the researchers have added the role of the OFC to their understanding of the brain circuitry involved in processing emotions and anxiety.

The researchers worked with colleagues and resources from the HealthEmotions Research Institute, Wisconsin National Primate Research Center, Harlow Center for Biological Psychology, and Laboratory for Functional Brain Imaging and Behavior at the Waisman Center. They studied 12 adolescent rhesus monkeys—six study animals and six controls.

“We assessed behavior and physiological parameters before and after specific lesions were made in the area of the OFC that is most interconnected with the amygdala,” Shelton said. “Following surgery the monkeys appeared and acted normally. The procedures succeeded in dampening only fearful and anxious behaviors; they did not affect the animal’s locomotion, vocalization, hostile behavior or any other behaviors unrelated to fear.”

The subtle changes the researchers were interested in were only revealed when they challenged the subjects on specific tasks, Shelton explained. One of the behavioral tasks was based on the monkeys’ innate tendency to be fearful of snakes. The animals were first adapted to the test cage and their food preferences were determined. On separate trials, the monkeys were challenged to reach for their favorite foods when placed, either atop an empty clear plastic box, or on one containing either a live northern pine snake, rubber snake, or roll of blue masking tape. All monkeys performed the same order of trials on a single day. Each stimulus was presented six times for 60 seconds; however, to prevent the initial encounter with the snake from affecting the monkeys’ response during successive trials, the real snake was never presented during the first five trials. Research technicians recorded up to a maximum of a minute the time it took for the monkeys to reach for the food above each of the objects. Another behavioral task was used to assess the length of time an animal freezes or was behaviorally inhibited in the presence of a human avoiding eye contact with the monkey.

After the behavioral test results, electroencephalograms (EEG), and stress hormones were analyzed. Kalin, Shelton and Davidson concurred that OFC disruption significantly decreased threat-induced freezing and marginally decreased fearful responses. The animals also presented a leftward shift in frontal brain electrical activity, which is also known to accompany a reduction in anxiety in people.

These findings clarify more of the biological mechanisms that drive both threat-induced freezing in adolescent rhesus monkeys and behavioral inhibition in children. By studying normal OFC function in nonhuman primates, then by altering it in targeted ways to elucidate different responses, the scientists learned more about the underpinnings of anxiety and fear. Understanding especially how the amygdala and the OFC work together generates new knowledge that researchers and clinicians can use to assess neural pathways and develop new therapies for either overly fearful individuals or, conversely, for those who lack healthy inhibitory responses.

“It was particularly interesting to find that the OFC lesions reduced threat-induced freezing in adolescent monkeys, since in humans anxiety and affective psychopathology emerge during adolescence,” Kalin said. “Furthermore, our finding in adolescent monkeys is consistent with a recent study in children and teenagers with brain injuries. We now have a better model for developing therapies for patients with severe anxieties and perhaps depression.”

For the past 25 years, the discoveries of Kalin, Shelton, and Davidson have shed light on the mechanisms underlying adaptive and maladaptive emotional responses and behaviors. Their findings have helped society better understand mental illnesses and have helped guide the development of potential new treatments including CRH antagonists for patients with illnesses such as depression and anxiety.

Kalin is professor and chair of the Psychiatry Department and directs the HealthEmotions Research Institute. Davidson, a Vilas professor of psychology and psychiatry, co-developed the institute with Kalin and directs the Laboratory and Behavior at the Waisman Center. Shelton is a distinguished researcher in psychiatry, is based in the Harlow Center for Biological Psychology, and coordinates the team’s work with the Wisconsin National Primate Research Center and the Laboratory for Functional Brain Imaging.

*Kalin NH, Shelton SE, Davidson RJ. Role of the primate orbitofrontal cortex in mediating anxious temperament. Biol Psychiatry. 2007 Nov 15;62(10):1134–1139.