Interactions of traumatic brain injury with pre-existing mild epilepsy on thalamocortical dysfunction, sensory processing, and seizures

在最近的伊拉克和阿富汗冲突中，数千名军人遭受轻微创伤。 脑损伤(MTBI)，不会造成大体解剖损伤或出血，仅产生 短暂的意识改变时期。尽管这些脑损伤被归类为“轻度”，但许多退伍军人 MTBI经历短期和长期的神经功能障碍，包括癫痫和躯体感觉(SS) 可能导致疼痛/头痛的失调。我们迫切需要新的mTBI疗法。 以往对mTBI的病理生理学研究主要集中在损伤对组织学、生理学的影响。 以及局部损伤点附近小脑区神经元的细胞生物学。然而，爆炸性爆炸 影响广泛的大脑区域组成了大多数现代战斗MTBI，因此通常没有单一的 局部损伤点。此外，新的数据表明，大规模脑网络的功能障碍(在空间上 分离但功能相连的大脑区域)会导致癫痫和SS处理障碍。因此，它 对于确定mTBI对大规模脑网络的影响以及是否进行治疗性调节至关重要 网络生理学(如脑刺激)可减少癫痫发作及其并存。之前的研究在 非创伤性患者和动物模型显示SS丘脑皮质内的异常生理 (SSTC)和躯体感觉皮质(SSCC)网络与局灶性和全身性密切相关 癫痫发作和SS加工障碍。因此，mTBI很可能还会改变SSCC和SSTC 生理学导致癫痫和生长抑素失调。 遗传风险因素可能在mTBI后癫痫的发生发展中起重要作用。家族史 癫痫的风险使mTBI后癫痫的风险从1.5-2.2倍增加到5.8倍，流行病学研究 提示9.3%的mTBI患者与癫痫有一级亲属关系。开发特定于网络的 治疗(例如，神经刺激)，有必要知道mTBI是否会导致不同的致痫改变 在遗传易感个体的SSTC和SSCC网络中。 这个应用程序将测试mTBI改变活动和 SSCC和SSTC网络的连通性导致mTBI后癫痫发作和SS功能障碍，这些 具有遗传脆弱性的受试者的变化更大。这一假设将使用自上而下的 临床可翻译的方法，以确定mTBI对1)癫痫发作/SS功能的影响(目标1)，2)长时间- 使用高密度EEG(HdEEG，AIM2 A/B)的范围SSCC连接和3)通过 HdEEG/立体定向EEG(SEEG，目标2C)。重要的是，(目标3)初级躯体感觉皮质(S1)活动将 然后被因果操纵，以确定对SSCC/SSTC网络连接和癫痫发作的影响，并 将观察扩展到仅仅是关联，并为未来对网络的研究提供基础- 特定的调节疗法(例如，神经刺激)。这一假设将在野生型(WT)小鼠身上进行验证 以及Pi的人类癫痫风险基因杂合(Het)表达的新小鼠模型 (Gabra1A322D)。目的1确定mTBI对WT和WT大鼠癫痫发作和体感功能的影响。 HET老鼠。MTBI对(A)癫痫发作的早期和长期影响 (B)通过神经行为测试测量SS功能。目标2将阐明mTBI对SSTC和 WT和Het小鼠的SSCC网络。PI建立的HdEEG方法将与创新的 微创MXene HdEEG阵列用于确定mTBI中SSCC网络活动和连通性 研究对象。其次，用HdEEG(B)和HdEEG(B)观察mTBI对SSCC(B)和SSTC(C)网络生理的影响 将确定HdEEG/SEEG(C)记录。最后，目标3将确定S1的效果 使用A)开环和B)神经刺激对mTBI后SSCC/SSTC网络连接和癫痫发作的影响 闭合环刺激。

During the recent conflicts in Iraq and Afghanistan, thousands of service personnel suffered mild traumatic brain injuries (mTBIs), those that do not cause gross anatomical damage or hemorrhage and produce only brief periods of altered awareness. Although these brain injuries are classified as “mild,” many veterans with mTBI experience short- and long-term neurological dysfunction including epilepsy and somatosensory (SS) dysregulation that may underlie pain/headache. We urgently need new mTBI therapies. Most previous investigations of mTBI pathophysiology focused on injury effects on the histology, physiology and cellular biology of neurons in small brain regions near a point of focal injury. However, explosive blasts impacting widespread brain regions comprise most modern combat mTBIs and thus there is often no single point of focal injury. Moreover, new data suggest that dysfunction of large-scale brain networks (spatially separate, but functionally connected brain regions) lead to epilepsy and SS processing disorders. Therefore, it is critical to determine the effects of mTBI on large scale brain networks and if therapeutically modulating network physiology (e.g. brain stimulation) reduces seizures and their comorbidities. Previous studies in nontraumatic patients and animal models demonstrated that abnormal physiology within SS thalamocortical (ssTC) and somatosensory corticocortical (ssCC) networks are strongly associated with focal and generalized seizures and SS processing disorders. Therefore, it is likely that mTBI will also alter ssCC and ssTC physiology to produce epilepsy and SS dysregulation. Genetic risk factors likely play an important role in the development of post-mTBI seizures. A family history of epilepsy increases the risk of post-mTBI epilepsy from 1.5-2.2-fold to 5.8-fold risk and epidemiology studies suggest that 9.3% mTBI patients have a first degree relative with epilepsy. To develop network-specific therapies (e.g. neurostimulation), it is necessary to know whether mTBI causes different epileptogenic changes in ssTC and ssCC networks in genetically susceptible individuals. This application will test the overarching hypothesis that mTBI alters the activity and connectivity of ssCC and ssTC networks to produce post-mTBI seizures and SS dysfunction and that these changes are greater in subjects with genetic vulnerabilities. This hypothesis will be tested using a top-down clinically translatable approach to determine the effects of mTBI on 1) seizures/SS function (Aim 1), 2) long- range ssCC connectivity using high density EEG (HdEEG, Aim2 A/B) and 3) ssTC connectivity by HdEEG/stereotactic EEG (SEEG, Aim 2C). Importantly, (Aim 3) primary somatosensory cortex (S1) activity will then be causally manipulated to determine the effects on ssCC/ssTC network connectivity and seizures and to extend the observations beyond mere correlation and provide a foundation for future studies of network- specific modulation therapies (e.g. neurostimulation). The hypothesis will be tested using wild type (WT) mice as well as the PI’s novel mouse model with heterozygous (Het) expression of a human epilepsy risk gene (Gabra1A322D). Aim 1 will determine the effects of mTBI on seizures and somatosensory function in WT and Het mice. Early and long-term effects of mTBI on (A) seizures quantified on continuous EEG monitoring and (B) SS function measured by neurobehavioral testing. Aim 2 will elucidate the effect of mTBI on ssTC and ssCC networks in WT and Het mice. The PI’s established HdEEG method will be compared with an innovative minimally invasive MXene HdEEG arrays for determining ssCC network activity and connectivity in mTBI subjects. Next, the effects of mTBI on ssCC (B) and ssTC (C) network physiology with HdEEG (B) and HdEEG/SEEG (C) recordings will be determined. Finally, aim 3 will determine the effects of S1 neurostimulation on post mTBI ssCC/ssTC network connectivity and seizures using A) open loop and B) closed loop stimulation.