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（由适用提供）：严重脑损伤后对意识障碍（DOC）患者的研究暗示前前前脑介质功能障碍的功能障碍是基础机制的关键。在大脑区域中，DOC中的前脑前脑代谢明显下调，这些区域是高度详细的认知行为，证明了一致的目标指导行为和唤醒调节所需的突触背景活动水平的崩溃。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器之一，因此我们建议研究创伤后文档中突触前和突触后多巴胺功能的特定贡献。本研究的目的是使用[11C] reclopride-pet在REST上测量D2/D3受体在主要多巴胺能途径中的表达，并在对右旋苯丙胺和右旋苯丙胺 + L-DOPA的短暂药理挑战中进行了短暂的药理挑战。我们在DOC中使用了这种新技术，我们在2名患者中表征了慢性最小意识状态的一种突触前缺乏症来合成和/或静止释放多巴胺，并且未能通过右旋苯丙胺刺激后，在合成裂隙处增加多巴胺水平。在由8位正常志愿者组成的对照组中，这两种现象都是看不见的。此外，两个受试者在中央丘脑（前脑前脑中循环的核心中心结构）中均显示出选择性的突触后缺陷。尚不清楚这种模式是突触前和突触后多巴胺能衰竭是针对这2名患者受试者的特异性，还是在患有DOC的受试者人群中更普遍地看到。此外，当这些受试者中发现的突触前缺陷被发现时，可能是多巴胺生物合成失败的继发性，因此原则上可通过提供合成过程的主要生物学底物可逆。因此，我们建议在休息时使用[11C] reclopride-pet研究创伤后DOC的患者，并在旨在增加多巴胺释放和多巴胺生物合成的短暂药物挑战之后。