Abstract
Cerebral vasospasm is a major cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH), causing delayed neurological deficits in as many as one third of cases. Existing therapy targets induction of cerebral vasodilation through use of various drugs and mechanical means, with a range of observed efficacy. Here, we perform a literature review supporting our hypothesis that transcranially delivered ultrasound may have the ability to induce therapeutic cerebral vasodilation and, thus, may one day be used therapeutically in the context of SAH. Prior studies demonstrate that ultrasound can induce vasodilation in both normal and vasoconstricted blood vessels in peripheral tissues, leading to reduced ischemia and cell damage. Among the proposed mechanisms is alteration of several nitric oxide (NO) pathways, where NO is a known vasodilator. While in vivo studies do not point to a specific physical mechanism, results of in vitro studies favor cavitation induction by ultrasound, where the associated shear stresses likely induce NO production. Two papers discussed the effects of ultrasound on the cerebral vasculature. One study applied clinical transcranial Doppler ultrasound to a rodent complete middle cerebral artery occlusion model and found reduced infarct size. A second involved the application of pulsed ultrasound in vitro to murine brain endothelial cells and showed production of a variety of vasodilatory chemicals, including by-products of arachidonic acid metabolism. In sum, nine reviewed studies demonstrated evidence of either cerebrovascular dilation or elaboration of vasodilatory compounds. Of particular interest, all of the reviewed studies used ultrasound capable of transcranial application: pulsed ultrasound, with carrier frequencies ranging between 0.5 and 2.0 MHz, and intensities not substantially above FDA-approved intensity values. We close by discussing potential specific treatment paradigms of SAH and other cerebral ischemic disorders based on MRI-guided transcranial ultrasound.
Highlights
Aneurysmal subarachnoid hemorrhage is a devastating neurological condition with an estimated incidence of 7–9 per 100,000 person-years [1]
A metaanalysis concluded that the odds of a good outcome were 1.86 times higher in patients treated with nimodipine and the odds of infarction were reduced by a factor of 0.46 [35]. The mechanism of this effect is not well understood, but it may be related to effects on microvasculature or its ability to restore the local autoregulatory increase in blood flow that occurs with neuronal activity and which is lost in subarachnoid hemorrhage (SAH) [36]
Delayed neurological deficits after subarachnoid hemorrhage remain a major cause of long-term morbidity and mortality, and the clinical tools available to treat the condition are fairly limited in efficacy
Summary
Aneurysmal subarachnoid hemorrhage is a devastating neurological condition with an estimated incidence of 7–9 per 100,000 person-years [1]. A metaanalysis concluded that the odds of a good outcome were 1.86 times higher in patients treated with nimodipine and the odds of infarction were reduced by a factor of 0.46 [35] The mechanism of this effect is not well understood, but it may be related to effects on microvasculature or its ability to restore the local autoregulatory increase in blood flow that occurs with neuronal activity and which is lost in SAH [36]. Given the unlikely occurrence of cavitation in the brain with these parameters [63, 64], we hypothesize this may have occurred through US-mediated enhancement of collateral flow in the volume of tissue surrounding the region of ischemic damage, due to local US-induced vasodilation of collateral blood vessels via stimulation of NO pathways as discussed, or production of enhanced flow via acoustic streaming. This study did not find changes in NO levels or NOS activity, a discrepancy which may be due to differences in US parameters and the experimental model; for example, in vitro systems are more likely to experience US-induced cavitation, which may influence NOS activity and NO production
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