Specification of background dopaminergic synaptic activity in disorders of consciousness following severe traumatic brain injury

 描述(由申请人提供)：对重型脑损伤后意识障碍(DOC)患者的研究表明，前脑中脑系膜回路功能障碍是一个关键的潜在机制。DOC的前脑代谢在支撑高度复杂的认知行为的脑区显着下调，表明一致的目标导向行为和觉醒调节所需的突触背景活动水平崩溃。由于多巴胺水平是这些前脑结构内突触背景活动水平的主要控制因素之一，我们建议研究突触前和突触后多巴胺功能在创伤后DOC中的具体作用。本研究的目的是在静息状态下和用右旋苯丙胺和右旋苯丙胺+L-多巴激发后，用[11C]拉氯普利PET测定D2/D3受体在主要多巴胺能通路中的表达。在DOC中使用这项新技术，我们在2名慢性最低意识状态的患者中描述了在静息状态下合成和/或释放多巴胺的突触前缺陷，以及在右旋苯丙胺刺激后突触间隙的多巴胺水平未能增加。在8名正常志愿者的对照组中，这两种现象都没有出现。此外，两名受试者都表现出中央丘脑选择性突触后缺陷，中央丘脑是前脑中环路的核心中枢结构。尚不清楚这种突触前和突触后多巴胺能衰竭模式是这两个患者特有的，还是更普遍地见于DOC患者群体。此外，在这些受试者中发现的突触前缺陷可能是多巴胺生物合成失败的次要原因，因此原则上是可逆的，因为提供了合成过程的主要生物底物。因此，我们建议对创伤后DOC患者进行静息状态下使用[11C]拉克洛必利-正电子发射计算机断层扫描(PET)的研究，并在短暂的药理学挑战之后增加多巴胺的释放和多巴胺的生物合成。

 DESCRIPTION (provided by applicant): Studies in patients with disorders of consciousness (DOC) after severe brain injury implicate dysfunction of the anterior forebrain mesocircuit dysfunction a key underlying mechanism. The anterior forebrain metabolism in DOC is markedly downregulated across brain regions underpinning highly elaborated cognitive behaviors demonstrating a collapse of the level of synaptic background activity required for consistent goal-directed behavior and arousal regulation. Since dopamine levels are one of the primary controllers of the level of synaptic background activity within these forebrain structures, we propose to investigate the specific contribution of presynaptic and postsynaptic dopamine function in posttraumatic DOC. The aim of the present study is to measure the expression of D2/D3 receptors in the main dopaminergic pathways using [11C]raclopride-PET at rest and following a short pharmacological challenge with dextroamphetamine and dextroamphetamine + L-DOPA. Using this novel technique in DOC we characterized in 2 patients in chronic minimally conscious state a presynaptic deficiency to synthesize and/or release dopamine at rest, and a failure to increase the dopamine level at the synaptic cleft following stimulation with dextroamphetamine. Both phenomena were unseen in a control group of 8 normal volunteers. In addition, both subjects showed a selective postsynaptic deficit in the central thalamus, the core hub structure of the anterior forebrain mesocircuit. It is unknown whether this pattern presynaptic and postsynaptic dopaminergic failure is specific for these 2 patient subjects or is more generally seen across the population of subjects with DOC. Moreover, when identified presynaptic deficits as found in these subjects may be secondary to a failure of biosynthesis of dopamine and therefore in principle reversible by providing the main biological substrate of the synthesis process. We therefore propose to investigate patients with posttraumatic DOC using [11C]raclopride-PET at rest and following short pharmacological challenges aimed at increasing dopamine release and dopamine biosynthesis.