DOPAMINERGIC MODULATION WORKING MEMORY TBI--FMRI STUDY

描述(改编自调查者摘要)：本报告的目标 建议更好地定义多巴胺能机制在记忆中的作用 个人在创伤性脑损伤后所经历的缺陷。许多人 一到两百万人患有轻度到中度的脑创伤 损伤(MTBI)在最初的几周内出现工作记忆(WM)缺陷 在受伤之后。事实上，最近的研究表明，WM是 与MTBI相关的核心赤字。尽管这些人中的大多数 随后恢复了相当多的人，特别是那些中度 受伤，有持续性的记忆缺陷。 人类和动物研究都表明，前额叶和顶叶皮质 面积是WM电路的重要组成部分。这些地区，特别是 额叶皮质在颅脑损伤中易受损伤。多巴胺能系统发挥作用 在WM的调制中起着突出的作用。额叶多巴胺能系统出现 是动物空间WM的重要调节因子[Arnsten，1998#90]。 有限的人体研究表明，额叶多巴胺能 系统和WM[Koechlin，1999#117；Muller，1998#88]。脑外伤的最新研究进展 患者在服用阿司匹林后发现一些WM成分有改善 D2受体激动剂(溴隐亭)[McDowell，1998#101；Whyte，1997#100； D‘Esposito，1998#39]。此外，这些与脑损伤相关的WM缺陷是相关的 功能性核磁共振显示额叶和顶叶异常激活模式 功能磁共振成像)[McAllister，1999#165]。 这个项目的目标是在两个方面使用神经认知和功能核磁共振测量 人群，一个具有正常的WM容量(健康对照)，一个具有低WM容量 工作记忆能力(患有MTBI的个人).to：(1)将工作记忆缺陷分为两个方面 在(MTBI)的一个月内(言语和空间领域)，(2)测试 多巴胺能激动剂改善两个脑区白质缺陷的能力 (口头和空间)在MTBI后一个月内，以及(3)探索 D_1和D_2受体在细胞激活和调控中的不同作用 WM的两个域。 我们建议对40名受伤一个月内的MTBI患者和40名健康患者进行研究。 采用前瞻性、双盲、安慰剂对照设计。MTBI 受试者和对照组将被随机分配接受安慰剂和 培高利特(d1/d2激动剂)或溴隐亭(d2激动剂)。两个小组都将 然后在接受功能磁共振的同时，给出一系列的语言和空间工作记忆任务， 然后进行进一步的神经认知测试。性能和功能磁共振成像可视化 WM回路的激活将在基线(安慰剂)和 在注射了多巴胺激动剂之后。

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.