Transcranial ultrasound neuromodulation facilitates isoflurane-induced general anesthesia recovery and improves cognition in mice

Delayed arousal and cognitive dysfunction are common, especially in older patients after general anesthesia (GA). Elevating central nervous system serotonin (5-HT) levels can promote recovery from GA and increase synaptic plasticity to improve cognition. Ultrasound neuromodulation has become a noninvasive physical intervention therapy with high spatial resolution and penetration depth, which can modulate neuronal excitability to treat psychiatric and neurodegenerative diseases. This study aims to use ultrasound to noninvasively modulate the brain 5-HT levels of mice to promote recovery from GA and improve cognition in mice. The dorsal raphe nucleus (DRN) of mice during GA was stimulated by the 1.1 MHz ultrasound with a negative pressure of 356 kPa, and the liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) method was used to measure the DRN 5-HT concentrations. The mice’s recovery time from GA was assessed, and the cognition was evaluated through spontaneous alternation Y-maze and novel object recognition (NOR) tests. After ultrasound stimulation, the mice’s DRN 5-HT levels were significantly increased (control: 554.0 ± 103.2 ng/g, anesthesia + US: 664.2 ± 84.1 ng/g, *p = 0.0389); the GA recovery time (return of the righting reflex (RORR) emergence latency time) of mice was significantly reduced (anesthesia: 331.6 ± 70 s, anesthesia + US: 223.2 ± 67.7 s, *p = 0.0215); the spontaneous rotation behavior score of mice was significantly increased (anesthesia: 59.46 ± 5.26 %, anesthesia + US: 68.55 ± 5.24 %; *p = 0.0126); the recognition index was significantly increased (anesthesia: 55.02 ± 6.23 %, anesthesia + US: 78.52 ± 12.21 %; ***p = 0.0009). This study indicates that ultrasound stimulation of DRN increases serotonin levels, accelerates recovery from anesthesia, and improves cognition, which could be an important strategy for treating delayed arousal, postoperative delirium, or even lasting cognitive dysfunction after GA.