# The coupled vascular hypothesis for transcranial direct current stimulation (tDCS)

> **NIH NIH R01** · CITY COLLEGE OF NEW YORK · 2021 · $343,438

## Abstract

PROJECT SUMMARY
Transcranial Direct Current Stimulation (tDCS) is investigated to treat a broad range of brain disorders and to
change cognition in healthy individuals. The scale and breadth of tDCS human trials has outpaced
understanding of cellular mechanisms. The flexibility of tDCS derives from use in combination with a training
task, with the goal to enhance “neuronal capacity” for plasticity (learning) on the specific task. tDCS is thus
applied either during or before a task, to produce an acute or persistent change in neural capacity. The rational
advancement of tDCS as a clinical/neuroscience tool requires knowing the cellular targets of stimulation, and
linking their activation with changes in neuronal capacity during and after tDCS. Neurons, and to a lesser
extent glia, have been studied as tDCS cellular targets. Endothelial cells of the blood-brain barrier (BBB) have
been unaddressed until recently by our team. Yet BBB function is well known to be sensitive to other forms of
electrical stimulation, and that changes in BBB will alter brain function. Indeed BBB stimulation is consistent
with the concept of tDCS acting to generally prime the brain (e.g. changing excitability or metabolic capacity).
This proposal addresses a novel hypothesis and scientific premise for how BBB modulation may enhance
neural capacity during or after tDCS. We propose that the conductive vascular network across the brain shunts
current and in the process generates electric fields across the BBB higher than around neurons. We believe
that BBB polarization by tDCS alters the transport of water and solutes across the BBB (during stimulation) and
activates the expression of genes leading to the production of neuroactive chemicals (including NO) by the
blood vessels of the BBB (after stimulation), all of which modulate the microenvironment of neurons and
neuronal capacity.
Given a natural bias toward interpreting any tDCS actions as reflecting direct neuron activation (and thus BBB
response as secondary/epiphenomena) we require state-of-the-art modeling and experimental tools to quantify
the direct stimulation of BBB by tDCS. We present substantial preliminary data from in silico, in vitro, and in
vivo studies that support our overall premise. This data reflects a successful R21 collaboration by our team;
having shown feasibly of a novel cellular target, this RO1 establishes the mechanism and potential impact of
direct BBB activation by tDCS. Aim 1: We will develop a multi-scale (from head anatomy to micro-vasculature)
multi-physics (coupling electric fields with electro-diffusion filtration transport) model. Aim 2: We will validate
acute (during DCS) changes in water and molecule permeability using a specially designed in vitro BBB model
system where the absence of neurons establishes a direct action of current on the BBB, as well as test the
activation of nitric oxide (NO) and other neuro-active genes (neurotrophins) by DCS in the absence of neurons.
Aim 3: Using ...

## Key facts

- **NIH application ID:** 10133745
- **Project number:** 5R01NS101362-05
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** MAROM BIKSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,438
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133745

## Citation

> US National Institutes of Health, RePORTER application 10133745, The coupled vascular hypothesis for transcranial direct current stimulation (tDCS) (5R01NS101362-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133745. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*