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 创伤性脑损伤导致创伤后应激障碍的潜在原因尚不清楚，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 可以加剧恐惧反应，并影响消除条件性恐惧反应的能力。其他人已经 在创伤后应激障碍模型中证明了边缘结构（前额叶皮层， 海马体和杏仁核）。令人惊讶的是，迄今为止， 这些行为变化背后的网络神经生理学如何受到TBI的影响。一个潜在 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 创伤性脑损伤会如何影响这种神经调节没有公认的理论或支持数据证明如何 恐惧学习和记忆的编码/回忆被TBI破坏，或者TBI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TBI的改变的潜在机制。 恐惧学习和脑外伤后的灭绝。如果不深入了解TBI如何影响这一点， 神经回路、神经调节和其他针对恐惧处理的疗法的合理设计仍然是不可能的。 当前应用的总体目标是确定扩展杏仁核中恐惧的编码是如何 脑外伤后神经回路是否受到影响，以及神经调节是否能使恐惧更快消失。我们的中央 有一种假说认为，脑外伤破坏了杏仁核和其他区域之间的正常交流 潜在的恐惧记忆，这导致过度的恐惧学习，泛化到其他 情况下，和无法扑灭学习恐惧。这一假设部分是基于 我们的初步数据表明，受伤的动物有更多的时间来消除恐惧， 边缘系统具有不同的激发特性并在受伤后以不同的方式引起振荡， 以及其他数据表明杏仁核中的神经调节可以消除PTSD样症状。在 为了验证上述假设，我们将首先确定TBI诱导大鼠恐惧反应的机制 使用多点同步记录和神经病理学。我们认为轴突损伤会影响自上而下的输入 从前额叶皮层，以及组织输入从海马（θ振荡），导致 杏仁核恐惧反应增强和记忆消失的巩固不良。这是我们第一次 还测试神经调节作为恢复扩展杏仁核回路中的正常平衡的治疗， 恢复恐惧的消失。我们假设杏仁核中恐惧反应的消失可以通过以下方式恢复： 调节剩余的前额和/或海马与杏仁核的连接。此外，我们将利用 临床前纯弥漫性轴索损伤的猪模型，以确定边缘系统之间的连接丢失是否 区域导致恐惧记忆的变化和无法消除恐惧。我们认为惯性脑损伤 诱导弥漫性轴突损伤，破坏前额叶皮层，海马和 杏仁核，导致TBI后恐惧表达增加和消退失败。完成 这些目标将首次对创伤性脑损伤诱导的创伤后应激障碍样的机制进行详细的生理学分析， 在多种弥漫性TBI模型中的表型。此外，实现这些目标将确定 电刺激对这些通路的因果作用以及它是否恢复啮齿动物模型的功能， 从而导致关键的机制结果，这些结果可以转化为临床前和未来的临床治疗， 合并创伤性脑损伤/创伤后应激障碍识别TBI相关PTSD的神经网络破坏， 这只会促进我们对这些疾病之间相互作用的理解，但允许发展 针对退伍军人中常见的合并症进行有针对性的治疗。

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.