Cerebral GABA and Fear Conditioning in PTSD

描述(申请人提供)：创伤后应激障碍(PTSD)是一种常见的、使人衰弱的神经精神障碍，在这种疾病中，对创伤事件的急性恐惧反应不会减弱。这种未能从创伤中恢复的情况被认为至少部分是由于在学习不害怕先前与创伤有关的情况和刺激方面的缺陷。因此， 创伤后应激障碍被概念化为一种“恐惧条件反射”障碍，它涉及到大脑中负责表达恐惧的神经元的高反应性和负责恐惧消退的神经元的低反应性。此外，越来越多的证据表明，神经递质的变化与神经元兴奋性的变化有关，包括抑制性神经递质伽马-氨基丁酸(GABA)的变化。这项拟议的研究将应用质子磁共振波谱(1H-MRS)方法来检验PTSD与大脑两个关键区域--腹内侧前额叶皮质(VMPFC)和前岛叶皮质--GABA变化有关的假设。我们还将使用一个经过充分验证的恐惧条件反射范式来检验VMPFC神经化学与创伤后应激障碍中的恐惧消退缺陷有关的假设。我们将招募93名受试者，其中包括31名创伤后应激障碍受试者、31名创伤暴露对照组和31名无创伤病史的健康对照组。受试者将使用MEGAPRESS序列进行单体素高场1H-MRS，该序列针对GABA的检测和量化进行了优化，并在这两个大脑区域产生了令人鼓舞的初步数据。我们将检查GABA水平与创伤后应激障碍的诊断和症状的关系，以及与恐惧消退、回忆和焦虑敏感性的行为指标的关系。这将使我们能够检查局部大脑GABA是否是创伤后应激障碍临床和行为表型的标志。未来的研究方向将包括检查创伤后应激障碍中的GABA改变是否对药物治疗敏感，以及检查它们的诊断特异性。事实上，GABA的改变很可能代表了行为表型的生物标记物，这些表型不仅在创伤后应激障碍中发现，而且在相关的精神障碍中也存在。通过这种方式，这项研究的目标与NIMH战略计划和RDoC倡议中描述的优先事项相关，特别是识别可能导致 生物学上有效的精神病因学的发展。

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a common and debilitating neuropsychiatric disorder in which an acute fear response to a traumatic event does not abate. This failure to recover from trauma is thought to be due at least in part to a deficit in learning not to fear situations and stimuli previously associated with the trauma. Thus, PTSD has been conceptualized as a disorder of 'fear conditioning' that involves a hyperresponsivity of neurons in brain regions mediating fear expression and a hyporesponsivity of neurons in brain regions mediating fear extinction. Moreover, converging evidence suggests that neurotransmitter alterations relate to these changes in neuron excitability, including alterations in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The proposed study will apply proton magnetic resonance spectroscopy (1H-MRS) methods to test hypotheses that PTSD is associated with altered GABA in two key brain areas: the ventromedial prefrontal cortex (VMPFC) and anterior insular cortex. We will also employ a well-validated fear conditioning paradigm to examine the hypothesis that VMPFC neurochemistry is associated with fear extinction deficits in PTSD. We will recruit 93 subjects comprised of 31 PTSD subjects, 31 trauma- exposed controls, and 31 healthy controls with no trauma history. Subjects will undergo single voxel high-field 1H-MRS using MEGAPRESS sequences that are optimized for detection and quantification of GABA, and have yielded encouraging preliminary data in these two brain regions. We will examine GABA levels in relation to PTSD diagnosis and symptoms, and in relation to behavioral indices of fear extinction recall and anxiety sensitivity. This will allow us to examine whether regional brain GABA is a marker of clinical and behavioral phenotypes of PTSD. Future research directions will include examination of whether GABA alterations in PTSD are sensitive to pharmacological treatment, and examination of their diagnostic specificity. Indeed, it is likely that GABA alterations represent biomarkers of behavioral phenotypes that are not only found in PTSD but also related psychiatric disorders. In this way, the goals of this research are relevant to priorities delineated in the NIMH strategic plan and RDoC initiative, particularly the identification of biobehavioral markers that may lead to the development of a biologically-valid psychiatric nosology.