Dissecting the circuit-level mechanisms of ultrasound neuromodulation - ABSTRACT Transcranial low-intensity focused ultrasound (LIFU) is an emerging modality for noninvasive and targeted modulation of cortical and deep targets in the human brain. LIFU has enormous potential to realize a transformative treatment for myriad neurological and psychiatric disorders, but significant challenges exist for the clinical translation of LIFU neuromodulation protocols due to the unknown underlying neurophysiological mechanisms and the relatively large parameter space that remains poorly understood. Dissecting the mechanistic underpinnings of LIFU neuromodulation with systematic and carefully controlled experimental approaches is a critical step to facilitate the effective development of therapeutic protocols. Recent studies have established that LIFU elicits differential responses in diverse neuronal cell types depending on the pulsing parameters . However, dynamic circuit-level effects resulting from synaptic interactions between cell types have remained largely undisclosed. In this project, we will develop a systematic approach based on cutting-edge technologies to generate new fundamental knowledge on the underlying mechanisms of LIFU neuromodulation in specific cell types, focusing on circuit and network-level effects. In our analysis of the temporal dynamic responses, we will directly assess whether LIFU can enhance gamma-frequency (30-100 Hz) neural oscillations, which play a key role in information processing and cognition and are implicated in the pathophysiology of many neuropsychiatric disorders, including autism, schizophrenia, and neurodegenerative disorders. In all the proposed experiments, we will implement carefully designed control conditions to disentangle direct neuromodulatory outcomes from potential nonspecific auditory effects. In Aim 1, we will use cell-type specific fluorescent calcium indicators to map the LIFU neuromodulation parameter space in excitatory neurons and in parvalbumin (PV) and somatostatin (SST)-positive inhibitory interneurons. These cell types are particularly interesting due to their specialized role in the generation of gamma oscillations. In Aim 2, we will record cell- type-specific transmembrane voltage dynamics from cortical excitatory and inhibitory neurons to shed light on the circuit-level responses to LIFU neuromodulation. In Aim 3, we will use functional ultrasound imaging to map whole-brain network-level responses. Taken together, our Aims will yield new fundamental insights on the underlying mechanisms of LIFU neuromodulation. Excitingly, our Aims will lay the groundwork for a clinically translatable approach to systematically modulate neural oscillations in deep brain regions.
