聚焦式超音波與超音波顯影劑應用於血腦屏障局部開啟之探討

Abstract

前人的研究指出聚焦式超音波結合超音波顯影劑能以非侵入方式將特定區域的血腦屏障暫時開啟。本研究是探討超音波顯影劑濃度與超音波聲壓力對局部開啟血腦屏障影響的定量分析。所使用的脈波超音波其操作頻率為1 MHz，重複頻率為1Hz。雄性Wistar大白鼠在分別注射不同的顯影劑濃度下施打超音波，之後並經股靜脈注射Evans blue 4小時後將其犧牲。由Evans blue在腦組織的滲出量得知，在相同的聲壓力下高濃度的顯影劑可造成較高的Evans blue的滲出量，而當顯影劑濃度相同時，較高的聲壓力也可以得到類似的結果。此外，在高濃度的顯影劑下，可以使血腦屏障的開啟較集中於焦點區域。從組織切片觀察得知，在適當的低濃度顯影劑時，可以在不傷害正常腦組織的情況下將血腦屏障開啟，然而在高濃度時會造成細胞凋亡的現象而其凋亡數量隨著距離焦點位置的增加而遞減。此研究驗證適當的顯影劑濃度能在不傷害正常腦組織的情況下增強穿顱式超音波將血腦屏障開啟的效率並且更集中於焦點區域。 在進行高能聚焦超音波腦部手術時，頭蓋骨對於超音波的相位扭曲以及振幅衰減有很大的影響。本研究探討半球狀超音波換能器在不須做相位修正的情形下，電子式焦點移動與聚焦能力評估。所選擇進行穿過頭蓋骨聚焦超音波頻率為0.1,0.15,0.25和0.5 MHz。換能器陣列是沿著頭蓋骨外型，以直接接觸頭皮的方式放置，使入射方向盡可能接近正向入射，俾使超音波束在通過不同介質面所發生的反射量降至最低。由模擬結果得知，當頻率為0.1 MHz時，在不產生重大側波瓣之情形下，焦點可成功以調整陣列相位的方式在幾乎全腦範圍內移動達到治療效果。

It has been shown that focused ultrasound (FUS) can disrupt the blood–brain barrier (BBB) noninvasively and reversibly at target locations when applied in the presence of ultrasound contrast agent (UCA). In this study, the dose-dependent effects of UCA on BBB disruption were investigated in the brains of male Wistar rats sonicated by 1.0-MHz pulsed FUS, with the UCA present at different doses. The BBB disruption was evaluated quantitatively based on the extravasation of Evans Blue (EB). The amount of EB extravasation in the brain increased with the quantity of UCA injected into the femoral vein prior to sonication. The use of a suitable dose of UCA resulted in the BBB disruption being concentrated in the focal region instead of the entire brain. From the histological examination, there was no neuronal damage when UCA was used at a low dose, but the higher doses result in the appearance of apoptotic cells and the number of apoptotic cells decreased symmetrically with distance from the focus. Moreover, comparing the effects of UCA at the various doses reveals no obvious differences in the temperature rise at the inner and outer skull surfaces. Our results indicate that a local BBB disruption combined with an acceptable impact on the brain tissue can be produced by using an appropriate UCA dose with transcranial FUS sonication. Finally, this study was to examine the steering and focusing ability of a contact hemispherical ultrasound transducer (80 mm radius of curvature, 160 mm diameter) for transskull brain diseases therapy without skull-specific aberration correction. A simulation program was used to investigate the effect of ultrasound transducer parameters on the steering and focusing ability for transskull therapy. The acoustic pressure distribution and the grating lobes in tissues were used to determine the steering and focusing ability of this transducer for a set of given conditions. Simulation results demonstrated that this hemispherical phased array transducer with low frequencies can steer a high-pressure focal zone for a large range in the brain. The peak and size of the high-pressure focal zone mainly depend on ultrasound frequency and the steering distance of the focal zone. By comparing the peak pressures between the focal zone and the grating lobe, 0.1 MHz transducer performed the desired results for large ranges (140 mm x-y direction and 138 mm z direction) of beam steering.The results reveal the feasibility of using a hemispherical phased array transducer with beam steering method at low frequency for brain diseases therapy within almost full range of the brain without performing a craniectomy.