Barbara O. Rothbaum - US grants

This proposal aims to test the feasibility of virtual reality exposure (VRE) treatment for the fear of flying (FoF). The FoF is a debilitating disorder that causes substantial impairment in occupational and social functioning, effecting an estimated 10-25% of the population. The difficulty and expense of using airplanes for exposure have daunted many researchers and therapists. VRE is potentially an efficient and cost- effective treatment of FoF. The primary goal of Phase I is to determine the relative efficacy of VRE versus standard exposure therapy (SE) compared to a wait list (WL) control. Sixty patients with FoF will be randomly assigned to one of three groups: VRE, SE, or WL. Standard paper and pencil measures pre- and post-treatment and at 6 and 12 month follow-ups and a post-treatment test flight will assess Ss' anxiety and avoidance. All assessments will be conducted by a blind Independent Assessor. Phase II will test the relative efficacy of VRE and SE versus WL for agoraphobia. The long-term objectives include the development of efficacious and affordable turnkey PC systems that will be commercially available to other researchers and therapists to deliver Virtually Better (TM) virtual reality exposure therapy. PROPOSED COMMERCIAL APPLICATION: The commercial applications include 1) the sale of these PC based systems to researchers and therapists to deliver Virtually Better(TM) virtual reality exposure therapy; 2) the delivery of Virtually Better(TM) virtual reality exposure therapy in clinics to individual patients; and 3) the training of researchers and therapists in this type of therapy.

DESCRIPTION: (adapted from applicant's abstract) Post-Traumatic Stress Disorder (PTSD) is an anxiety disorder characterized by symptoms of re-experiencing the trauma, emotional numbing and avoidance, and increased arousal. PTSD is one of the most disabling psychopathological conditions affecting the veteran population. An estimated 830,000 Vietnam veterans currently have symptoms of chronic combat-related PTSD. The purpose of this Phase I STTR is to test the feasibility of a new Virtual Reality Exposure (VRE) treatment in the treatment of Vietnam War veterans with PTSD. The relative efficacy of VRE versus a waitlist control group will be explored. Random assignment of participants, standardized treatment delivery, homogeneous DSM inclusion criteria, standardized measures, and blind independent assessment will assure a methodologically rigorous study, although with a relatively small sample size (n=20). Psychophysiological assessment incorporating the virtual Vietnam VE as an activating stimulus will be tested. Virtually Better, Inc. will collaborate with The National Center for PTSD, the foremost program internationally for research and treatment on combat-related PTSD, according to the applicant. If this Phase I project is successful, Phase II will test the Virtual Vietnam against other standard treatments for PTSD in Vietnam combat veterans in a larger controlled study. There are 172 VA treatment facilities, the potential market for this product. PROPOSED COMMERCIAL APPLICATION: There are 172 VA treatment facilities, the potential market for this product.

Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Behavioral; CRISP; Chromosome Pairing; Common Rat Strains; Computer Retrieval of Information on Scientific Projects Database; Conditioned Stimulus; Cycloserine; Depotentiation; Exposure to; Extinction; Extinction (Psychology); Fear; Fright; Funding; Grant; Homosynaptic Depression; Human; Human, General; Institution; Investigators; Learning; Mammals, Rats; Man (Taxonomy); Man, Modern; NIH; National Institutes of Health; National Institutes of Health (U.S.); Process; Psychotherapy; R-4-Amino-3-isoxazolidinone; Rat; Rattus; Recovery; Recruitment Activity; Reporting; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Stimulus; Synapses; Synapsis; Synapsis, Chromosomal; Synaptic; Time; Translational Research; Translational Research Enterprise; Translational Science; United States National Institutes of Health; Work; amygdaloid nuclear complex; base; behavioral extinction; conditioned fear; fear conditioning; recruit; response; translation research enterprise

DESCRIPTION (provided by applicant): Extinction of fear is thought to use similar learning mechanisms as learning or conditioning of fear, and both are blocked by antagonists at the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Futhermore, agonists at this site appear to augment some forms of learning in animal and human trials. The process of extinction of conditioned fear has recently been shown to be facilitated by D-Cycloserine (DCS), an NMDA agonist, given in individual doses prior to extinction training in an animal model. We have preliminary evidence that a similar effect is found in human subjects undergoing controlled exposure therapy for specific phobia. This translational research application represents a blinded, randomized, placebo-controlled efficacy study with the goal of determining whether a drug that acutely enhances learning in animal models will facilitate the extinction of fear that occurs with behavioral exposure therapy and whether a drug that has been shown to interfere with the extinction of fear will decrease the efficacy of exposure therapy. Specifically, it is proposed that a single dose of DCS, given shortly before each of 2 individual virtual reality exposure (VRE) therapy sessions, will significantly enhance the rate of response and possibly the efficacy of treatment, and that a single dose of alprazolam, a benzodiazepine, given shortly before each of 2 VRE therapy sessions, will significantly retard the long term efficacy of treatment. To this end, we propose to enroll 176 participants with the fear of public speaking to achieve 132 completers, or approximately 44 per group. Participants will be randomly assigned to receive VRE in combination with 50 mg DCS, placebo, or .5mg Alprazolam. Comprehensive multi-modal outcomes will be assessed by independent assessors blind to subject condition on interviews, self-report measures, psychophysiological measures, and a behavioral avoidance test consisting of an actual speech in front of a live audience. Participants will be assessed pre- and post-treatment and at follow-ups of 3 and 12 months to assess long-term effects. This type of combined treatment - specific pharmacotherapeutic augmentation of psychotherapy - would be novel and would potentially be generalizable to many different forms of psychotherapy for a wide range of disorders. If this translational research is successful, the ability of a relatively benign agent administered acutely before a psychotherapy session to facilitate the psychotherapeutic process could have important clinical, humanitarian, and economic advantages.

DESCRIPTION (provided by applicant): In a world of increasing trauma exposure, post-traumatic stress disorder (PTSD) is a major public health concern. With estimates ranging between 37%-92% of individuals exposed to severe trauma during their lifetime, both civilian and combat PTSD are common and debilitating. Despite this prevalence and despite our advancing knowledge of the neurobiology of fear, there are no currently accepted interventions for the early intervention and prevention of PTSD in the immediate aftermath of trauma. The initial symptoms of PTSD can be considered part of the normal reaction to trauma, but, those who suffer from chronic PTSD do not recover in the weeks and months following a trauma the way others do. Those with PTSD may not worsen, but they don't extinguish their original fear reactions. Therefore, PTSD can be viewed as a failure of recovery caused in part by a failure of fear extinction following trauma. We propose a pilot study, based on translational models of the consolidation of fear memories, to begin to examine the effects of early interventional extinction training in an ultimate effort to know when it is best to intervene with humans following exposure to trauma. The existing evidence suggests that 1) the debriefing literature is equivocal at best with some studies indicating it can cause harm, 2) there are no good candidates for immediate intervention;3) the animal evidence suggests that some immediate extinction training can result in decreases in spontaneous recovery and renewal and reinstatement;4) the animal evidence suggests that incomplete extinction training may cause sensitization, and finally;5) the timing of extinction training after exposure/conditioning is crucial. Therefore, we propose to test very early interventions following exposure to trauma in humans in the emergency department (ED). For this pilot study, we will randomly assign rape survivors presenting at the ED to one of the following 2 conditions: 1) `Immediate Treatment'Group: which includes immediate prolonged exposure therapy (PE) in ED plus delayed PE (3 sessions total);2) or `Assessment only'group. Additionally for a secondary predictive outcome analysis, in all subjects we will examine predictors for response including biomarkers - biological and genetic measures, sociological predictors, and psychological predictors in the ED, and at 4 and 12 week follow-up sessions. The overall aim of this project is to gather pilot data to begin to determine if exposure therapy in the immediate aftermath of trauma can prevent the development of PTSD. The long term goals are to establish pharmacological and psychotherapeutic interventions in the immediate aftermath of trauma to reduce the likelihood of developing a durable fear response such as PTSD.

DESCRIPTION (provided by applicant): Consolidation is a series of cellular and system processes that stabilize a memory trace after the initial acquisition into a more permanent, stable memory. However, when that memory is recalled, it may again exist in a labile state. Reconsolidation refers to processes that return this labile memory trace back into a more permanent, stable memory. It has been clear for decades that stored information becomes amenable to change when retrieved. This is how we treat patients with anxiety disorders, by accessing the fear memory, changing it via treatment, with the updated less fearful memory becoming incorporated. It is also how patients relapse, when this memory becomes accessed and re-stored in a more fearful state during reconsolidation. An innovative preclinical study recently reported that providing a reminder of the fear 10 minutes prior to extinction training in humans decreased fear up to one year later (Schiller et al., 2010). For this pilot study, we will use virtual reality exposure therapy (VRE) for the methodological rigor that VRE allows. With VR, each research participant receives exactly the same exposure and testing as the others in the experimental session and there will be no exposure to the VR stimulus in between sessions or under different conditions. It is a nonpharmacological, safe, non-invasive intervention. We will use the virtual airplane for patients with the fear of flying (FOF) as: 1) it is a fairly discrete ear that is both serious in its interference yet expensive and difficult to treat in vivo; 2) there is limited exposure to the feared stimulus on a daily basis outside of the experimental conditions; 3) it is a clinical population with impairment and motivation for change yet without significant comorbidity; 4) a virtual airplane is available; 5) VRE FOF treatment is well documented in several controlled studies; 5) there is ample opportunity for the return of fear (relapse) as there tends to be limited exposure to actual flying for most patients; and 6) patients with the FOF are easy to recruit in Atlanta, the site of the proposed study and the world's busiest airport. We propose to treat 64 participants with VRE for the FOF and present a VR clip in the head mounted display 10 minutes prior to all VR exposure therapy sessions during this 3-year R34 pilot study. Participants will be randomly assigned to receive either a reminder of the feared stimulus (a VR clip of a virtual airplane taxiing and taking off) or a neutral cue (a VR clip of a virtual living room). The overall aim of this project is to determine if using a cue to recall the feared stimulus 10 minutes prior to exposure treatment sessions (and thus reactivate the memory trace) leads to less anxiety and return of fear in patients with an anxiety disorder compared to using a cue that does not recall the feared stimulus prior to treatment. The long term goals are to establish if targeting the reconsolidation of fear with a nonpharmacological, noninvasive reminder of the fear is effective for human clinical populations in reducing relapse (return of fear). PUBLIC HEALTH RELEVANCE: Targeting Memory Reconsolidation to Prevent the Return of Fear in a Pilot RCT Narrative We will test a brief, easy-to-implement manipulation (i.e., recall of a feared stimulus presented in virtual reality) that triggers the fear memory and presumably allows it to be changed in a way that prevents the fear from returning later (i.e., prevents relapse). We will use this recall before virtual reality exposure therapy for the fear of flying usng a virtual airplane so that every patient in the study will receive exactly the same exposure. If ths is successful, it is a very simple, safe, easy, inexpensive, efficient, nonpharmacological manipulation that could be used with all patients with anxiety disorders to help prevent the return of fear.