The mechanisms of cerebral microcirculation response to transcranial stimulation.

Transcranial alternating current stimulation (tACS) is a relatively new non-invasive electrical stimulation
technique (tES) where a sinusoidal oscillating low-voltage electric current is applied to the brain through
electrodes on the scalp. TACS is investigated for a broad range of medical and performance indications to
manipulate brain activity. The physiological mechanisms underlying tACS effects are still under debate. The
effects of tACS are generally mixed and controversial since they depend on many stimulation parameters, such
as stimulation duration, intensity, electrodes montage and size, stimulation phase, and frequency. Therefore,
further pre-clinical mechanistic investigation is needed to reach a comprehensive understanding of tACS effects.
Understanding the cellular mechanisms of tACS will increase the rigor of enduring studies and provide a rational
foundation for dose optimization. The majority of mechanistic studies have focused exclusively on the direct
effects of tACS on neuronal membranes. A recent study showed that tACS rapidly and transiently increases
cerebral blood flow in anesthetized mice, but the mechanism remained unclear. In previous studies, we have
demonstrated nitric oxide-dependent direct effects on cerebral vascular endothelium and microcirculation of
another tES modality – transcranial direct current stimulation (tDCS). However, the dose-dependent effects and
the NOS subtype involved were not studied and thus unknown. Drs. Mersedeh Bahr-Hosseini and Marom
Bikson, in the recent review in Brain Stimulation Journal, concluded that a primary vascular effect of transcranial
electrostimulation is highly suggested based on various preclinical and clinical studies and that further studies
are warranted to investigate the mechanisms underlying the vascular response. Based on our results obtained
for tDCS and considering that the effects of tACS and tDCS might be both similar and dissimilar, we propose to
test the hypothesis that tES directly and transiently modulates the endothelial function of microvasculature, which
could modulate neuronal activity. Thus, the objective of the proposed work is to dissect and differentiate the
mechanisms of tACS and tDCS effects on vascular endothelium and cerebral microcirculation. The rationale is
that tACS and tDCS facilitate sustained nitric oxide-dependent changes in cerebral microvasculature and so in
the neuronal microenvironment. The approach includes in-vivo awake multiphoton laser scanning microscopy of
cerebral microvascular tone, circulation, and blood-brain barrier permeability during and after tACS and tDCS
with the use of nitric oxide synthase modulators and eNOS and nNOS knockout mice and the determination of
molecular responses of microvascular endothelium. As understanding each cellular target of stimulation is
necessary for a complete mechanism, the modulation of microvasculature by tACS and tDCS, combined with
neuronal effects, is significant and innovative to research. This proposed research will determine the feasibility
of the direct effects of tACS and tDCS on cerebral microvasculature and foresee the influence of these changes
on neuronal activity.

Grant Number: 1R21AG089266-01
NIH Institute/Center: NIH
Principal Investigator: Olga Bragina