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

• 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
• 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

 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，前脑中间回路功能障碍是关键的潜在机制。 DOC 中前脑代谢在支撑高度复杂的认知行为的大脑区域中显着下调，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。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-PET在休息时以及在右旋苯丙胺和右旋苯丙胺+L-DOPA的短暂药理挑战后测量主要多巴胺能通路中D2/D3受体的表达。在 DOC 中使用这项新技术，我们对 2 名处于慢性最低意识状态的患者进行了表征，他们在休息时合成和/或释放多巴胺的突触前缺陷，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均未出现。此外，两名受试者的中央丘脑（前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。目前尚不清楚这种突触前和突触后多巴胺能衰竭模式是否是这 2 名患者受试者特有的，还是在 DOC 受试者群体中更常见。此外，当在这些受试者中发现的突触前缺陷被识别时，可能是继发于多巴胺生物合成失败的，因此原则上通过提供合成过程的主要生物底物是可逆的。因此，我们建议在休息时使用[11C]雷氯必利-PET 来研究创伤后 DOC 患者，并在短期药物挑战后进行旨在增加多巴胺释放和多巴胺生物合成的治疗。