Transcranial ultrasound neuromodulation facilitates isoflurane-induced general anesthesia recovery and improves cognition in mice
Jiaru He, Yiyue Zhu, Canwen Wu, Junwei Wu, Yan Chen, Maodan Yuan, Zhongwen Cheng, Lvming Zeng, Xuanrong Ji
Ultrasonics 2023, 135, 107132 · 10.1016/j.ultras.2023.107132
Abstract
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.
Abstract via europepmc.
Exposures
Exposure 1: Dorsal raphe nucleus (DRN) stimulation, 1.1 MHz
Target: raphe nuclei — “dorsal raphe nucleus (DRN)”
Device: custom-built
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,100 | ✓✓✓ |
| Pulse duration (ms) | 0.5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 1,000 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | measurementsingle value | |
| In-situ pressure (kPa) | 356, 500, 714swept | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Low-intensity pulsed ultrasound delivered to the DRN with a 1-second interstimulus interval between 1-second sonication trains, applied during the last 40 minutes of a 1-hour 2.0% isoflurane anaesthesia session (c-Fos and 5-HT-level experiments used the same 40-minute stimulation window; the 5-HT2A antagonist experiment also used 356 kPa for 40 minutes).
Flags from extraction
n_subjects— Study comprises several separate sub-experiments (c-Fos, dose-response 5-HT, GA-recovery/cognition, 5-HT2A antagonist) each with its own ultrasound-exposed group(s); no single total across the whole study is stated, so exposed-group sizes are listed rather than summed (86 mice were used in total across the whole study, but not all received ultrasound).sham_type— The sham/control groups in each sub-experiment received no ultrasound at all during the anaesthesia window; the paper does not state whether an inactive transducer was placed on the head for these animals, so the sham mechanism is not fully described.n_sessions_per_subject— Each animal appears to receive a single stimulation session per sub-experiment, but this is not explicitly stated as a session count.