Brain Gain: New Applications for MR-guided Focused Ultrasound

MR-guided focused ultrasound (MRgFUS) has spent 20 years upending the way certain conditions are treated. The noninvasive thermal ablation method can replace a number of surgical procedures for treating bone metastases and uterine fibroids. Now, researchers are pushing the technique into new realms, with very encouraging results. What does the literature say about where MRgFUS is headed next?

Taming Tremors

With prevalence estimates of up to 5 percent, essential tremor is the most common movement disorder in adults. It can cause embarrassment, early retirement and generally affect quality of life.

Medications can be beneficial for some, but when they are not effective, surgical therapies such as lesioning and deep brain stimulation in the thalamus become an option. With deep brain stimulation, electrodes are implanted into the thalamus or subthalamic region, and lesioning can be done with thalamotomy—both of which have risks. Intracerebral hemorrhage and neurological deficits are a concern.

Enter focused ultrasound, which researchers in Toronto have used in a pilot study to treat essential tremor. And based on the results, it has the potential to totally change the way patients with essential tremor are treated.

As the name suggests, the technique uses stereotactically guided MRI instead of diagnostic ultrasound to obtain accurate target definition, and delivers focused ultrasound to noninvasively produce ablative lesions. MR thermography also can monitor temperatures to better control energy delivery.

Nir Lipsman, MD, of the division of neurosurgery in the Krembil Neuroscience Centre at Toronto Western Hospital, and colleagues conducted the study between May 2012 and January 2013, publishing the findings in Lancet Neurology. While the study was small—four patients with chronic, medication-resistant essential tremor were treated with MRgFUS—the researchers were very encouraged by the findings.

“On the basis of the clinical benefits we observed with this non-invasive procedure, we believe that MR-guided focused ultrasound could represent a substantial advance for the management of disabling tremor,” they wrote.

Patients underwent tremor evaluation at baseline, and then were treated with MRgFUS to ablate tremor-mediating areas of the thalamus. They were reevaluated one and three months after surgery.

Lipsman and colleagues reported that patients showed immediate and sustained improvements in tremor in the dominant hand. Tremor scores were reduced an average of 89.4 percent at one month and 81.3 percent at three months. Results were clearly visible in improved ability to write and perform other motor tasks.

In addition to being effective, the procedure was also safe with an acceptable profile of adverse effects. One patient experienced paraesthesias—sensations of tingling or burning—which persisted at three months. This is not an uncommon side effect of other treatments for essential tremor—nearly four out of five patients treated with deep brain stimulation experience paraesthesias at three months, according to Lipsman and colleagues. Another patient developed a deep vein thrombosis, which the authors suspected was due to the length of the procedure.

“With technological advances in imaging software allowing easier positioning and target localization and with more experience of the treatment team, the procedure time will decrease substantially and the occurrence of adverse effects could decrease,” they wrote.

Lipsman and colleagues noted that the exact mechanism by which sonications alleviate tremor is not known, though it is likely related to the thermal ablation mediating the thalamocortical relay neurons, or “tremor cells.” There is much more to learn, but even at this early stage the authors celebrated the potential of MRgFUS for tremor.

“Our sample size is small, but the results show a large effect on tremor reduction that is remarkably robust and similar between patients,” they wrote.

Opening the Door to Alzheimer’s Relief

Alzheimer’s disease is one of the highest profile neurodegenerative diseases, with societal costs set to soar in the coming decades. More than 14 million Alzheimer’s patients in the U.S. will need treatment by 2050, at a price tag of more than $1.2 trillion.

Fortunately, preliminary research has shown that MRgFUS can play a role in Alzheimer’s treatment by opening the blood-brain barrier and improving drug delivery.

The work was done by Alison Burgess, PhD, of the Sunnybrook Research Institute in Toronto, and colleagues who sought to validate whether repeated treatments with MRgFUS targeted to the hippocampus could modulate abnormalities and behavior in a mouse model. Findings were published in the December 2014 edition of Radiology.

The blood-brain barrier consists of microvessels that prevent large molecules from entering the brain, hampering drug delivery. The theory behind utilizing MRgFUS is that it can be used in conjunction with microbubble contrast agents to open the gates for therapeutic agents. The intravascular microbubbles oscillate under focused ultrasound, widening the junctions in the blood-brain barrier and allowing antiamyloid antibodies to pass.

Seven-month-old transgenic mice and their nontransgenic littermates were treated weekly by Burgess and colleagues. Treatments lasted a total of two minutes, consisting of a series of 10-msec bursts. A maze was used as a memory test one month after treatment.

Untreated mice spent 61 percent less time exploring the novel arm of the testing maze due to spatial memory impairments, according to the researchers. However, the mice treated with MRgFUS performed as well as controls.

The behavioral changes were backed up by imaging results showing a 20 percent reduction in amyloid plaque load in the animals treated with MRgFUS, even those with advanced disease. There was also a remarkable 250 percent increase in the number of newborn neurons among the treated population, and these neurons were supersized at more than triple the dendrite length compared with untreated mice.

Burgess and colleagues noted that they used a high-frequency transducer with a smaller focal volume to more finely target brain substructures.

“MR imaging provides superior image contrast and spatial resolution required to target specific brain structures,” they wrote. “By targeting focused ultrasound to relevant brain regions, the effect of [blood-brain barrier] opening is limited to areas most affected by pathologic abnormalities.”

In an associated editorial, Ferenc A. Jolesz, MD, of the department of radiology at Brigham and Women’s Hospital in Boston, wrote that techniques that open the blood-brain barrier for treatment could “revolutionize neuropharmacology” and change the way we think of providing therapy for central nervous system disorders.

Given that MRgFUS technology is already commercially available and there is a pressing need for a breakthrough in Alzheimer’s, Jolesz called for the findings of Burgess et al to be confirmed in humans as soon as possible.

“The fascinating new results reported here by the investigators raise the hope that a groundbreaking noninvasive image-guided therapy for [Alzheimer’s disease] will soon emerge,” he wrote. “It is time for this dream to be realized. The unique, unconventional therapeutic approach described in this study may be used to not only slow the progress of AD but also might reverse tissue damage already present or even prevent its progression.”