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

基本信息

批准号：
8497753
负责人：
ISABELLE M ROSSO
金额：
$ 36.25万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/8497753
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

项目摘要

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.

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种常见且令人衰弱的神经精神疾病，其中对创伤事件的急性恐惧反应不会减弱。人们认为，这种未能从创伤中恢复的情况至少部分是由于无法学会不害怕先前与创伤相关的情况和刺激。因此，创伤后应激障碍（PTSD）被概念化为一种“恐惧调节”障碍，涉及介导恐惧表达的大脑区域神经元的高反应性和介导恐惧消退的大脑区域神经元的低反应性。此外，一致的证据表明，神经递质的改变与神经元兴奋性的这些变化有关，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 与两个关键大脑区域的 GABA 改变相关的假设：腹内侧前额皮质 (VMPFC) 和前岛叶皮质。我们还将采用经过充分验证的恐惧调节范式来检验 VMPFC 神经化学与 PTSD 恐惧消退缺陷相关的假设。我们将招募 93 名受试者，其中包括 31 名 PTSD 受试者、31 名遭受过创伤的对照者和 31 名没有创伤史的健康对照者。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 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大脑区域 GABA 是否是 PTSD 临床和行为表型的标志。未来的研究方向将包括检查 PTSD 中的 GABA 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 的改变很可能代表行为表型的生物标志物，不仅存在于创伤后应激障碍 (PTSD) 中，而且还存在于相关的精神疾病中。通过这种方式，这项研究的目标与 NIMH 战略计划和 RDoC 倡议中规定的优先事项相关，特别是识别可能导致生物学上有效的精神病学分类学的发展。