Explaining the variability in focused ultrasound neuromodulation

PROJECT SUMMARY While conventional electromagnetic approaches to non-invasive brain stimulation are limited in their spatial resolution and penetration depth, ultrasonic neuromodulation carries the potential of millimeter scale stimulation of deep brain regions without the need for surgery. Abundant evidence shows that low intensity focused ultrasound stimulation (FUS) modulates brain activity. However, there have been several reports of substantial variability in the neural response to ultrasound, with the same "dose" producing disparate effects. Understanding the source of variability is critical to harnessing the vast potential of FUS in basic neuroscience, neurology, and psychiatry. The long term goal of this research is to develop FUS into a personalized, closed loop technology that can drive brain activity towards desirable states. As the first step towards this goal, the overall objective of this proposal is to identify the primary source of the variability in neuronal responses to FUS. Based on our group's preliminary data, our central hypothesis is that response to FUS is greatly influenced by brain state, and that the outcome of stimulation may be accurately predicted by taking into account the dynamics of neural activity leading up to stimulation. In the proposed work, we will thoroughly test the notion that FUS is state dependent by probing the influence of oscillatory dynamics and cell type during both sleep and wake states. Our specific aims are: (1) Identify the relationship between baseline LFP dynamics and neuronal response during sleep, (2) Identify the role of cell type in response to FUS during sleep, and (3) Identify the determinants of neuronal response to FUS in the awake state. We will work with both urethane-anesthetized and head-fixed awake rats, and will target the hippocampus with FUS while simultaneously capturing electrophysiological activity. The proposed work is significant because it addresses the central problem with ultrasonic neuromodulation: how to make its effects more robust and predictable. This research is innovative because it explicitly links neural dynamics leading up to stimulation with the subsequent response to FUS. The products of this research have the potential to solve a central problem in FUS: variability of response. By delineating the conditions that lead to robust effects, this research will bring the FUS field one step closer to closed-loop capabilities, which clearly necessitate predictable responses. Moreover, we will obtain a clearer understanding of the mechanism of FUS by considering the neurobiological substrates of the responsive states identified in this research. For example, if we do confirm a link between FUS response and baseline gamma, this will shed light on the (gamma generating) circuits that FUS is modulating. This knowledge will then immediately inform the rapidly growing FUS neuromodulation research community as well as future pilot studies in neurology and psychiatry.