在超音波開啟血腦屏障之中，監控微氣泡穴蝕效應的一大挑戰是偵測穴蝕效應產生的特徵上面的限制。被動式穴蝕效應成像是一已經被注意到，可以藉由穴蝕效應產生的聲學訊號，而即時成像得到穴蝕效應位置的方法。然而使用治療用超音波中常使用的長脈衝波型會造成軸向解析度很差的結果，為了解決在穴蝕效應中非線性響應在成像上的影響，本研究整合了編碼激發與雙頻啾聲訊號的激發方式，使用由兩種不同頻率所組成的雙頻啾聲訊號(波形一 = 1.35 MHz + 1.65 MHz; 波形二 = 1.3 MHz + 1.7 MHz; 波形三 = 1.25 MHz + 1.75 MHz)，各個訊號上面有一低頻啾聲訊號封包(0.4 MHz; 0.5 MHz; 0.6 MHz)去激發微氣泡。這個雙頻啾聲訊號可以激發微氣泡產生穴蝕效應的同時，讓微氣泡產生封包中的啾聲訊號出來，這個產生的訊號可以被動式接收，並且經過脈衝壓縮成像之後，可以保持足夠的影像強度又不會在軸向解析度上面有所損失，可以更加精準的得到產生穴蝕效應的位置。體外實驗結果展現了與一般常見的長脈衝波形相比，在相同脈衝長度下，雙頻啾聲訊號影像的軸向解析度可以得到4.1倍的提升，訊雜比也得到42.2%的提升。除此之外，在沒有進行開顱手術的大鼠(N=3)的腦中，使用從0到0.9 MPa聲壓(間隔0.3 MPa)下使用雙頻啾聲訊號激發微氣泡得到的被動式影像，也展現出定位血腦屏障開啟的能力。我們成功的證實了使用雙頻啾聲訊號的方法可以監控微氣泡產生穴蝕效應導致的血腦屏障開啟，此方法也可以作為一評估超音波穴蝕效應藥物遞送的工具。並且此方法也有方便與現行超音波系統整合以及即時的優點。

One of the main challenges in monitoring cavitating microbubbles (MBs) during the treatment of the blood–brain barrier (BBB) opening is the limitation of detecting cavitation-mediated features transcranially. Passive cavitation imaging (PCI) has been noticed that it had the ability of real-time showing the position of cavitation by capturing the acoustic signal of cavitation. However, the utilize of long burst waveform degraded axial resolution of PCI image. In order to avoid the interference of cavitation nonlinear, the present study integrate coded excitation with dual-frequency chirp (DFC) excitation method. The DFC waveform excites MBs with a pulse consisted of two different frequencies (waveform1 = 1.35 MHz + 1.65 MHz; waveform2 = 1.3 MHz + 1.7 MHz; waveform3 = 1.25 MHz + 1.75 MHz) with a lower frequency chirp envelope (0.4 MHz; 0.5 MHz; 0.6 MHz) on it. The DFC waveform excited MBs cavitating and generating chirp envelope component in emitted signal. The signal was passively received and compressed that beamformed image would keep sufficient intensity without axial resolution loss and present more precision position of cavitation. Comparing with conventional long-burst waveforms, the axial resolution and signal-to-noise ratio of DFC excitation image can be enhanced 4.1-fold and 42.2% as shown in in vitro experiments, respectively. Furthermore, the PCI images of exciting MBs with different acoustic pressure from 0 to 0.9 MPa (spacing of each level is 0.3 MPa) in rat brain without craniotomy (N = 3 for each group) still showed the ability of locating BBB opening by DFC. We successfully validated the utilizing the DFC technique can monitor MBs cavitation caused BBB opening affords an alternative tool for evaluating cavitation- related drug delivery to the brain. It also has the advantage of high handy integration with current ultrasound systems and real-time.

中文摘要 ........................................................................................................................... iii Abstract ............................................................................................................................. iv 致謝…………….......................................................................................................................... vi List of Symbols ............................................................................................................... vii List of Figures ............................................................................................................... viii List of Tables ..................................................................................................................... x Chapter 1 Introduction 1.1 Concept ................................................................................................................................ 1 1.2 Ultrasound image with contrast agent microbubble ............................................................ 2 1.3 Ultrasound noninvasively blood brain barrier opening with microbubbles cavitation …... 3 1.3.1 Blood-brain barrier………….....…………………………………………….……..3 1.3.2 Cavitation of microbubbles….....…………………………………………….……..3 1.3.3 Temporary opening of the BBB……………………………………………...……..4 1.3.4 Transcranial ultrasound............................................................................................ 6 1.4 Monitoring of BBB opening.................................................................................................7 1.4.1 MRI guided................................................................................................................7 1.4.2 Passive cavitation detection and passive cavitation image…………………………7 1.5 Self-demodulation (intermodulation) ……………………………………………...………9 1.6 Aim of the study……………………………………………………………….…………..10 Chapter 2 Cavitation Monitoring with Passive Cavitation Imaging by Dual-Frequency Chirp Coded Excitation in the Brain 2.1 Introduction ………………………………………………………………...…….....……11 2.2 Materials and Methods……………………………………………………...……...…..…14 2.2.1 Composition of DFC waveform……………………………..……...……......……14 2.2.2 Preparation and composition of MBs………………………..……......……...……17 2.2.3 DFC excitation PCI phantom images………………………..……...……...……19 2.2.4 In vivo DFC excitation PCI images………………………..………...……...……23 2.2.4.1 Preparation of animal………………………..………...……............……23 2.2.4.2 Performance of DFC excitation PCI in animal BBB opening......………….23 2.2.4.3 Determination of BBB opening……………..………...……............……24
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2.2.4.4 Data processing and image Beamforming…..………...……............……24 2.2.4.5 Statistical analyses…………………………………………...…......……25 2.3 RESULTS………………………………………………………………...…...…...……27 2.3.1 Interference between difference-component and sub-harmonics...…...…...….…27 2.3.2 Performance of DFC excitation PCI phantom images…………...…...…...…….…28 2.3.3 Image resolution comparison……………………………………...….....…...……30 2.3.4 SNR and CTR comparisons of DFC……………………………………….....……30 2.3.5 Performance of in vivo image……………………………………...…...…....……30 Chapter 3 Discussion…………………………………………………………………………………….35 Chapter 4 Conclusions and Future Work………………………………………………………...……….39 References……………………………………………………………………………………40

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