低頻超音波定位顯微成像用於偵測戊四氮誘發之癲癇發作

Abstract

中樞神經系統的超音波影像技術可用於觀察腦部血流變化，但受限於穿透顱骨所需之低頻訊號，其影像品質常受到顱骨衰減、視野範圍與空間解析度的限制。超音波定位顯微成像透過優化微氣泡訊號，可突破繞射極限、提升成像解析度，惟現有實驗多使用高頻超音波，限制其經顱應用的可行性。本研究提出一套低頻率超音波定位顯微成像方法，用以偵測並調控戊四氮誘發之癲癇模型中血管動態的變化。我們使用一具500 kHz、64通道、球面聚焦之線性陣列換能器，並以Prodigy系統驅動進行平面波影像資料擷取。透過五角度複合式平面波發射（-15°至15°），提升了影像的訊噪比。實驗中透過靜脈注射MBs增強血管對比度，並以腹腔注射PTZ誘發癲癇發作。同一支換能器亦用於發送低頻聚焦超音波，以進行癲癇抑制之神經調控。影像處理方面，採用奇異值分解技術分離組織與血管訊號，並藉由理論點擴散函數進行互相關濾波，以濾除低信賴度之MBs訊號。低階SVD成分用以定義組織運動，高階成分則反映腦部血流動態。在體外交叉管實驗中，證實500 kHz球面換能器可精確定位MBs，並實現橫向解析度突破繞射極限。在體內實驗中，傳統500 kHz之B-mode影像對大鼠腦部解剖結構顯示有限，而ULM技術則成功提供高解析之皮質血管影像。癲癇大鼠顯示出明顯增加之MBs檢測數與血管訊號亮度，相較於對照組，顯示癲癇期間腦部灌流量上升。進一步施以低頻FUS治療後，癲癇大鼠的血管活動與MBs數量明顯下降，顯示其具備有效抑制癲癇的潛力。本研究所建構之雙模態系統，具備同一平台下即時監測與介入腦部疾病的潛能。總結而言，本研究驗證了低頻率ULM可行於經顱成像與非侵入式神經調控，未來有望作為功能性腦部成像與超音波癲癇治療的新興工具。

Ultrasound imaging in central nervous system enables observing cerebral blood flow variation, but is mostly limited by the skull attenuation, field of view, and spatial resolution due to low frequencies required for penetrating the skull. With the implementation of Ultrasound Localization Microscopy (ULM), imaging resolution can overcome the diffraction limit by optimizing the microbubble (MBs) signals, but experiment mostly relies on high-frequency ultrasound, restricting its transcranial applicability. In this study, we propose a low-frequency ULM approach for detecting and modulating seizure-induced vascular changes in a rat model of pentylenetetrazol induced epilepsy. A 500 kHz, 64-channel, spherically focused linear array transducer was driven by the Prodigy system to acquire plane-wave image data. Five-angle compounded plane-wave transmissions (-15° to 15°) improved signal-to-noise ratio (SNR). MBs were administered intravenously to enhance vascular contrast, while seizures were induced via intraperitoneal injection of PTZ. In addition to imaging, the same transducer was used to deliver low-frequency focused ultrasound (FUS) for seizure suppression. Singular Value Decomposition (SVD) was applied to separate tissue and vascular signals. A cross-correlation filter using a theoretical point spread function further suppressed low-confidence MBS signals. Low-rank SVD components were used for tissue motion defining, while high-rank components captured cerebral hemodynamics. Results from the in vitro cross-tube experiment confirmed the feasibility of accurate MBs localization and lateral resolution beyond the diffraction limit with the 500 kHz spherical transducer. In vivo, conventional 500kHz B-mode imaging provided limited anatomical detail of rat brain, whereas ULM enabled high-resolution visualization of cortical vasculature. Epileptic rats exhibited significantly increased MBs detection counts and brighter vascular signals compared to sham controls, indicating elevated cerebral perfusion during seizures. Epileptic rats were then received low-frequency FUS, reduced the vascular activity and MBs count relative to untreated epilepsy rats, suggesting a successful suppression effect. This dual-mode capability highlights the potential for real-time brain disorder monitoring and intervention with the same hardware platform. In conclusion, this study demonstrates the feasibility of low-frequency theranostic ultrasound for transcranial ULM imaging and noninvasive neuromodulation. The proposed system offers a promising tool for both functional brain imaging and ultrasound-based seizure therapy.