Transcranial Ultrasound Stimulation Reverses Behavior Changes and the Expression of Calcium-Binding Protein in a Rodent Model of Schizophrenia
Che-Wen Tsai, Shih-Jen Tsai, Yi-Ju Pan, Hsin-Mei Lin, Tsung-Yu Pan, Feng-Yi Yang
Neurotherapeutics 2022, 19, 649-659 · 10.1007/s13311-022-01195-x
Abstract
Cognitive dysfunctions are a core feature of schizophrenia that may be linked to abnormalities in gamma-aminobutyric-acid (GABA)ergic neurons. Traditional antipsychotics show poor efficacy in treating cognitive symptoms. The purpose of this study was to investigate the restorative role of transcranial ultrasound stimulation (TUS) in counteracting dizocilpine (MK-801)-induced cognitive deficits and GABAergic interneuron dysfunction in a simulation of schizophrenia. Some rats subjected to MK-801 administration were treated with low-intensity pulsed ultrasound (LIPUS) daily for 5 days, while other rats subjected to MK-801 administration received no LIPUS treatment. After LIPUS treatment, the neuroprotective effects of LIPUS in the LIPUS-treated rats were assessed through behavioral analysis, western blotting, and histological observations. Compared with the MK-801-treated group, the MK-801 plus LIPUS-treated rats revealed a preference for novel objects. The MK-801 plus LIPUS-treated rats also exhibited a significant decrease in swim times compared to the MK-801-treated rats. LIPUS stimulation significantly increased hippocampal levels of CB and PV and restored the cell densities of PV + and CB + in the cingulate cortex in the MK-801 plus LIPUS-treated group. In addition, LIPUS stimulation rebalanced the BDNF levels in the hippocampus and medial prefrontal cortex. Our findings indicate that LIPUS improves cognitive deficits and ameliorates neuropathology in MK-801-treated rats. These results suggest that LIPUS may constitute a potential novel therapeutic approach for the treatment of schizophrenia.
Abstract via europepmc.
Exposures
Exposure 1: LIPUS to brain region near bregma in MK-801 rat model of schizophrenia
Target: hippocampus — “desired region (3.0 mm posterior and 2.5 mm lateral to the bregma) of the brain”
Device: Olympus / Panametrics · Panametrics · A392S ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,000 | ✓✓✓ |
| Pulse duration (ms) | 50 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 1 | ✓✓✓ |
| Duty cycle (%) | 5pulse duration × PRF gives 5% | ✓✓✓ |
| Sonication duration (s) | 300 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | 0.528 | ✓✓✓ |
| 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 |
The focused transducer was positioned using a stereotaxic apparatus in order to direct the acoustic beam to the desired region (3.0 mm posterior and 2.5 mm lateral to the bregma) of the brain. Each rat hemisphere was treated by LIPUS daily with triple sonications. The duration of each sonication was 5 min, and there was an interval of 5 min between each sonication. LIPUS would be turned on when the LIPUS group and the MK-801 + LIPUS group accepted treatment while the Sham group and MK-801 group were just anesthetized.
Flags from extraction
n_subjects— Paper reports per-group n=8 for behavioral cohorts (LIPUS group and MK-801+LIPUS group are the two groups receiving ultrasound) but never a combined total; a subset of n=5 per group was used for histology. Recorded as the list of the two ultrasound-exposed group sizes [8,8].n_sessions_per_subject— Computed from 'daily with triple sonications' over the treatment period; paper states LIPUS stimulation lasted 5 days (sacrificed 24 h after last treatment), so 5 daily sessions (each with 3 sonications) is inferred from the described schedule.exposures[0].target.terms— Target coordinates (3.0 mm posterior, 2.5 mm lateral to bregma) are not explicitly named by the paper as a specific brain structure; classified as hippocampus based on typical rat stereotaxic coordinates and the paper's focus on hippocampal CB/PV/BDNF outcomes, but this is an inference and not the paper's own terminology.direction_of_effect— Study reports behavioral-rescue and molecular (PV/CB/BDNF) outcomes rather than a measured direction of neuromodulatory (excitatory/inhibitory) neural effect, so 'not_assessed' was used.adverse_events— Paper does not include a dedicated safety/histology evaluation section (unlike the companion Song et al. 2022 paper using the same device/parameters), so adverse_events could not be confirmed from the text.