Modulation of solute diffusivity in brain tissue as a novel mechanism of transcranial direct current stimulation (tDCS)

Abstract

The breadth of brain disorders and functions reported responsive to transcranial direct current stimulation (tDCS) suggests a generalizable mechanism of action. Prior efforts characterized its cellular targets including neuron, glia and endothelial cells. We propose tDCS also modulates the substance transport in brain tissue. High resolution multiphoton microscopy imaged the spread across rat brain tissue of fluorescently-labeled solutes injected through the carotid artery after tDCS. The effective solute diffusion coefficient of brain tissue (Deff) was determined from the spatio-temporal solute concentration profiles using an unsteady diffusion transport model. 5–10 min post 20 min–1 mA tDCS, Deff increased by ~ 10% for a small solute, sodium fluorescein, and ~ 120% for larger solutes, BSA and Dex-70k. All increases in Deff returned to the control level 25–30 min post tDCS. A mathematical model for Deff in the extracelluar space (ECS) further predicts that this dose of tDCS increases Deff by transiently enhancing the brain ECS gap spacing by ~ 1.5-fold and accordingly reducing the extracellular matrix density. The cascades leading ECS modulation and its impact on excitability, synaptic function, plasticity, and brain clearance require further study. Modulation of solute diffusivity and ECS could explain diverse outcomes of tDCS and suggest novel therapeutic strategies.

Direct Current Stimulation Disrupts Endothelial Glycocalyx and Tight Junctions of the Blood-Brain Barrier in vitro

“…This dose and duration were the optimal and also safe for the in vivo tDCS treatment on rats (Jackson et al, 2017;Shin et al, 2020;Xia et al, 2020). Current was applied transcranially to the frontal cortex of a rat head (approximately 2 mm anterior to Bregma and 2 mm right to Sagittal suture) to obtain similar physiological outcomes as in the human tDCS application studies (Marceglia et al, 2016;Jackson et al, 2017;Shin et al, 2020;Xia et al, 2020). Specifically, an epi-cranial anode (1 mm diameter, Ag/AgCl) in a plastic cannula (4 mm inner diameter) filled with conductive electrolyte gel (Signa, Parker Laboratory, NJ) was positioned onto the rat skull with the location described above.…”

“…tDCS was administered using a constant current stimulator (1x1 tDCS, Soterix Medical Inc., New York, United States) to deliver a 1 mA current (the current density 8.0 mA/cm 2 ) for 20 min. This dose and duration were the optimal and also safe for the in vivo tDCS treatment on rats (Jackson et al, 2017;Shin et al, 2020;Xia et al, 2020). Current was applied transcranially to the frontal cortex of a rat head (approximately 2 mm anterior to Bregma and 2 mm right to Sagittal suture) to obtain similar physiological outcomes as in the human tDCS application studies (Marceglia et al, 2016;Jackson et al, 2017;Shin et al, 2020;Xia et al, 2020).…”

Direct current stimulation modulates gene expression in isolated astrocytes with implications for glia-mediated plasticity

“…With the goal of clearly isolating action on cell types, we do not access secondary inter-cell-type interactions (e.g., how astrocyte BDNF would impact neuronal plasticity). Extending these experiments to in vivo models would be difficult to interpret precisely because of their functional coupling 15,[48][49][50] . There is a large space of stimulation waveform to explore (e.g., duration), and we start here with intensity.…”

Influence of Anisotropic White Matter on Electroosmotic Flow Induced by Direct Current

“…These values are taken from the literature related to the zeta-potential measurement of rat brains (Guy et al, 2008;Guy et al, 2009). Given that the direct current stimulation enlarges the extracellular space and increases the effective solute diffusion coefficient of brain tissue (Avramov, 2009;Xia et al, 2020), the viscosity η of the extracellular solution is adjusted to be 5.8 × 10 -4 Pas.…”