Identification and treatment of brain regions causing post-traumatic headache

导致创伤后头痛的大脑区域的识别和治疗

• 批准号: 9215538
• 负责人: Levi P Sowers
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215538
• 关键词: Address; Alder plant; Amygdaloid structure; Anatomy; Area; Award; Behavior; Behavioral; Biological Assay; Blast Cell; Blast Injuries; Blindness; Brain; Brain region; Budgets; Calcitonin Gene-Related Peptide; Cell Nucleus; Chronic; Chronic Headaches; Clinical; Clinical Trials; Collaborations; Comorbidity; Darkness; Data; Deep Brain Stimulation; Development; Diagnosis; Epilepsy; Etiology; Foundations; Functional disorder; Future; Goals; Grant; Grant Review; Headache; Human; Incidence; Injectable; Intervention; Iraq; K-Series Research Career Programs; Knowledge; Learning; Light; Link; Manuscripts; Mentors; Methods; Migraine; Military Personnel; Modeling; Mus; Neuroanatomy; Neuropeptides; Neurosciences; Ophthalmologist; Outcome; Patients; Peptide antibodies; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Photophobia; Photosensitivity; Play; Population; Post-Traumatic Headaches; Prevalence; Prevention; Psychiatrist; Quality of life; Recording of previous events; Research; Research Methodology; Research Personnel; Risk; Role; Scientist; System; Techniques; Testing; Thalamic structure; Therapeutic; Therapeutic Intervention; Time; TimeLine; Training; Translations; Traumatic Brain Injury; Veterans; Wild Type Mouse; Work; associated symptom; base; career; combat; effective therapy; experience; injured; innovation; multidisciplinary; negative affect; neurophysiology; novel; novel therapeutics; optogenetics; patch clamp; pre-clinical; programs; public health relevance; skills; symposium; targeted treatment; therapeutic development; therapy development; treatment center

 DESCRIPTION (provided by applicant): Objective: A major objective of this proposal is to train Dr. Sowers to become an independent translational neuroscientist in the VA system. To accomplish this, he has prepared a research plan that will allow training in state-of-the-art optogenetic techniques to address a major issue facing Veterans, post-traumatic headache. Veterans returning from active duty are at an increased risk for post-traumatic headache that includes migraine. U.S. military personnel screened within 90 days of returning from a one-year combat tour in Iraq had 2-4 times the rate of migraine compared to civilians. One debilitating aspect of post traumatic headache is concurrent photophobia which can negatively affect Veterans daily lives. Interventions and treatments for post- traumatic headache and photophobia remain inadequate due to a poor understanding of the relevant neuroanatomical correlates. This proposal aims to identify brain regions that are directly involved with the development of post-traumatic headache and photosensitivity and test pharmacological agents to mitigate light sensitivity. As a starting point we plan to focus on areas implicated in light aversion and modulated by the neuropeptide calcitonin gene-related peptide (CGRP). Our findings will overcome two major hindrances in the development of future treatments for Veterans with traumatic brain injury (TBI) by determining: first, which brain regions are sufficient to induce photophobia, and second, whether these regions are necessary for the development of TBI induced photophobia. The results from these studies will guide future innovative therapeutic interventions, such as deep brain stimulation and transcranial stimulation, for the treatment of this debilitating chronic condition of TBI. This stuy will be aided by clinical interactions with his multidisciplinary mentoring team, two of which are practicing psychiatrists within the VA system, as well as a neuro-ophthalmologist. Dr. Sowers will have access to a large TBI population at the Center for the Treatment and Prevention of Visual Loss. The training plan will also take advantage of interactions with clinicians and basic scientists in the VA Center. Moreover, Dr. Sowers' mentor has ongoing collaborations with two pharmaceutical companies (Alder and Eli Lilly) that will facilitate the translation of the expected findings to clinical trials. These clinical perspectives will not only aid with the applicant's traning, but will also focus the research plan on a fast translational timeframe. Methods: We have established a pre-clinical blast-induced light-aversion model as an objective indicator of post-traumatic headache. In Aim 1, we will use optogenetic applications to target specific brain regions we hypothesize to be involved with the development of post-traumatic headache. In Aim 2 we will use pharmacological manipulation of CGRP to alleviate post-traumatic headache in C57BL/6J wild type mice. Expected results: This proposal will have three main outcomes: 1) It will establish the applicant as an expert in pre-clinical TBI models that are closely linked to translational testing of novel therapeutics. 2) It will significantly advance our understanding of the neuroanatomy underlying post-traumatic headache and photophobia by identifying brain regions that could be targets for specific deep brain stimulation or transcranial stimulatory treatments. 3) The proposed work will benefit Veterans by identifying future pharmacological treatments to ameliorate post-traumatic headache.

 描述(由申请人提供)： 目标：这项提议的一个主要目标是培养索尔斯博士成为VA系统中的一名独立的翻译神经学家。为了实现这一目标，他准备了一项研究计划，允许对最先进的光遗传技术进行培训，以解决退伍军人面临的一个主要问题--创伤后头痛。从现役归来的退伍军人患创伤后头痛的风险增加，其中包括偏头痛。在伊拉克进行了为期一年的战斗访问后，在90天内对美国军事人员进行了筛查，与平民相比，偏头痛的发生率是2-4倍。创伤后头痛的一个令人虚弱的方面是并发恐光，这可能会对退伍军人的日常生活产生负面影响。对创伤后头痛和畏光的干预和治疗仍然不充分，因为对相关的神经解剖学相关知识缺乏了解。这项建议旨在确定与创伤后头痛和光敏反应的发展直接相关的大脑区域，并测试减轻光敏感的药物。作为起点，我们计划将重点放在与光线厌恶有关的区域，并受神经肽降钙素基因相关肽(CGRP)的调节。我们的发现将通过确定以下两个主要障碍来克服未来治疗创伤性脑损伤(TBI)退伍军人的障碍：第一，哪些大脑区域足以引发恐光；第二，这些区域是否对发展TBI诱导的恐光是必要的。这些研究的结果将指导未来的创新治疗干预措施，如脑深部刺激和经颅刺激，用于治疗这种令人衰弱的慢性脑损伤。这项研究将得到与他的多学科指导团队的临床互动的帮助，其中两人是退伍军人管理局系统内的执业精神病学家，以及一名神经眼科医生。Sowers博士将可以在视力丧失治疗和预防中心接触到大量的脑损伤患者。培训计划还将利用与退伍军人管理局中心的临床医生和基础科学家的互动。此外，Sowers博士的导师正在与两家制药公司(Alder和Eli Lilly)进行合作，这将促进预期的 将发现提交给临床试验。这些临床观点不仅有助于申请者的培训，还将使研究计划集中在快速翻译的时间表上。方法：我们建立了一个临床前的冲击波诱导的光厌恶模型，作为创伤后头痛的客观指标。在目标1中，我们将使用光遗传学应用程序来定位特定的大脑区域，我们假设这些区域与创伤后头痛的发展有关。在目标2中，我们将使用降钙素基因相关肽的药理操作来缓解C57BL/6J野生型小鼠创伤后头痛。预期结果：这项建议将有三个主要结果：1)它将使申请者成为与新疗法的翻译测试密切相关的临床前脑损伤模型方面的专家。2)通过识别可能成为特定脑深部刺激或经颅刺激治疗目标的大脑区域，它将显著促进我们对创伤后头痛和恐光背后的神经解剖学的理解。3)拟议的工作将通过确定未来改善创伤后头痛的药物治疗而使退伍军人受益。