Circuit Specific Electrical Brain Stimulation

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ABSTRACT Over the past decade, a revolution in genetic tools has allowed neuroscientists to probe the function of well- defined brain circuits and specific cell types within those circuits. Those studies have revealed likely underpinnings of mental illness, in the form of specific circuits that can be modulated to dramatically change emotion-related behaviors in laboratory animals. The challenge is that those circuit insights do not readily translate into psychiatric treatments. Laboratory tools such as optogenetics are far from being validated in humans, particularly for the 40+ years that a human lives with a mental illness. Electrical/magnetic brain stimulation, on the other hand, is a known, safe, and long-term-sustainable technology that already in clinical use. Unfortunately, electrical stimulation has its own challenge: although it can limit its intervention to a focused anatomical area, the stimulating field activates many cell types and affects neurons projecting to many brain regions. In other words, although electrical methods are anatomically specific, they are not functionally- or circuit- specific. We propose to overcome these challenges by developing electrical stimulation methods that limit their effects to defined circuits and physiologic signatures within those circuits. Specifically, local field potential (LFP) oscillations and their synchrony (coherence) between brain regions are increasingly implicated as a mechanism by which circuits organize and communicate. Controlling coherence within defined circuits and frequencies might thus be a way to limit electrical stimulation's effects to a specific target/function. My lab recently showed that by precisely controlling the timing of stimulation pulses, we can dramatically increase inter-area coherence. We can limit the effect to a narrow frequency band, and in some cases, the stimulation leads to persistent synaptic change. We propose to continue our rodent investigations and test four key properties of these new methods: behavioral efficacy, directionality, specificity, and generalizability. We expect to show that controlling coherence through our methods can modulate animals' behavior, that we can both enhance and inhibit a desired behavior, that we can limit our effects to a specific anatomic projection, and that these methods work on multiple circuits and LFP frequencies. These studies also provide a causal test of the hypothesis that LFP coherence is a mechanism of circuit function, by showing whether behavior directly tracks coherence. If successful, we will have developed a new set of tools that are clinically safe and capable of controlling specific brain circuits. The PI is a brain stimulation psychiatrist with extensive experience in human and animal experiments, positioning us to then take the next step into human pilots. These methods could become a "translational bridge" that lets clinical psychiatry more efficiently leverage the growing scientific knowledge base.