Mismatch vs. Standard Intervention During Memory Reconsolidation Blockade With Propranolol: Effect on Psychophysiological Reactivity During Traumatic Imagery

Overview

The proposed R21 project will attempt to further develop a novel intervention for posttraumatic stress symptoms inspired by the science of memory reconsolidation. Work in normal humans has shown that when a stable, consolidated memory is reactivated (i.e., retrieved) under appropriate conditions, it reverts to an unstable state, a process referred to herein as deconsolidation. In such a state, the memory is susceptible to the action of various "amnestic" agents that may inhibit its reconsolidation, thereby weakening it. The β-adrenergic blocker propranolol (PPNL) possesses such amnestic properties. More recent research has found that in order to initiate deconsolidation, there must be a prediction error, or mismatch, between what is expected and what occurs when the memory is reactivated. Prior placebo-controlled, randomized clinical trials (PBO-RCT) from our laboratory have found that when propranolol is administered concomitant with the reactivation of a psychologically traumatic memory, the memory is weakened, as revealed by subsequent lower physiological (heart rate, skin conductance, facial electromyogram) responding during script-driven mental imagery. Clinical applicability was evaluated in a PBO-RCT, in which PTSD participants receiving propranolol underwent six weekly sessions of 10-20 min of "standard" (STD) traumatic memory reactivation stimulated by reading a narrative. At post-treatment, these participants showed a greater reduction of PTSD symptoms compared to participants who had taken PBO. The goal of the proposed study is to test whether intentionally incorporating innovative mismatch (MM) into traumatic memory reactivation can improve upon physiological responding during script-driven mental imagery. Participants will be randomized to one of 2 treatment arms: STD/PPNL and MM/PPNL. A baseline assessment will measure psychophysiological responsivity to script-driven mental imagery (target measure). PPNL will be administered 90-min prior to each of six weekly 10-20 min. traumatic memory reactivation sessions. In the MM condition, a different, unexpected mismatch (e.g., singing the narrative) will be incorporated into the reactivation. In the STD condition, the participant will read the narrative the same way each time. The focus of the R21 proposal will be to assess whether the MM/PPNL group shows lower subsequent physiological responses than the STD/PPNL group

The proposed project under the R21 Basic Experimental Studies Involving Humans (BESH) mechanism aims to test whether adding 'mismatch' (MM) to traumatic memory reactivation under the influence of the beta-(nor)adrenergic blocker propranolol (PPNL), compared to no mismatch reactivation, further reduces physiological reactivity during script driven imagery of the traumatic event. We propose that the mechanism for the propranolol MM treatment is a) deconsolidation of the traumatic memory instigated by MM, followed by b) blockade of the reconsolidation of the memory by the amnestic agent PPNL. The efficacy of the MM intervention will be contrasted with a standard (STD) reactivation condition that does not include an intentional MM component. We will randomize individuals who have experienced a traumatic event and meet our entry criteria (please see research strategy) to one of the two treatment arms: STD/PPNL and MM/PPNL. Participants' psychophysiological (heart rate, skin conductance, corrugator electromyogram (EMG)) responses during script driven imagery of their traumatic event will constitute the R21 target. On the initial assessment day, participant candidates will be screened for eligibility based upon the inclusion/exclusion criteria. After the candidate provides written informed consent, a doctoral-level clinician will administer the psychometric instruments. Participant candidates will complete a narrative describing the traumatic event that caused PTSD. Based on the narrative, the psychologist will then prepare a 100-word script portraying the most salient aspect ("hot spot") of the narrative, which will be recorded for audio playback in the psychophysiology laboratory. Participants not physiologically reactive to the traumatic script will be excluded. If all of the foregoing is completed successfully, participants will be randomized to one of the two arms above. The participant will return to the clinic one week later for the first of six weekly intervention sessions. Ninety min. prior to its commencement, the participant will ingest the study medication. The participant will then recite the narrative aloud for 10-20 min. In the STD condition, the participant will recite the narrative in an expected manner, i.e., in the same way during each session. In the MM condition, the participant will recite the narrative in an unexpected manner, different for each weekly session. Examples of unexpected conditions will include such things as reciting their narrative while skipping over each word that contains the letter "e", and reciting the narrative in a make-believe accent. A week following the final intervention session, the participant will return for the post-treatment psychophysiological testing. These will be repeated at the one-month follow-up session. The data will be analyzed by hierarchical linear modeling and regression techniques. The projected sample sizes will provide adequate power to test the proposed study's hypotheses (see Design and Power Analysis section).