Cortical Excitability: Biomarker and Endophenotype in Combat Related PTSD

描述(由申请人提供)： 创伤后应激障碍(PTSD)的特点是各种症状，从情绪绝望到与创伤暴露有关的认知障碍。该项目提出了一种新的理论，即创伤后应激障碍的发展源于调节情绪、认知和运动控制的大脑抑制网络的损害。用于检测这些抑制回路的神经生物学测量技术可能导致各种中间结构，称为内型，这可能为理解PTSD发生的机制提供有价值的见解。我们的初步数据表明，通过经颅磁刺激(TMS)测量的GABA介导的、多巴胺/5-羟色胺敏感的短间隔皮质抑制(SICI)和皮质内促进(ICF)与战斗相关的创伤后应激障碍有关。该应用程序的目标是整合临床评估、神经生理学测量和分子遗传学，以调查暴露在战斗压力下的退伍军人的皮质抑制控制和心理健康的关系，特别是关注伊拉克自由行动/持久自由行动(OIF/OEF)退伍军人中与战斗相关的创伤后应激障碍症状。我们提出了三个具体目标：1)确定PTSD患者的皮质抑制和兴奋性缺陷(内表型)。2)确定影响SICI/ICF的单胺转运蛋白基因：3)探讨GABA/谷氨酸系统遗传变异与SICI/ICF和PTSD的关系。在拟议的研究中，我们计划招募患有和不患有创伤后应激障碍的OIF/OEF战斗退伍军人，以及没有创伤暴露的文明健康对照。受试者的表型和症状严重程度将使用创伤后应激障碍诊断和评定量表进行全面评估。将在运动皮质上进行单脉冲和双脉冲TMS，以评估SICI和ICF。单胺转运蛋白基因和GABA/谷氨酸系统基因的多态将被检测。精细作图技术将通过标记单核苷酸多态(SNP)来覆盖感兴趣基因座的常见变异。将分析诊断类别、症状严重程度、SICI/ICF波幅和基因类型之间的关系。将估计成对连锁不平衡(LD)。数量性状基因座(QTL)方法将被应用于确定与创伤后应激障碍(PTSD)内表型密切相关的遗传标记。将应用几个统计模型来分析基因对创伤后应激障碍表型和内表型的影响。我们预计SICI/ICF受损与PTSD有关，功能性单胺转运体基因和GABA/谷氨酸能系统基因多态性与SICI/ICF受损和PTSD症状相关联。这项拟议的工作是创新的，因为该假说是新颖的，它整合了分子遗传学和神经生理学内表型方法，试图阐明创伤后应激障碍的发生机制。拟议研究的结果将对未来的遗传、诊断和治疗研究产生重大影响。

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is characterized by a variety of symptoms ranging from emotional despair to cognitive impairments related to trauma exposure. This project proposes a novel theory that the development of PTSD stems from impairments of brain inhibitory networks regulating emotion, cognition, and motor control. Neurobiological measurement techniques used to examine these inhibitory circuits may result in various intermediate constructs, referred to as endophenetypes, which may provide valuable insight about the mechanisms underlying PTSD development. Our preliminary data indicate a GABA-mediated, dopamine/serotonin- sensitive, short interval cortical inhibition (SICI) and intra-cortical facilitation (ICF) measured through transcranial magnetic stimulation (TMS) is associated with combat related PTSD. The objective of this application is to integrate clinical assessments, neurophysiological measurements, and molecular genetics to investigate the relationship of cortical inhibitory control and the mental health of veterans exposed to combat stress, specifically focusing on combat-related PTSD symptoms in Operation Iraq Freedom / Operation Enduring Freedom (OIF/OEF) Veterans. We propose three specific aims: 1) To identify cortical inhibition and excitability deficit (endophenotype) in PTSD. 2) To Determine monoamine transporter genes influencing SICI/ICF; 3) To explore GABA/glutamate system genetic variants in relation to SICI/ICF and PTSD. In the proposed study, we plan to recruit OIF/OEF combat Veterans with and without PTSD, and civilan healthy control without trauma exposure. Subject phenotype and symptom severity will be fully assessed using PTSD diagnostic and rating scales. Single and pair-pulse TMS over the motor cortex will be performed to assess SICI and ICF. Polymorphisms in monoamine transporter genes and GABA/glutamate system genes will be examined. Fine mapping techniques will be utilized via tagging single nucleotide polymorphisms (SNP) to cover the common variation of genetic loci of interest. Association among diagnostic category, symptom severity, SICI/ICF amplitude, and genotypes will be analyzed. Pairwise linkage disequilibrium (LD) will be estimated. The quantitative trait loci (QTL) approach will be applied to determine genetic markers that are strongly associated with the PTSD endophenotype. Several statistical models will be applied to analyze gene effects on endophenotype and PTSD phenotype. We expect that impaired SICI/ICF are related to PTSD, and that functional monoamine transporter genotypes and GABA/glutamatergic system gene polymorphisms are associated with both impaired SICI/ICF and PTSD symptomatology. The proposed work is innovative, because the hypothesis is novel and it integrates both molecular genetics and neurophysiologic endophenotype approaches in attempting to elucidate the mechanisms of PTSD development. The outcomes of the proposed study will have a significant impact in future genetic, diagnostic, and treatment research.