Mechanisms of Cortico-Limbic Network Dysfunction Underlying PTSD after TBI

TBI 后导致 PTSD 的皮质边缘网络功能障碍的机制

• 批准号: 9007890
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9007890
• 关键词: Acceleration; Affect; Amygdaloid structure; Anatomy; Anesthesia procedures; Animal Model; Animals; Architecture; Area; Behavior; Behavioral; Biological; Biomechanics; Brain; Brain Injuries; Brain region; Cognition; Cognitive deficits; Communication; Comorbidity; Complex; Conditioned Reflex; Conflict (Psychology); Development; Differential Diagnosis; Diffuse; Diffuse Axonal Injury; Diffuse Brain Injury; Electrodes; Electrophysiology (science); Emotional; Extinction (Psychology); Face; Failure; Family suidae; Fright; Functional disorder; Hippocampus (Brain); Impaired cognition; Implant; Individual; Injury; Limbic System; Link; Measures; Memory; Memory impairment; Military Personnel; Modeling; Monitor; Multiple Trauma; Pathology; Pathway interactions; Pattern; Phenotype; Population; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevalence; Process; Qualifying; REM Sleep; Recovery; Rehabilitation therapy; Reporting; Risk; Services; Sleep; Structure; Symptoms; System; Testing; Time; Traumatic Brain Injury; Veterans; associated symptom; attenuation; awake; base; brain circuitry; brain pathway; conditioned fear; coping mechanism; cortico-limbic circuits; diagnostic biomarker; dual diagnosis; effective therapy; emotion dysregulation; experience; improved; injured; interest; member; memory process; mild traumatic brain injury; network dysfunction; neuropathology; neurophysiology; public health relevance; rapid eye movement; research study; response; sleep abnormalities; symptom treatment; symptomatology; therapy resistant

 DESCRIPTION: Traumatic Brain Injury (TBI) is considered the "signature" injury of the recent US wartime conflicts, with approximately 15% of warfighters experiencing single or multiple mild TBIs (mTBI). PTSD is a frequent comorbidity in this population, with almost 35% of mTBI exposed Veterans reporting qualifying symptoms associated with their service in theater. A great deal of controversy remains over whether mild traumatic brain injury (mTBI) contributes to the susceptibility for post-traumatic stress disorder (PTSD), or whether mTBI mechanistically underlies some aspects of presenting PTSD symptoms. There is a great deal of overlap in the symptomatology of mTBI and PTSD, suggesting that either a large subpopulation of mTBI exposures are also psychologically traumatic, or that there is an underlying biological substrate after single or multiple mTBIs that predisposes Veterans to PTSD or its associated symptoms. The presenting symptomatology of PTSD (i.e., emotion dysregulation and cognitive deficits) may have an underlying basis in the biomechanical disruption by TBI of the coordination of brain areas for emotional processing and memory. This same disruption may interfere with effective treatment, in particular prolonged exposure (PE), which incorporates an extinction paradigm. Animal models are necessary in order to unravel the effect of TBI on the brain circuitry underlying PTSD. We will therefore utilize the most biomechanically realistic model of diffuse brain injury, the porcine rotational acceleration model, in order to elucidate how mTBI affects the circuitry underlying PTSD and the acquisition and extinction of PTSD-like behavioral phenotypes. We will utilize fear conditioning in order to produce a PTSD-like phenotype in swine. The limbic system, a group of brain regions involved in cognition, memory and processing of emotional salience, is highly linked via oscillatory activity between these networks. Our central hypothesis is that diffuse TBI leads to a disruption within and between areas of the corticolimbic system, increasing dominance of the amygdala over other limbic structures and thus leading to a susceptibility to PTSD-like phenotypes and failure of extinction. TBI may also disrupt the very circuitry required to extinguish post-traumatic symptoms, and adversely affect sleep patterns involved in reconsolidation of memory. We will investigate the mechanisms underlying TBI- related PTSD symptoms and treatment resistance by examining neurophysiological changes in the cortico-limbic system and related behaviors, including sleep-wake architecture, after single and repetitive rotational acceleration injury. To accomplish these aims, swine will be injured repetitively (2x) at acceleration levels inducing mTBI, and then experiments will proceed at multiple time-points post-injury. Multiple electrode arrays that allow for extensive coverage of the cortico-limbic circuit will be implanted under anesthesia and monitored over a period of 3-4 weeks post-injury, during behavioral tasks dependent on cortico-limbic circuitry. Another group of animals will be fear conditioned post-injury in order to detect changes in fear acquisition (i.e., the development of a PTSD-like phenotype) post-TBI. Another group of animals will be fear-conditioned prior to injury so that the effect of subsequent injury (compared to sham injury) on the extinction of fear can be examined. As sleep disruption is a prominent overlapping symptom of PTSD and TBI, all animals, injured and sham injured will be monitored for changes in sleep-wake architecture. Rapid eye movement (REM) s eep macro- and microarchitecture will be examined as there is substantial evidence for REM sleep abnormalities in PTSD. In all experiments, sleep measures will be correlated with electrophysiological measures. The animals will then be sacrificed, and the electrophysiological findings correlated with histopathological analysis of the hippocampus, prefrontal cortex, and amygdala and their connecting axonal tracts. The proposed studies will therefore assess the mechanism(s) underlying comorbid TBI and PTSD by examining the neurophysiological changes in the relevant cortico-limbic networks in a porcine model of diffuse brain injury.

 描述： 创伤性脑损伤（TBI）被认为是最近美国战时冲突的“签名”伤害，大约15％的战士经历了单一或多个轻度TBI（MTBI）。 PTSD在该人群中经常是合并症，近35％的MTBI暴露了退伍军人报告与剧院服务相关的合格症状。关于轻度创伤性脑损伤（MTBI）是否有助于创伤后应激障碍（PTSD）的易感性，还是MTBI是否机械地基于表现PTSD症状的某些方面，这一争议仍然存在。 MTBI和PTSD的症状存在很大的重叠，这表明MTBI暴露的大量亚群在心理上是创伤性的，或者在单个或多个MTBI后有一种潜在的生物学基质，使PTSD偏见PTSD或其相关症状。 PTSD的症状（即情绪失调和认知缺陷）的症状可能在TBI的生物力学破坏中可能存在基础，从而对大脑区域的协调进行情感处理和记忆的协调。同样的破坏可能会干扰有效的治疗，特别是延长暴露（PE），其中包含扩展范式。为了揭示TBI对PTSD基础脑电路的影响，动物模型是必要的。因此 PTSD的基础电路以及PTSD样行为表型的采集和扩展。我们将利用恐惧调节来在猪中产生类似PTSD的表型。边缘系统是一组参与认知，记忆和情感显着性处理的大脑区域，通过这些网络之间的振荡活动高度联系。 我们的中心假设是，弥漫性TBI导致了皮质胶体系统区域内和之间的破坏，从而增加了杏仁核的优势，而不是其他边缘结构，从而导致对PTSD样表型的敏感性和延期失效。 TBI还可能破坏扑灭创伤后症状所需的电路，并对记忆重新整合涉及的睡眠模式产生不利影响。我们将通过检查皮质膜系统和相关行为的神经生理学变化（包括睡眠效果结构），在单一和重复性旋转加速度损伤之后，通过检查与TBI相关的PTSD症状和治疗耐药性的基础机制。为了实现这些目标，猪将在加速度诱发的MTBI下重复受伤（2倍），然后实验将在伤害后多个时间点进行。多个电极阵列允许广泛覆盖的另一组动物将是恐惧受伤的后伤害后，以检测恐惧获取的变化（即，在TBI之后的PTSD样表型的发展）。另一组动物将在受伤前得到恐惧，以便可以检查随后的伤害（与假伤害）对恐惧的延伸作用。由于睡眠中断是PTSD和TBI的突出重叠症状，因此所有动物，受伤和假手术受伤的症状将受到监控，以使睡眠效果结构的变化。快速眼动（REM）的EEP宏观和微体系结构将被检查，因为有大量证据表明PTSD中REM睡眠异常。在所有实验中，睡眠度量将与电生理措施相关。然后将处死动物，电生理发现与海马，前额叶皮层和杏仁核的组织病理学分析及其连接的轴突区。因此，拟议的研究将通过检查弥漫性脑损伤的猪模型中相关皮质膜网络的神经生理变化来评估合并症TBI和PTSD的基本机制。