Focused Ultrasound for ET: Six Lessons Lead to Mastery

In 2016 the U.S. Food and Drug Administration (FDA) approved MRI-guided Focused Ultrasound (MRgFUS) for the treatment of medication-resistant essential tremor (ET). That decision opened a whole new world for patients who desperately want to regain normal hand use but are put off by the idea of a hole drilled in the skull and hardware inserted into their brain. Up till 2016, there were two invasive neurosurgical procedures to control tremors:

  1. Radiofrequency thalamotomy (RF thalamotomy) – a slender probe inserted through a hole in the skull to deliver an electrical current that deadens the VIM nucleus of the thalamus, and
  2. Deep Brain Stimulation (DBS) – implanting electrodes at the thalamus, connected by wires threaded through the neck to a power unit in the chest. When current is on, tremors diminish.

Thus, the availability of a safe and effective noninvasive treatment that could accomplish the same goal as RF thalamotomy or DBS while avoiding the need to cut skin or drill skull holes is a tremendous breakthrough. But it didn’t happen overnight. It would take nearly a century’s worth of lessons.

Think of developing a new skill you don’t have, like sailing or downhill skiing. You don’t start by renting a sailboat or flying to the Alps to zip down black diamond slope. Instead you invest in lessons, and start with baby steps. You make some mistakes: maybe you end up in the drink or sprain an ankle, but you gain effective methods and equipment upgrades as your skills improve until you achieve mastery.

Six earlier lessons in Focused Ultrasound

Here are just a few of the lessons that were stepping stones to today’s mastery of MRgFUS.

  • Lesson One: Ultrasound has the ability to damage tissue in certain conditions. Using quartz crystals to generate sound at frequencies too high for the human ear (ultrasound) was discovered by Pierre Curie in 1880. He called it the piezoelectric effect. In the 1910s, Paul Langevin experimented with the piezoelectric effect for echolocation of underwater objects, now called sonar. While beaming ultrasound into a tank of water he found that “fish placed in the beam in the neighborhood of the source operation in a small tank were killed immediately, and certain observers experienced a painful sensation on plunging the hand in this region.”i Later, in 1932 Freundlich et al. published a theory that ultrasound had therapeutic potential.
  • Lesson Two: Ultrasound can be focused in a way that exerts greater effect on a target. In 1935, Johannes Gruetzmacher applied a concave shape to the ultrasound generator, effectively focusing the ultrasound energy waves. This gives control over aiming them at a target where they create heat when they meet. Thus, focused ultrasound (FUS) began.
  • Lesson Three: FUS is a virtual neurosurgery without incisions or holes. In fulfillment of Freundlich’s 1932 theory, a study came out 10 years later by a small research team from Columbia University’s Neurology and Anatomy Departments, and the Piezo-Electric Research Laboratories in North Bergen, NJ. This paper by John Lynn et al. reported using FUS to create lesions in the brains of animals, as demonstrated by behavioral disabilities seen in the animals. “This local brain effect was achieved through intervening scalp, skull, and meninges [membranes that line the skull and enclose the brain] … To date, it has not been possible to produce such brain changes without incidental injury to the skin and subcutaneous tissue…”ii
  • Lesson Four: For treatment consistency and success, FUS requires accurate image planning and guidance, the optimum energy dose needed to penetrate the skull, and a way to monitor FUS temperature during treatment. 20 years after the Lynn team experimented with living animals, in 1962 William Fry and Russell Meyers applied FUS to the brains of humans with neurological disorders, including Parkinson’s disease. They generated FUS from different directions to the target, but variances in skull bone density weakened some “beams” by absorbing their energy, so results were uneven. Also, efforts to use imaging ultrasound for guiding FUS were inadequate for precision targeting and heat tracking. FUS was not yet ready for prime time.
  • Lesson Five: A phased array of ultrasound emitters could compensate for uneven skull density, allowing correct power levels to ultimately converge on the target. How to deposit sonic energy evenly through the skull was a problem of physics and engineering. During the 1990s, a helmet-like device was eventually designed with over 1,000 ultrasound transducers, each of which could be separately aimed and adjusted to emit a specific “beam power” toward the target, thus allowing beams of greater power that would weaken back to normal as dense parts of the skull absorbed their energy. This phased array of transducers allowed a hemispheric treatment over the entire top half of the skull. A CT scan before treatment was added in order to identify more dense skull regions in order to know where to apply greater power.
  • Lesson Six: MRI is the ideal imaging. As the 20th century drew to a close, all that remained was high resolution, accurate imaging that could be used to identify the target, plan the treatment, monitor temperature levels in real time during treatment, and confirm the final treatment effect. Enter Magnetic Resonance Imaging (MRI). Technologic advances in MRI, which provides a precise, 3-dimensional portrait of even tiny structures in the brain, allowed accurate targeting of the VIM nucleus in the thalamus in order to block tremor signals from the cerebellum to the motor cortex. Interrupting this pathway restores normal use of the dominant hand.
  • From these past lessons, MRgFUS now integrates a) heat destruction of the VIM nucleus using FUS, b) MRI planning, treatment guidance, and real-time monitoring with heat-sensitive software, and c) phased array “beam” delivery to correct for bone density. Other developments lie ahead, e.g. the ability to treat both hands during the same outpatient session, but for now it’s safe to say that FUS has gained mastery.

    iO’Brien WD. Assessing the risks for modern diagnostic ultrasound imaging. Japanese Journal of Applied Physics. 1988. Volume 37, Part 1, Number 5B http://www.brl.illinois.edu/Projects/Bioeffects/bioeff.pdf
    iiLynn JG1, Zwemer RI, Chick AJ, Miller AE. A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol. 1942 Nov 20;26(2):179-93.

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