The purpose of this study is to evaluate the safety, tolerability, and feasibility of Blood-Brain Barrier (BBB) opening using transcranial MRI-guided focused ultrasound in conjunction with an intravenous ultrasound contrast agent in patients with Amyotrophic Lateral Sclerosis (ALS).

Inclusion Criteria:

1. Diagnosed with laboratory supported probable, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria (Brooks et al. 2000).
2. Right-hand dominant male or female aged 18 years or older.
3. Capable of providing informed consent and complying with study procedures, including tolerability in the supine position and MRI examination without significant claustrophobia.
4. If taking riluzole, on a stable dose for at least 30 days prior to Screening Visit.
5. Slow Vital Capacity equal to or more than 50% predicted value for gender, height and age in the 30 days prior to the Screening Visit and able to lie supine without BiPAP.
6. Severe left arm weakness and functional impairment, defined as Medical Research Council muscle strength score equals 3 or less in the index finger abduction and thumb abduction on the left side; OR severe left leg weakness and functional impairment, defined as Medical Research Council muscle strength score equals 3 or less at the hip flexors and ankle dorsiflexors on the left side.
7. Able to communicate during the ExAblate® MRI-guided FUS procedure.

Exclusion Criteria:

1. Unable to complete high-density CT and MRI studies of the head at the Screening Visit or any other MRI contraindication, such as:

   • Large body habitus and not fitting comfortably into the scanner
   • Difficulty lying supine and still for up to 3 hours in the MRI unit or significant claustrophobia

2. MRI findings:

   • Active infection/inflammation
   • Acute or chronic brain hemorrhages, specifically lobar or subcortical microbleeds, siderosis or macrohemorrhages
   • Tumor/space occupying lesion
   • Meningeal enhancement

3. More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp.

4. Clips or other metallic implanted objects in the skull or the brain, except shunts.

5. Significant cardiac disease or unstable hemodynamic status including:

   • Documented myocardial infarction within six months of enrollment
   • Unstable angina on medication
   • Unstable or worsening congestive heart failure
   • Left ventricular ejection fraction below the lower limit of normal
   • History of a hemodynamically unstable cardiac arrhythmia
   • Cardiac or phrenic pacemaker
   • Known right-to-left, bidirectional, or transient right-to-left cardiac shunt
   • Patients with relative contraindications to perflutren including subjects with a family or personal history of QT prolongation or taking concomitant medications known to cause QTc prolongation,
   • QT prolongation observed on screening ECG (QTc > 450 for men and >470 for women)

6. Uncontrolled hypertension (systolic > 150 or diastolic BP > 100 on medication).

7. On medications that increase the bleeding risk, specifically: a) aspirin or another antiplatelet medication (clopidogrel, prasugrel, ticlopidine, abciximab) for the last 7 days prior to treatment; b) oral, subcutaneous or intravenous anticoagulant medications, such as oral vitamin K inhibitors for the last 7 days, non-vitamin K inhibitor oral anticoagulant (dabigatran, apixaban, rivaroxaban) for the last 72 hours, and intravenous or subcutaneous heparin-derived compounds for the last 48 hours.

8. History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage.

9. Known frontotemporal dementia.

10. Abnormal coagulation profile, specifically: platelet <100,000/μl, Prothrombin Time >14 seconds, activated partial thromboplastin time (aPTT) >36 seconds, and INR > 1.3.

11. Known cerebral or systemic vasculopathy, specifically cerebral amyloid angiopathy or systemic or central nervous system vasculitis.

12. Known auto-immune condition with or without neurological manifestations (e.g., multiple sclerosis (MS), systemic lupus erythematous (SLE), Rheumatoid arthritis).

13. Current or planned use of oral, intramuscular or intravenous steroid drugs (such as prednisone, prednisolone, dexamethasone, triamcinolone, methylprednisolone, oxandrolone, and others) or immunosuppressant drugs (azathioprine, mycophenolate, tacrolimus, sirolimus, cyclophosphamide, and others) for more than 7 days.

14. Known sensitivity/allergy to gadolinium (an alternative product may be used), DEFINITY® contrast or any of its components.

15. Untreated, uncontrolled sleep apnea.

16. Impaired renal function with cystatin C-based estimated glomerular filtration rate <30 mL/min/1.73m2 and acute renal injury.

17. Currently in a clinical trial involving an investigational product or non-approved use of a drug or device.

18. Known respiratory diseases, specifically: chronic pulmonary disorders e.g., severe/uncontrolled COPD, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, asthma or hay fever.

19. Patients with a history of drug allergies or multiple allergies where the benefit/risk of administering DEFINITY® is considered unfavorable by the study physicians in relation to the product monograph for DEFINITY®.

20. Unqualified fit for the anesthesia by an anesthesiologist assessment, ASA I-III.