The Specific Aim of this proposal is to test the feasibility of using vagus nerve stimulation (VNS) as an adjunct to prolonged exposure therapy (PE) for treating PTSD patients who are refractory to PE. PE is the treatment of choice for such patients. However, PE is successful in as few as 50% of cases. Refractory PTSD patients have high rates of suicide, substance abuse and addiction, violent crimes, depression, and general loss of productivity. There is an urgent need to develop a therapy for patients with refractory PTSD. PE aims to reduce the conditioned fear response by training patients to develop new situation-appropriate responses. Treatment of patients with memory-enhancing drugs appears to be an effective adjunct to exposure therapy for a number of conditions, including PTSD. However, the number of studies is few and even in those studies there remains a significant number of refractory patients. Thus, the use of memory enhancing techniques appears promising; but more effective options are needed. We have found that VNS paired with training can greatly enhance neuroplasticity and rehabilitation (in sensory, motor, and limbic systems). These findings include the discovery that pairing VNS with extinction trials increases the rate of extinction in normal rats, a study that was supported by a successful Phase I SBIR that set the stage for the current proposal. We also demonstrated that VNS pairing with extinction training reverses fear conditioning-related synaptic changes in the rat brain, and collected preliminary data showing that we can produce a well-established rodent model of PTSD in our laboratory. We have a record of extending our positive VNS-pairing findings in pre-clinical animal models to clinically meaningful results in humans for tinnitus and stroke. Because these clinical findings were both predicted by our pre-clinical animal models, it is reasonable to test pairing VNS with PE to reverse the effects of conditioned fear in refractory PTSD patients, if animal studies support such a therapy. While we previously demonstrated positive effects in a rat model of fear conditioning, to test feasibility of moving our therapy forward in refractory patients, we will cary out a study in a model of refractory PTSD. To this end, we will use a rat model of PTSD in which rats are resistant (refractory) to extinction: Single Prolonged Stressor (SPS). Test of Feasibility The VNS group must show complete reversal of the fear response following extinction. The reversal in the VNS SPS group must be larger than any reversal in the Sham stimulated SPS group (P
Public Health Relevance Statement: Public Health Relevance: Posttraumatic stress disorder (PTSD) is an increasing public health concern. According to the National Center for PTSD (NCPTSD), approximately 8% of the US population suffers from PTSD. The disorder is often accompanied by severe depression, anxiety, substance abuse, suicide, and crime. A large fraction of PTSD patients are refractory to all current treatments. This project aims to develop the first effective therapy for treating this population of refractory patients.
Project Terms: Animal Model; Animals; Anxiety; Basic Science; Brain; Clinic; Clinical; Clinical Trials; Computer software; conditioned fear; Conditioned Reflex; Crime; Cues; Data; Disease; effective therapy; experience; Exposure to; Extinction (Psychology); Fright; Funding; Human; human subject; improved; Laboratories; Learning; learning extinction; Limbic System; Memory; Mental Depression; Methods; Modeling; Motor; Neuronal Plasticity; Patient Education; Patients; Pharmaceutical Preparations; Phase; phase 2 study; Phase II Clinical Trials; Population; Post-Traumatic Stress Disorders; pre-clinical; Process; productivity loss; Protocols documentation; public health medicine (field); public health relevance; Rattus; Recruitment Activity; Refractory; Rehabilitation therapy; Resistance; response; Rodent Model; Sensory; Small Business Innovation Research Grant; Staging; stressor; stroke; Substance abuse problem; Substance Addiction; Suicide; suicide rate; Survivors; Synapses; Techniques; Testing; Tinnitus; Training; Upper Extremity; vagus nerve stimulation; violent crime; Work; Working stroke
