PLAsticity, Security and Tolerance to Intermittent Hypoxic Conditioning Following Stroke

By inducing endogenous neuroprotection, hypoxic post-conditioning following stroke may represent a harmless and efficient non-pharmacological innovative neuro-therapeutic modality aiming at inducing neuroplasticity and brain repair, as supported by many preclinical studies.

The investigators thus hypothesize that hypoxic post-conditioning represents a safe therapeutic strategy post-stroke. The investigators further hypothesize that hypoxic conditioning could enhance neuroplasticity and function in combination with conventional rehabilitative care.

The primary study endpoint will be safety. Safety will be assessed through the clinical review of the adverse events over the duration of the study, every 48 hours by a trained evaluator, blinded for the therapeutic intervention.

The investigators will further investigate the potential functional benefits of such a therapeutic approach on motor function, gait, balance, and cognition. The neurophysiological substrates of hypoxic conditioning-triggered neuroplasticity at a subacute delay post-stroke will also be investigated, based on biological and imagery markers.

Stroke is the second leading cause of death and the third leading cause of disability-adjusted life-years worldwide. If acute stroke therapy has decreased mortality, more than 50% of stroke survivors are left with sensorimotor and cognitive deficiencies. Recovery and rehabilitation treatments, aiming at inducing neuroplasticity, maximizing function in unaffected brain areas or implementing compensatory strategies to improve overall function, benefit from an extensive time window that ranges from days to months. Their development is urgently needed.

Several endogenous neuroprotective mechanisms are spontaneously engaged following stroke to achieve neuroprotection and stimulate brain repairing processes. Conditioning the central nervous system can trigger endogenous mechanisms of neuroprotection. Conditioning refers to a procedure by which a potentially deleterious stimulus is applied near to but below the threshold of damage to the organism. While hypoxia is well recognized as a common underlying mechanism of many pathological conditions, experimental data indicate that exposure to specific doses of hypoxia (by breathing a hypoxic gas mixture) can be neuroprotective.

Preconditioning is defined as the exposure to the conditioning stimulus before injury onset, to induce tolerance or resistance to the subsequent injury. Postconditioning refers to the application of the conditioning stimulus after injury or damage, to stimulate tissue reparation or neuroplasticity. As stroke is an unpredictable event, translating hypoxic preconditioning to clinical practice seems difficult. However, developing postconditioning strategies seems of clinical and rehabilitative relevance. Thus, an increase in neuronal salvage and neurogenesis, along with an increase in brain-derived neurotrophic factor expression and a reduced neuroinflammation were shown in murine models of hypoxic conditioning following ischemic stroke.

By inducing endogenous neuroprotection, hypoxic conditioning may represent a harmless and efficient non-pharmacological innovative neuro-therapeutic modality aiming at inducing neuroplasticity and brain repair, as supported by many preclinical studies.

The main working hypothesis is that hypoxic postconditioning may represent a safe therapeutic strategy post-stroke.

The investigators further hypothesize that hypoxic conditioning could enhance neuroplasticity and function in combination with conventional rehabilitative care.

The primary study endpoint will be safety. Safety will be assessed through the clinical review of the adverse events over the duration of the study, every 48 hours by a trained evaluator, blinded for the therapeutic intervention.

All adverse events will be evaluated and quoted in accordance with National Institute of Health Common Criteria for Terminology for Adverse Events 5.0 (NIH CCTAE) recommendations, particularly with respect to Sub-sections "Cardiac disorders ", "Nervous system disorders" and "Vascular Disorders". Safety assessments will be performed every 48 hours, throughout the 8-week conditioning period, in addition to the conventional clinical follow-up performed in the rehabilitation unit.

The potential functional benefits of such a therapeutic approach on motor function, gait, balance, and cognition will also be further investigated. The neurophysiological substrates of hypoxic conditioning-triggered neuroplasticity at a subacute delay post-stroke will be investigated, based on biological (serum inflammatory markers, growth and neurogenesis biomarkers) and imagery markers (morphological MRI sequences, functional connectivity (resting state), and brain vascularization).

Eligibility Criteria:
Inclusion Criteria:

* Patients with minor cerebral infarction with NIHSS \< or equal to 5 will be included in the protocol;
* Cerebral infarction occurring one month (±1 week) before the planned start of hypoxic exposure;
* Age ≥18 years;
* A first, unilateral, ischemic, supra-tentorial hemispheric stroke, confirmed by magnetic resonance imaging;
* Modified Rankin Scale score between 1 and 3, defining mild to moderate residual functional disability.
* A person affiliated with the social security system or benefits from such a system;
* A person who has given written informed consent.

Exclusion Criteria:

* Patients who are minors or over 85 years of age, pregnant or breastfeeding women, or women of childbearing potential in the absence of highly effective contraception;
* Stroke of the brainstem or cerebellum ;
* Severe aphasia, limiting the ability to understand the protocol;
* History of central or peripheral neurological pathology;
* Modified Rankin Scale score \>0 before stroke;
* Known severe untreated obstructive sleep apnea syndrome, defined as an apnea-hypopnea index ≥ 30 events per hour of sleep;
* Pre-existing hypoxemic lung disease (such as chronic obstructive pulmonary disease);
* Heart failure, defined as an ejection fraction ≤40% ;
* History of high altitude pathology;
* Scheduled stay at altitude (\> 2500 m) during the study period ;
* Migraine;
* History of rheumatological or orthopedic disease of the lower limbs, amputation of the lower limb.
* Contraindication to magnetic resonance imaging;
* Subjects who cannot be contacted in an emergency;
* Subject in exclusion period of another study;
* Subject under administrative or judicial supervision;
* Persons referred to in Articles L1121-5 to L1121-8 of the "Code de la Santé Publique" (corresponds to all protected persons: pregnant women, women in labor, nursing mothers, persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure).