血腦屏障為哺乳類動物大腦中所擁有的特殊結構，其能阻斷外來物質進入腦內並保護大腦維持正常生理活動，血腦屏障同時阻礙了腦內疾病藥物的遞送，而降低腦內疾病治療效果，近年來研究指出聚焦式超音波搭配微氣泡能促使血腦屏障開啟，可有效幫助藥物釋放與基因治療的成效。此外，為了增加臨床實用性，血腦屏障開啟的現象已被多種生物醫學影像所偵測，其中最被廣泛應用的為磁振造影，使用T1權重影像掃瞄並透過Gd-DTPA對比劑的滲漏便能很方便得知血腦屏障開啟位置的資訊，此外使用T2權重掃描序列便能得知顱內出血性傷害的位置，然而磁振造影缺乏較高的時間解析度而無法觀察到細微的生理變化，且無法同時偵測因超音波刺激所導致的微循環血流變化。
本研究的目的為運用高頻超音波影像系統搭配微氣泡擊破回沖影像，透過較高的空間解析度於大鼠上監測微循環血流變化提供可判別血腦屏障開啟程度之活體內工具，且可同時偵測因聚焦式超音波過度刺激所形成的顱內損傷。
研究方法為運用2 MHz低頻超音波搭配微氣泡刺激S.D.品系大鼠使其血腦屏障開啟，並觀察傷害性的產生與否對腦內血流產生的變化，施打的參數為脈衝重複頻率1 Hz，正弦波形長度1 ms，施打時間為60 sec，聲壓為0.5 - 0.7 MPa，於施打超音波後以微氣泡擊破回沖影像觀察不同時間點變化，觀察的時間點為施打超音波前、施打超音波後20 sec、30 sec與60 sec之血流變化並對其定量。最後運用磁振造影進一步驗證本研究之結果。
結果顯示聚焦式超音波搭配微氣泡施打過後，該區血液流速明顯變緩，與血腦屏障開啟的位置相當一致，特別的是，在傷害性血腦屏障開啟的組別中，施打超音波20秒後觀察到時間強度曲線呈現特異變化，其回沖後的高原區高於微氣泡擊破前之影像強度，該特殊表現可用以偵測傷害性的產生，此外血塊的產生會阻斷血流而干擾血液循環。然而血液流速改變的程度正比於聲壓的強度，且在磁振造影的通透性影像上亦呈現高度正相關性，因此腦內微循環血流的改變極具潛力發展為定量聚焦式超音波所誘發之血腦屏障開啟與腦內傷害性的偵測。
本研究成功開發出有效偵測血腦屏障開啟之活體內工具，且透過時間強度曲線的表現與血流改變的程度可同時偵測出血性傷害的產生，未來運用本研究結果期望可開發出具有回饋控制機制之影像系統以防止顱內出血傷害的產生，實際運用於臨床診斷。

Blood-brain barrier (BBB) is an unique structure in the mammalian brain, which prevents poisonous substances from entering the brain and maintains the normal physiological activities of the brain. However, BBB also hinders the drug delivery into the brain, which further decreases the efficiency of treating cerebral diseases. Recently, blood-brain barrier disruption (BBBD) has been performed by focused ultrasound (FUS) combining with microbubbles (MBs), and has been approved to enhance the local drug or gene delivery. Furthermore, the BBBD effect has been widely observed by several biomedical imaging methods to broaden its clinical practicability. The magnetic resonance imaging (MRI) is one of the most commonly used tools to indicate the BBBD location via monitoring the contrast agent such as Gd-DTPA leakage into the brain tissues by T1-weighted sequences. Moreover, the intracerebral hemorrhage (ICH) caused by FUS sonication could be recognized by the MRI T2*-weighted sequence. However, the low temporal resolution property of MRI restricts the dynamic observation of physiological changes within the brain. Also, MRI fails to detect micro-circulation shortage induced by FUS with MBs.
In this paper, we proposed a high-resolution ultrasound imaging system with destruction/reperfusion technique, which can be used to identify BBBD region and even brain tissue damage according to cerebral blood flow variation in the rat model.
The BBB was disrupted by a 2 MHz FUS combining with MBs at 0.5 - 0.7 MPa (pulse repetition frequency: 1 Hz, pulse length: 1 ms, sonication time: 60 s). The D/R B-mode images were then acquired at three time points including (1) 15 min before; (2) 20 s after; and (3) 60 s after FUS sonication to dynamically investigate the relationship between BBBD and brain perfusion/damage. Finally, MRI images were used to further confirm the proposed technique and the results of this study.
The results showed that the velocity of blood flow decreased after BBBD induced by FUS sonication. Particularly, the plateau of blood flow time-intensity curve (TIC) was higher at 20 s after MB destruction by FUS sonication than that obtained prior to sonication. Besides, the blood flow was found to be obstructed at 60 s after sonication due to blood coagulation. The pattern of hemorrhagic damage caused by FUS can be monitored by the TIC. In addition, we also observed that the location of blood flow velocity decrease was consistent with the areas of BBBD and the variation of blood flow depends on the applied acoustic pressure, and the extent of permeability presented by MRI Ktrans images were highly correlative with the blood flow variation measured by our methods.
In conclusion, our proposed imaging technique provided a useful tool to monitor both the extent of BBBD and presence of hemorrhage by the flow velocity variation map and the TIC pattern, individually. The results can be used to establish an immediate-feedback control tool for preventing the induction of intracerebral hemorrhage during FUS treatment.

1 第一章 緒論 1
1.1 血腦屏障 (Blood Brain Barrier, BBB) 1
1.1.1 提高血腦屏障通透性的方法 3
1.1.2 聚焦式超音波 (Focused Ultrasound, FUS) 3
1.1.3 超音波造成之物理效應 5
1.1.4 微氣泡對比劑 6
1.1.5 超音波與微氣泡在生物體內的協同作用 8
1.2 血腦屏障的開啟與超音波聲學參數的相互關係 12
1.2.1 超音波中心頻率與聲壓 12
1.2.2 脈衝重複頻率、脈衝波數、微氣泡的粒徑和劑量 13
1.3 偵測血腦屏障開啟及其傷害產生之方法 14
1.4 超音波微氣泡對比劑擊破回沖模型 17
1.4.1 微循環血流 17
1.4.2 時間強度曲線擬合模型 18
1.5 研究動機與目的 21
2 第二章 實驗材料與方法 22
2.1 概論 22
2.2 超音波微氣泡對比劑製備方法 22
2.2.1 微氣泡對比劑之物理特性測量 24
2.3 超音波系統設備 24
2.3.1 高頻超音波影像系統 24
2.3.2 聚焦式超音波 26
2.3.2.1 聚焦式超音波輸出 26
2.3.2.2 合併雙頻探頭及聲壓校正 27
2.4 體外仿體實驗 30
2.4.1 仿體製作 30
2.4.2 微氣泡擊破回沖模型 30
2.4.2.1 體外實驗 32
2.4.3 慣性穴蝕效應劑量 33
2.5 活體實驗 36
2.5.1 實驗動物 36
2.5.2 活體實驗流程 37
2.5.3 組織切片與切片染色 39
2.5.4 超音波射頻訊號分析 40
2.6 商用超音波影像系統與磁振造影 41
2.7 窗型觀測腔 44
2.7 數據統計分析 45
3 第三章 實驗結果與討論 46
3.1 微氣泡性質量測 46
3.2 擊破回沖模型實驗參數選定與評估 47
3.2.1 高頻影像系統參數 48
3.2.2 慣性穴蝕效應劑量 48
3.2.3 以影像強度變化偵測微氣泡破裂參數 52
3.2.4 擊破回沖模型可行性測試 55
3.2.5 實驗參數應用於活體測試 59
3.3 以微氣泡促進血腦屏障通透性之活體內測試 60
3.3.1 微氣泡濃度於活體內穩定性測試 60
3.3.2 以聚焦式超音波搭配微氣泡造成不同程度血腦屏障開啟 61
3.4 微循環血流於血腦屏障開啟前後之變化 64
3.4.1 時間強度曲線分析 64
3.4.2 生物組織切片結果驗證 67
3.4.3 平均流速變化量 69
3.5 Vevo2100 高頻影像系統結果 72
3.5.1 時間強度曲線分析 72
3.5.2 磁振造影於血腦屏障開啟之驗證 76
3.5.3 超音波影像與磁振造影相關性分析 78
3.6 窗型觀測腔實驗結果 81
4 第四章 結論與未來展望 86
4.1 結論 86
4.2 未來展望 87
5 參考文獻 88

[1] F. Y. Yang, W. M. Fu, R. S. Yang, H. C. Liou, K. H. Kang, and W. L. Lin, "Quantitative evaluation of focused ultrasound with a contrast agent on blood-brain barrier disruption," Ultrasound Med Biol, vol. 33, pp. 1421-7, Sep 2007.
[2] F. Wang, Y. Cheng, J. Mei, Y. Song, Y. Q. Yang, Y. Liu, et al., "Focused ultrasound microbubble destruction-mediated changes in blood-brain barrier permeability assessed by contrast-enhanced magnetic resonance imaging," J Ultrasound Med, vol. 28, pp. 1501-9, Nov 2009.
[3] F. Xie, M. D. Boska, J. Lof, M. G. Uberti, J. M. Tsutsui, and T. R. Porter, "Effects of transcranial ultrasound and intravenous microbubbles on blood brain barrier permeability in a large animal model," Ultrasound Med Biol, vol. 34, pp. 2028-34, Dec 2008.
[4] N. Vykhodtseva, N. McDannold, and K. Hynynen, "Progress and problems in the application of focused ultrasound for blood-brain barrier disruption," Ultrasonics, vol. 48, pp. 279-96, Aug 2008.
[5] W. M. Pardridge, "Blood-brain barrier drug targeting: the future of brain drug development," Mol Interv, vol. 3, pp. 90-105, 51, Mar 2003.
[6] M. Malakoutikhah, M. Teixido, and E. Giralt, "Shuttle-mediated drug delivery to the brain," Angew Chem Int Ed Engl, vol. 50, pp. 7998-8014, Aug 22 2011.
[7] H. L. Liu, M. Y. Hua, P. Y. Chen, P. C. Chu, C. H. Pan, H. W. Yang, et al., "Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment," Radiology, vol. 255, pp. 415-25, May 2010.
[8] H. L. Liu, C. H. Pan, C. Y. Ting, and M. J. Hsiao, "Opening of the blood-brain barrier by low-frequency (28-kHz) ultrasound: a novel pinhole-assisted mechanical scanning device," Ultrasound Med Biol, vol. 36, pp. 325-35, Feb 2010.
[9] F. Y. Yang, W. M. Fu, W. S. Chen, W. L. Yeh, and W. L. Lin, "Quantitative evaluation of the use of microbubbles with transcranial focused ultrasound on blood-brain-barrier disruption," Ultrason Sonochem, vol. 15, pp. 636-43, Apr 2008.
[10] N. McDannold, N. Vykhodtseva, and K. Hynynen, "Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index," Ultrasound Med Biol, vol. 34, pp. 834-40, May 2008.
[11] S. Mitragotri, "Healing sound: the use of ultrasound in drug delivery and other therapeutic applications," Nat Rev Drug Discov, vol. 4, pp. 255-60, Mar 2005.
[12] R. Kunstfeld, G. Wickenhauser, U. Michaelis, M. Teifel, W. Umek, K. Naujoks, et al., "Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a "humanized" SCID mouse model," J Invest Dermatol, vol. 120, pp. 476-82, Mar 2003.
[13] L. H. Treat, N. McDannold, N. Vykhodtseva, Y. Zhang, K. Tam, and K. Hynynen, "Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound," Int J Cancer, vol. 121, pp. 901-7, Aug 15 2007.
[14] E. L. Yuh, S. G. Shulman, S. A. Mehta, J. Xie, L. Chen, V. Frenkel, et al., "Delivery of systemic chemotherapeutic agent to tumors by using focused ultrasound: study in a murine model," Radiology, vol. 234, pp. 431-7, Feb 2005.
[15] S. Tinkov, G. Winter, C. Coester, and R. Bekeredjian, "New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: Part I--Formulation development and in-vitro characterization," J Control Release, vol. 143, pp. 143-50, Apr 2 2010.
[16] W. Xing, W. Z. Gang, Z. Yong, Z. Y. Yi, X. C. Shan, and R. H. Tao, "Treatment of xenografted ovarian carcinoma using paclitaxel-loaded ultrasound microbubbles," Acad Radiol, vol. 15, pp. 1574-9, Dec 2008.
[17] J. Kang, X. Wu, Z. Wang, H. Ran, C. Xu, J. Wu, et al., "Antitumor effect of docetaxel-loaded lipid microbubbles combined with ultrasound-targeted microbubble activation on VX2 rabbit liver tumors," J Ultrasound Med, vol. 29, pp. 61-70, Jan 2010.
[18] P. J. Frinking, A. Bouakaz, J. Kirkhorn, F. J. Ten Cate, and N. de Jong, "Ultrasound contrast imaging: current and new potential methods," Ultrasound Med Biol, vol. 26, pp. 965-75, Jul 2000.
[19] J. W. Barnard, W. J. Fry, F. J. Fry, and R. F. Krumins, "Effects of high intensity ultrasound on the central nervous system of the cat," J Comp Neurol, vol. 103, pp. 459-84, Dec 1955.
[20] J. J. Choi, M. Pernot, S. A. Small, and E. E. Konofagou, "Noninvasive, transcranial and localized opening of the blood-brain barrier using focused ultrasound in mice," Ultrasound Med Biol, vol. 33, pp. 95-104, Jan 2007.
[21] H. L. Liu, Y. Y. Wai, P. H. Hsu, L. A. Lyu, J. S. Wu, C. R. Shen, et al., "In vivo assessment of macrophage CNS infiltration during disruption of the blood-brain barrier with focused ultrasound: a magnetic resonance imaging study," J Cereb Blood Flow Metab, vol. 30, p. 674, Mar 2010.
[22] P. Dayton, A. Klibanov, G. Brandenburger, and K. Ferrara, "Acoustic radiation force in vivo: a mechanism to assist targeting of microbubbles," Ultrasound Med Biol, vol. 25, pp. 1195-201, Oct 1999.
[23] S. Qin and K. W. Ferrara, "Acoustic response of compliable microvessels containing ultrasound contrast agents," Phys Med Biol, vol. 51, pp. 5065-88, Oct 21 2006.
[24] J. Collis, R. Manasseh, P. Liovic, P. Tho, A. Ooi, K. Petkovic-Duran, et al., "Cavitation microstreaming and stress fields created by microbubbles," Ultrasonics, vol. 50, pp. 273-9, Feb 2010.
[25] W. Wiedemair, Z. Tukovic, H. Jasak, D. Poulikakos, and V. Kurtcuoglu, "On ultrasound-induced microbubble oscillation in a capillary blood vessel and its implications for the blood-brain barrier," Phys Med Biol, vol. 57, pp. 1019-45, Feb 21 2012.
[26] S. B. Raymond, J. Skoch, K. Hynynen, and B. J. Bacskai, "Multiphoton imaging of ultrasound/Optison mediated cerebrovascular effects in vivo," J Cereb Blood Flow Metab, vol. 27, pp. 393-403, Feb 2007.
[27] H. Chen, W. Kreider, A. A. Brayman, M. R. Bailey, and T. J. Matula, "Blood vessel deformations on microsecond time scales by ultrasonic cavitation," Phys Rev Lett, vol. 106, p. 034301, Jan 21 2011.
[28] E. E. Cho, J. Drazic, M. Ganguly, B. Stefanovic, and K. Hynynen, "Two-photon fluorescence microscopy study of cerebrovascular dynamics in ultrasound-induced blood-brain barrier opening," J Cereb Blood Flow Metab, vol. 31, pp. 1852-62, Sep 2011.
[29] Y. S. Tung, F. Vlachos, J. A. Feshitan, M. A. Borden, and E. E. Konofagou, "The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice," J Acoust Soc Am, vol. 130, pp. 3059-67, Nov 2011.
[30] N. McDannold, N. Vykhodtseva, and K. Hynynen, "Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption," Ultrasound Med Biol, vol. 34, pp. 930-7, Jun 2008.
[31] D. E. Goertz, C. Wright, and K. Hynynen, "Contrast agent kinetics in the rabbit brain during exposure to therapeutic ultrasound," Ultrasound Med Biol, vol. 36, pp. 916-24, Jun 2010.
[32] J. J. Choi, K. Selert, Z. Gao, G. Samiotaki, B. Baseri, and E. E. Konofagou, "Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies," J Cereb Blood Flow Metab, vol. 31, pp. 725-37, Feb 2011.
[33] F. Vlachos, Y. S. Tung, and E. Konofagou, "Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI," Magn Reson Med, vol. 66, pp. 821-30, Sep 2011.
[34] J. Park, Y. Zhang, N. Vykhodtseva, F. A. Jolesz, and N. J. McDannold, "The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound," J Control Release, vol. 162, pp. 134-42, Aug 20 2012.
[35] B. Baseri, J. J. Choi, Y. S. Tung, and E. E. Konofagou, "Multi-modality safety assessment of blood-brain barrier opening using focused ultrasound and definity microbubbles: a short-term study," Ultrasound Med Biol, vol. 36, pp. 1445-59, Sep 2010.
[36] J. J. Choi, K. Selert, F. Vlachos, A. Wong, and E. E. Konofagou, "Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles," Proc Natl Acad Sci U S A, vol. 108, pp. 16539-44, Oct 4 2011.
[37] K. Hynynen, N. McDannold, N. Vykhodtseva, and F. A. Jolesz, "Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits," Radiology, vol. 220, pp. 640-6, Sep 2001.
[38] K. J. Lin, H. L. Liu, P. H. Hsu, Y. H. Chung, W. C. Huang, J. C. Chen, et al., "Quantitative micro-SPECT/CT for detecting focused ultrasound-induced blood-brain barrier opening in the rat," Nucl Med Biol, vol. 36, pp. 853-61, Oct 2009.
[39] H. L. Liu, P. H. Hsu, P. C. Chu, Y. Y. Wai, J. C. Chen, C. R. Shen, et al., "Magnetic resonance imaging enhanced by superparamagnetic iron oxide particles: usefulness for distinguishing between focused ultrasound-induced blood-brain barrier disruption and brain hemorrhage," J Magn Reson Imaging, vol. 29, pp. 31-8, Jan 2009.
[40] H. L. Liu, Y. Y. Wai, W. S. Chen, J. C. Chen, P. H. Hsu, X. Y. Wu, et al., "Hemorrhage detection during focused-ultrasound induced blood-brain-barrier opening by using susceptibility-weighted magnetic resonance imaging," Ultrasound Med Biol, vol. 34, pp. 598-606, Apr 2008.
[41] J. Folkman, "Tumor angiogenesis," Adv Cancer Res, vol. 43, pp. 175-203, 1985.
[42] K. Wei, A. R. Jayaweera, S. Firoozan, A. Linka, D. M. Skyba, and S. Kaul, "Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion," Circulation, vol. 97, pp. 473-83, Feb 10 1998.
[43] S. J. Rim, H. Leong-Poi, J. R. Lindner, D. Couture, D. Ellegala, H. Mason, et al., "Quantification of cerebral perfusion with "Real-Time" contrast-enhanced ultrasound," Circulation, vol. 104, pp. 2582-7, Nov 20 2001.
[44] K. Wei, M. Ragosta, J. Thorpe, M. Coggins, S. Moos, and S. Kaul, "Noninvasive quantification of coronary blood flow reserve in humans using myocardial contrast echocardiography," Circulation, vol. 103, pp. 2560-5, May 29 2001.
[45] J. K. Willmann, R. Paulmurugan, K. Chen, O. Gheysens, M. Rodriguez-Porcel, A. M. Lutz, et al., "US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice," Radiology, vol. 246, pp. 508-18, Feb 2008.
[46] K. Kalantarinia, J. T. Belcik, J. T. Patrie, and K. Wei, "Real-time measurement of renal blood flow in healthy subjects using contrast-enhanced ultrasound," Am J Physiol Renal Physiol, vol. 297, pp. F1129-34, Oct 2009.
[47] R. Kern, A. Diels, J. Pettenpohl, M. Kablau, J. Brade, M. G. Hennerici, et al., "Real-time ultrasound brain perfusion imaging with analysis of microbubble replenishment in acute MCA stroke," J Cereb Blood Flow Metab, vol. 31, pp. 1716-24, Aug 2011.
[48] J. J. Rychak, J. Graba, A. M. Cheung, B. S. Mystry, J. R. Lindner, R. S. Kerbel, et al., "Microultrasound molecular imaging of vascular endothelial growth factor receptor 2 in a mouse model of tumor angiogenesis," Mol Imaging, vol. 6, pp. 289-96, Sep-Oct 2007.
[49] C. K. Yeh, S. Y. Lu, and Y. S. Chen, "Microcirculation volumetric flow assessment using high-resolution, contrast-assisted images," IEEE Trans Ultrason Ferroelectr Freq Control, vol. 55, pp. 74-83, Jan 2008.
[50] J. M. Hudson, R. Karshafian, and P. N. Burns, "Quantification of flow using ultrasound and microbubbles: a disruption replenishment model based on physical principles," Ultrasound Med Biol, vol. 35, pp. 2007-20, Dec 2009.
[51] J. M. Hudson, R. Williams, B. Lloyd, M. Atri, T. K. Kim, G. Bjarnason, et al., "Improved flow measurement using microbubble contrast agents and disruption-replenishment: clinical application to tumour monitoring," Ultrasound Med Biol, vol. 37, pp. 1210-21, Aug 2011.
[52] J. M. Hudson, K. Leung, and P. N. Burns, "The lognormal perfusion model for disruption replenishment measurements of blood flow: in vivo validation," Ultrasound Med Biol, vol. 37, pp. 1571-8, Oct 2011.
[53] S. T. Kang and C. K. Yeh, "A maleimide-based in-vitro model for ultrasound targeted imaging," Ultrason Sonochem, vol. 18, pp. 327-33, Jan 2011.
[54] W. L. Nyborg, "Biological effects of ultrasound: development of safety guidelines. Part II: general review," Ultrasound Med Biol, vol. 27, pp. 301-33, Mar 2001.
[55] Y. S. Tung, J. J. Choi, B. Baseri, and E. E. Konofagou, "Identifying the inertial cavitation threshold and skull effects in a vessel phantom using focused ultrasound and microbubbles," Ultrasound Med Biol, vol. 36, pp. 840-52, May 2010.
[56] C. K. Yeh and S. Y. Su, "Effects of acoustic insonation parameters on ultrasound contrast agent destruction," Ultrasound Med Biol, vol. 34, pp. 1281-91, Aug 2008.
[57] C. H. Fan, H. L. Liu, C. Y. Huang, Y. J. Ma, T. C. Yen, and C. K. Yeh, "Detection of intracerebral hemorrhage and transient blood-supply shortage in focused-ultrasound-induced blood-brain barrier disruption by ultrasound imaging," Ultrasound Med Biol, vol. 38, pp. 1372-82, Aug 2012.
[58] M. Ichihara, K. Sasaki, S. Umemura, M. Kushima, and T. Okai, "Blood flow occlusion via ultrasound image-guided high-intensity focused ultrasound and its effect on tissue perfusion," Ultrasound Med Biol, vol. 33, pp. 452-9, Mar 2007.
[59] M. E. van Raaij, L. Lindvere, A. Dorr, J. He, B. Sahota, F. S. Foster, et al., "Quantification of blood flow and volume in arterioles and venules of the rat cerebral cortex using functional micro-ultrasound," Neuroimage, vol. 63, pp. 1030-7, Nov 15 2012.
[60] F. Y. Yang, C. C. Chen, S. C. Horng, W. H. Chiu, and C. F. Yeh, "Microbubble-enhanced functional changes in arteries induced by pulsed high-intensity focused ultrasound exposure," Medical Engineering & Physics, vol. 34, pp. 313-317, Apr 2012.
[61] W. M. Bayliss, "On the local reactions of the arterial wall to changes of internal pressure," J Physiol, vol. 28, pp. 220-31, May 28 1902.
[62] N. Hosseinkhah and K. Hynynen, "A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels," Phys Med Biol, vol. 57, pp. 785-808, Feb 7 2012.
[63] H. Girouard, A. D. Bonev, R. M. Hannah, A. Meredith, R. W. Aldrich, and M. T. Nelson, "Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction," Proc Natl Acad Sci U S A, vol. 107, pp. 3811-6, Feb 23 2010.
[64] J. Park, Z. Fan, R. E. Kumon, M. E. El-Sayed, and C. X. Deng, "Modulation of intracellular Ca2+ concentration in brain microvascular endothelial cells in vitro by acoustic cavitation," Ultrasound Med Biol, vol. 36, pp. 1176-87, Jul 2010.
[65] R. E. Kumon, M. Aehle, D. Sabens, P. Parikh, Y. W. Han, D. Kourennyi, et al., "Spatiotemporal effects of sonoporation measured by real-time calcium imaging," Ultrasound Med Biol, vol. 35, pp. 494-506, Mar 2009.
[66] W. J. Tyler, Y. Tufail, M. Finsterwald, M. L. Tauchmann, E. J. Olson, and C. Majestic, "Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound," PLoS One, vol. 3, p. e3511, 2008.
[67] J. H. Hoger, V. I. Ilyin, S. Forsyth, and A. Hoger, "Shear stress regulates the endothelial Kir2.1 ion channel," Proc Natl Acad Sci U S A, vol. 99, pp. 7780-5, May 28 2002.
[68] D. J. Adams and M. A. Hill, "Potassium channels and membrane potential in the modulation of intracellular calcium in vascular endothelial cells," J Cardiovasc Electrophysiol, vol. 15, pp. 598-610, May 2004.
[69] J. Hu, X. Yuan, M. K. Ko, D. Yin, M. R. Sacapano, X. Wang, et al., "Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model," Mol Cancer, vol. 6, p. 22, 2007.
[70] L. Cucullo, M. Hossain, V. Puvenna, N. Marchi, and D. Janigro, "The role of shear stress in Blood-Brain Barrier endothelial physiology," BMC Neurosci, vol. 12, p. 40, 2011.
[71] E. VanBavel, "Effects of shear stress on endothelial cells: possible relevance for ultrasound applications," Prog Biophys Mol Biol, vol. 93, pp. 374-83, Jan-Apr 2007.
[72] C. Ayata, H. K. Shin, S. Salomone, Y. Ozdemir-Gursoy, D. A. Boas, A. K. Dunn, et al., "Pronounced hypoperfusion during spreading depression in mouse cortex," J Cereb Blood Flow Metab, vol. 24, pp. 1172-82, Oct 2004.
[73] Y. Gursoy-Ozdemir, J. Qiu, N. Matsuoka, H. Bolay, D. Bermpohl, H. Jin, et al., "Cortical spreading depression activates and upregulates MMP-9," J Clin Invest, vol. 113, pp. 1447-55, May 2004.