Functional activation during cerebral ischemia

描述(申请人提供)：在正常情况下，功能刺激导致局部脑血流量(CBF)增加，称为“激活-流动耦合”(AFC)。虽然人们通常认为局部CBF增加是供应氧气和营养物质所必需的，但对响应功能激活的大脑能量代谢的研究表明，局部CBF增加超过了新陈代谢，而且最近的数据证实，脑血流变化不受糖酵解或氧化需求的调节。此外，血流效应可以从药物上与大脑的激活脱钩，而至少不会损失电生理反应。我们实验室的研究表明，在各种病理生理条件下，AFC反应在广泛的基线流量值范围内保持不变，包括轻度和严重的缺血以及茶碱、乙酰唑胺和二氧化碳对CBF的药理调节。这一数据表明，AFC可能由一种独立的机制来调节，而不是由调节基线CBF的机制来调节。我们将检查分级缺血期间的AFC，并假设AFC的反应依赖于残留的神经活动，并与体感诱发电位相关。初步数据显示，在MCA卒中大鼠模型中，功能性前爪刺激对侧而不是同侧的缺血半球具有神经保护作用。我们提出了一系列研究来检验功能刺激对急性MCA卒中大鼠脑血流量、氧代谢和缺血性损伤的影响，以更好地表征功能刺激对大鼠脑血管病理生理、脑损伤和神经预后的影响。据推测，功能性前爪刺激改善了局灶性前脑缺血的预后，因为AFC反应通过侧支血流来源增加了CBF，超过了刺激的代谢需求。CBF和血液氧合的变化将被光学监测，氧代谢的变化将根据这些参数计算出来。与公共健康相关：尽管进行了多年的研究，但还没有得到证实的中风治疗方法。这个项目将描述和扩展在大鼠身上令人兴奋的初步数据，表明在缺血期间的功能刺激减少了随后对大脑的损害。使用功能刺激治疗中风具有明显的翻译潜力。

DESCRIPTION (provided by applicant): Under normal circumstances, functional stimulation results in a regional increase in cerebral blood flow (CBF) termed "activation-flow coupling" (AFC). While it is often assumed that a regional CBF increase is required to supply oxygen and nutrients, studies of brain energy metabolism in response to functional activation have demonstrated that regional CBF increases in excess of metabolism, and more recent data confirm that cerebral blood flow changes are not regulated by either glycolytic or oxidative demands. Additionally, blood flow effects can be pharmacologically decoupled from brain activation without loss of at least electrophysiological responses. Studies from our laboratory have demonstrated that the AFC response is preserved over a broad range of baseline flow values caused by a variety of pathophysiological conditions including mild and severe ischemia and pharmacological modulation of CBF with theophylline, acetazolamide, and CO2. This data suggest that AFC may be mediated by an independent mechanism than that which regulates baseline CBF. We will examine AFC during graded ischemia, and hypothesize that the AFC response is dependent on residual neural activity and is correlated with the somatosensory evoked potential. Preliminary data demonstrate a neuroprotective effect of functional forepaw stimulation contralateral but not ipsilateral to the ischemic hemisphere in the rat filament model of MCA stroke. We propose a series of studies to examine the effects of functional stimulation on CBF, oxygen metabolism, and ischemic injury in acute MCA stroke to better characterize the effects of functional stimulation on cerebrovascular pathophysiology, brain injury, and neurological outcome in rats. It is hypothesized that functional forepaw stimulation improves outcome from focal forebrain ischemia because the AFC response produces an incremental CBF increase through collateral flow sources that exceeds the metabolic demands of stimulation. Changes in CBF and blood oxygenation will be monitored optically, and changes in oxygen metabolism will be calculated from these parameters. PUBLIC HEALTH RELEVANCE: Despite many years of research, there are no proven treatments for stroke. This project will characterize and extend exciting preliminary data in the rat showing that functional stimulation during the period of ischemia reduces the subsequent damage to the brain. The use of functional stimulation as treatment for stroke has obvious translational potential.