非侵入式閉迴路超音波系統於大鼠癲癇發作之抑制效果評估

Abstract

癲癇是一種神經系統疾病，特徵為大腦神經元的異常同步放電。部分病患無法以傳統抗癲癇藥物進行治療，需使用替代療法，如反應式神經刺激、迷走神經刺激、深部腦刺激、經顱磁刺激、經顱直流電刺激等，而這些療法多屬侵入式。近年，聚焦式超音波(Focus Ultrasound, FUS) 作為一種非侵入式，且被認為具有神經調控潛力。故本研究基於腦電訊號(Electroencephalography, EEG) 回饋，開發一套閉迴路(Closed-Loop) 超音波系統，並使用EEG, 功能性磁振造影(functional MRI)，及組織切片等多模態評估方式，以驗證癲癇的抑制效果及系統的可行性。 本研究建構一癲癇大鼠模型，並採用閉迴路與開放迴路兩種模式，結合不同機械指數（0.25 MI 與0.75 MI），對視丘進行超音波治療。EEG 結果顯示，0.25 MI下閉迴路模式在後期具有較佳的抑制效果；0.75 MI 雖在中期表現良好，惟後期癲癇尖波略有上升。fMRI 分析顯示，開放迴路組BOLD 訊號於第40 分鐘下降，但隨後回升，顯示其抑制效果有限。區域分析發現，視丘與海馬迴呈現明顯調控反應，後扣帶皮質與初級聽覺皮質則變化不明顯。功能性連結分析顯示，癲癇發作後腦區連結性上升，經開放迴路治療後下降，其中0.25 MI 效果優於0.75 MI。雖視丘與其他腦區的連結未達統計顯著，0.25 MI 仍展現出明確的抑制趨勢。組織切片分析顯示，癲癇發作後c-Fos 表現上升，反映神經過度活化，經閉迴路治療可恢復至接近對照組，具神經抑制效果。GAD65/67 表現則於癲癇後下降，顯示抑制性神經元功能受損，閉迴路刺激後回升，維持抑制網路穩定性。結果驗證閉迴路聚焦式超音波具神經調控潛力。 綜合三個評估方式結果，基於EEG 的閉迴路fcFUS 系統在抑制癲癇發作、穩定神經網絡與維持神經功能方面展現潛力，尤以低機械指數（0.25 MI）表現最穩定。惟0.25 與0.75 MI 間差異仍需更大樣本與長期研究佐證。整體結果支持閉迴路聚焦式超音波為具發展潛力的癲癇干預工具，未來可望實現即時監控與個體化刺激的精準神經調控應用。

Epilepsy is a neurological disorder characterized by abnormal synchronous neuronal discharges. While various neuromodulatory therapies such as RNS, VNS, DBS, TMS, and tDCS have shown efficacy, most are invasive. Focused ultrasound (FUS) offers a non-invasive alternative with neuromodulatory potential. This study developed a closed-loop FUS system driven by electroencephalography (EEG) feedback and evaluated its efficacy using EEG, functional MRI (fMRI), and histological analysis in a rat epilepsy model. Closed-loop and open-loop stimulation modes were applied to the thalamus using two acoustic pressures (0.25 MI and 0.75 MI). EEG results showed that 0.25 MI under closed-loop conditions provided better seizure suppression in the later phase. fMRI analysis indicated limited effects in the open-loop group, with transient BOLD signal reduction. Regional and connectivity analyses revealed modulation in the thalamus and hippocampus, with 0.25 MI showing more consistent inhibitory trends. Histology showed that closed-loop stimulation reduced seizure-induced c-Fos expression and restored GAD65/67 levels, suggesting reduced neuronal hyperactivity and preserved inhibitory function. Overall, the EEG-based closed-loop FUS system demonstrated potential in seizure suppression and network stabilization, especially under low acoustic pressure. These findings support its development as a precise and non-invasive neuromodulation strategy for epilepsy.