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

严重创伤性脑损伤后意识障碍背景多巴胺能突触活动的规范

基本信息

批准号：
9066823
负责人：
Esteban Andres Fridman
金额：
$ 21.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066823
关键词：
Affect Amphetamines Anabolism Anterior Arousal Behavior Binding Biological Biological Markers Biological Preservation Brain Injuries Brain region Chronic Cognitive Conscious Consciousness Disorders Control Groups Data Deafferentation procedure Development Dextroamphetamine Diagnosis Diagnostic Procedure Dopamine Dopamine Receptor Electric Stimulation Enzymes Evaluation Exhibits Failure Focal Brain Injuries Functional disorder Future Goals Health Injury Knowledge Ligands Measurement Measures Metabolic Metabolism Methodology Minimally Conscious States Neurons Outcome Pathway interactions Patients Pattern Population Positron-Emission Tomography Premedication Process Prosencephalon Raclopride Recovery Regulation Research Rest Role Secondary to Source Staging Structure Synapses Synaptic Cleft System TBI Patients Techniques Testing Thalamic structure Therapeutic Intervention Traumatic Brain Injury Tyrosine 3-Monooxygenase Work cognitive function cost disability glucose metabolism improved motor control nerve supply neuron loss neuroregulation neurotransmitter release new therapeutic target novel patient population postsynaptic postsynaptic neurons presynaptic receptor research study response reuptake social treatment strategy volunteer

项目摘要

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.

描述（由申请人提供）：对严重脑损伤后意识障碍（DOC）患者的研究表明，前前脑介导电路功能障碍是关键的潜在机制。DOC 中前脑代谢在支撑高度精细认知的大脑区域中显着下调。行为表明一致的目标导向行为和唤醒调节所需的突触背景活动水平崩溃，因为多巴胺水平是突触水平的主要控制器之一。根据这些前脑结构内的背景活动，我们提出了突触前和突触后多巴胺功能在创伤后 DOC 中的具体贡献。本研究的目的是使用 [11C]雷氯必利测量主要多巴胺能通路中 D2/D3 受体的表达。休息时的 PET 以及右旋苯丙胺和右旋苯丙胺 + L-DOPA 的短暂药理学挑战后，我们在 DOC 中使用了这种新技术。 2 名处于慢性最低意识状态的患者在休息时存在突触前合成和/或释放多巴胺的缺陷，并且在用右旋苯丙胺刺激后未能增加突触间隙的多巴胺水平，这两种现象在由 8 名正常志愿者组成的对照组中未见。此外，两名受试者的中央丘脑（前脑中枢回路的核心枢纽结构）均表现出选择性突触后缺陷，目前尚不清楚这种模式是否存在。突触前和突触后多巴胺能衰竭是这 2 名患者受试者特有的，或者在患有 DOC 的受试者群体中更常见。此外，当确定这些受试者中发现的突触前缺陷可能继发于多巴胺生物合成失败时，因此原则上。通过提供合成过程的主要生物底物，我们建议在休息和短期药理学后使用[11C]雷氯必利-PET 来研究创伤后 DOC 患者。旨在增加多巴胺释放和多巴胺生物合成的挑战。