Noninvasive Ultrasound Stimulation of Ventral Tegmental Area Induces Reanimation from General Anaesthesia in Mice
Tianyuan Bian, Wen Meng, Meihong Qiu, Zhigang Zhong, Zhengrong Lin, Junjie Zou, Yibo Wang, Xiaowei Huang, Lisheng Xu, Tifei Yuan, Zhili Huang, Lili Niu, Long Meng, Hairong Zheng
Research 2021, 2021 · 10.34133/2021/2674692
Abstract
Evidence in animals suggests that deep brain stimulation or optogenetics can be used for recovery from disorders of consciousness (DOC). However, these treatments require invasive procedures. This report presents a noninvasive strategy to stimulate central nervous system neurons selectively for recovery from DOC in mice. Through the delivery of ultrasound energy to the ventral tegmental area, mice were aroused from an unconscious, anaesthetized state in this study, and this process was controlled by adjusting the ultrasound parameters. The mice in the sham group under isoflurane-induced, continuous, steady-state general anaesthesia did not regain their righting reflex. On insonation, the emergence time from inhaled isoflurane anaesthesia decreased (sham: 13.63 ± 0.53 min, ultrasound: 1.5 ± 0.19 min, p p p < 0.01). This noninvasive strategy could be used on demand to promote emergence from DOC and may be a potential treatment for such disorders.
Abstract via europepmc.
Exposures
Exposure 1: VTA sonication (arousal/reanimation experiments)
Target: ventral tegmental area — “Collimators to focus ultrasound to the VTA”
Device: custom-built
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 3,300 | ✓✓✓ |
| Pulse duration (ms) | 1 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 500 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| Free-field pressure (kPa) | 360, 586, 758swept | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | ⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 7.94 | ✓✓✓⚑ |
Ultrasound stimulation was initiated after 40 min of anaesthesia and continued for two doses of 30 min or until the righting reflex behavior returned, with an interstimulus interval (ISI) of 2 s. In the TBI experiment, 15 min of US stimulation was given to each injured mouse 15 min after injury.
Exposure 2: V1 sonication (control target)
Target: primary visual cortex — “V1 (related to the bregma: 1.10 mm anterior/posterior, −1.50 mm medial/lateral, and −0.50 mm dorsal/ventral)”
Device: custom-built
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 3,300 | ✓✓✓ |
| Pulse duration (ms) | 1 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 500 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| Free-field pressure (kPa) | 586 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
We repeated the arousal experiment with US stimulation of the primary visual cortex (V1) to demonstrate the specificity of US stimulation, using the same stimulation protocol as for the VTA.
Flags from extraction
n_subjects— Multiple sub-experiments report different ultrasound-exposed group sizes (c-Fos n=6, dose-response n=8 per pressure, antagonist NS-US n=4, V1-comparison n=6, TBI+US n=8); the paper never states a combined total and cohort overlap across experiments is unclear, so group sizes are listed rather than summed.exposures[0].free_field.pressure_kpa— Three acoustic pressures (360, 586, 758 kPa) were tested to find behavioral thresholds; 586 kPa was used for the main follow-on experiments.exposures[0].unspecified_domain.isppa_w_cm2— This ISPPA value (7.94 W/cm2) is mentioned in the Discussion as the intensity used in the study compared to a regulatory limit, but is not clearly labeled free-field or in-situ.exposures[0].in_situ.pressure_kpa— Paper reports that skull/dura attenuation was about 54% and gives transcranial focus dimensions, but never states a resulting derated in-situ pressure value in kPa.device.manufacturer— The custom wearable ultrasound transducer's manufacturer/model is not given; only the driving function generator and amplifier models are specified.