A Prospective, Randomized, Controlled Trial to Test Safety and Effectiveness of Unilateral Exablate MR-guided Focused Ultrasound Subthalamotomy in Patients With Early-Stage Parkinson's Disease

Inclusion Criteria:

• Men and women; age 30 to 65 years old

• Subjects who are able and willing to give consent and able to attend all studyvisits. - Subjects with a diagnosis of PD according to the modified clinicalcriteria by the Movement Disorders Society, for less than 5 years and more than 12months.

• Off-medication MDS-UPDRS part III of the most affected body side ≥ 10

• Motor signs predominantly present in one body side: Asymmetry index (MDS-UPDRS IIIof the most affected side/MDS-UPDRS III of the least effected side) ≥ 2.

• Patients should have a stable pharmacological regime for the last 4-weeks prior tobaseline evaluation.

• Topographic coordinates of the subthalamic nucleus are localizable on MRI so that itcan be targeted by the Exablate device.

• Skull density ratio (SDR) score of 0.40 or higher*. The SDR is a determinant factorfor the suitability to MRgFUS ablation. SDR is a ratio of ultrasound energypenetration through the skull. The SDR threshold for using Exablate 4000 isestablished at 0.4 with patients having SDR below that value considered unsuitablecandidates.

• Able to communicate sensations during the Exablate MRgFUS treatment.

Exclusion Criteria:

• MDS-UPDRS part III OFF medications > 32 in the off state and/or Hoehn and Yahr stateON medication greater than 2.

• Significative evidence (by clinical history) of having developed features indicativeof PD motor onset 2 or more years prior to formal diagnosis.

• Presence of clinically relevant levodopa-induced dyskinesia and/or motorfluctuations as noted by a score > 1 on questions 4.2 or 4.4 of the MDS-UPDRS, thatassess disability resulting from motor complications.

• Levodopa daily dose higher than 500mg or 750 levodopa-equivalents daily.

• Presence of any symptoms or signs suggesting other central neurodegenerative diseasesuch as multisystem atrophy, progressive supranuclear palsy, cortico-basal syndrome,dementia with Lewy bodies, and Alzheimer's disease.

• Any suspicion that parkinsonian symptoms are a side effect attributable to intake ofneuroleptic or other medications.

• Subjects who have had deep brain stimulation or a prior stereotactic ablation forthe treatment of movement disorders.

• Presence of significant cognitive impairment measured by standard of care method atthe center.

• Patients with clinically relevant co-morbidity such as severe hypertension,diabetes, cardiac, metabolic, and psychiatric conditions

• Other exclusion criteria for the Exablate system.

• Subjects with significant depression as determined following a comprehensiveassessment by a neuropsychologist. Significant depression is being definedquantitatively as a score of greater than 14 on the Beck Depression Inventory.

• Legal incapacity or limited legal capacity as determined by the neuropsychologist.

• Subjects exhibiting any behavior(s) consistent with ethanol or substance abuse asdefined by the criteria outlined in the DSM-IV as manifested by one (or more) of thefollowing occurring within the preceding 12-month period:

• Recurrent substance use resulting in a failure to fulfill major roleobligations at work, school, or home (such as repeated absences or poor workperformance related to substance use; substance-related absences, suspensions,or expulsions from school; or neglect of children or household).

• Recurrent substance use in situations in which it is physically hazardous (suchas driving an automobile or operating a machine when impaired by substanceuse).

• Recurrent substance-related legal problems (such as arrests for substancerelated disorderly conduct).

• Continued substance use despite having persistent or recurrent social orinterpersonal problems caused or exacerbated by the effects of the substance (for example, arguments with spouse about consequences of intoxication andphysical fights).

• Subjects with unstable cardiac status including:

• Unstable angina pectoris on medication

• Subjects with documented myocardial infarction within six months of protocolentry

• Significant congestive heart failure defined with ejection fraction <40.

• Subjects with unstable ventricular arrhythmias

• Subjects with atrial arrhythmias that are not rate controlled.

• Severe hypertension (diastolic BP >100 on medication).

• History of or current medical condition resulting in abnormal bleeding and/orcoagulopathy.

• Receiving anticoagulant (e.g., warfarin) or antiplatelet (e.g., aspirin) therapywithin one week of focused ultrasound procedure or drugs known to increase risk orhemorrhage (e.g., Avastin) within one month of focused ultrasound procedure.

• Subjects with risk factors for intraoperative or postoperative bleeding as indicatedby: platelet count less than 100,000 per cubic millimeter, a documented clinicalcoagulopathy, or INR coagulation studies exceeding the institution's laboratorystandard.

• Patient with severely impaired renal function with estimated glomerular filtrationrate <30mL/min/1.73m2 (or per local standards should that be more restrictive)and/or who is on dialysis.

• Subjects with standard contraindications for MR imaging such as non-MRI compatibleimplanted metallic devices including cardiac pacemakers, size limitations, etc.

• Significant claustrophobia that cannot be managed with mild medication.

• Subject who weighs more than the upper weight limit of the MR table and who cannotfit into the MR scanner.

• Subjects who are not able or willing to tolerate the required prolonged stationarysupine position during treatment.

• History of intracranial hemorrhage.

• History of multiple strokes, or a stroke within past 6 months.

• Subjects with a history of seizures within the past year.

• Subjects with malignant brain tumors.

• Subjects with intracranial aneurysms requiring treatment or arterial venousmalformations (AVMs) requiring treatment.

• Any illness that in the investigator's opinion preclude participation in this study.

• Subjects unable to communicate with the investigator and staff.

• Pregnancy or lactation.

• Patients without clinically relevant parkinsonism in the off- state as evaluated bytwo examining neurologists (or MDS- UPDRS III in the most affected side <10).