Development of fMRI Methods for Neurpharmacology

神经药理学功能磁共振成像方法的发展

• 批准号: 6929933
• 负责人: Shi-Jiang Li
• 金额: $ 33.75万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929933
• 关键词: autonomic agents; bioimaging /biomedical imaging; blood pressure; brain circulation; brain imaging /visualization /scanning; brain mapping; electroencephalography; functional magnetic resonance imaging; halothane; isoflurane; laboratory rat; method development; methoxamine; neuropharmacology; oxygen consumption; respiratory oxygenation; ultrasound blood flow measurement; urethan

DESCRIPTION (provided by applicant): This proposal is in response to NIBIB RFA EB-03-002, "Systems and Methods for Small Animal Imaging." We will focus on development of functional MRI (fMRI) methods for neuropharmacology in rats. The main goal is to extend application of fMRI method to neuropharmacology. Four specific aims are proposed. For Specific Aim 1, we will determine and characterize the systemic cardiovascular effects induced by anesthetic and autonomic agents on the fMRI blood oxygenation level dependent (BOLD) response in the rat brain produced by forepaw stimulation, a) Determine the dose effects of four anesthetic agents, halothane, isoflurane, alpha-chloralose and urethane, on the functional BOLD response. b) Methoxamine, an alpha-1 receptor agonist that has no direct cerebrovascular effect, will be used to determine if acute increases in mean arterial blood pressure, either within or outside of the physiological range of cerebral blood flow autoregulation, affect the functional BOLD response in the rat brain. Specific Aim 2 is to develop a tailored fMRI pulse sequence on the 3T scanner for overcoming susceptibility artifacts present in air-brain tissue boundaries, to detect BOLD signals in the rat brain. In Specific Aim 3, we will test the hypothesis that fMRI technology is a valid method to map drug-induced activities in the rat brain by using a class of drugs whose pharmacological functions are well characterized. We will test the hypothesis that upon administration of an agonist, fMRI methods can detect BOLD signals originating from the neural events of the agonist-receptor interaction. Further, we will test the hypothesis that such neural events can be blocked by pretreatment or reversed by post treatment with a particular receptor's antagonist. The biggest challenge in extending applications of fMRI technology to neuropharmacology is to interpret the neural mechanisms of the BOLD signals induced by drug administration. In Specific Aim 4, we will develop a biophysical model to calculate cerebral metabolic rate of oxygen consumption (CMRO2) and interpret the BOLD signal changes induced by drugs. We will also conduct Laser Doppler Flowmetry and EEG experiments to validate this biophysical model.

描述（由申请人提供）：该提案是对 NIBIB RFA EB-03-002“小动物成像系统和方法”的回应。我们将重点开发用于大鼠神经药理学的功能性 MRI (fMRI) 方法。主要目标是将功能磁共振成像方法的应用扩展到神经药理学。提出了四个具体目标。对于具体目标 1，我们将确定并表征麻醉剂和自主神经药物对前爪刺激产生的大鼠大脑中 fMRI 血氧水平依赖性 (BOLD) 反应引起的全身心血管效应，a) 确定四种麻醉剂的剂量效应、氟烷、异氟烷、α-氯醛糖和氨基甲酸乙酯，对功能性 BOLD 反应的影响。 b) 甲氧明是一种 α-1 受体激动剂，没有直接的脑血管作用，将用于确定平均动脉血压的急剧升高（无论是在脑血流自动调节的生理范围内还是之外）是否会影响功能性 BOLD 反应在老鼠的大脑中。具体目标 2 是在 3T 扫描仪上开发定制的 fMRI 脉冲序列，以克服气脑组织边界中存在的磁化率伪影，以检测大鼠大脑中的 BOLD 信号。在具体目标 3 中，我们将检验以下假设：fMRI 技术是一种通过使用一类药理功能已得到充分表征的药物来绘制大鼠大脑中药物诱导活动的有效方法。我们将测试以下假设：在施用激动剂后，功能磁共振成像方法可以检测源自激动剂-受体相互作用的神经事件的 BOLD 信号。此外，我们将测试这样的假设：此类神经事件可以通过预处理来阻断或通过用特定受体拮抗剂进行后处理来逆转。将功能磁共振成像技术应用扩展到神经药理学的最大挑战是解释给药诱导的 BOLD 信号的神经机制。在具体目标4中，我们将开发一个生物物理模型来计算脑耗氧代谢率（CMRO2）并解释药物引起的BOLD信号变化。我们还将进行激光多普勒血流测量和脑电图实验来验证该生物物理模型。