MR-Guided Focused Ultrasound Surgery

The feasibility of focused ultrasound for thermal therapy has been well established for more than 50 years. However, it has yet to reach wide application in the clinic. The main reason for this has been the lack of a way to monitor procedures. The earliest attempts at focused ultrasound therapy were simply targeted by using x-rays or ultrasound imaging. While these imaging modalities allow for targeting of the ultrasound beam, they cannot depict the target and correctly define margins, so are not applicable for complete tumor ablation. In addition, they do not yet have the capability to monitor the thermal exposure or to image the resulting tissue response with acceptable accuracy.

Magnetic Resonance Imaging (MRI) has been applied to focused ultrasound thermal therapy (Cline HE, Schenck JF, Hynynen K, Watkins RD, Souza SP, Jolesz FA. J Comput Assist Tomogr. 1992 Nov-Dec;16(6):956-65). It offers the following capabilities:

• Superior soft tissue contrast: MRI can distinguish the desired target tissue (cancer, etc.) with high resolution and contrast.
• Imaging in any orientation: MR images can be acquired in any plane in two and three dimensions. This capability allows for superior treatment planning ensuring that surrounding tissues are not in the path of the ultrasound beam.
• Temperature sensitivity: Several MRI parameters, including T1, the diffusion coefficient, and the proton resonant frequency (PRF) of water, are temperature sensitive. Currently the PRF method is the most sensitive method (<1°C sensitivity) and is apparently independent of the tissue type and the tissue state (thermally coagulated or not).
• Superior targeting: Because very low temperatures can be imaged with MRI, the precise location of the ultrasound beam can be visualized with a low power exposure. This ensures that the ultrasound is going to the correct target.
• Thermal quantification: With its accuracy in thermometry, the thermal exposure (dose) can be quantified. This allows the capability of monitoring online whether the tissue at the target is receiving a sufficient thermal dose to cause the desired damage and whether the surrounding tissue is receiving a safe dose. This exposure control is essential for successful thermal therapies.
• Post-therapy imaging: The resulting tissue damage (or lack thereof) can be imaged after the treatment with standard MR sequences. Contrast agents can be given to establish whether the tissue’s blood supply has been compromised (a good indicator of thermal damage).
• Repeatability: Because MRI does not use ionizing radiation (unlike x-rays and CT scans), it can be repeated multiple times. Thus, many images can be safely acquired during the therapy, and the patient can be repeatedly imaged after the therapy to establish proper treatment.

FUS Therapy of the Uterine Fibroid

The first clinical application of MRgFUS of breast fibroadenoma (Hynynen K, Pomeroy O, Smith DN, Huber PE, McDannold NJ, Kettenbach J, Baum J, Singer S, Jolesz FA. Radiology. 2001 Apr;219(1):176-85) and the first clinical trial for uterine fibroids (Tempany CM, Stewart EA, McDannold N, Quade BJ, Jolesz FA, Hynynen K. Radiology. 2003 Mar;226(3):897-905) were conducted in our hospital with the active involvement of the FUS Lab. Since then, thousands of patients have been treated with MRgFUS.

• MRgFUS treatment of symptomatic uterine fibroids received the CE mark in 2002 and FDA approval in 2004.
• MRgFUS for pain palliation of bone metastases received the CE mark in June 2007 and FDA approval in 2012.
• ExAblate Neuro received the CE mark in December 2012..
• Other clinical applications under trial are prostate and breast cancer.

FUS Therapy Through the Intact Skull

It has been known for decades that it is possible to treat brain tumors non-invasively through the skull using focused ultrasound. An ultrasound beam causes elevation in tissue temperature at its focus; the size of this focus can be tightly controlled to produce a highly discrete effect on the tissue, triggering local cell death due to thermal coagulation. The major hurdle to non-invasive intracranial focused ultrasound has been solving the problem of focusing the waves despite the irregular thickness of the skull bone. Our lab performed pioneering work to resolve this problem (Hynynen K, Jolesz FA. Ultrasound Med Biol. 1998 Feb;24(2):275-83 and Clement, et al. Phys. Med. Biol. 2002). The solution is to correct the phase aberration caused by these irregularities by determining the optimum driving inputs to a multi-segmented ultrasound transducer array so that a tight ultrasound focus is created inside the skull. Recent success of clinical studies for treating brain tumors and using FUS for functional neurosurgical applications proved that transcranial MR-guided FUS is feasible (McDannold N, Clement GT, Black P, Jolesz F, Hynynen K.Neurosurgery. 2010 Feb;66(2):323-32; discussion 332. Martin E, Jeanmonod D, Morel A, Zadicario E, Werner B. Ann Neurol. 2009 Dec;66(6):858-61. Elias WJ, Huss D, Voss T, Loomba J, Khaled M, Zadicario E, Frysinger RC, Sperling SA, Wylie S, Monteith SJ, Druzgal J, Shah BB, Harrison M, Wintermark M. N Engl J Med. 2013 Aug 15;369(7):640-8). Currently, research is being performed on acoustic analysis based on the geometric and material properties of cranial tissues extracted from CT and MRI data.

Targeted Drug Delivery to the Brain by MRI-guided Focused Ultrasound

The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). For example, doxorubicin has been a strong candidate for chemotherapy of malignant brain tumors, the intact BBB prevents cytotoxic levels from being achieved in glioma tissue. In some metastatic breast cancer, Herceptin is an effective chemotherapy except in the brain where the BBB blocks the drug to reach the targeted tumors. Non-localized, diffuse opening of the BBB permits drugs to reach the brain but can have dose-limiting side effects due to the spread of neurologically active agents within the central nervous system. MRI-guided focused ultrasound (FUS) can be applied to the brain to disrupt the BBB in a transient and targeted manner. We are developing a drug delivery technique using MRI-guided focused ultrasound to enable the noninvasive treatment of primary and metastatic brain tumors.

By applying focused ultrasound in the presence of microbubble ultrasound contrast agent, we have achieved focal opening of the BBB (Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Radiology. 2001 Sep;220(3):640-6) and targeted drug delivery to the brain in vivo (Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31)). Drug concentrations measured in sonicated brain tissue corresponded with cytotoxic levels measured in vivo in various human tumors. A strong correlation between MRI signal enhancement and drug absorption may indicate the capacity of MRI to be used as an indicator of BBB permeability during treatment. These results suggest the potential of MRI-guided focused ultrasound as an alternative to ionizing radiation therapy or invasive surgical resection, for use in the treatment of primary or metastatic brain tumors. Further investigation is required to evaluate the efficacy of this technique and to optimize its parameters for clinical application.

Intra-operative Ultrasound Monitoring

Brain shift during neurosurgery results in misregistration between the presurgical MRI or CT scan and the operating field and leads to inaccurate surgical margins. If the degree of brain shift is well known then the presurgical imaging can be adjusted to correspond with the current surgical field. Ultrasound may offer a portable, noninvasive, non-ionizing, rapid, real -time method of tracking brain shift during surgery or in ambulatory/emergency settings. The FUS lab has been testing techniques of 3D motion tracking using an array of low frequency ultrasound transducers positioned around ex vivo human skulls. Current results show that four 500KHz transducers placed exterior to acoustic windows in the skull can accurately track sub-millimeter 3D motion of objects within the skull.

Ultrasound enhanced glomerular filtration rate of kidney

Objectives: To demonstrate the cavitation events during sonication in the glomerular capillary wall. To demonstrate the increasing filtration fraction during sonication. To investigate the optimal sonication parameters to produce the desired physiological or histological end points using in vivo rabbit kidney studies.
This method would open an alternative way for dialysis and further its effectiveness in the treatment of chronic kidney diseases (progrediating towards End Stage Renal Disease).

Background: It is a histological fact that during the progression of chronic renal diseases the glomerular part of the kidney goes though mesangial proliferation. Parts of the capillary wall, such as the epithelial layer (podocyte flake) increases in thickness and become heterogonous, while the glomerular space shrinks. The filtration function of the kidney deteriorates by these processes leading to renal failure.

Laboratory experiments have shown that focused ultrasound beams can non-invasively destroy tissue, close blood vessels and increase the cell membrane permeability to molecules. It has also been shown that focused ultrasound can enhance transportation of molecules through the blood-brain barrier with the use of microbubbles. Based on these facts, we hypothesize that focus ultrasound exposures could increase the glomerular filtration rate of kidney.

Immunoelectron microscopic investigation of tight junctional proteins after ultrasound-evoked opening of the blood-brain barrier:

a). To determine the involvement of tight-junction specific proteins (occludin, claudin-1 and 5, ZO-1 protein) in intercellular pathway opening by ultrasound.
b). To determine the reversibility of the ultrastructural changes and the time for restoration of the BBB to small (lanthanum nitrate, m.w. 433 Da) and large (horseradish peroxidase, m.w. 40,000 Da) tracer molecules, i.e. to estimate the duration of the therapeutic window for tight-junction-based drug delivery to the brain.

Transcranial sonications (ac.power 0.6 W, 1.5 MHz) on rats are used. Immunolabeling of the proteins and morphometrical evaluation of immunosignals are performed.

Microbubble interactions with ultrasound

FDA- approved uses of ultrasound contrast agents are currently limited to cardiology, so more studies are required in order to extend their use to a wider range of clinical applications. The needed studies range from basic physics experiments and mathematical modeling to experiments in animal models and clinical trials. These investigations are important to ascertain ultrasound contrast agents’ safety and their effectiveness, to detect and quantify blood flow, to image microcirculation, and to facilitate localized drug and gene delivery across the vessel wall.