High frequency electrical stimulation and the brain: neurovascular coupling and long-term effects

对中枢和周围神经系统的电刺激被用来研究大脑的连通性、学习能力，甚至被用于治疗。尽管它被广泛使用，但它是如何改变神经系统和影响脑血流量的还不清楚。我的研究项目的长期目标是了解电刺激影响神经可塑性的基本机制。***我的实验室一直在研究高频刺激（HFS）对正常啮齿动物丘脑皮质系统的直接影响。神经递质耗竭在几秒钟内发生，大脑振荡在几分钟到几小时内发生变化。我们最近用本征光学成像描述了丘脑刺激的电参数（脉冲持续时间、频率、幅度）和运动皮质灌注之间的关系。这项工作在理解神经活动和组织灌注之间的关系方面发现了一个根本性的差距，并为我的实验室提出了这个新的研究方向。神经血管耦合仅通过应用低频（1-20赫兹）电刺激或外周刺激来研究。利用这些刺激参数，大脑的成像变化与整体诱发局部场电位（LFP）或突触活动密切相关。然而，神经血管耦合从未研究过HFS (bbb100 Hz)，这是用于诱导学习和学习连接的频率。此外，长期HFS对神经系统的影响的研究很少，而且从未使用电生理学或成像。我未来五年的短期目标是：***1。研究清醒和麻醉啮齿动物在不同频率和模式刺激下脑灌注与电生理（神经血管耦合）的关系。* * * 2。确定HFS如何长期改变脑灌注，包括其与行为、电生理和突触发生的关系。***根据我的初步数据，我将提出以下假设：神经血管耦合将保持，这意味着脑血流量/容量和总LFP将随着急性刺激频率的增加而逐渐增加。HFS将改变LFP振荡模式。慢性HFS会导致长期抑郁和与刺激部位相连的大脑区域的组织灌注减少。***了解高频刺激如何改变神经血管耦合对于成像数据的有意义解释至关重要。高频刺激如何影响正常啮齿动物的大脑，可以为基本理解学习、记忆和行为提供基础

Electrical stimulation applied to the central and peripheral nervous system is used to study brain connectivity, learning, and has even been applied for therapy. Despite its widespread use, how it alters the nervous system and affects cerebral blood flow is not understood. The LONG-TERM OBJECTIVE of my research program is to learn the fundamental mechanisms whereby electrical stimulation affects neural plasticity.***My lab has been studying the immediate effects of high frequency stimulation (HFS) on the thalamocortical system in normal rodents. Neurotransmitter depletion occurs over seconds, and brain oscillations change over minutes to hours. We recently described the relationship between the electrical parameters of thalamic stimulation (pulse duration, frequency, amplitude) and motor cortical perfusion using intrinsic optical imaging. This work identified a fundamental gap in understanding the relationship between neural activity and tissue perfusion and prompted this new direction of research program for my lab. Neurovascular coupling has only been studied by applying low frequency (1-20 Hz) electrical or peripheral stimulation. Using such stimulus parameters, imaging changes in the brain are strongly correlated with integrated evoked local field potentials (LFP) or synaptic activity. However, neurovascular coupling has never been studied with HFS (>100 Hz), which are the frequencies applied to induce learning and study connectivity. Furthermore, the effects of long-term HFS on the nervous system have been minimally investigated and never with electrophysiology or imaging. ***My short-range GOALS for the next 5 years are: ***1. To characterize the relationship between brain perfusion and electrophysiology (neurovascular coupling) with different frequencies and patterns of stimulation in awake and anesthetized rodents. ***2. To determine how HFS alters brain perfusion over the long-term, including its relationship to behavior, electrophysiology and synaptogenesis.***Based on my preliminary data, I will address the following HYPOTHESIS: Neurovascular coupling will be maintained, meaning cerebral blood flow/volume and summed LFP will progressively increase with increasing frequencies of stimulation when applied acutely. HFS will alter LFP oscillation patterns. Chronic HFS will result in long-term depression and reduced tissue perfusion in brain regions connected to the site of stimulation. ***Understanding how high frequency stimulation alters neurovascular coupling is of paramount importance for the meaningful interpretation of imaging data. How high frequency stimulation influences the normal rodent brain can provide the basis for fundamental understanding of learning, memory, and behavior.**