開發一種新型非侵入性物理治療方法，透過間歇性 Theta 突發波重複磁刺激大鼠骶神經來治療膀胱過動症

Background: Roughly one-fifth of the global population encounters a decline in their quality of life due to overactive bladder (OAB) syndrome, with its prevalence generally rising with age. Initial management of this chronic and debilitating ailment involves strategies such as restricting fluid intake, engaging in pelvic floor muscle training, and using antimuscarinic drugs. However, addressing OAB with existing treatments remains intricate, especially for recurring cases that might require invasive procedures. Although surgical interventions are available, it is expensive, with varying rates of success, and a substantial risk of complications. Patients find these situations deeply frustrating, and healthcare professionals encounter significant challenges in managing them. Consequently, there is a growing interest in exploring different forms of electrical stimulation for OAB. While conventional electrical neuromodulation necessitates direct contact between the electrode and the nerve, in contrast, magnetic stimulation doesn't require direct induction of electric current into the body, making it a completely non-invasive technique. In addition, it offers deep-tissue penetration capabilities. However, limited research has investigated the potential benefits of repetitive peripheral magnetic stimulation (rPMS) for treating OAB. Intermittent theta burst stimulation (iTBS) represents a patterned form of stimulation involving fewer pulses and shorter durations than standard repetitive magnetic stimulation while preserving the clinical benefits. To the best of our knowledge, there have been no studies that have investigated the potential of utilizing sacral rPMS with an iTBS waveform as a treatment for OAB.

Aims: To assess the potential effect of rPMS targeting sacral roots to treat OAB in acute and chronic OAB female rat model

Material and Methods: The study of rPMS iTBS treatment in acute OAB model involved a total of 33 female rats, which were divided into three distinct experimental phases. In study of rPMS iTBS treatment in chronic OAB model involved a total of 20 female rats which devided into 2 groups, sham and control. In all cases, cystometry measurements were conducted by inserting a polyethylene 50 tube into the bladder dome through a midline abdominal incision. We investigated the impact of rPMS stimulation on two specific parameters: the first voiding time (Tv), which represents bladder capacity, and the inter-contraction interval (ICI). To create the acute OAB model, rats were infused with saline after being pretreated with a continuous transvesical infusion of 0.5% acetic acid (AA) to induce bladder overactivity. In the first phase of the experiment (n=11), we assessed the effects of various frequencies (1Hz, 5Hz, 10Hz, 15Hz, 20Hz, iTBS, cTBS - continuous theta burst stimulation) of rPMS on normal rats. The second phase of the experiment (n=12) was built upon the findings of the first phase to determine the optimal frequency for rPMS. The third phase of the experiment (n=10) was conducted based on the outcomes of the second phase and aimed to investigate the urodynamic effects of rPMS using the iTBS procedure in the acute model of OAB rats. Then we applied the rPMS iTBS in the chronic OAB model for 4 days. In chronic OAB model, rats were divided into control (n=2), sham (n=8) and treatment (n=8) groups. To create the chronic OAB model, rats were transurethral infused with 0.75% Retinyl Acetate (RA) solution until bladder pressure reached 10cmH2O. For the control group, the bladder was infused with a mixture of saline and Polysorbate 80. During bladder infusion, the intravesical pressure was monitored using a cystometrogram (CMG) to examine the effects of sacral rPMS iTBS intervention in acute and chronic manner. Data analysis involved in the acute OAB experiment was repeated-measures analysis of variance (ANOVA) and t-tests, and all results are presented as the mean ± standard deviation (SD). In chronic OAB experiment, the statistical analysis was done using an independent Mann-Whitney test, and data are presented as median (IQR). A significance level of p < 0.05 was set for all statistical tests.

Results: Our findings indicate that in the initial phase of the experiment, among all the different frequencies tested, only iTBS at 100% intensity significantly prolonged the Tv in normal healthy rats, extending it to 132%. In the second phase of the experiment, the results demonstrated that among various intensities of iTBS (25%, 50%, 75%, and 100%), only Acute rPMS iTBS at 100% intensity led to a significant increase in the ICI, elevating it to 121%. The model of OAB was successfully established by continuously infusing saline after treatment with 0.5% AA. This resulted in significant reductions in Tv to 42% and ICI to 56% compared to their respective control values. In the third phase of the experiment, the application of rPMS with iTBS at 100% intensity on the sacral nerve effectively suppressed bladder overactivity induced by AA, leading to a substantial increase in the ICI to a range of 167% to 222% in OAB model rats. In the chronic OAB model, the sham group showed a 39.54% reduction in Tv (p=0.08) and a 35% reduction in ICI (p=0.17) compared to the control group. Although these results suggest that RA was effective in inducing a chronic OAB model, the lack of statistical significance is likely due to the imbalance in sample size between groups. Nevertheless, the treatment group in the chronic OAB model successfully increased a significant difference in median scores of 100.5% for Tv and 69% for ICI (p<0.05).

Conclusions: Acute and chronic application of sacral rPMS with iTBS 100% intensity demonstrated the capability to alleviate bladder overactivity. The urodynamics results of this study offered valuable perspectives on potential alternative approaches for OAB treatment.