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）的特点是各种各样的症状，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PTSD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伤。用于检查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，称为内表型，这可能提供有关PTSD发展机制的有价值的见解。我们的初步数据表明，GABA介导的，多巴胺/5-羟色胺敏感的，短间隔皮层抑制（SICI）和皮层内易化（ICF）通过经颅磁刺激（TMS）测量与战斗相关的创伤后应激障碍。本申请的目的是整合临床评估、神经生理学测量和分子遗传学，以调查暴露于战斗压力的退伍军人的皮质抑制控制和心理健康的关系，特别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的目标：1）确定皮质抑制和兴奋性缺陷（内表型）的PTSD。2)探讨影响SICI/ICF的单胺转运体基因; 3）探讨GABA/谷氨酸系统基因变异与SICI/ICF和PTSD的关系。在拟议的研究中，我们计划招募OIF/OEF战斗退伍军人和没有创伤后应激障碍，以及没有创伤暴露的公民健康对照。将使用PTSD诊断和评定量表对受试者表型和症状严重程度进行全面评估。将对运动皮层进行单脉冲和双脉冲TMS，以评估SICI和ICF。将检查单胺转运蛋白基因和GABA/谷氨酸系统基因的多态性。精细定位技术将通过标记单核苷酸多态性（SNP）来覆盖感兴趣的遗传基因座的常见变异。将分析诊断类别、症状严重程度、SICI/ICF幅度和基因型之间的关联。将估计成对连锁不平衡（LD）。数量性状基因座（QTL）的方法将被应用于确定与PTSD内表型密切相关的遗传标记。几个统计模型将被应用于分析基因对内表型和PTSD表型的影响。我们认为，受损的SICI/ICF与PTSD有关，功能性单胺转运蛋白基因型和GABA/γ-氨基丁酸能系统基因多态性与受损的SICI/ICF和PTSD相关。这项工作是创新的，因为假设是新颖的，它整合了分子遗传学和神经生理学内表型的方法，试图阐明创伤后应激障碍的发展机制。这项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.