Bret S. Stetka, MD

Disclosures

June 10, 2014

In This Article

Clinical Implications and Manipulating Memory

The ultimate goal of this work is, of course, to treat patients suffering from anxiety. The data suggest that it might be possible to predict who will respond to certain therapies on the basis of their genetic profile and its correlation with fear extinction.

One study[10] showed that adults with posttraumatic stress disorder who have the BDNF Val66Met polymorphism do not respond well to exposure CBT. Collaborative work between Casey and Lee looked at fear conditioning across all ages to determine whether certain age groups are better or less able to extinguish fear memories.[11]

In response to the same negative cues as in their previous work, preadolescent and adult mice showed considerable fear extinction, whereas adolescent mice showed little to none. Humans showed a similar response pattern. Using expression of the c-Fos gene -- an indirect marker of neuronal activity -- the investigators showed that the PFC is not heavily recruited in adolescents; hence, their fear does not extinguish as well with repeated presentation of empty threat cues.

These data suggest that individuals of certain ages may not be as responsive to exposure-based CBT. Examination of existing clinical data by Casey and her colleague Dr. John Walkup indicate that this may be the case, but further research is needed, Collectively, this work provides evidence for whom and when exposure forms of CBT may be most effective.[12]

Bringing it back to the neurobiological underpinnings of anxiety, Casey concluded by highlighting ongoing work in her laboratory looking at how anxiety might be alleviated by bypassing the reliance on the crucial projections from the PFC to the amygdala that are still developing during adolescence and altering fear memories themselves at the level of the amygdala. "Memory is not static, but dynamic," said Casey. "When we learn something, we store it in memory. But every time we retrieve it, we update it with new information. We can attach new meaning to that memory."

Is altering a memory that easy? Possibly. Casey and her colleagues wanted to attenuate fear memories by altering the memory during the so-called memory "reconsolidation window," which appears to be between 10 minutes and a few hours after retrieval of an existing memory. Building on work in adults by Monfils and colleagues[13] and Schiller and colleagues,[14] they first applied their reliable unpleasant noise/colored square method to induce fear acquisition. Before extinction training of the fear memory, they presented the square that had been paired with unpleasant noise as a reminder.

After waiting 10-15 minutes -- to coincide with the reconsolidation window -- extinction learning was initiated. Those not exposed to the reminder cue before extinction learning showed an arousal response when retested the next day. Those reminded did not.

"This finding suggests that one way to work around exposure-resistant fear and anxiety is by taking advantage of this period of reconsolidation," said Casey, nearing the end of her talk. It's not that CBT doesn't work across the board in adolescents, but rather that the correct type and timing of the CBT are essential.

Casey suggests that clinicians build on the reconsolidation window findings in the clinic. First, the patient comes in to the clinic and is reminded of why they are there (reminder cue). Then, clinicians establish a positive and safe rapport with the patient for 10-15 minutes -- waiting for that critical window of apparent plasticity (reconsolidation window) -- and then they initiate exposure therapy. "Many clinicians are already doing this," Casey commented, "but [previously], we just didn't have the evidence for why this timing may be so effective for some and not others."

Following Casey's talk, during the Q&A session, an audience member asked whether the data presented during the previous hour suggest that the "preadolescent anxious kid inevitably becomes the adolescent anxious kid."

Casey's response suggested that all hope is not lost -- that intervening early before the circuitry becomes hard-wired may be the best hope for alleviating anxiety. This will require better and earlier identification of those at risk in order to intervene and ultimately prevent the anxiety from escalating. "I treat a lot of college students with social phobia who are terrified to speak in classes," she responded, "If they'd gotten exposure therapy earlier, would they by more amenable to therapy now? It's possible. But we just don't know."

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