DOPAMINERGIC MODULATION WORKING MEMORY TBI--FMRI STUDY

描述（改编自研究者摘要）：本研究的目标 一项建议是更好地定义多巴胺能机制在记忆中的作用， 创伤性脑损伤后个体经历的缺陷。许多 一到两百万人遭受轻度到中度的脑外伤 在最初的几周内，MTBI的工作记忆（WM）出现缺陷 在受伤之后。事实上，最近的研究表明，WM是一种 与MTBI相关的核心缺陷。虽然这些人中的大多数 随后恢复，相当多的人，特别是那些中度 受伤，有持续的记忆缺陷。 人类和动物的研究都表明，前额叶和顶叶皮层 区域是WM电路的重要组成部分。这些领域，特别是 额叶皮层在创伤性脑损伤中易受损伤。多巴胺能系统 在WM的调制中起重要作用。额叶多巴胺能系统 是动物空间WM的重要调节剂[Arnsten，1998 #90]。 有限的人类研究表明额叶多巴胺能神经 系统和WM [Koechlin，1999 #117; Muller，1998 #88]。TBI的最新研究 患者发现，在给予一种 D2受体激动剂（溴隐亭）[McDowell，1998 #101; Whyte，1997 #100; D'Esposito，1998 #39]。此外，这些TBI相关的WM缺陷与 功能性磁共振成像显示额叶和顶叶激活模式异常 fMRI）[麦卡利斯特，1999 #165]。 该项目的目的是使用神经认知和功能磁共振成像测量在两个 人群，一个具有正常WM容量（健康对照），一个具有低WM容量 WM能力（MTBI个体）：（1）表征两种WM缺陷 域（语言和空间）在一个月内（MTBI），（2）测试 多巴胺能激动剂改善两个领域WM缺陷的能力 （语言和空间）在MTBI的一个月内，和（3）探索 D1和D2受体在激活和调节 WM的两个域。 我们建议研究40名受伤后一个月内的MTBI患者和40名健康人 前瞻性、双盲、安慰剂对照设计。mTBI 受试者和对照将被随机分配接受安慰剂， 培高利特（一种D1/D2激动剂）或溴隐亭（一种D2激动剂）。两组将 然后在接受功能磁共振成像的同时，接受一系列言语和空间WM任务， 然后进行进一步的神经认知测试性能和fMRI可视化 WM回路的激活将在基线（安慰剂）表征， 多巴胺受体激动剂的作用。

DESCRIPTION (Adapted from the Investigator's Abstract): The goal of this proposal is to better define the role of dopaminergic mechanisms in the memory deficits experienced by individuals after a traumatic brain injury. Many of the one to two million individuals who sustain a mild to moderate traumatic brain injury (MTBI) suffer deficits in working memory (WM) in the first several weeks following the injury. in fact, recent studies suggest that WM is one of the core deficits associated with MTBI. Although the majority of these individuals subsequently recover, a significant number, particularly those with moderate injuries, have persistent memory deficits. Both human and animal studies suggest that prefrontal and parietal cortical areas are important components of WM circuitry. These areas, particularly frontal cortex, are vulnerable to injury in TBI. The dopaminergic system plays a prominent role in the modulation of WM. Frontal dopaminergic systems appear to be important modulators of spatial WM in animals [Arnsten, 1998 #90]. Limited human studies suggest similar links between frontal dopaminergic systems and WM [Koechlin, 1999 #117; Muller, 1998 #88]. A recent study of TBI patients found improvement in some WM components following administration of a D2 receptor agonist (bromocriptine) [McDowell, 1998 #101; Whyte, 1997 #100; D'Esposito, 1998 #39]. Further, these TBI-related WM deficits are associated with abnormal frontal and parietal activation patterns seen with functional MRI fMRI)[McAllister, 1999 #165]. The aims of this project are to use neurocognitive and fMRI measures in two populations, one with normal WM capacity (healthy controls), and one with low WM capacity (individuals with MTBI).to: (1 ) characterize WM deficits in two domains (verbal and spatial) within one month of (MTBI), (2) to test the ability of dopaminergic agonists to ameliorate WM deficits in two domains (verbal and spatial) within one month of MTBI, and (3) to explore the differential roles of D1 and D2 receptors in the activation and modulation of two domains of WM. We propose to study 40 MTBI patients within one month of injury and 40 healthy controls in a prospective, double blind, placebo controlled design. MTBI subjects and controls will be randomly assigned to receive placebo and either pergolide (a D1/D2 agonist) or bromocriptine (a D2 agonist). Both groups will then be given a series of verbal and spatial WM tasks while undergoing fMRI, followed by further neurocognitive testing. Performance and fMRI visualized activation of WM circuitry will be characterized at baseline (on placebo) and following administration of a dopamine agonist.