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

对中枢和外周神经系统的电刺激被用来研究大脑的连通性、学习，甚至被应用于治疗。尽管它被广泛使用，但它如何改变神经系统和影响脑血流尚不清楚。我的研究计划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。神经递质耗尽在几秒钟内发生，大脑振荡在几分钟到几小时内发生变化。我们最近利用本征光学成像技术描述了丘脑刺激的电参数(脉冲持续时间、频率、幅度)与运动皮质血流灌注之间的关系。这项工作确定了在理解神经活动和组织灌流之间的关系方面的一个根本差距，并推动了我的实验室的这一新的研究方向。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。使用这样的刺激参数，大脑中的成像变化与积分诱发的局部场电位(LFP)或突触活动密切相关。然而，神经血管耦合从未用高频(&gt；100赫兹)研究过，高频是用来诱导学习和研究连通性的频率。此外，长期HFS对神经系统的影响已经被最小限度地研究过，而且从未进行过电生理学或成像研究。*我未来5年的短期目标是：*1.研究清醒和麻醉啮齿动物不同刺激频率和模式下脑血流和电生理(神经血管耦合)之间的关系。*2.确定HFS如何在长期内改变脑血流灌注，包括其与行为、电生理和突触发生的关系。*基于我的初步数据，我将解决以下假设：神经血管耦合将保持，即当急性应用时，脑血流量/容量和总和LFP将随着刺激频率的增加而逐渐增加。HFS将改变LFP振荡模式。慢性HFS将导致长期的抑郁和与刺激部位相连的脑区组织灌注量的减少。*了解高频刺激是如何改变神经血管偶联的，对于有意义的影像数据解释至关重要。高频刺激如何影响正常啮齿动物的大脑，可以为基本了解学习、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.**