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: 8856874
• 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/8856874
• 关键词: Acceleration; Affect; Amygdaloid structure; Anatomy; Anesthesia procedures; Animal Model; Animals; Architecture; Area; Behavior; Behavioral; Biological; Biological Markers; Biomechanics; Brain; Brain Injuries; Brain region; Cognition; Cognitive deficits; Communication; Comorbidity; Complex; Conditioned Reflex; Conflict (Psychology); Development; Diagnostic; 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; Resistance; Risk; Services; Sleep; Structure; Symptoms; System; Testing; Time; Traumatic Brain Injury; Veterans; attenuation; awake; base; brain circuitry; brain pathway; conditioned fear; coping mechanism; cortico-limbic circuits; 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

 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“标志性”伤害，大约 15% 的战士经历过一次或多次轻度 TBI (mTBI)，这是该人群中常见的合并症，其中近 35% 的人患有创伤性脑损伤 (TBI)。暴露于 mTBI 的退伍军人报告了与他们在战区服役相关的合格症状，关于轻度创伤性脑损伤 (mTBI) 是否会导致对 mTBI 的易感性仍然存在很大争议。创伤后应激障碍 (PTSD)，或者 mTBI 是否在机制上导致 PTSD 症状的某些方面 mTBI 和 PTSD 的症状有很多重叠，这表明大量 mTBI 暴露也会造成心理创伤，或者在单次或多次 mTBI 后存在潜在的生物基础，使退伍军人容易患 PTSD 或其相关症状（即情绪失调和相关症状）。认知缺陷）可能是 TBI 对情绪处理和记忆的大脑区域协调的生物力学破坏的潜在基础，这种破坏可能会干扰有效的治疗，特别是长期暴露（PE），其中包含了消退模型。为了揭示 TBI 对 PTSD 背后的大脑回路的影响，我们将利用最生物力学上最真实的弥漫性脑损伤模型，即猪旋转加速模型，来阐明 mTBI 如何影响 PTSD。 PTSD 背后的电路以及 PTSD 样行为表型的获得和消失 我们将利用恐惧调节来在猪中产生类似 PTSD 的表型，边缘系统是一组涉及认知、记忆和情绪处理的大脑区域。显着性，通过这些网络之间的振荡活动高度相关。 我们的中心假设是，弥漫性 TBI 会导致皮质边缘系统内部和区域之间的破坏，增加杏仁核相对于其他边缘结构的主导地位，从而导致对 PTSD 样表型的易感性，并且 TBI 的消退失败也可能会破坏。我们将通过检查神经生理学变化来研究 TBI 相关 PTSD 症状和治疗抵抗的机制。在单次和重复的旋转加速损伤后，猪的皮质边缘系统和相关行为（包括睡眠-觉醒结构）将受到重复（2x）损伤，从而诱发 mTBI，然后实验将以多次进行。将在麻醉下植入多个电极阵列，以广泛覆盖皮质边缘回路，并在受伤后 3-4 周的行为期间进行监测。另一组动物将在受伤后进行恐惧调节，以检测 TBI 后恐惧习得的变化（即 PTSD 样表型的发展）。 -在受伤前进行调节，以便可以检查随后的伤害（与假伤相比）对恐惧消除的影响，因为睡眠中断是 PTSD 和 TBI 的一个突出的重叠症状，所有受伤和受伤的动物。将监测假受伤的睡眠-觉醒结构的变化，因为有大量证据表明 PTSD 中的 REM 睡眠异常，因此将检查快速眼动 (REM) 睡眠结构。然后处死动物，并将电生理学结果与海马体、前额皮质和杏仁核及其连接轴突束的组织病理学分析相关。因此，研究将通过检查弥漫性脑损伤猪模型中相关皮质边缘网络的神经生理学变化来评估共病 TBI 和 PTSD 的机制。