Dopamine Enhancement of fear extinction learning in PTSD

多巴胺增强 PTSD 患者的恐惧消退学习

基本信息

批准号：
9447442
负责人：
Joshua M Cisler
金额：
$ 32.83万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-07 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9447442
关键词：
Acute Adult Animals Basic Science Behavior Benserazide Biological Neural Networks Brain Chronic Clinical Clinical Trials Code Cognition Combined Modality Therapy Comorbidity Corpus striatum structure Cues DRD1 gene Development Diagnosis Dopamine Dose Emotional Enzymes Exhibits Exposure to Extinction (Psychology)Fright Functional Magnetic Resonance Imaging Generic Drugs Genes Genetic Genetic Polymorphism Genetic Variation Genotype Goals Human Impairment Individual Individual Differences Ingestion Knowledge Laboratories Lead Learning Levodopa Measures Mediating Memory Mental disorders Modeling Oral Outcome Study Patient Self-Report Pharmacology Phase Placebos Post-Traumatic Stress Disorders Protocols documentation Psychophysiology Public Health Quality of life Regulation Research Research Support Rest Role Sampling Signal Transduction Source Testing Therapeutic Translating Trauma Treatment Efficacy Treatment outcome Violence Vulnerable Populations Woman assault base clinical efficacy conditioned fear dopamine system genetic predictors improved indexing learning extinction neuroimaging neurotransmission novel physical assault psychologic public health relevance receptor relating to nervous system response sex sexual assault success therapy outcome transmission process

项目摘要

DESCRIPTION (provided by applicant): This R21/R33 application in response to RFA-MH-15-300 seeks to demonstrate target engagement and clinical viability for a novel combination therapy for Posttraumatic Stress Disorder. PTSD is associated with poor quality of life and comorbidity with both physical and mental illness. While exposure-based psychological treatments have proven efficacious, up to 40% retain PTSD diagnoses following treatment. Thus, new protocols to boost treatment efficacy can have a significant public health impact. Recent basic research suggests that consolidation of fear extinction learning memories is at least partly dopamine-mediated and that boosting dopamine signaling in the consolidation window can decrease fear responding during subsequent exposure to fear cues. The overall goal of the proposed project is to demonstrate the viability of boosting dopamine signaling in the post-learning consolidation window as a novel means of boosting therapy outcomes among adult women with PTSD related to assaultive violence (physical or sexual assault). In the R21 target engagement phase, we will test the impact of endogenous and exogenous manipulations of dopamine neurotransmission on 1) acute functional organization of dopaminergic resting-state networks, and 2) the consolidation of generic (i.e., laboratory-induced) fear extinction learning using concurrent neuroimaging, psychophysiological, and self-report assessments among women with PTSD (Aim 1). In the R33 clinical phase, we seek to replicate and extend target engagement to the clinical context of fear extinction learning for ideographic trauma memories and emotional responding to trauma cues among women with PTSD using concurrent neuroimaging, psychophysiological, and self-report assessments (Aim 2). Successful demonstration of target engagement (Aim 1) and efficacy for the clinical target of trauma memories and emotional responding to trauma cues (Aim 2) would provide critical scientific support of the viability of combining exposure-based therapy with pharmacological agents that boost dopamine signaling as a means to improve treatment outcomes for PTSD.

描述（由应用程序提供）：此R21/R33响应RFA-MH-15-300的应用旨在证明目标参与和临床生存能力，以实现创伤后应激障碍的新型组合疗法。 PTSD与身体和精神疾病的生活质量和合并症差有关。尽管基于暴露的心理疗法已被证明有效，但治疗后多达40％的人保留PTSD诊断。这是提高治疗效率的新协议可能会对公共卫生产生重大影响。最近的基础研究表明，恐惧扩展学习记忆至少是部分多巴胺介导的，并且在巩固窗口中促进多巴胺信号传导可以减少随后暴露于恐惧提示的恐惧。拟议项目的总体目标是证明在学习后的合并窗口中促进多巴胺信号传导的可行性，这是促进与攻击性暴力有关的PTSD妇女（身体或性侵犯）中PTSD的一种新颖手段。在R21目标参与阶段，我们将测试多巴胺神经传递的内源性和外源操纵对1）多巴胺能静止状态网络的急性功能组织的急性功能组织，以及2）害怕使用与妇女的神经际交往的女性学评估（即，在实验室诱发的范围）的巩固（即，恐惧）的整合（即）。 1）。在R33临床阶段，我们试图通过使用并发的神经影像，心理生理学和自我报告评估来复制和将目标参与到恐惧扩展学习的临床环境以及对PTSD女性的创伤性线索的情感反应（AIM 2）。成功地展示了目标参与（目标1）和创伤记忆的临床目标的效率和对创伤提示的情绪反应（AIM 2）将提供对将基于暴露的治疗与药物相结合的可行性的重要科学支持，从而将多巴胺信号作为改善PTSD的治疗方法的一种手段。