Neuromodulation as a Therapy for PTSD following Chronic TBI

神经调节作为慢性 TBI 后 PTSD 的治疗方法

• 批准号: 10116979
• 负责人: John Allen Wolf
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116979
• 关键词: Affect; Amygdaloid structure; Animal Model; Animals; Behavioral; Biomechanics; Brain Injuries; Brain region; Chronic; Clinical; Clinical Treatment; Code; Cognitive deficits; Communication; Conflict (Psychology); Data; Deep Brain Stimulation; Development; Diffuse; Diffuse Axonal Injury; Disease; Electric Stimulation; Electrophysiology (science); Emotional; Equilibrium; Extinction (Psychology); Failure; Family suidae; Fright; Functional disorder; Future; Goals; Hippocampus (Brain); Human; Impairment; Injury; Intervention; Investigation; Lead; Learning; Limbic System; Memory; Modality; Modeling; Neurons; Outcome; Output; Pathology; Pathway interactions; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Property; Qualifying; Rattus; Reporting; Research; Rodent; Rodent Model; Role; Services; Site; Structure; Symptoms; System; Testing; Time; Translating; Traumatic Brain Injury; Veterans; associated symptom; awake; axon injury; base; behavioral outcome; behavioral phenotyping; brain circuitry; common treatment; comorbidity; conditioned fear; density; design; effective therapy; emotion dysregulation; experience; fear memory; functional restoration; improved; injured; insight; learning extinction; memory recall; mild traumatic brain injury; network dysfunction; neural circuit; neural network; neuromechanism; neuropathology; neurophysiology; neuroregulation; overexpression; porcine model; pre-clinical; response; symptomatology; targeted treatment; theories; warfighter

Although PTSD is a frequent co-morbidity of traumatic brain injury in Veterans, the neurophysiological basis underlying the contribution of TBI to PTSD remains unknown, and there are currently few effective treatments available for this prevalent co-morbidity. A number of human and rodent studies have demonstrated that TBI can exacerbate fear responses, and affect the ability to extinguish a conditioned fear response. Others have demonstrated in PTSD models that there is a shift in the balance between limbic structures (prefrontal cortex, the hippocampus and amygdala) after fear conditioning. Surprisingly, there have been few reports to date of how the network neurophysiology underlying these behavioral changes are affected by TBI. A potential treatment for PTSD using neuromodulation is in trials in Veterans, but we don’t have a clear understanding of how TBI would affect this neuromodulation. There is no accepted theory or supporting data demonstrating how the encoding/recall of fear learning and memory are disrupted by TBI, or how TBI affects the ability to extinguish fear. Therefore, a critical need exists to determine the underlying mechanism of how TBI leads to alteration of fear learning and extinction after traumatic brain injury. Without a deeper understanding of how TBI affects this circuitry, rational design of neuromodulatory and other therapies targeting fear processing remains improbable. The overall objective of the current application is to determine how the coding of fear in extended amygdalar circuitry is affected following TBI, and whether neuromodulation can enable faster fear extinction. Our central hypothesis is that TBI disrupts normal communication between the amygdala and other regions underlying fear memory, which leads to overexpression of fear learning, generalization to other situations, and an inability to extinguish learned fear. This hypothesis is based in part on predictions from our preliminary data demonstrating that injured animals have increased time to extinguish fear, that neurons in the limbic system have different firing properties and entrain to oscillations in a different manner following injury, and others data demonstrating that neuromodulation in the amygdala can eliminate PTSD-like symptoms. In order to test the above hypothesis, we will first determine the mechanism of TBI induced fear responses in rats using simultaneous multi-site recordings and neuropathology. We believe axonal injury affects top down input from the prefrontal cortex, as well as organizing input from the hippocampus (theta oscillations), leading to heightened amygdalar fear responses and poor consolidation of extinction memory. For the first time, we will also test neuromodulation as a treatment to restore normal balance in the extended amygdalar circuitry and restore extinction of fear. We hypothesize that extinction of fear responses in the amygdala can be restored by modulating the remaining prefrontal and/or hippocampal connections to the amygdala. In addition, we will utilize a preclinical pig model of pure diffuse axonal injury to determine whether loss of connections between limbic regions leads to changes in fear memory and an inability to extinguish fear. We believe inertial brain injury induces diffuse axonal injury which disrupts connections between prefrontal cortex, hippocampus and the amygdala, leading to an increase in fear expression and failure of extinction following TBI. Accomplishment of these goals will provide the first detailed physiological analysis of the mechanisms of TBI induced PTSD-like phenotypes across multiple diffuse TBI models. Furthermore, accomplishment of these aims will identify the causal effects of electrical stimulation on these pathways and whether it restores function in rodent models, leading to crucial mechanistic results that can be translated to preclinical and future clinical treatment for comorbid TBI/PTSD. Identification of the neuronal network disruption underlying TBI associated PTSD will not only advance our understanding of the interplay between these disorders, but allow for the development of targeted treatments for this common co-morbidity in our Veterans.

尽管PTSD经常是退伍军人创伤性脑损伤的合并症，但神经生理基础 TBI对PTSD的贡献的基础仍然未知，目前几乎没有有效的治疗方法 可用于这种普遍的合并症。许多人类和啮齿动物的研究表明TBI 会加剧恐惧反应，并影响扑灭条件恐惧反应的能力。其他人有 在PTSD模型中证明，边缘结构之间的平衡发生了变化（前额叶皮层， 恐惧调节后，海马和杏仁核）。令人惊讶的是，迄今为止的报告很少 这些行为变化的基础网络神经生理学如何受到TBI的影响。潜力 在退伍军人的试验中，使用神经调节治疗PTSD的治疗 TBI将如何影响这种神经调节。没有公认的理论或支持数据，证明了如何 恐惧学习和记忆的编码/回忆被TBI破坏了，或者TBI如何影响熄灭的能力 害怕。因此，存在批判性需求，以确定TBI如何导致改变的基本机制 害怕脑损伤后的学习和扩展。没有更深入地了解TBI如何影响这一点 电路，靶向恐惧处理的神经调节和其他疗法的理性设计仍然不可能。 当前应用的总体目的是确定较长杏仁核中恐惧的编码如何 TBI之后会影响电路，以及神经调节是否可以使恐惧延伸。我们的中心 假设是TBI破坏了杏仁核与其他区域之间的正常交流 恐惧记忆的基本记忆会导致恐惧学习的过度表达，对其他人的概括 情况，以及无法扑灭的恐惧。该假设部分基于 我们的初步数据表明，受伤的动物有增加的时间来消除恐惧，神经元中的神经元 边缘系统在受伤后以不同的方式具有不同的射击特性和振荡的入口， 其他数据表明，杏仁核中神经调节可以消除PTSD样症状。在 为了检验上述假设，我们将首先确定TBI引起的恐惧反应的机制 使用同时的多站点记录和神经病理学。我们认为轴突损伤会影响自上而下的输入 从前额叶皮层，以及从海马（theta振荡）组织输入，导致 杏仁核的恐惧反应增强，扩展记忆的巩固不良。这是我们第一次 还测试神经调节作为一种治疗方法，以恢复扩展的杏仁核电路中的正常平衡和 恢复恐惧的扩展。我们假设杏仁核中恐惧反应的扩展可以通过 调节剩余的前额叶和/或海马连接到杏仁核。此外，我们将使用 纯弥漫性轴突损伤的临床前猪模型，以确定边缘之间的连接丧失 区域导致恐惧记忆的变化和无法消除恐惧。我们相信惯性的脑损伤 诱导弥散的轴突损伤，破坏了前额叶皮层，海马和 杏仁核，导致TBI后恐惧表达和延伸的失败的增加。成就 这些目标将对TBI引起的PTSD样的机制进行首次详细的生理分析 跨多个弥漫性TBI模型的表型。此外，这些目标的完成将确定 电刺激对这些途径的因果影响，以及它是否恢复啮齿动物模型中的功能， 导致至关重要的机械结果，可以转化为临床前和未来的临床治疗 合并TBI/PTSD。识别与TBI相关PTSD的神经元网络中断不会 只有我们对这些疾病之间的相互作用的理解，但允许发展 对我们退伍军人中这种共同的合并症的有针对性治疗。