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Neuroprotective effects of neuromodulation in acute stroke


Stroke is a leading cause of death and disability worldwide resulting in an enormous social and economic burden in developed as well as in developing countries. Ischemic stroke accounts for up to 80% of the cases. In the acute phase, in the ischemic brain there is typically a central area ("core") characterized by very low perfusion that undergoes necrotic cell death. The core is surrounded by a dysfunctional ischemic region that can be potentially salvaged if blood flow is restored, the "penumbra". Plastic processes that lead to recovery depend on viable brain tissue and hence, on preservation of the penumbra. If blood flow is not restored after several hours from onset of ischemia, the penumbra may progress to ischemic core and become permanently dysfunctional. Since 1995, intravenous thrombolysis has been an approved treatment for acute stroke. Thrombolysis leads to dissolution of thrombi and recanalization, but can only be administered up to 4.5 hours from onset of symptoms. This narrow therapeutic window limits the impact of this treatment, since most patients arrive at emergency departments at a later stage. Within the past few years, mechanical thrombectomy has become established as a state-of-the-art treatment for patients with proximal arterial occlusions in the anterior circulation territory. Raul Nogueira, the Principal Investigator (PI) of this proposal from Emory University, was co-PI in the DAWN trial, a landmark study that showed benefits of thrombectomy from 6 up to 24 hours after onset of symptoms in selected patients. Despite great progress in the field of reperfusion in acute stroke, there remains a great unmet need of further improving patients' outcomes. Only 46% of the treated patients become functionally independent at 90 days post-stroke, and only 10%, neurologically normal. In the DAWN study, the rate of functional independence at 90 days was 49%. Therefore, more than half of the patients with occlusion of large arteries in the anterior circulation become permanently disabled, despite recanalization therapies. The mechanisms underlying these results may involve blood-brain barrier damage, oxidative stress, lack of reperfusion within the microcirculation and irreversible neuronal loss. Considering this scenario, the association of neuroprotective interventions to recanalization therapies is the logical next step to improve stroke outcomes. Neuromodulation interventions are powerful, game-changing candidates to reach this goal. Repetitive peripheral sensory stimulation (RPSS) is a non-invasive neuromodulation intervention consisting in the delivery of trains of electric pulses to peripheral nerves by surface electrodes. The PI Adriana Conforto pioneered studies about RPSS in stroke. She and other researchers around the world showed that RPSS increases brain excitability and ameliorates upper limb motor function. A key question that remains to be answered is whether RPSS can also enhance brain perfusion or promote neuroprotection. Through this SPRINT proposal, we will establish the collaboration between Emory and Hospital das Clínicas/USP. This proof-of-principle study will extend the knowledge to be gained by project FAPESP 2018/03737-8 and will combine expertise from the two PIs by bringing together two solid lines of investigation: neuromodulation in stroke (Conforto) and acute stroke treatment (Nogueira). This combination will foster innovative projects in both institutions. Two visits will be conducted by the PI from São Paulo to the Emory/ Marcus Stroke Center and other two, from the Emory PI to Brazil. Each visit will last for 3 days. Visits will involve discussion of the pilot data collected for this project, planning of a larger comprehensive project to be submitted in the future, scientific meetings/seminars (by teleconferences) and a symposium in Brazil, open to researchers not involved in the project to strengthen connections between researchers from São Paulo and Emory. (AU)

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