Focused Ultrasound Therapy

Among the currently developed thermal therapy methods, focused ultrasound (FUS) appears to be the most promising, since its use does not require any invasive intervention. The potential therapeutic use of ultrasound energy for intracranial pathology has long been acknowledged (38). There is no more convincing example for the FUS benefits than in the brain, where deep lesions can be induced without any associated damage along the path of the acoustic beam. In the brain, where most injuries have detectable functional consequences, it is extremely important to limit tissue damage to the targeted area. This necessitates the use of an imaging technique for localization, targeting, and real-time intraoperative monitoring and to control the spatial extent and intensity of the deposited energy.

MRI can be used for targeted and controlled image-guided FUS procedures. It can provide detection of tumor margins, functional mapping of the surrounding cortex, definition of the adjacent fiber tracts, and temperature-sensitive imaging during sonications. High resolution anatomic imaging and flow-, perfusion-, and diffusion-sensitive MRI methods are used for planning the procedures, and temperature-sensitive methods are used to monitor and control energy deposition. By combining FUS with MRI-based guidance and control, it may be possible to achieve complete tumor ablation without any associated structural injury or functional deficit.

Beyond thermal coagulation of tissue, FUS has various other effects that can be therapeutically exploited and thus open the way for potentially innovative vascular and functional neurosurgery applications and for targeted drug delivery to the central nervous system. Among the most important, the capability of occluding vessels could make FUS a therapeutic tool for the treatment of vascular malformations. Both arterial and venous occlusion can be achieved with FUS (39,40). Using averaged power levels two- to threefold lower than the levels necessary for tissue coagulation, FUS can be used to open the blood-brain barrier selectively without damaging the surrounding brain parenchyma (41). For this effect to be achieved, preformed gas bubbles must be introduced into the vasculature, as is routinely done with ultrasound contrast agents. The gas bubbles implode and release cavitation-related energy, which transiently inactivates the tight junctions. As a consequence, large molecules can pass through the artificially created "window" in the blood-brain barrier. These large molecules can be chemotherapeutic or neuropharmacological agents. FUS-based targeted selective drug delivery to the brain could result in novel therapeutic interventions for movement and psychiatric disorders.

Such MRI-guided focal opening of the blood-brain barrier, combined with ultrasound technology that permits sonications through the intact skull, will open the way for new, noninvasive, targeted therapies. Specifically, it would provide targeted access for chemothearapeutic and gene therapy agents (42), as well as monoclonal antibodies, and could even provide a vascular route for performing neurotransplantations.

Ultrasound has also proved useful in accelerating thrombolysis (43) and increasing cell membrane permeability.

Since the skull bone scatters and attenuates the propagation of the ultrasound beam, most clinical trials have been performed following craniotomy in order to provide an ultrasound window (44). However, the transcranial application of FUS, although challenging, is not impossible. Although bone scatters and absorbs most of the acoustic energy, a small fraction can penetrate through the skull.

Recent simulation (45) and experimental studies (46,47) have demonstrated the feasibility of accurately focusing ultrasound through the intact skull by using an array of multiple ultrasound transducers arranged over a large surface area. To correct for beam distortion, the driving signal for the transducer elements of the array is individually adjustable, either based on measurements obtained with an invasive hydrophone probe, or better, based on detailed MRI. Because of the large surface area, the ultrasound energy is distributed in such a manner as to avoid heating and consequent damage of skin, bone, meninges, or surrounding normal brain parenchyma, while at the same time being able to coagulate the tissue at the focus (47). The experimental data are extremely promising; it appears possible to coagulate brain tumors thermally through the intact skull under MRI thermometry control using MR-compatible arrays.

By applying multiple, smaller transducers around the skull in a helmet-like phased-array system, sufficient amounts of energy can be deposited in the target tissue. Unfortunately, the skull thickness is uneven, causing variable delays of the acoustic waves originating from individual phased array elements. Phase incoherence can be corrected, however, if the skull thickness is known from preoperative X-ray computed tomography scans. In an experimental setup, successful focusing through the skull was achieved and verified by MRI, thus providing the foundation for developing the first human MRI-guided FUS system for brain tumor treatment.

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