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 Movement Disorders  - Workshop Discussion 

Issues related to Pilot Studies

In considering Parkinson's Disease (PD), Essential Tremor (ET) and dystonia, essential tremor is best suited to initial evaluation using MR guided focused ultrasound surgery (MRgFUS). Deep brain stimulation (DBS) is the best current therapy given its efficacy similar to that of lesioning, but without the same risk of permanent complication. However, stimulators do have associated mechanical malfunction or infection risks that are more significant. The progressive nature of Parkinson's disease also makes essential tremor a more favorable indication for the initial assessment of this technology.  Dystonia patients are not as favorable because they often take a longer time to show symptomatic improvement.

Deep brain stimulation works best in Parkinson's patients who are dopamine responsive.  Ideally, a procedure would be very effective even when the patients are resistant to medical therapy. But the reversibility of DBS is very appealing if the risk of neurologic complication is high from a misplaced lesion.

The main limitations of DBS for movement disorders are cost in both money and time, and the necessity of a neurosurgical operation that entails some risk of hemorrhage, infection, mechanical failure, neurologic damage, etc. One tremendous advantage of FUS is the non-invasive nature of the technique. Any form of lesioning, including FUS, gains significant advantage through targeting techniques that assure a safe, effective lesion location. 

One might consider that Parkinson's disease patients exist along a spectrum from tremor-dominant to akinesia-dominant. Akinesia may be linked to the limbic system, which is not as well understood as the motor system associated with tremor.  Parkinson's disease involves the supplementary motor area and the entire paralimbic frontal system.  Stress can play a major role in the symptoms of the disease.

Patient age can play a role in treatment decision-making.  Reversibility may be more important in younger patients, who will be dealing with the disease for a longer time. In more elderly or infirm patients, DBS is much less attractive. The elderly are not as likely to live long enough to benefit from gene insertion or cellular implantation, techniques that might be options in a decade or so. The simpler lesioning procedure, without all of the time and effort spent in programming a DBS system, might be preferable for them.

The nucleus intermedius (Vim) has been a preferred target for thalamotomy. The best general coverage of symptoms is through the regulatory pallido-thalamic pathways. The subthalamic nucleus of Luys (STN) does not cover the relevant pathways as completely. Stimulation of STN is limited by dyskinesias. Lesioning of pallidal output can be utilized bilaterally, if necessary. The relevant discussion is where to focus treatment, not whether to use lesioning or stimulation.

Placebo effects can play a significant role in pain patients and in those with Parkinson's disease.

Relevant Models

The MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxin model performed in vivo in pigs is a good animal model for Parkinson's Disease, being less politically charged than the non-human primate model. This might be useful for studying more advanced techniques, such as blood brain barrier (BBB) disruption for drug or gene fragment delivery, or arrest of apoptosis.

Some dogs have spontaneous essential tremor.  Various animal models have been tried at the different sites using the Exablate 4000 in the 660 kHz configuration, including dogs, monkeys and pigs.  MR guidance in animal models has been at the Brigham & Women's Hospital and in Paris.


Neuromodulation to Optimize Targeting

The use of focused ultrasound surgery for neuromodulation, specifically for functional mapping and ideal target localization during the FUS procedure before making the permanent lesion, is an exciting prospect. There is much research to be done before this might become routine. If it yields much higher assurance of a lesion being in exactly the right site for maximum effect and minimal complications, it may well enable the optimal treatment to be FUS lesioning, even in the subthalamic nucleus (STN, a current favorite for DBS placement) guided by FUS neuromodulation. 

In addition, FUS may offer the prospect of thermal release of heat shock proteins, manipulation of apoptosis, or transient blood-brain barrier (BBB) opening for drug or gene fragment delivery as a more refined treatment than thermal lesioning alone.

Astrocytes are ten times more sensitive to non-thermal FUS effects than neurons, and mediate spreading depression. FUS can be used to stimulate an action potential (AP). One might even stimulate an AP with FUS, observe some suppression, and then use for lesioning.  There is no refractory period.

Acoustic beam imaging might be used to assess treatment effect, by measuring tissue motion with ultrasound but without using thermal effects.

Feasibility study in Essential Tremor 

The proposed study would involve unilateral MRgFUS treatment. This will be a non-inferiority study against DBS in 20 patients over 12 months.   Sites would include the University of Virginia and the Kindershospital in Zurich, Switzerland, as well as possible contributions from the University of Toronto, the Brigham & Women's Hospital in Boston, the University of California in San Diego, and Sheba Medical Center in Israel.

The feasibility study will measure tremor reduction and complications as end points in patients who are surgical candidates with uni- or bi-lateral tremor.  The worst side will be the one treated in bilateral cases. Evaluation of various pulse stimulations as an intraoperative physiologic localization tool would not be incorporated in this trial, but await evaluation later. Patients should stop anticoagulants for two days before MRgFUS, until there is no evidence of increased risk of hemorrhage.

It is important to determine the level of energy and temperature dosing that will allow for reversibility.  This necessitates a slow, progressive temperature increase. If the patient develops hemiparesis, sonication is discontinued until neurologic function normalizes. If the temperature reaches 45 deg C without any neurological effect, the surgeon decides whether to adjust the target location or discontinue the procedure. Using the 650 kHz ExAblate 4000 system (Insightec, Inc, Haifa, Israel), the surgeon will employ a progressive rise in temperature technique to assess neurological effect in the target region.  Motor ing in the arms and legs is easily accomplished without moving the patient out of the bore of the magnet, which is critical in maintaining sub mm accuracy.  The patient may be moved out of the bore to assess facial motor function if necessary, but this will entail significant time in re-imaging to verify accurate repositioning of the target.

After stimulation has been used to determine the correct site, the surgeon will make a 3-4 mm ablative lesion (~75 uL) in the Vim (nucleus intermedius of the thalamus) using a 10 to 20 sec sonication, with a target maximum temperature of 55 to 59 deg C.  The surgeon has discretion of the exact target location within Vim, and is able to make decisions about relocalization of the target within that region based on stimulation results.  Patients who undergo stimulation and assessment will be included in the study, even if no lesion is actually made.

Outcome measures will include video, accelerometer, and MRI.  These will be obtained at 24-48 hours, 1-2 weeks (clinical assessment without MRI), 3 months and 1 year.

The follow up pivotal trial will compare DBS vs. MRgFUS in the same patient, one technique on each side. Which technique is used on the more affected side will be randomized.  Endpoint will be a validated rating system for tremor.

Outstanding questions for trial design:

  • What is the threshold for reversible change?
  • Can one stimulate with FUS pulse sequences?
  • What is the durability of the clinical result after a FUS lesion for tremor?

Summary: The Way Forward

The next step is to create the clinical protocol for the study of Essential Tremor, primarily by Dr. Jeff Elias at the University of Virginia and Dr. Daniel Jeanmonod at the University of Zurich.  In addition, the Neuromodulation Research Program Planning Group (NM-RPPG), created during the Brain Workshop, will create a research roadmap to plan the specific collaborative research that will enable FDA approval of neurophysiologic techniques to verify target localization during functional neurosurgical procedures.

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