Low‐Intensity Focused Ultrasound Ameliorates Cisplatin‐Induced Cognitive Impairment by Attenuating Hippocampal Neuroinflammation and Enhancing Synaptic Plasticity in Rats
Xiaowei Han, Hagiwara Akifumi, Pin Lv, Jiahuan Liu, Xiaowei Huang, Renyuan Liu, Xiaojing Long, Yang Liu, Jiangong Zhang, Guolin Ma, Bing Zhang
iRADIOLOGY 2025 · 10.1002/ird3.70003
Abstract
Platinum can cause chemotherapy‐related cognitive impairment. Low‐intensity focused ultrasound (LIFUS) is a promising noninvasive physical stimulation method with a unique advantage in neurological rehabilitation. We aimed to investigate whether LIFUS can alleviate cisplatin‐induced cognitive impairment in rats and explore the related neuropathological mechanisms. After confirming the target position for LIFUS treatment in 18 rats, 64 rats were randomly divided into four groups: control, model, sham, and LIFUS groups. Before and after LIFUS treatment, detailed biological behavioral assessments and magnetic resonance imaging were performed. Finally, the rats were euthanized, and relevant histopathological and molecular biological experiments were conducted and analyzed. In the Morris water maze, the model group showed fewer platform crossings (1.25 ± 0.93 vs. 5.69 ± 1.58), a longer escape latency (41.65 ± 36.55 s vs. 6.38 ± 2.11 s), and a lower novel object recognition index (29.77 ± 11.83 vs. 83.69 ± 5.67) than the control group. LIFUS treatment improved these metrics, with more platform crossings (3.13 ± 0.34), a higher recognition index (65.58 ± 8.71), and a shorter escape latency (6.45 ± 2.27 s). Longitudinal analysis of the LIFUS group further confirmed these improvements. Neuroimaging revealed significant differences in diffusion tensor imaging metrics of specific brain regions pre‐ and post‐LIFUS. Moreover, neuropathology showed higher dendritic spine density, less myelin loss, fewer apoptotic cells, more synapses, and less mitochondrial autophagy after LIFUS treatment. The neuroimaging indicators were correlated with behavioral improvements, highlighting the potential of LIFUS for alleviating cognitive impairment (as demonstrated through imaging and analysis). Our investigation of the molecular biological mechanisms revealed distinct protein expression patterns in the hippocampus and its subregions. In the model group, glial fibrillary acidic protein (GFAP) and ionized calcium‐binding adaptor molecule 1 (IBA1) expression levels were elevated across the hippocampus, whereas neuronal nuclei (NeuN) expression was reduced. Subregional analysis revealed higher GFAP and IBA1 and lower NeuN, especially in the dentate gyrus subregion. Moreover, positive cell areas were larger in the cornu ammonis (CA)1, CA2, CA3, and dentate gyrus regions. In the CA2 and CA3, significant differences among the groups were observed in GFAP‐positive cell counts and areas, and there were variations in NeuN expression. Our results suggest that LIFUS can reverse cisplatin‐induced cognitive impairments. The neuroimaging findings were consistent with the behavioral and histological results and suggest a neuropathological basis that supports further research into the clinical applications of LIFUS. Furthermore, LIFUS appeared to enhance the plasticity of neuronal synapses in the rat hippocampus and reduce hippocampal inflammation. These findings highlight the clinical potential of LIFUS as an effective, noninvasive therapeutic strategy and monitoring tool for chemotherapy‐induced cognitive deficits.
Abstract via crossref.
Exposures
Exposure 1: LIFUS to bilateral hippocampal dentate gyrus
Target: dentate gyrus — “hippocampal DG subregion, bilateral hippocampus”
Device: other named manufacturer · Zhongke Green Valley Shenzhen Medical Technology · GVBT-1-A001 LIFUS treatment system ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,000 | ✓✓✓ |
| Pulse duration (ms) | 0.2 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 500 | ✓✓✓⚑ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 10% | |
| Sonication duration (s) | 0.001 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| 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 |
Pulse width 200 us, pulse repetition period 2 ms, stimulus duration 1 ms, stimulus period 4 s; 30 min per side, once daily to each bilateral hippocampus for 14 consecutive days (Methods also say twice daily and once on one side).
Flags from extraction
exposures[0].timing.sonication_duration_s— Paper gives 'stimulus duration (T3) of 1 ms' with a 4 s stimulus period; recorded as written, looks like it may be 1 s but not corrected.exposures[0].timing.pulse_repetition_frequency_hz— Converted from stated pulse repetition period of 2 ms (500 Hz).exposures[0].timing.pulse_duration_ms— Converted from 200 us.n_subjects— 16 per group in the comparative experiment (64 rats total); a separate 18-rat targeting experiment also used LIFUS and is not counted.n_sessions_per_subject— Text says 14 consecutive days once daily per side but also 'twice daily and once on one side'; unclear.exposures[0].timing.protocol_description— Timing parameters do not fit the four numbers cleanly (nested pulse, stimulus and stimulus-period structure).exposures[0].device.manufacturer— Manufacturer inferred from the instrument list entry; no pressure or intensity reported anywhere.