Neurovascular-modulation: A review of primary vascular responses to transcranial electrical stimulation as a mechanism of action

Background: The ubiquitous vascular response to transcranial electrical stimulation (tES) has been attributed to the secondary effect of neuronal activity forming the classic neurovascular coupling. However, the current density delivered transcranially concentrates in: A) the cerebrospinal fluid of subarachnoid space where cerebral vasculature resides after reaching the dural and pial surfaces and B) across the blood-brain-barrier after reaching the brain parenchyma. Therefore, it is anticipated that tES has a primary vascular influence. Objectives: Focused review of studies that demonstrated the direct vascular response to electrical stimulation and studies demonstrating evidence for tES-induced vascular effect in coupled neurovascular systems. Results: tES induces both primary and secondary vascular phenomena originating from four cellular elements; the first two mediating a primary vascular phenomenon mainly in the form of an immediate vasodilatory response and the latter two leading to secondary vascular effects and as parts of classic neurovascular coupling: 1) The perivascular nerves of more superficially located dural and pial arteries and medium-sized arterioles with multilayered smooth muscle cells; and 2) The endothelial lining of all vessels including microvasculature of blood-brain barrier; 3) Astrocytes; and 4) Neurons of neurovascular units. Conclusion: A primary vascular effect of tES is highly suggested based on various preclinical and clinical studies. We explain how the nature of vascular response can depend on vessel anatomy (size) and physiology and be controlled by stimulation waveform. Further studies are warranted to investigate the mechanisms underlying the vascular response and its contribution to neural activity in both healthy brain and pathological conditions -recognizing many brain diseases are associated with alteration of cerebral hemodynamics and decoupling of neurovascular units. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).