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Previous studies in animals and humans has shown that brief periods of reduced blood flow to one organ or tissue in the body can help protect other tissues from subsequent injury caused by reduced blood flow such as a stroke. This phenomenon is known as remote ischemic preconditioning and may help protect brain cells after a stroke. The investigators are studying a specific stroke type called subcortical stroke that is very common and has a high rate of recurrent stroke and cognition problems despite intensive prevention measures.

In this study, the investigators will enroll 60 patients. All patients will receive best standard medical therapy for 2 years. In addition, the investigators will randomly assign 40 patients to undergo daily active remote ischemic preconditioning for 1 year, and 20 patients to 1 year of standard medical therapy followed by 1 year of daily active remote ischemic preconditioning. Patient structured interviews will be performed to assess if the treatment is well tolerated and easy for stroke patients to use. Magnetic resonance (MR) pictures of the brain will be used to determine if the active treatment stops the progression of brain injury. Cognitive tests and wireless sensor technology measures will used to learn what happens to the patient's brain and body during the active treatment.

After a subject consents to participate in the study, he/she will first participate in a study screening phase to ensure a basic level of tolerability of Remote Ischemic Conditioning (autoRIC™) device. The subject will undergo one full cycle of treatment under observation of the study team, including 4 cycles of alternating 5 minute inflation and 5 minute off periods

If the subject indicates willingness to continue receiving such treatment (screening success), she/she will enter the randomized trial phase, and be randomly allocated to the treatment or control group.

If subject indicates unwillingness to continue receiving such treatment (screening failure), he/she will not advance to the randomized phase of the trial. Screen failure subjects will be followed up with a 3-day post-device screening phone call to ensure safety and obtain information regarding any adverse events.

Inclusion Criteria:

I. Clinical

1. Clinical lacunar stroke syndrome within the past 6 months
2. Absence of signs or symptoms of cortical dysfunction
3. No proximal large vessel atherosclerosis, intracranial atherosclerosis or cerebellar stroke.
4. No major cardioembolic source requiring anticoagulation or other specific therapy

II. Imaging

1. Magnetic Resonance Imaging (MRI) presence of a small subcortical ischemic, any 1 or more of:

   1. Diffusion-weighted imaging (DWI) lesion < 2.0cm in size at largest dimension and corresponding to the clinical syndrome.
   2. Well delineated focal hyperintensity <2.0 cm in size at largest dimension (including rostro-caudal extent) on FLAIR or T2 and clearly corresponding to the clinical syndrome. If other focal hyperintensities are present, the case will be discussed with the principal investigator prior to randomization
   3. Multiple (at least 2) hypointense lesions of size 0.3-1.5 cm at largest dimension (including rostro-caudal extent) only in the cerebral hemispheres on FLAIR or T1 in patients whose qualifying event is clinically hemispheric
   4. Well delinated hypointense lesion <1.5 cm in size at the largest dimension (including rostro-caudal extent) on FLAIR or T1 corresponding to the clinical syndrome. MRI must be done at least 1 months after the qualifying stroke

2. Absence of cortical stroke and large (> 1.5cm) subcortical stroke, recent or remote

3. White matter hyperintensity score of 2 (moderate) or 3 (severe) on the European Scale of Age-Related White Matter Change

4. Absence of cerebral amyloid antipathy (CAA) as per Boston Criteria.

Exclusion Criteria:

1. Disabling stroke (Rankin Scale ≥4)
2. Previous intracranial hemorrhage (excluding traumatic) or hemorrhagic stroke
3. Age under 40 years
4. High risk of bleeding (e.g. recurrent GI or GU bleeding, active peptic ulcer disease, etc.)
5. Anticipated requirement for long term use of anticoagulants (e.g. recurrent deep venous thrombosis (DVT)
6. Prior cortical or retinal stroke (diagnosed either clinically or by neuroimaging), or other prior cortical or retinal transient ischemic attack (TIA)
7. Prior ipsilateral carotid endarterectomy
8. Impaired renal function: estimated GFR <40
9. Intolerance or contraindications to aspirin or clopidogrel (including thrombocytopenia, prolonged INR)
10. Mini Mental Status Exam score < 24 (adjusted for age and education)
11. Medical contraindication to MRI
12. Pregnancy or women of child-bearing age who are not following an effective method of contraception
13. Pre-existing neurologic, psychiatric, or advanced systemic disease that would confound the neurological or functional outcome evaluations
14. SBP <90 or > 200
15. Known history of limb vascular disease, limb vascular bypass surgery, or limb deep venous thrombosis
16. Prisoners
17. Homeless individuals
18. Patient unable to give informed consent and no available legally authorized representative to provide informed consent
19. Patient unlikely to be compliant with therapy/ unwilling to return for follow up visits
20. Concurrent participation in another study with investigational drug or device treatment
21. Other likely specific cause of stroke (e.g. dissection, vasculitis, prothrombotic diathesis, drug abuse)

12 months

We faced recruitment challenges over the course of the study. Many patients declined enrollment due to the 12-month time commitment of the study. We faced tolerability and compliance concerns with the few patients enrolled in the study. Despite our efforts, early termination of the trial led to small numbers of subjects analyzed.