From the first experimental observation concerning the role of SCS in the regulation of CBF, researchers soon started to think about the possible application of the same stimulation in pathological models that could resemble so-called low-perfusion syndromes. Thus, several experimental studies on animals came along, each one of which was designed to mimic a pathological status such as SAH and/or related vasospam [50], or cerebral ischemia and brain injury, searching in this particular condition for some possible blood flow changes after SCS application. A large number of papers about this matter have been published since the late 1980s (Table 3). The first to describe some evidence in this field was Matsui, in 1989 [34], who reported the effects of cervical SCS on an experimental stroke model. Matsui induced a middle cerebral artery occlusion (MCAO) in a group of 31 cats, dividing them into three subgroups, one of which underwent MCAO and subsequent cervical SCS. Data on infarct size were checked in the three group underwent middle cerebral artery occlusion; among them just one group underwnt spinal cord stimualtion after the occlusion, using a computer system model, and compared. The analysis showed a prolonged survival rate within 24 h after ischemia and prevention of infarct size progression in the SCS group, demonstrating that cervical SCS prevents the progression of brain infarction. In 1991 Gonzales-Darder [19] discovered the role of SCS in reducing brain edema in an experimental stroke model induced by bilateral carotid artery occlusion in rats. That study suggested that the stimulation could have the most relevant role just during the reperfusion period, because the hemodynamic effect was described only when SCS was applied 60 min before ischemia or at the beginning of the reperfusion period. The basilar mechanism mediating such an effect of SCS could be related to a global increase in CBF, protecting the brain against ischemia, or it could be related to the activation of vascular regulation systems. A similar experience was published by Broseta et al. [3] in 1994, in 45 rabbits with different stroke models (bilateral carotid ligation, unilateral microcoagulation of the middle cerebral artery [MCA], and microcoagulation of the vertebral artery). More recently, Sagher et al. [51] used an MCA occlusion model in rats and observed that SCS reduced stroke extension; they proposed SCS as feasible for the treatment and prevention of stroke. Visocchi et al. [63] carried on these studies, building an experimental model combining head trauma and ischemic injury in 20 rabbits. They reported some results indicating the ‘preventive’ effect of SCS on the secondary damage induced by trauma in an already established vascular insufficiency setting. Since 2001 various authors have carried out experimental studies on SCS in cerebral vasospasm and SAH models, focusing attention on this possible therapeutic subset. Goksel et al. [18] investigated the mechanism of the SCS-induced increase in CBF and its relation with physiological vasomotor mediators, using an NO synthase inhibitor in an animal model of SAH. They concluded that the effect of SCS on CBF could be attenuated but not completely suppressed by NG-nitro-L-arginine methyl ester (L-NAME). Gurelik et al. [20] were the only ones to propose a study in which the hemodynamic effect of SCS in a vasospasm model was measured indirectly, recording motor evoked potentials and changes occurring in the latency and amplitudes of the signal. The studies published by Karadag et al. [26] and Lee et al. [28] reported similar animal models (rabbits and rats) enhancing the remarkable effect of SCS on vasospasm in the anterior and posterior circulation. Visocchi et al. [60, 62, 65] pointed out the protective role of SCS in SAH regarding the prevention of ‘early’ vasospasm. TCD provides an easy and reliable indication of corresponding CBF modifications both in homeostatic conditions (CBF augmentation with increase in TCD velocities along with a reduction in the resistive index) and during vasospasm (decrease in CBF with increase in TCD velocities, as well as an increase in the resistive index). These pioneer observations were followed by Ebel et al. [12, 13], who evaluated the effect of cervical SCS on CBF in rats with SAH, demonstrating an enhancement of cerebral and cerebellar blood flow (Table 4).

The fruitful research on the hemodynamic effects of cervical SCS has been applied in clinical studies since 1989, as the preliminary observations in experimental models of SCS in low-perfusion syndromes had led to great interest in their possible applications in humans. The clinical studies published in the literature deal with patients I a persistent vegetative-state, and those with cerebral ischemia, cerebral vasospasm within SAH [43, 55, 74], and brain tumors.