Ultrasound Stimulation of Prefrontal Cortex Improves Lipopolysaccharide-Induced Depressive-Like Behaviors in Mice

Sha-sha Yi, Jun-jie Zou, Long Meng, Hou-minji Chen, Zhong-qiu Hong, Xiu-fang Liu, Umar Farooq, Mo-xian Chen, Zheng-rong Lin, Wei Zhou, Li-juan Ao, Xi-quan Hu, Li-li Niu

Frontiers in Psychiatry 2022, 13 · 10.3389/fpsyt.2022.864481

rodentdepressionanxietybehaviourhistology molecular

Abstract

Increasing evidence indicates that inflammatory responses may influence brain neurochemical pathways, inducing depressive-like behaviors. Ultrasound stimulation (US) is a promising non-invasive treatment for neuropsychiatric diseases. We investigated whether US can suppress inflammation and improve depressive-like behaviors. Mice were intraperitoneally injected with lipopolysaccharide to induce depressive-like behaviors. Ultrasound wave was delivered into the prefrontal cortex (PFC) for 30 min. Depressive- and anxiety-like behaviors were evaluated through the forced swimming test (FST), tail suspension test (TST), and elevated plus maze (EPM). Biochemical analyses were performed to assess the expression of inflammatory cytokines in the PFC and serum. The results indicated that US of the PFC significantly improved depressive-like behaviors in the TST ( p p p p < 0.05) by US. In addition, no tissue damage was observed. Overall, US of PFC can effectively improve lipopolysaccharide-induced depressive-like behaviors, possibly through the downregulation of inflammatory cytokines in the PFC. US may be a safe and promising tool for improvement of depression.

Abstract via europepmc.

Speciesmouse (C57BL/6J)

Subjectsnot reported animals

Sessions per subject1

Randomisednot reported

Blindingnot reported

Sham / controlinactive transducer

Auditory controlnot reported

Readout timingoffline

Anaesthesiaanaesthetised

Readoutsbehaviour, histology molecular — forced swimming test; tail suspension test; elevated plus maze; open field test; c-Fos immunofluorescence; Western blot (IL-6, IL-1β, TNF-α); ELISA

Direction of effectexcitatoryUS of the PFC increased c-Fos expression (neuronal excitability) and reduced LPS-induced depressive- and anxiety-like behaviors and pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in the PFC.

Adverse eventsnone observedH&E and Nissl staining showed no tissue damage or hemorrhage in the PFC and no change in neuronal morphology/density after 30 min of ultrasound stimulation.

Exposures

Exposure 1: Ultrasound stimulation of the prefrontal cortex (PFC)

Target: prefrontal cortex — “prefrontal cortex (PFC)”
Device: other named manufacturer · ndtXducer · 1905055

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	5	✓✓✓
Pulse repetition frequency (Hz)	100	✓✓✓
Duty cycle (%)	50pulse duration × PRF gives 50%	✓✓✓
Sonication duration (s)	60	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	620	✓✓✓⚑
Free-field Isppa (W/cm²)	10.09	✓✓✓
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

Protocol, in the paper’s words

Ultrasound (or sham with the power amplifier off) was delivered to the PFC for a total of 30 min under isoflurane anesthesia, composed of repeated 60-s stimulation trains (100 Hz PRF, 50% duty cycle, 5 ms tone-burst duration) separated by an inter-stimulus interval (ISI) whose value is not stated in the text.

Flags from extraction

n_subjects — Cohort sizes vary by assay (e.g. FST n=12, TST n=13, EPM n=12, c-Fos n=6, normal-mice n=4, histology n=3) and no single total of US-exposed animals is stated.
exposures[0].timing.protocol_description — Figure legend defines an inter-stimulus interval (ISI) abbreviation but the paper never states its value; nested structure of the 30-min session vs 60-s trains could not be fully resolved.
exposures[0].free_field.pressure_kpa — Pressure/intensity were measured 'without skull' per the Figure 1D legend, so classified as free-field; no in-situ (through-skull) value is given.