Neuromodulation as a Therapy for PTSD following Chronic TBI

虽然创伤后应激障碍是退伍军人创伤性脑损伤的常见并发症，但其神经生理学基础 创伤性脑损伤对创伤后应激障碍的作用仍不清楚，目前几乎没有有效的治疗方法。 可用于这种普遍的并存疾病。许多人类和啮齿动物的研究表明，脑损伤 会加剧恐惧反应，并影响消除条件性恐惧反应的能力。其他人则有 在创伤后应激障碍模型中显示边缘结构(前额叶皮质， 海马体和杏仁核)。令人惊讶的是，到目前为止，几乎没有关于 这些行为变化背后的网络神经生理学是如何受到脑损伤的影响的。一种潜力 使用神经调节治疗创伤后应激障碍正在退伍军人中进行试验，但我们对 脑外伤将如何影响这种神经调节。没有公认的理论或支持数据来证明 恐惧学习和记忆的编码/回忆被脑外伤打乱，或者脑外伤如何影响消除恐惧的能力 恐惧。因此，迫切需要确定TBI如何导致改变的潜在机制 创伤性脑损伤后害怕学习和灭绝。没有更深入地了解TBI如何影响这一点 针对恐惧处理的电路、神经调节和其他疗法的合理设计仍然是不可能的。 目前应用程序的总体目标是确定扩展杏仁核中恐惧的编码方式 脑外伤后的神经回路会受到影响，以及神经调节是否能够更快地消除恐惧。我们的中央 假设脑外伤会破坏杏仁核和其他区域之间的正常通讯。 潜在的恐惧记忆，这导致过度表达恐惧的学习，概括到其他 情况，以及无法消除习得的恐惧。这一假设在一定程度上是基于 我们的初步数据显示，受伤的动物有更多的时间消除恐惧，神经元 边缘系统具有不同的激发特性，并在受伤后以不同的方式缠绕到振荡， 和其他数据表明，杏仁核的神经调节可以消除创伤后应激障碍样症状。在……里面 为了验证上述假设，我们将首先确定脑创伤诱导大鼠恐惧反应的机制 使用同步的多点录音和神经病理学。我们认为轴突损伤会影响自上而下的输入 来自前额叶皮质的，以及来自海马体的组织输入(theta振荡)，导致 杏仁核恐惧反应增强，消亡记忆巩固不良。第一次，我们将 也测试神经调节作为一种治疗方法，以恢复扩展的杏仁核回路的正常平衡 恢复恐惧的消亡。我们假设杏仁核中恐惧反应的消退可以通过 调节剩余的前额叶和/或海马区与杏仁核的连接。此外，我们还将利用 临床前猪单纯弥漫性轴索损伤模型的建立 区域会导致恐惧记忆的变化，并导致无法消除恐惧。我们认为惯性脑损伤 导致弥漫性轴突损伤，破坏前额叶皮质、海马体和 杏仁核，导致脑损伤后恐惧表达的增加和灭绝的失败。成就 这些目标将为脑创伤后创伤后应激障碍的机制提供第一个详细的生理学分析 多个弥漫性脑损伤模型的表型。此外，这些目标的实现将确定 电刺激对这些通路的因果影响以及它是否能在啮齿动物模型中恢复功能， 导致关键的机械性结果，可转化为临床前和未来的临床治疗 合并脑损伤/创伤后应激障碍。与创伤相关的创伤后应激障碍的神经网络损害的鉴定不会 只能促进我们对这些障碍之间相互作用的理解，但允许发展 有针对性地治疗退伍军人中这种常见的并存疾病。

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.