2012 Keynote Speaker: Dr. BJ Casey

Development of Fear-Related Processes: From Human Imaging to Mouse Genetics

Invited address by BJ Casey, Ph.D., Sackler Professor and Director of the Sackler Institute at Weill Medical College of Cornell University

Dr. BJ Casey delivered an address that detailed her decades-long program of research looking to understand the changes in the brain during the transitions into and out of adolescence. Why do impulsivity and risk-taking peak during this time? And on the other hand, why do anxiety and mood disorders become so prevalent in this age range? Whereas some have argued the characteristic emotional reactivity and behavioral recklessness of the teenage years is driven by an immature prefrontal cortex (PFC), a region of the brain associated with executive control, Casey points out that younger children have even less mature frontal cortices. And yet adolescence is uniquely marked by increases in emotional lability and risky behaviors. Rather than focusing entirely on the PFC, then, Casey contends that research concerned with the ways in which frontal regions interact with limbic regions relating to emotions and desires—what she calls the "imbalance model" of adolescence— is the way forward.

Casey went on to present evidence to support this claim from a wide range of studies in both humans and animals. For example, in a 2008 study published in Biological Psychiatry, Casey and colleagues demonstrated that—compared to both younger children and older adults—adolescents showed increased reactivity of the amygdala (a region involved in processing fear) to threat cues, suggesting that adolescents are more emotionally reactive than both children and adults, and might need more executive control to regulate their responses. Upon repeated presentation of these threatening stimuli, the amygdala response decreased in all participants—a process known as habituation. However, the more anxious an adolescent was, the less habituation was observed. Moreover, this decrease in habituation was related to fewer connections between frontal regions and the amygdala, suggesting the frontal cortex was less successful at regulating emotional responses in these adolescents. Thus, it appears that the fewer connections an adolescent has between these two regions, the less success he or she will have in damping down their emotional response, and the more at risk they will be for psychological disorders.

Further research in humans has also shown adolescents are less adept at "unlearning" fear once it's learned (a process known as "extinction"), again compared to both adults and children—and this deficit appears to be tied again to development of both frontal cortical sites and limbic sites, as well as the connections between them. As Casey notes, these findings go a long way to explaining why cognitive behavioral therapies—which appear to rely in part on the ability of frontal areas to re-train limbic areas—are least effective between the ages of 11 and 17.

To follow up on this research, Casey and her colleagues genetically-modified a group of mice—Casey calls them "wallflower" mice—to see whether mice with a certain variant of the brain-derived neurotrophic factor (BDNF) gene, which has been linked to depression, would show the same difficulties in habituation. And indeed, the wallflower mice not only continued to show a heightened fear response to fear cues, they also failed to activate frontal regions to the same extent as the normal mice during the process of extinction learning.

Using these—and many other—studies as a foundation, Casey and her colleagues are currently exploring how it is they might make adolescents look more like adults (or children) in terms of their ability to un-learn fear. In a series of studies that Casey is calling "way cool but way early," her team is exploring what happens when, prior to beginning extinction of a conditioned fear, adolescents are presented with a reminder of the conditioned fear cue during a process known as the reconsolidation period. "Memories are dynamic," says Casey, noting that, during this reconsolidation period, the memory of the fear cue is activated and made more labile. When adolescents undergo this reminder-reconsolidation procedure, they do indeed look more like adults and children—fear extinction occurs. Though this is an ongoing study, the results are promising—and, if they bear out, indicate a path by which therapies for adolescents could be made more effective.