Modulation of the noradrenergic system using transcranial ultrasonic stimulation targeted to the brainstem locus coeruleus in awake mice

Abstract Transcranial ultrasound stimulation (TUS) is a novel neuromodulation technique that can be used to non-invasively target the locus coeruleus (LC). The LC provides the majority of noradrenergic input to the brain and has been implicated in several neurological and psychiatric disorders. Before translation to human studies, establishing a dose-response relationship requires systematic characterization of two distinct effects: (1) the influence of stimulation protocol variations on norepinephrine (NE) release in LC target structures, and (2) the broader brain and bodily effects of LC-targeted TUS. We used fiber photometry to measure TUS-induced activation of LC neurons and release of NE in one of its major projection areas, the hippocampus. To evaluate widespread functional effects, we investigated changes in [ 18 F]FDG uptake in the brain and body in response to LC-targeted TUS using small-animal PET imaging. Five-second trains of TUS resulted in intracellular calcium level increases in the LC, accompanied by a biphasic change in NE levels in the hippocampus and LC, i.e., an initial rise followed by a transient decrease. The same TUS protocol showed a decrease in [ 18 F]FDG uptake across the brain and a strong increase in [ 18 F]FDG uptake in brown adipose tissue. If TUS was prolonged to 30 s the initial biphasic change in hippocampal NE levels was followed by a secondary increase that persisted throughout the remainder of the stimulation period. This study provides the first demonstration that TUS can modulate the LC–NE system in awake mice. Adjusting the stimulation protocol resulted in distinct patterns of hippocampal NE release, highlighting the therapeutic potential of LC-targeted TUS as distinct stimulation protocols may differentially restore disrupted NE levels across disorders. PET imaging further revealed engagement of both central and peripheral systems, emphasizing the broad physiological reach of this approach.