Pre-iTBS alleviates perioperative neurocognitive disorders by inducing long-term neuroprotection against inflammatory injury

Perioperative neurocognitive disorders (PND), encompassing cognitive impairments linked to anesthesia and surgery, significantly impact elderly patients and increase postoperative risks. Intermittent theta burst stimulation (iTBS), a non-invasive neuromodulation protocol, has shown cognitive-enhancing potential in clinical studies. However, its utility for preventing PND remains unexplored. This study investigated whether preoperative iTBS mitigates PND in aged rats undergoing exploratory laparotomy. Eighteen-month-old male rats (n = 5/group) received 10 daily iTBS sessions or sham stimulation (only noise without real stimulation) prior to 3-hour isoflurane anesthesia (3 %) and laparotomy. Cognitive function was assessed via the Morris water maze (MWM) pre- and postoperatively. Rats were euthanized at 72 h post-surgery to quantify hippocampal microglial polarization (Iba1⁺/CD86⁺), pro-inflammatory cytokines (Milliplex cytokine assays), and neuronal apoptosis (Nissl staining). iTBS-treated rats exhibited faster anesthesia recovery (17.4 ± 3.6 min vs. 35.2 ± 11.2 min; P = 0.009) and reduced postoperative cognitive decline (MWM escape latency: 39.5 ± 5.0 s vs. 50.0 ± 5.8 s; P = 0.006). These improvements correlated with decreased M1-polarized microglia (39.0 ± 7.0 vs. 58.8 ± 12.2; P = 0.014), lower TNF-α levels (2690.6 ± 542.2 pg/mL vs. 3532.7 ± 623.8 pg/mL; P = 0.035), and reduced hippocampal apoptosis (87.8 ± 8.3 % vs. 69.1 ± 13.8 %; P = 0.006). Pre-iTBS has potential therapeutic efficacy in perioperative neurocognitive disorders by reducing M1-type pro-inflammatory factors and enhancing neuronal activity and resistance to anesthesia and surgery-induced damage.