植入式電刺激器脈衝射頻波形於神經性疼痛抑制之效應研究

Abstract

現行臨床雖已使用射頻(RadioFrequency,RF)電刺激治療神經病變性疼痛及相關疾病。臨床上針對背根神經節(Dorsal Root Ganglion, DRG)做脈衝射頻(Pulse RF,PRF)電刺激治療後，通常僅能維持三到六個月的效果，目前雖也有植入式電刺激器採低頻刺激方式，讓病人不用一再回診進行治療，但因有體積龐大、需定期更換電池、價格昂貴、手術風險高、容易感染之問題。 本研究目標在於利用研究團隊完成之SoC技術與無線傳輸模組，發展一無電池植入式低功率PRF電刺激器，藉由雙極式電極於背根神經節的刺激達到疼痛抑制的效果。因目前文獻上僅有探討低頻電刺激波形於治療上的差異，但缺乏在脈衝射頻的波形研究，故本研究以探討PRF電刺激之輸出波形(方波與弦波)對小動物的疼痛行為影響為重點。方法上將L5脊椎神經結紮後執行單次脈衝射頻電刺激療程，利用Von Frey方法評估動物疼痛耐受閥值，並用脊椎組織切片因疼痛發炎反應的表現蛋白(c-fos、pp38)變化做PRF效果評估。 結果發現在相同PRF參數下(射頻頻率500KHz、脈衝頻率2Hz、脈衝持續時間25ms、電壓1.25V)，脈衝射頻治療都能提升耐受閥值，此效果相較於控制組能維持五天之顯著差異(P<0.05)，且弦波相較於方波更具有提高耐受閥值之效果，在不同弦波電壓下(2.5V vs 1.25V)，有劑量相關性(Dose-Dependent)之趨勢。在弦波電壓2.5V下，手術一天後c-fos有顯著減少而三天後pp38也有減少的趨勢。但在方波電壓1.25V下，手術三天後c-fos與pp38仍有大量表現。根據以上的動物行為及脊髓切片的實驗結果，方波與弦波都有提高對疼痛反應耐受力閥值之效果，但方波在低電壓下相較於控制組仍造成發炎分子的大量表現，而2.5V弦波則具有抑制蛋白分子的表現。

It has been a common practice in clinics to use Radiofrequency (RF) for the treatment of neuropathic pains and associated diseases in recent years. However, even the state of art, i.e. using Pulsed Radio-Frequency (PRF) on Dorsal root ganglion (DRG), the effect can only last for 3-6 months and thus require repeated procedures for some patients. The implantable stimulator with low frequency stimulation has been used for long term applications to overcome above mentioned issue. However, current devices have technical challenges in size due to battery, replacement of battery, high cost, risks due to surgical procedures, and infections, etc. The long term goal of this research is to develop a batterless implantable PRF stimulator for pain control based on low power system-on-chip (SoC) and wireless coupling module with bi-polar electrode on DRG. Due to the fact that stimulating waveforms has been an active study area in low frequency stimulator but not systematically study in PRF stimulation, this study focuses on the pain control effects of PRF stimulating waveform (square vs. sinusoidal) in animal model. After ligation of the L5 spinal nerve, a single PRF treatment was delivered to the DRG via a pair of bi-polar electrodes. The pain relief effect due to PRF is evaluated by using Von Frey method (VF score) for the pain threshold index based on behavior response to mechanical stimulus of various strengths. Both fast and secondary expressed proteins of c-fos and pp38 are measured from spinal cord tissue sectioning slides to characterize the pain associated inflammatory responses and their responses due to PRF stimulation. From experimental results, it was found that both square and sinusoidal waveforms of the specific PRF parameters (RF 500KHz, Pulse frequency 2Hz, Pulse duration 25 msec, and amplitude 1.25 V) can have significant effects on the VF scores up to 5 days comparing to the control group. The responses are higher in the sinusoidal group than the square ones. It also exhibits dose-dependent responses under different stimulating amplitude (2.5 V vs. 1.25 V) of sinusoidal waveform. Moreover, we found at 2.5 V of sinusoidal stimulation both c-fos and pp38 were significantly reduced after one day and three days, respectively. However, at 1.25 V of square stimulation, both proteins over-expressed significantly at day 3 after procedure. According to the above mentioned behavior and molecular studies, it clearly demonstrates that both square and sinusoidal stimulation can increase the pain threshold. And yet square wave might induce inflammatory responses even at low amplitude of 1.25 V, while sinusoidal wave can effectively inhibit the expression of inflammatory proteins.