Transcranial Magnetic Resonance–Guided Focused Ultrasound Thalamotomy for Tremor

Historical Uses of Focused Ultrasonography in the Brain

Neurosurgeons have rarely used ultrasonography (US) other than for diagnostic imaging. The concept of using high-intensity focused ultrasonography (HIFU) in the brain was first conceived in the early 1950s, during a time of rapid growth in stereotactic neurosurgery. William and Frank Fry, both physicists who studied US technology, described the use of HIFU to produce precise, focal lesions deep in the feline brain without violating the dura and without causing damage to the intervening tissues or blood vessels. ^, These seminal experiments used a four-element, 1-MHz transducer to reliably produce a US beam about 1 mm in diameter that was capable of contouring lesions with slight movements of the focus. Sonication intensities approaching 210 W/cm ² for 4 seconds created “reversible” brain lesions in craniectomized cats and nonhuman primates. The Fry brothers collaborated with Russell Meyers, a pioneer in open surgery of the basal ganglia, to produce ultrasonic lesions in patients with Parkinson disease (PD) and other movement disorders. These treatments involved a custom stereotactic apparatus, contrast ventriculography, and a craniotomy to transmit acoustic energy to the pallidothalamic tracts. The results were favorable, with improvements in tremor and rigidity and relatively few serious side effects.

Around the same time that the Fry brothers were studying the therapeutic uses of focused US (FUS), the field of diagnostic US was developing in Lund, Sweden. Ultrasonic reflectoscopes had been designed to test material integrities in shipyards and factories. The first echocardiograms were obtained when cardiologists used these scopes to image heart motion and the mitral valve. Lars Leksell borrowed a device in 1956 and successfully identified the pineal shift in a 16-month-old child with a subdural hematoma. Although US transmission was possible in the neonatal skull, Leksell eventually became disenchanted by the limitations of transcranial US delivery through the mature, human skull because it required a cranial window. Even though Leksell acquired several patents for the use of US in the brain, he eventually pursued ionizing radiation as a less invasive method for the treatment of pain and other neurologic disorders.

Others utilized US through craniotomies for deep lesioning in the brain. Lindstrom treated 25 patients with cancer for their pain and anxiety with US leucotomy as an alternative to surgical lobotomy. ^, Histologic findings were ultimately available in these patients. Sixteen patients exhibited clinical improvement without microscopic change, a finding that was interpreted as a “functional lesion” selective to white matter tracts. ^, Heimburger reported prolonged survival in patients with glioma after sonicating through their craniotomies following initial resection. Despite these early successes, FUS lesioning necessitated craniotomy for acoustic transmission, so US therapy in the brain never gained widespread popularity among neurosurgeons.

Ultrasound Properties

Ultrasound can be defined as an acoustic pressure wave beyond the range of normal human hearing (>20 kHz). As with other waveform energies that follow simple harmonic motion, US is characterized by its frequency, wavelength, amplitude, power, and intensity. Safe medical imaging US at frequencies ranging from 2 to 20 MHz creates waveforms with peak intensities less than 1 W/cm , as regulated by the U.S. Food and Drug Administration (FDA). ^, Therapeutic HIFU for brain ablation uses lower frequencies (0.2 to 1 MHz), which better propagate through bone, and the peak intensities may exceed 1000 W/cm ² and are therefore capable of tissue ablation or cavitation.

As US pressure waves travel through a given medium, molecules are displaced and oscillate according to the magnitude of the wave and the elasticity of the medium. Frictional energy and ultimately heat are generated by the molecules as they oscillate next to each other – a phenomenon not dissimilar to that of radiofrequency (RF) energy. With FUS, the pressure at the focus is exponentially increased, so thermal tissue ablation can be achieved in the focus without damage to surrounding tissue. ^,

At high intensities, the acoustic pressure wave moving through tissue can also induce cavitation, which results when the acoustic pressure wave extracts gas that coalesces into microbubbles that oscillate in the ultrasonic field. ^, At lower intensities, these bubbles can expand and contract in a sustainable, periodic fashion termed stable cavitation. However, if the bubbles are subjected to higher intensities, they can potentially collapse violently (inertial cavitation) and damage tissues with extremely high temperatures, powerful jet streams, and/or free radicals. ^, The propensity for microbubble formation and cavitation raises concerns for HIFU ablation and has resulted in the implementation of cavitation monitoring. Theoretically, stable cavitation could be monitored and harnessed to enhance therapeutic ablations or mechanical opening of the blood-brain barrier, but inertial cavitation poses great risk to tissue because its mechanical effects are more difficult to predict and control.

Modern Transcranial Focused Ultrasonography

The skull is the major limiting factor for efficient delivery of US to the brain. Depending on the US frequency, the skull may reflect or absorb about 90% of the US energy. The potential for heating of the skull and adjacent soft tissues (dura and periosteum) exists if the skull overheats from absorbed US energy. Another challenge of transcranial US delivery relates to the variable thickness and density of the skull, which diffracts acoustic waves and leads to difficulty achieving a sharp acoustic focus.

Over the past two decades, two technologic advancements have addressed the high acoustic impedance and attenuation of the skull, allowing for transcranial HIFU. In the first, Clement and Hynynen and their colleagues developed a large-aperture, hemispherical transducer to maximize the area of transcranial acoustic energy delivery, thus minimizing local skull heating by distributing energy over the large surface area of the scalp and skull. Furthermore, an interface containing cold water is used to decrease the baseline temperature of the skull and keep it cooled during treatment ( Fig. 117.1 ). This also serves as a coupling medium for the US transducer with the scalp. The second advance, to account for the variability of the skull, was development of a phase-correction technology in parallel with multi-element, hemispherical transducers to correct aberrations in the acoustic beam traveling through the inhomogeneous skull. In this technology, a CT-based correction algorithm reconstructs the skull and computes the local characteristics of each location where an acoustic wave interfaces with the skull. Each element on the transducer can then be electronically adjusted and “phase shifted” to bring all of the beams to a sharp focus.

Magnetic Resonance Thermography

MR thermography measures temperature-dependent changes in water proton resonance frequency, thus enabling thermal monitoring during transcranial sonication. ^, Pre-sonication images are subtracted on a voxel-by-voxel basis from images obtained during tissue heating by US sonication. Images are acquired every 3 seconds, and tissue temperature is updated and plotted during the prescribed sonication ( Fig. 117.2 ). The images can be acquired in any of three planes (axial, coronal, and sagittal) to form a two-dimensional temperature map of change that is accurate to approximately 1°C in the plane perpendicular to the resonance frequency.

Thermal Dose

The intraoperative measurement of temperature can also be accumulated to represent the thermal dose delivered to each voxel. The Sapareto and Dewey equation was developed to estimate the thermal dose delivered to tissue on the basis of time-temperature profiles. Exposure of tissue for 240 minutes to 43°C is considered the critical dose for permanent tissue damage and cell death. Using the Sapareto and Dewey equation, one can calculate the equivalent time to achieve cell death for any temperature. This determination of thermal dose is necessary because of its nonlinear relationship with temperature, in which small increases in temperature can lead to large increases in thermal dose. This determination enables an intraoperative assessment of the ablated tissue and supports clinical decision making about additional treatment.

Technique: Transcranial Magnetic Resonance–Guided Focused Ultrasound Thalamotomy