Cerebral GABA and Fear Conditioning in PTSD

创伤后应激障碍 (PTSD) 中的大脑 GABA 和恐惧调节

• 批准号: 8399764
• 负责人: ISABELLE M ROSSO
• 金额: $ 37.5万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399764
• 关键词: Abate; Acute; Affect; Aminobutyric Acids; Anterior; Antiepileptic Agents; Anxiety; Area; Behavior; Behavioral; Biological Markers; Brain; Brain Chemistry; Brain region; Cerebrum; Chemicals; Chronic; Clinical; Clinical Markers; Conditioned Stimulus; Data; Detection; Development; Diagnosis; Diagnostic Specificity; Dimensions; Disease; Event; Exposure to; Extinction (Psychology); Failure; Fright; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Galvanic Skin Response; Goals; Hyperactive behavior; Impairment; Individual; Insula of Reil; Knowledge; Laboratories; Lead; Learning; Literature; Magnetic Resonance Spectroscopy; Maintenance; Measures; Mediating; Mental disorders; Methods; Modeling; National Institute of Mental Health; Nature; Neurobiology; Neurons; Neurotransmitters; Patients; Pharmacological Treatment; Phase; Phenotype; Post-Traumatic Stress Disorders; Prefrontal Cortex; Protons; Recording of previous events; Recruitment Activity; Relative (related person); Reporting; Research; Role; Serum; Severities; Stimulus; Strategic Planning; Symptoms; Technology; Testing; Trauma; base; biobehavior; conditioned fear; conditioning; disease classification; experience; gamma-Aminobutyric Acid; improved; in vivo; indexing; neurochemistry; neuronal excitability; neuropsychiatry; response

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. PUBLIC HEALTH RELEVANCE: The proposed study may provide the first direct, in vivo evidence that altered levels of the brain chemical GABA are "markers" of persistent clinical symptoms and fear responses in post- traumatic stress disorder (PTSD). In the short-term, our findings will improve our understanding of brain chemistry in PTSD and of how brain chemistry relates to certain maladaptive behaviors that cause impairment in patients. In the longer term this research may help understand how current treatments affect brain chemistry, and ultimately may lead to better diagnosis and treatment of PTSD and related disorders.

描述（由申请人提供）：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，其中对创伤事件的急性恐惧反应不会减轻。这种无法从创伤中恢复的情况被认为至少部分是由于学习不害怕先前与创伤相关的情况和刺激的缺陷。因此，在本发明中， 创伤后应激障碍已被概念化为“恐惧条件反射”的障碍，其涉及介导恐惧表达的脑区域中的神经元的高反应性和介导恐惧消退的脑区域中的神经元的低反应性。此外，越来越多的证据表明，神经递质的改变与神经元兴奋性的变化有关，包括抑制性神经递质γ-氨基丁酸（GABA）的改变。拟议的研究将应用质子磁共振波谱（1H-MRS）方法来检验PTSD与两个关键脑区（腹内侧前额叶皮层（VMPFC）和前岛叶皮层）中GABA改变相关的假设。我们还将采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PTSD中的恐惧消退缺陷相关的假设。我们将招募93名受试者，包括31名PTSD受试者、31名创伤暴露对照组和31名无创伤史的健康对照组。受试者将使用MEGAPRESS序列进行单体素高场1H-MRS，该序列针对GABA的检测和定量进行了优化，并在这两个脑区获得了令人鼓舞的初步数据。我们将研究GABA水平与PTSD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数的关系。这将使我们能够检查区域脑GABA是否是PTSD临床和行为表型的标志物。未来的研究方向将包括检查创伤后应激障碍中GABA的改变是否对药物治疗敏感，以及检查其诊断特异性。事实上，GABA的改变很可能代表了行为表型的生物标志物，这些生物标志物不仅存在于PTSD中，也存在于相关的精神疾病中。通过这种方式，本研究的目标与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 发展出一种生物学上有效的精神疾病分类法 公共卫生关系：这项拟议中的研究可能提供了第一个直接的体内证据，证明大脑化学物质GABA水平的改变是创伤后应激障碍（PTSD）持续临床症状和恐惧反应的“标志”。在短期内，我们的研究结果将提高我们对PTSD脑化学的理解，以及脑化学如何与导致患者损伤的某些适应不良行为相关。从长远来看，这项研究可能有助于了解目前的治疗方法如何影响脑化学，并最终可能导致更好的诊断和治疗创伤后应激障碍和相关疾病。