Cortical GABA in MDD and Primary Insomnia with Magnetic Resonance Spectroscopy

皮质 GABA 在 MDD 和原发性失眠中的磁共振波谱分析

• 批准号: 8658476
• 负责人: John W Winkelman
• 金额: $ 41.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658476
• 关键词: Affinity; Agonist; Analysis of Variance; Anterior; Arousal; Benzodiazepine Receptor; Biogenic Amines; Brain; Brain imaging; Brain region; Characteristics; Clinical; Clinical Research; Comorbid Insomnia; Creatine; Data; Diagnostic; Disease; Electroencephalography; Etiology; Functional disorder; Glutamates; Grant; Guidelines; Image; Indium; Individual; Lead; Left; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Major Depressive Disorder; Measures; Medical; Mental disorders; Modeling; Moods; Neurobiology; Neurons; Neurotransmitters; Occipital lobe; Outcome; Patients; Pharmacological Treatment; Physiological; Play; Polysomnography; Prevalence; Primary Insomnia; Protons; Regression Analysis; Relapse; Relative (related person); Reporting; Research; Role; Sleep; Sleep disturbances; Sleeplessness; Subgroup; Syndrome; System; Testing; Thalamic structure; United States; Water; actigraphy; cingulate cortex; cost; diaries; disturbance in affect; follow-up; gamma-Aminobutyric Acid; heart rate variability; hypothalamic-pituitary-adrenal axis; in vivo; interest; lifetime risk; neurochemistry; preoptic nucleus; receptor

DESCRIPTION (provided by applicant): To investigate GABA levels in anterior cingulate cortex (ACC) and occipital cortex (OC) in major depressive disorder (MDD) and primary insomnia with proton magnetic resonance spectroscopy imaging (1H- MRS). BACKGROUND: The prevalence of MDD as well as its personal and societal costs have motivated over four decades of research into its pathophysiology and neurobiological correlates. Although the preponderance of studies have focused on the role of the biogenic amines and the hypothalamic-pituitary-adrenal (HPA) axis, recent evidence suggests that the neurotransmitter gamma-aminobutyric acid (GABA) may play a key role in the pathophysiology of MDD. Supporting this conclusion are recent studies utilizing proton magnetic resonance spectroscopy (1H-MRS), which permits in vivo analysis of brain neurochemistry. Most of these studies concurred in finding reduced GABA levels in multiple brain regions in MDD including the OC and ACC. Recently, we utilized 1H-MRS to reveal GABA deficits in subjects with primary insomnia, e.g., insomnia without other accompanying medical or psychiatric disorders. Relative to good sleeper controls, subjects with primary insomnia not only had reduced levels of GABA, but within subjects with primary insomnia, GABA levels correlated with polysomnographic (PSG) measures of sleep maintenance. The proposed study will test the hypothesis that GABA deficits in MDD in fact reflect the sleep disturbance characteristic of that disorder rather than the mood state per se. Confirmation of this hypothesis could have a significant impact on management strategies and guidelines for the pharmacological treatment of this subgroup (those with comorbid MDD and insomnia), which constitutes the majority of patients with MDD. Direct treatment of comorbid insomnia in these patients may contribute to a positive clinical outcome through the restorative effects of sleep, as has been suggested by other clinical studies. Left untreated, insomnia may have a negative impact on clinical outcome and prospects for relapse. METHOD: We plan to perform 1H-MRS imaging for GABA levels (referenced to both creatine and water) in the ACC and OC in 50 subjects with MDD (half of whom will have insomnia and the other half will not), 25 subjects with primary insomnia (insomnia without mood disturbance) and 25 control subjects. All subjects will have sleep diaries and actigraphy for 2 weeks prior to their PSG and MRI. The primary endpoint, GABA levels, will be analyzed by repeated measures ANOVA (using linear mixed model) with diagnostic group (4 study groups) as the main effect and the 2 ROIs (OC and ACC) as repeats. We will also use regression analysis to correlate PSG and sleep diary information, with 1H-MRS-derived GABA data.

描述（由申请人提供）：研究主要抑郁症（MDD）和质子磁共振光谱成像（1H- MRS）的主要抑郁症（MDD）和原发性失眠的前扣带回皮层（ACC）和枕皮层（OC）的GABA水平。背景：MDD的流行及其个人和社会成本的促进了四十年来研究其病理生理学和神经生物学相关的研究。尽管大量研究集中在生物胺和下丘脑 - 垂体 - 肾上腺（HPA）轴的作用上，但最近的证据表明，神经递质γ-氨基丁酸（GABA）可能在MDD的病理学中起关键作用。支持这一结论的是使用质子磁共振光谱（1H-MR）的最新研究，该研究允许对脑神经化学的体内分析。这些研究大多数同意发现MDD多个大脑区域的GABA水平降低，包括OC和ACC。最近，我们利用1H-MRS揭示了主要失眠受试者，例如失眠症，而没有其他医学或精神疾病。相对于良好的卧铺控制，主要失眠的受试者不仅具有降低的GABA水平，而且在主要失眠的受试者中，GABA水平与多孕症（PSG）的睡眠维持度量相关。拟议的研究将检验以下假设：MDD中的GABA缺陷实际上反映了该疾病的睡眠障碍特征，而不是情绪状态本身。确认这一假设可能会对该亚组的药理治疗（患有合并MDD和失眠的人）的药理治疗的指南产生重大影响，这构成了大多数MDD患者。正如其他临床研究所表明的那样，这些患者在这些患者中直接治疗合并症可能会通过睡眠的恢复作用导致积极的临床结果。剩下的未经治疗，失眠可能会对临床结果和复发前景产生负面影响。方法：我们计划在50名患有MDD的受试者的ACC和OC中对ACC和OC中的GABA水平（参考肌酸和水）进行1H-MRS成像（其中一半将患有失眠，而另一半将不会），25名受试者具有原发性失眠症（失眠症而无需进行情绪干扰）和25个控制受试者和25个控制受试者。所有受试者都将在PSG和MRI之前进行2周的睡眠日记和精神分裂症。将通过重复测量方差分析（使用线性混合模型）与诊断组（4个研究组）作为主要效应，将主要端点（使用线性混合模型）作为主要效应，将2个ROI（OC和ACC）作为重复分析。我们还将使用回归分析将PSG和睡眠日记信息与1H-MRS衍生的GABA数据相关联。