Disclosed are devices, systems and methods for non-invasive neuromodulation system for prompt treatment of cerebral and/or ocular strokes caused by acute dysregulated reduced cerebral blood flow (CBF) and/or ocular blood flow (OBF) by up regulation of trigemino-vascular system (TVS), and trigeminal autonomic brain reflexes (TABRs) through stimulation of ophthalmic nerve. Additionally or alternatively, the subject's sympathetic nervous system (SNS) is down regulated centrally by intravenous administration of pharmacological dose of ascorbic acid. The site of stimulation of ophthalmic nerve includes but not limited to nasal vestibule, nasal bridge, and forehead and upper eyelid. In some embodiments, the devices are handheld, portable with nose supported, having one or more intra-nasal or extra-nasal application heads. The signal can include vibration, chemical, ultrasonic, optical, electrical, hybrid electro-optical or combination of two or more of these types of stimuli. The subject's TVS and autonomic nervous system (ANS) are modulated in a manner that is effective to treat the subject for cerebral and ocular strokes. The invention, in some embodiments thereof, relates to a method for decreasing vascular resistance, enhancing vasodilatation in cerebral arteries, leptomeningeal collaterals and ophthalmic artery by the release of Vasoactive intestinal peptide (VIP),substance P and CGRP thereof increasing cerebral and/or OBF to the brain and the eye in subject's with acute dysregulated, reduced cerebral and/or OBF. The invention, in some embodiments thereof, is also relates to upregulation of TVS in a manner that is effective to induce acute development of leptomeningeal collateral circulation sufficient to ameliorate the ischemic effect of occluded cerebral artery, enhances successful recanalization, decreases the infarction volume and improves brain functional recovery without hemorrhagic transformation. In some embodiments TVS and ANS are also modulated in a manner that induce an acute increase in choroidal blood flow sufficient to ameliorate the ischemic effect of occluded artery until spontaneous recanalization of the occluded artery is accomplished. The invention is related to targeting the affected side via ipsilateral ONS without inducing intracerebral vascular steal phenomenon. The invention, in some embodiments thereof, is also relates to the methods for improving delivery of oxygen, glucose, anticoagulants, hormones, humoral mediators, growth factors and pharmacological agents to the targeted ischemic tissues of the brain, retina and optic nerve. The methods of the invention, when combined with r-tPA treatment and/or endovascular recanalization increases window time of treatment of stroke, enhance the efficacy of treatment and reduce its side effects. The methods of the invention, in some embodiments thereof, include priming of the brain, retina and/or optic nerve thereof to enhance the efficacy of cell transplantation therapy after exposure to stroke. Methods of the invention, in some embodiments thereof, may also include monitoring the subject for prophylactic treatment. The cerebral/and or OBF of subjects who had received neuromodulation treatment may also be monitored for re-treatment.