CLOTBUST Hands-Free: A Phase I/II Pilot Safety Trial

INCLUSION CRITERIA: Phase I Safety (healthy volunteers): * Presence of temporal windows as measured first by an FDA-approved diagnostic TCD device. * Age ≥ 18 years old. * Signed informed consent. Phase II (0-3 hours ischemic stroke patients): * Disabling focal neurological deficit (NIHSS \> 4 points); * No evidence of hemorrhage on non-contrast head CT scan; * Intravenous rt-PA (0.9 mg/kg, 10% bolus 90% infusion over 1 hour, maximum dose 90 mg) infusion initiated within 3 hours of symptom onset; * Diagnostic TCD completed and HF-TCD placed before rt-PA bolus. * Diagnostic TCD confirms intracranial arterial occlusion of the middle cerebral artery (MCA), anterior cerebral artery (ACA), internal carotid artery (ICA), posterior cerebral artery (PCA) or distal basilar artery. * Age ≥ 18 years old. * Signed informed consent. Phase II (3-6 hours ischemic stroke patients): * Measurable focal neurological deficit (NIHSS \> 4 points); * No evidence of hemorrhage on non-contrast head CT scan; * Diagnostic TCD confirms intracranial arterial occlusion of the middle cerebral artery (MCA), anterior cerebral artery (ACA), internal carotid artery (ICA), posterior cerebral artery (PCA) or distal basilar artery. * Presence of neuroimaging defined mismatch (CT or MRI prior to enrollment) 1. CT-perfusion * ≥ 20% difference between affected territories on Time to Peak (TTP) and Cerebral Blood Volume (CBV) maps. 2. MRI Diffusion-Perfusion mismatch * ≥ 20% difference between diffusion-weighted imaging (DWI) lesion and territory of perfusion delay perfusion weighted imaging (PWI). * Age ≥ 18 years old. * Signed informed consent. EXCLUSION CRITERIA: Phase I Safety (healthy volunteers): * History of any neurological disease affecting the central nervous system; * Lack of temporal windows. * History of renal disease or glomerular filtration rate (GFR) \< 60. * Contraindication to MRI (e.g., pacemaker, spinal cord stimulator, severe claustrophobia) Phase II (0-3 hours ischemic stroke patients): * Absent temporal windows in patients with anterior circulation ischemia; * Intra-arterial thrombolysis; * Patient refusal to give informed consent to participate in the CLOTBUST-HF trial; * Contraindications for intravenous rt-PA (NINDS rt-PA Stroke Study Protocol)2. * Phase II (3-6 hours ischemic stroke patients): * Absent temporal windows in patients with anterior circulation ischemia; * Intra-arterial thrombolysis; * Patient refusal to give informed consent to participate in the CLOTBUST-HF trial; * History of allergic response to Definity® microspheres or microbubbles currently being tested (MRX-801); * Baseline imaging consistent with a malignant ischemic pattern (low CBV values or DWI territory \>100cc of tissue); * Baseline MRI imaging demonstrating delayed perfusion of \> 8 seconds in \>100cc of brain parenchyma26; * Patients receiving other investigational drugs, procedures, or therapies within 30 days prior to study treatment; * Significant concurrent medical/neurological conditions or deviation from normal laboratory test values at baseline that, in the opinion of the investigator, pose significant risk to the patient and warrant exclusion from the study; * Known severe chronic obstructive pulmonary disease (COPD) (baseline oxygen saturation \< 80% on room air); * Known right-to-left cardiac shunt.