Neurobiology and Experimental Treatment of TBI Pain and Anxiety

TBI 疼痛和焦虑的神经生物学和实验治疗

• 批准号: 8840067
• 负责人: PRODIP K. BOSE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840067
• 关键词: Affect; Amygdaloid structure; Animals; Anxiety; Behavior; Behavioral; Brain region; Cell Nucleus; Cervical; Chronic; Cognition; Cognitive; Community Services; Craniocerebral Trauma; Development; Dorsal; Exercise; Functional disorder; Head; Healthcare Systems; Hippocampus (Brain); Immune; Impaired cognition; Inflammation; Injury; Intervention; Lesion; Magnetism; Mass Spectrum Analysis; Measures; Modeling; Morbidity - disease rate; Neurobiology; Neurologic; Neurologic Manifestations; Neurons; Norepinephrine; Outcome; Outcome Measure; Pain; Rattus; Severities; Societies; Spinal; System; TBI treatment; Testing; Therapeutic; Time; Translations; Traumatic Brain Injury; Treatment Efficacy; Up-Regulation; Veterans; anxiety sensitivity; base; disability; effective intervention; gray matter; immunocytochemistry; interest; knowledge base; multiple disability; noradrenergic; pregabalin; programs; safety testing

DESCRIPTION (provided by applicant): Closed head traumatic brain injury (CH-TBI) results in a broad spectrum of neurological deficits. Recently, those involving cognition, pain sensitivity, and anxiety, have risen to the level of urgency for the development of new information that can enhance therapy for CH-TBI. This study proposes a unifying hypothesis regarding the multiple-morbidity that frequently following CH-TBI. It proposes that that dysfunction of the central noradrenergic (NA) system is a common underlying denominator of these multiple disabilities. Four aims are proposed to investigate specific neurological deficits induced by CH-TBI, how these are correlated with noradrenergic injury, and the potential for these deficits to be modified by three treatments that target upregulation of the central noradrenergic system. A fifth aim proposes a proof of principle sudy. Aim 1 will determine the severity and time-course of the three neurological manifestations following mild/moderate CH-TBI in a rat head injury model. Aims 2 will correlate the magnitude of behavioral changes after CH-TBI with measures of NA expression in regions of the brain predominantly involved in the specific behaviors of interest (i.e., hippocampus CA1 and CA3, central nucleus of the amygdala, and cervical and lumbar dorsal spinal gray matter). The third Aim will test the safety, feasibility, and efficacy of three therapies - activity wheel locomotor (AWL) exercise, transcortical magnetic stimulation (TMS), and pregabalin alone or in combination - on cognitive, pain, and anxiety outcomes of mild and moderate CH-TBI. Aim 4 will examine how these treatments affect regional NA expression using mass spectrometry and norepinephrine (NE) immunocytochemistry. Aim 5 will further test the central hypothesis by evaluating treatment efficacy (using the best treatment combination) in animals following selective immune-lesion of central noradrenergic neurons. The proposed studies will increase our knowledge base of: 1) CH-TBI-induced cognitive dysfunctions, anxiety, pain disabilities, and chronic inflammation; 2) the relationship of these disabilities with dysregulation of the central NA system; 3) the value of specific treatments to decrease the severity of long term disabilities; and 4) the impact of therapeutic program to significantly alter central NA levels and decrease the magnitude of CH-TBI-induced chronic inflammation. Translation of these findings may provide safe, timely, and effective intervention strategies which can significantly benefit the veterans' health care system.

描述(由申请人提供)： 闭合性头部创伤性脑损伤(CH-TBI)导致广泛的神经功能障碍。最近，那些涉及认知、疼痛敏感和焦虑的问题已经上升到迫切需要开发新的信息来加强对CH-TBI的治疗。这项研究提出了一个统一的假设，即脑出血后经常出现的多种并发症。它提出，中枢去甲肾上腺素(NA)系统功能障碍是这些多重残疾的共同潜在因素。提出了四个目标来研究CH-TBI引起的特定神经损伤，这些损伤如何与去甲肾上腺素能损伤相关，以及三种针对中枢去甲肾上腺素系统上调的治疗方法来改善这些缺陷的可能性。第五个目标提出了一种原则证明。目的1在大鼠颅脑损伤模型上确定轻、中度颅脑损伤后三种神经学表现的严重程度和时程。AIMS 2将把CH-TBI后行为改变的幅度与脑中主要涉及特定行为的区域(即，海马CA1和CA3，杏仁中央核，以及颈和腰椎背侧灰质)中NA表达的测量相关联。第三个目标将测试三种疗法-活动轮运动(AWL)运动、经皮质磁刺激(TMS)和普瑞巴林单独或联合使用-对轻、中度脑外伤患者的认知、疼痛和焦虑结果的安全性、可行性和有效性。目的4将使用质谱学和去甲肾上腺素(NE)免疫细胞化学来研究这些治疗如何影响局部NA的表达。目的5将通过评估中枢去甲肾上腺素能神经元选择性免疫损伤后的动物的治疗效果(使用最佳治疗组合)来进一步检验中枢假说。拟议中的研究将增加我们关于以下方面的知识库：1)CH-TBI导致的认知功能障碍、焦虑、疼痛残疾和慢性炎症；2)这些残疾与中央NA系统调节失调的关系；3)特定治疗方法的价值，以降低长期残疾的严重程度；以及4)治疗计划显著改变中央NA水平和降低CH-TBI诱导的慢性炎症的程度的影响。这些发现的翻译可能会提供安全、及时和有效的干预策略，从而显著有利于退伍军人的医疗保健系统。