Neuronal, glial, and endothelial brain tissue express myriad sensors for mechanical force, osmotic pressure, and shear stress. Focused ultrasound (fUS) can create pressure fields on deep brain regions to engage these endogenous sensory mechanisms. Numerous studies have demonstrated that fUS can alter resting membrane potential, local molecular content, or the frequency of spiking events [1]. However, electromechanical properties and mechanosensory gene expression profiles are highly heterogeneous across the brain, and the fUS responsiveness of sub-cortical therapeutically tractable targets is largely unknown.

In addition to fUS suppression of wake circuitry, other strategies may have potential as sleep therapeutics. For instance, chronic low-intensity fUS stimulation of the mouse prefrontal cortex increased REM sleep duration and improved memory consolidation [4]. Both ultrasound-based entrainment of hippocampal oscillations in phase with slow activity and fUS modulation of theta waves affect sleep architecture [5]. Targeting the centromedial thalamus (CMT) may also be a viable strategy for enhancing slow wave sleep since glutamatergic CMT neurons are powerfully activated by fUS [2]. The reticular nucleus of the thalamus (RTN) contains GABAergic inputs to the CMT, but is spatially segregated to a shell structure outside of the larger thalamus. Furthermore, ultrasonic neuromodulation of the preoptic area in mice lowers core body temperature suggesting that torpor-like states may also be used to alter vigilance states in non-hibernating animals [6]. These collective findings suggest that optimizing fUS for cell-type specific neuromodulation is a critical step towards future studies attempting to translate FUS in clinical studies for treatment of neuropsychiatric conditions and sleep disorders.

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