電刺激神經調控對膀胱功能的影響

Abstract

脊髓損傷(Spinal Cord Injury, SCI)或腦損傷(Traumatic brain injury, TBI)病人常會伴隨著膀胱過動症或排尿功能失調的現象，若長時間處在此病症下，容易造成腎臟及輸尿管水腫和腎功能病變，腎功能衰竭是此類患者晚期死亡的主要原因，目前仍無任何方便又有效的治療方式，因此電刺激神經調控可能是一種替代的新治療發展方向。 本研究主要分成兩個部分，第一部分為使用實驗室已完成開發之脈衝式射頻電刺激器(射頻頻率500-kHz、脈衝頻率2-Hz、脈衝持續時間80ms、電壓 ±3V)，在急性與慢性膀胱過動症的老鼠模型上進行周邊神經 (骨盆神經、會陰神經) 電刺激調控，另一部分使用自動回饋式低頻電刺激器(脈衝頻率50-Hz、脈衝寬度1.82ms、電壓1.5 V)，在腦損傷老鼠模型上進行中樞神經電刺激調控，兩部分皆使用膀胱壓力容積檢測法來量化電刺激前後的膀胱功能差異。經由研究結果觀察脈衝射頻電刺激抑制了骨盆神經與會陰神經上的神經訊號傳導，膀胱容積從過動症的65% 顯著上升至110%，膀胱收縮間期從66%回復至 92%，改善的效果可維持4小時以上，有別於以往需要重複電刺激才能夠達到改善的效果有著顯著的提升。在中樞神經電刺激部分，腦損傷鼠的膀胱排尿效率在經過電刺激調控後從22%上升至74%，而我們系統在判斷自動給予電刺激時機的準確率高於90%。 經由研究發現，電刺激神經調控在周邊神經與中樞神經對於不同的病症使用不同的電刺激參數就有其顯著的改善效果，運用能夠暫時阻斷神經傳導的脈衝射頻電刺激於骨盆神經，能夠增加膀胱容積，降低膀胱過動的症狀，而使用低頻電刺激於中樞神經就能夠促進膀胱排空，解決尿液滯留的問題。希望未來在臨床上可作為醫生治療下泌尿道障礙病人的一種新的電刺激模式。

Spinal cord injury and traumatic brain injury (TBI) often permanently result in severe voiding dysfunction. Urinary retention and overactive bladder syndrome are often refractory to standard therapies, and most patients require self-catheterization, resulting in frequent urinary tract infections and a reduction of the quality of life. Therefore, this study investigates electrical stimulation neuromodulation as a potentially feasible alternative for the future treatment of bladder disorders. This research can be separated into 2 parts: The first part involved applying pulsed radiofrequency (PRF) electrical stimulation (frequency = 500 kHz; pulse frequency = 2 Hz; pulse duration = 80 ms; amplitude = ±3 V) neuromodulation on the peripheral (pudendal and pelvic) nerves of rats with overactive bladders, whereas the second part entailed applying automatic closed-loop low-frequency (50 Hz; pulse width = 1.82 ms; amplitude = 1.5 V) deep brain stimulation (DBS) on the central nerves of rats with TBI. According to the first cystometrogram (CMG) recording, acetic acid treatment significantly reduced bladder capacity (BC) and the intercontraction interval (ICI) to 65% and 66% of the corresponding control values, respectively. Subsequently, PRF electrical stimulation of the pelvic nerve inhibited AA-induced detrusor overactivity and significantly increased BC to 102%–110% and ICI to 79%–92%, effects which persisted for at least 4 h. Furthermore, caspase-3 activity demonstrated that PRF did not cause significant neural damage to the stimulated target nerves. In addition, we successfully implemented a closed-loop algorithm for DBS control, and the bladder voiding phase detection accuracy was >90%. Moreover, our system significantly improved voiding efficiency in the TBI rats from 22% to 74%. The results show that using electrical stimulation with various parameters and in various positions represents a potential treatment for LUT disease. PRF could block nerve conduct, enabling bladder activity to return from overactive to normal levels. In addition, the application of low-frequency DBS could trigger detrusor contractions, which may be a potential mode of treatment for urinary retention. To conclude, this study is the first step in exploring the effects of electrical stimulation on LUT function. The animal experience gathered from this research can be a basis for developing a newer treatment approach for patients with LUT disease in the future.