Implementing a novel, multimodal technique for monitoring cerebrovascular hemodynamics in mice as a diagnostic and prognostic tool for single and repeated mild TBI

项目摘要 创伤性脑损伤是一个主要的社会和公共卫生问题，有超过280万个脑损伤 在美国每年都有报道。轻型颅脑损伤(MTBI)占脑损伤的80%以上，很难诊断。 因为没有FDA批准的对mTBI的治疗干预，所以有一段时间的休息以允许症状 消解是主要的治疗方法。当务之急是，虽然有症状，但正在康复的人 MTBI避免持续第二次MTBI，因为多个MTBI极大地增加了长期残疾的风险。 然而，mTBI后的大脑脆弱期超出了临床症状的解决范围， 强调迫切需要准确评估神经生理学恢复，以减轻 与反复头部损伤相关的风险。与中度和重度创伤性脑损伤不同的是，它们通常与 随着神经元死亡和血管破坏，mTBI会导致更微妙的生理和细胞变化， 如代谢障碍和脑血流量(CBF)改变。我们假设mTBI诱导了 CBF的急性、短暂变化，再加上代谢失调，构成了 易受重复mTBI的影响。因此，我们预测，在急性肺炎期间造成的第二次伤害 CBF改变将导致预后恶化，反映在CBF和代谢方面的更大扰动。 我们团队开发了一种新的多波长散斑对比漫相关层析成像(MW-CT)。 ScDCT)技术，可对小鼠的脑血流量和氧合进行非侵入性、纵向、区域性标测。我们 我用已建立的方法验证了我们的技术，并展示了它在检测CBF中的有效性 啮齿动物的变化。在目标1中，我们将首先使用MW-SCDCT测量大脑皮质和海马区的CBF和 单发闭合性颅脑损伤(CHI)后氧合监测时间变化及恢复时间 恢复。然后，我们将确定是否需要CBF正常化来防止 第二气论脑血流动力学。神经血管偶联和脑血管反应性 在选定的时间点进行评估，以告知潜在的CBF变化机制。最后， 将进行脑血管结构和沟通的定量分析，以确定解剖结构 可塑性或损坏。在目标2中，将使用靶向代谢组学方法来识别 皮质组织和血浆是单发或反复mTBI小鼠所特有的。我们将进一步测试是否 MTBI后代谢组的恢复与CBF的正常化相一致。这样的发现将支持 双管齐下评估脑震荡恢复通过无创脑血流监测和 血浆代谢物生物标志物的评价。这些研究将把代谢组学与我们创新的MW- SCDCT脑血流动力学监测技术为神经生理研究提供新的视角 大脑对反复mTBI易感性的决定因素并支持诊断和 多发性脑损伤的预后生物标志物。

Project Summary Traumatic brain injuries (TBIs) are a major societal and public health concern with over 2.8 million TBIs reported each year in the US. Mild TBIs (mTBIs), accounting for over 80% of TBIs, can be difficult to diagnose. Because no FDA-approved therapeutic intervention for mTBI exists, a period of rest to allow symptom resolution is the primary treatment approach. It is imperative that while symptomatic, a person recovering from mTBI avoid sustaining a second mTBI, as multiple mTBIs greatly increases the risk for prolonged disability. The period of brain vulnerability after mTBI, however, extends beyond the resolution of clinical symptoms, underscoring the vital need for accurate assessment of neurophysiological recovery in order to mitigate the risks associated with repeated head injury. Unlike moderate and severe TBI, which are typically associated with neuron death and vascular disruption, mTBI results in more subtle physiological and cellular changes, such as metabolic distress and alterations in cerebral blood flow (CBF). We hypothesize that mTBI induces acute, transient changes in CBF that, coupled with metabolic dysregulation, form the basis of the window of vulnerability to repeated mTBI. We predict, therefore, that a second injury induced during the period of acute CBF alteration will result in worsened outcome as reflected by greater perturbations in CBF and metabolism. Our group has developed a novel multiple-wavelength speckle contrast diffuse correlation tomography (MW- scDCT) technique that yields non-invasive, longitudinal, regional mapping of CBF and oxygenation in mice. We have validated our technique against established methods and demonstrated its utility in detecting CBF changes in rodents. In Aim 1, we will first use MW-scDCT to measure cortical and hippocampal CBF and oxygenation after single closed head injury (CHI) to monitor temporal changes and determine the time to recovery. We will then determine whether normalization of CBF is required to prevent synergistic effects of a second CHI on cerebral hemodynamics. Neurovascular coupling and cerebrovascular reactivity will be assessed at selected time points to inform potential mechanisms underlying CBF changes. Finally, quantitative analysis of cerebrovascular structure and communication will be performed to identify anatomical plasticity or damage. In Aim 2, a targeted metabolomics approach will be used to identify metabolite profiles in cortical tissue and plasma which are unique to mice with single or repeated mTBI. We will further test whether restoration of the metabolome coincides with normalization of CBF after mTBI. Such a finding would support a dual-pronged approach for assessing concussion recovery through noninvasive CBF monitoring and assessment of plasma metabolite biomarkers. These studies will pair metabolomics with our innovative MW- scDCT technique for monitoring cerebral hemodynamics to provide new insights into the neurophysiological determinants of the brain’s vulnerability to repeated mTBI and support the development of diagnostic and prognostic biomarkers for mTBI.