Clinical trials

Inclusion

1. Severe TBI: GCS ≤8 and within 48 hours of injury
2. Age > 16 years (with exception of Quebec where patients will be ≥ 18 years of age)

Exclusion

1. Known Hypersensitivity to FRAGMIN (Dalteparin), or its constituents including benzyl alcohol or to other low molecular weight heparins and/or heparins or pork products
2. Known history of confirmed or suspected immunologically-mediated heparin-induced thrombocytopenia (delayed-onset severe thrombocytopenia), and/or in patients with a known history of a positive in vitro platelet-aggregation test in the presence of FRAGMIN (Dalteparin) is positive
3. Known septic endocarditis
4. Uncontrollable active bleeding
5. Known major blood clotting disorders
6. Known acute gastroduodenal ulcer (with active bleeding)
7. Severe uncontrolled hypertension (i.e. BP>210 despite medications)
8. Known diabetic or hemorrhagic retinopathy
9. Confirmed complete acute spinal cord injury
10. Unable to receive bilateral SCDs due to femur fracture, below-knee injury requiring external fixation device, critical lower leg ischemia
11. Unstable pelvic fracture requiring external or internal fixation
12. Presence of another confounding factor that can adequately explain the poor GCS at time of presentation (e.g. drug toxicity, seizure).
13. Known presence of irreversible coagulopathies
14. Known Pregnancy
15. Participants extremely low weight (<45 kg), or extremely high weight (>120kg)

Inclusion

1. Severe TBI: GCS ≤8 and within 48 hours of injury
2. Age > 16 years (with exception of Quebec where patients will be ≥ 18 years of age)

Exclusion

1. Multi-focal tumor, gliomatosis cerebri (≥3 lobes of the brain affected), tumors crossing the midline, or leptomeningeal enhancement
2. Previous craniotomy for tumor excision (stereotactic biopsy is permitted)
3. Intraoperative histopathological diagnosis not consistent with HGG
4. Known metastatic cancer
5. Uncorrectable coagulopathy
6. Unable to obtain GAD-enhanced brain MRI.

Inclusion

1. Radiographic evidence of a GAD-enhancing intra-axial tumor consistent with HGG
2. Age ≥18- <80 years
3. Karnofsky Performance Score > 60
4. location of tumor in a safe anatomical location
5. Patient or substitute decision maker (SDM) able to understand and consent to study participation.

Exclusion

1. Known Hypersensitivity to FRAGMIN (Dalteparin), or its constituents including benzyl alcohol or to other low molecular weight heparins and/or heparins or pork products
2. Known history of confirmed or suspected immunologically-mediated heparin-induced thrombocytopenia (delayed-onset severe thrombocytopenia), and/or in patients with a known history of a positive in vitro platelet-aggregation test in the presence of FRAGMIN (Dalteparin) is positive
3. Known septic endocarditis
4. Uncontrollable active bleeding
5. Known major blood clotting disorders
6. Known acute gastroduodenal ulcer (with active bleeding)
7. Severe uncontrolled hypertension (i.e. BP>210 despite medications)
8. Known diabetic or hemorrhagic retinopathy
9. Confirmed complete acute spinal cord injury
10. Unable to receive bilateral SCDs due to femur fracture, below-knee injury requiring external fixation device, critical lower leg ischemia
11. Unstable pelvic fracture requiring external or internal fixation
12. Presence of another confounding factor that can adequately explain the poor GCS at time of presentation (e.g. drug toxicity, seizure).
13. Known presence of irreversible coagulopathies
14. Known Pregnancy
15. Participants extremely low weight (<45 kg), or extremely high weight (>120kg)

Inclusion:

1. Men or women between age 35 and 75 years, inclusive.
2. Able and willing to give informed consent.
3. Diagnosis of PD satisfying MDS Clinical Diagnostic Criteria for PD
4. At least 2 years from initial diagnosis
5. Hoehn and Yahr Stage 1-3 on PD medication
6. On stable regiment of PD medications for at least 90 days prior to the study
7. American Society of Anesthesiologists (ASA) score 1-3
8. Able to communicate during the ExAblate MRgFUS procedure.
9. Able to attend all study visits (i.e., life expectancy of at least 3 months).

Exclusion:

1. Previous neurosurgical procedure for PD
2. Parkinsonism plus symptoms, secondary parkinsonism
3. Mini-mental status exam (MMSE) < 25 at screening visit
4. Contraindication to GCase enzyme therapy, specifically previous hypersensitivity reaction to GCase enzyme therapy
5. Patients presenting with the following imaging characteristics:
   1. Brain edema and/or mass effect that causes midline shift or shift in wall of the third (3rd) ventricle of more than 10 mm.
   2. Evidence of recent intracranial hemorrhage.
   3. Containing calcifications in the focused ultrasound sonication beam path in the event system tools cannot tailor the treatment around these calcification spots.
6. The sonication pathway to the putamen involves:
   1. 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.
   2. Clips or other metallic implanted objects in the skull or the brain, except shunts.
7. Patient at increased risk of bleeding, including the following reasons:
   1. Anti-coagulant therapy, or medications known to increase risk of hemorrhage within washout period prior to treatment (i.e., antiplatelet or vitamin K inhibitor anticoagulants within 7 days, non-vitamin K inhibitor anticoagulants within 72 hours, or heparin-derived compounds within 48 hours of treatment).
   2. History of a bleeding disorder, coagulopathy or with a history of spontaneous tumour hemorrhage.
   3. Abnormal level of platelets (< 100,000) or INR > 1.3.
8. Patient receiving bevacizumab (Avastin) therapy.
9. Currently participating in another clinical therapeutic trial
10. Cardiac disease or unstable hemodynamics including:
    1. Documented myocardial infarction within six months of enrollment.
    2. Unstable angina on medication.
    3. Congestive heart failure.
    4. Left ventricular ejection fraction <50%.
    5. History of a hemodynamically unstable cardiac arrhythmia.
    6. Cardiac pacemaker.
11. Severe hypertension (diastolic BP > 100 on medication).
12. Documented cerebral infarction within the past 12 months or TIA in the past 1 month.
13. Cerebral or systemic vasculopathy.
14. Insulin-dependent diabetes mellitus that is not well-controlled or that in the Investigator’s opinion precludes participation in the study.
15. Known sensitivity to gadolinium-DTPA.
16. Known sensitivity to DEFINITY ultrasound contrast agent or perflutren.
17. Contraindications to MRI such as non-MRI-compatible implanted devices.
18. Large subjects not fitting comfortably into the MRI scanner.
19. Difficulty lying supine and still for up to 4 hours in the MRI unit or claustrophobia.
20. Untreated, uncontrolled sleep apnea.
21. Positive pregnancy test (for pre-menopausal women).
22. Known life-threatening systemic disease.
23. Severely impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2 and/or on dialysis.
24. Right to left or bi-directional cardiac shunt.
25. Subjects with evidence of cranial or systemic infection.
26. Subjects with uncontrolled chronic pulmonary disorders.
27. Subjects with a history of severe asthma, hay fever, or multiple allergies that is not well-controlled (e.g. with anaphylaxis) or that in the Investigator’s opinion precludes participation in the study.
28. Subjects with a family or personal history of QT prolongation or taking concomitant medications known to cause QTc prolongation, or QT prolongation observed on screening ECG (QTc > 450 for men and >470 for women).
29. Liver injury as indicated by liver function tests (AST>37 U/L; ALT >31 U/L).

Inclusion:

1. Men or women between 18 and 80 years, inclusive
2. Able and willing to give informed consent
3. Metastatic Her2-positive breast cancer with brain metastases of any size at least fourweeks following standard of care chemo-radiation.
4. Brain metastases are clearly defined on pre-therapy contrast enhanced MRI scans
5. Standard treatment with radiation and/or surgery is allowed after the first week evaluation
6. At least 14 days passed since last brain surgery
7. At least 6 weeks passed since last radiation treatment
8. Any previous systemic treatments are allowed, but a time interval of 1-3 weeks should have passed since the last systemic treatment

Exclusion:

1. Brain metastases not visible on the pre-therapy imaging
2. Following steroid treatment, brain edema and/or mass effect that causes midline shift or shift in wall of the third (3rd) ventricle of more than 10 mm
3. Recent intracranial hemorrhage
4. Cardiac disease or unstable hemodynamics including myocardial infarction within last six months, unstable angina, congestive heart failure, right-to-left, bidirectional, or transient right-to-left cardiac shunts, history of a hemodynamically unstable cardiac arrhythmia, cardiac pacemaker
5. Abnormal level of platelets (< 100000) or INR > 1.3
6. Cerebral infarction within the past 12 months or TIA in the last 1 month
7. Cerebral or systemic vasculopathy
8. Contraindications to MRI such as non-MRI-compatible implanted devices, clips or other metallic implanted objects in the skull or the brain (except shunts), or large subjects not fitting comfortably into the MRI scanner (>250 lbs.), Impaired renal function with GFR <30 mL/min/1.73m2 and/or on dialysis
9. Chronic pulmonary disorders

Inclusion:

1. Men and women ≥20 and ≤80 years of age.
2. Patients who are able and willing to give consent and physically and practically able to attend study visits, as determined by both study Psychiatrist and the surgeon.
3. DSM-V diagnosis of major depressive episode, as a component of an Axis I disorder, such as Major Depressive Disorder, Bipolar Disorder, Anxiety Disorder, Eating Disorder, Substance Abuse/Dependence Disorder ,or Personality Disorder
4. At least 5-year illness history of the primary disorder and at least 6 months since the onset of the first episode of major depression.
5. A minimum score of 20 on the Hamilton Depression Rating Scale (HAMD) when depressed (patients with bipolar disorder may be rapid cycling, but have to have at least 2 weeks of major depression at the time the HAMD is conducted)
6. Medication-refractoriness as determined by an adequate dose and duration of standard psychiatric treatments (including psychotherapy and/or pharmacology) as determined by two psychiatrists associated with the study. Including specifically:
   1. Failed to respond or tolerate adequate trial of three or more medications accepted as first line in the treatment of depression
   2. Failed to respond or tolerate augmentation with or combination of at least 2 medications known to be first line treatments for depression
   3. An adequate trial of cognitive behavioural therapy or other evidence-supported psychotherapy, delivered by a therapist experienced in treating depression
7. Able to communicate sensations during the ExAblateMRgFUS treatment
8. A consistent dose of any and all medications in the 30 days prior to study entry.
9. Women of childbearing potential must agree to use a contraception method throughout the study.

Exclusion:

1. Patients with unstable cardiac status [e.g. Unstable angina pectoris on medication, Patients with documented myocardial infarction within six months, Congestive heart failure requiring medication (other than diuretic), Patients on anti-arrhythmic drugs, Severe hypertension (diastolic BP > 100 on medication)]
2. Patients with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc.
3. Severely impaired renal function (estimated glomerular filtration rate < 30ml/min/1.73 m2) or receiving dialysis
4. Laboratory biochemical evidence ofabnormalbleedingand/or coagulopathy, including risk factors for intraoperative or postoperative bleeding (platelet count less than 100,000 per cubic millimeter or abnormal INR)
5. Cerebrovascular disease (e.g. CVA within 6 months) or history of intracranial hemorrhage
6. Untreated, uncontrolled sleep apnea
7. Receiving anticoagulant (e.g. warfarin) or antiplatelet (e.g. aspirin) therapy within one week of focused ultrasound procedure or drugs known to increase risk or hemorrhage (e.g. Avastin) within one month of focused ultrasound procedure
8. Individuals who are not able or willing to tolerate the required prolonged stationary supine position during treatment
9. Are participating or have participated in another clinical trial in the last 30 days
10. Patients unable to communicate with the investigator and staff.
11. Presence of significant cognitive impairment.
12. Presence of psychosis on clinical evaluation.
13. Patients with brain tumors already known or revealed on pretreatment MRI
14. Currently pregnant (as determined by history and serum HCG) or lactating.

Inclusion:

1. Men and women ≥20 and ≤80 years of age, inclusive.
2. Patients who are able and willing to give consent and able to attend study visits, as determined by both study Psychiatrist and the surgeon.
3. DSM-V diagnosis of Obsessive Compulsive Disorder (OCD), at least 5-year illness history with a minimum score of 28 on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
4. Medication-refractoriness as determined by an adequate dose and duration of standard psychiatric treatments (including psychotherapy and/or pharmacology) as determined by two psychiatrists associated with the study. Including specifically:
   1. Failed adequate trial of three or more medications accepted as first line in the treatment of OCD
   2. Attempted augmentation, if tolerated, by at least 2 medications known to be first line treatments for OCD
   3. An adequate trial of cognitive behavioural therapy, delivered by a therapist experienced in treating OCD
5. Able to communicate sensations during the ExAblateMRgFUS treatment
6. A consistent dose of all medications in the 30 days prior to study entry.

Exclusion:

1. Patients with unstable cardiac status [e.g. Unstable angina pectoris on medication, Patients with documented myocardial infarction within six months, Congestive heart failure requiring medication (other than diuretic), Patients on anti-arrhythmic drugs, Severe hypertension (diastolic BP > 100 on medication)]
2. Patients with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc.
3. Known intolerance or allergies to MRI contrast agent (e.g. Gadolinium or Magnevist) including advanced kidney disease
4. Severely impaired renal function (estimated glomerular filtration rate < 30ml/min/1.73 m2) or receiving dialysis
5. Laboratory biochemical evidence ofabnormalbleedingand/or coagulopathy, including risk factors for intraoperative or postoperative bleeding (platelet count less than 100,000 per cubic millimeter or abnormal INR)
6. Cerebrovascular disease (e.g. CVA within 6 months) or history of intracranial hemorrhage
7. Untreated, uncontrolled sleep apnea
8. Receiving anticoagulant (e.g. warfarin) or antiplatelet (e.g. aspirin) therapy within one week of focused ultrasound procedure or drugs known to increase risk or hemorrhage (e.g. Avastin) within one month of focused ultrasound procedure
9. Individuals who are not able or willing to tolerate the required prolonged stationary supine position during treatment
10. Are participating or have participated in another clinical trial in the last 30 days
11. Patients unable to communicate with the investigator and staff.
12. Presence of significant cognitive impairment
13. Presence of psychosis on clinical evaluation.
14. Patients with brain tumors already known or revealed on pretreatment MRI
15. Currently pregnant (as determined by history and serum HCG) or lactating.
16. Chemical abuse or dependence within the previous six months

Inclusion:

1. Female or Male patients between age 18-70
2. DSM-V diagnosis of Obsessive Compulsive Disorder (OCD), at least 5-year illness history with a minimum score of 24 on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
3. SF-36 <40
4. Medication-refractoriness as determined by an adequate dose and duration of psychiatric treatments (including psychotherapy and/or pharmacology) as determined by two psychiatrists associated with the study. Including specifically:
   1. Failed adequate trial of two or more medications accepted as first line in the treatment of OCD
   2. Attempted augmentation, if tolerated, by at least 1 medications known to be first line treatments for OCD
5. An adequate trial of cognitive behavioural therapy
6. Ability to provide informed consent and comply with all testing, follow-ups and study appointments and protocols

Exclusion:

1. Any past or current evidence of psychosis or mania (patients with co-morbid depression will not be excluded from the study)
2. Active neurologic disease, such as epilepsy
3. Alcohol or substance dependence or abuse in the last 6 months, excluding caffeine and nicotine
4. Current suicidal ideation
5. Any contraindication to MRI scanning
6. No contraindication for DBS surgery
7. Presence of significant cognitive impairment
8. Likely to relocate or move out of the country during the study’s duration
9. Presence of clinical and/or neurological conditions that may significantly increase the risk of the surgical procedure.
10. Currently pregnant (as determined by history and serum HCG) or lactating; for females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation

Inclusion:

1. Female or Male patients between age 18-70
2. Diagnosis of alcohol use disorder (AUD) as defined by the Diagnostic and Statistical Manual fifth edition (DSM-5).
3. History of AUD for at least 2 years, with evidence of repeated failure to respond to evidence-based AUD treatments (psychosocial treatments plus pharmacotherapies such as disulfiram, naltrexone and acamprosate).
4. Alcohol Use Disorders Identification Test (AUDIT) Scale Score >8
5. Ability to provide informed consent and comply with all testing, follow-ups and study appointments and protocols

Exclusion:

1. Any past or current evidence of psychosis or mania
2. Current suicidal or homicidal ideation
3. Active neurologic disease, such as epilepsy (patients will not be excluded for a history of withdrawal seizures)
4. Visible brain damage or atrophy in CT or MRI scan
5. Any contraindication to MRI or PET scanning
6. Likely to relocate or move during the study’s one year duration
7. Presence of clinical and/or neurological conditions that may significantly increase the risk of the surgical procedure.
8. Patients with renal dysfunction (GFR<60)
9. Pregnancy

Inclusion:

1. Men and women ≥20 and ≤80 years of age.
2. Patients who are able and willing to give consent and physically and practically able to attend study visits, as determined by both study Psychiatrist and the surgeon.
3. DSM-V diagnosis of major depressive disorder or bipolar II,
4. At least 5-year illness history of the primary disorder and at least 6 months since the onset of the first episode of major depression.
5. 5A minimum score of 20 on the Hamilton Depression Rating Scale (HAMD) when depressed)
6. Medication-refractoriness as determined by an adequate dose and duration of standard psychiatric treatments (including psychotherapy and/or pharmacology) as determined by two psychiatrists associated with the study. Including specifically:
   1. Failed to respond or tolerate adequate trial of three or more medications accepted as first line in the treatment of depression
   2. Failed to respond or tolerate augmentation with or combination of at least 2 medications known to be first line treatments for depression
   3. An adequate trial of cognitive behavioural therapy or other evidence-supported psychotherapy, delivered by a therapist experienced in treating depression
7. A consistent dose of any and all medications in the 30 days prior to study entry.
8. Women of childbearing potential must agree to use a contraception method throughout the study.

Exclusion:

1. Past or current evidence of psychosis or mania
2. Active neurologic disease, such as epilepsy
3. Alcohol or substance dependence or abuse in the last 6 months, excluding caffeine and nicotine
4. Current active suicidal ideation
5. Any contraindication to MRI scanning
6. Presence of significant cognitive impairment
7. Likely to relocate or move out of the country during the study’s duration
8. Presence of clinical and/or neurological conditions that may significantly increase the risk of the surgical procedure.
9. Currently pregnant (as determined by history and serum HCG) or lactating; for females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation

Inclusion:

1. Female or Male patients between age 18-70
2. Diagnosis of posttraumatic stress disorder as defined by the Diagnostic and Statistical Manual fifth edition (DSM V).
3. Treatment Resistance as defined by the persistence of clinical symptoms despite adequate treatment with four modalities, including a) selective serotonin reuptake inhibitors, b) cognitive behavioral therapy, c) other classes of medications and/or psychotherapy.
4. Severe forms of the disease as measured by Clinician Administered PTSD scale (CAPS) scores ≥ 50.
5. A pattern of chronic stable PTSD lasting at least 1 year.
6. Ability to provide informed consent and comply with all testing, follow-ups and study appointments and protocols

Exclusion:

1. Any past or current evidence of psychosis or mania (patients with co-morbid depression will not be excluded from the study)
2. Active neurologic disease, such as epilepsy
3. Alcohol or substance dependence or abuse in the last 6 months, excluding caffeine and nicotine
4. Current suicidal ideation
5. Any contraindication to MRI or PET scanning
6. Likely to relocate or move out of the country during the study’s one year duration
7. Presence of clinical and/or neurological conditions that may significantly increase the risk of the surgical procedure.
8. Currently pregnant (as determined by history and serum HCG) or lactating; for females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation