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

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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.**