Glia: A Neglected Player in Non-invasive Direct Current Brain Stimulation

Abstract

Non-invasive electrical brain stimulation by application of direct current (DCS) promotes plasticity in neuronal networks in vitro and in in vivo. This effect has been mainly attributed to the direct modulation of neurons. Glia represents approximately 50% of cells in the brain. Glial cells are electrically active and participate in synaptic plasticity. Despite of that, effects of DCS on glial structures and on interaction with neurons are only sparsely investigated. In this perspectives article we review the current literature, present own dose response data and provide a framework for future research from two points of view: first, the direct effects of DCS on glia and second, the contribution of glia to DCS related neuronal plasticity.

Glial responses to implanted electrodes in the brain

“…Several models have demonstrated the direct modulation of plasticity, inflammation, neurogenesis and cerebrovascular functions by glial cells following neurostimulation 118,127 . For example, stimulation evokes astrocyte-induced cortical plasticity, as demonstrated in studies using transcranial direct current stimulation (tDCS) 128 .…”

“…Implanted-electrode stimulation upregulates inflammatory receptors (toll-like receptors) in microglia 131 , favouring a shift to a proinflammatory state 117 . However, the timing 132 and intensity 133 of stimulation may differentially affect reactivity and inflammation, suggesting a gradient of glial responses 127 . In the context of neurogenesis, neuromodulation is gaining traction as a reparative tool for brain injury and disease 118,134 .…”

Safety parameter considerations of anodal transcranial Direct Current Stimulation in rats

“…However, damage was not consistently observed for 0.5 mA cathodal and 1.0 mA anodal stimulation groups (Pikhovych et al, 2016a, Pikhovych et al, 2016b), which indirectly suggests a role for polarity. More recently, lesions have been reported at an anodal current intensity of 0.6 mA (47.8 A/m 2 electrode current density) (Gellner et al, 2016), suggesting the lesion threshold in rats may be lower than previously reported. Rodent studies evaluating tDCS safety through microglial analysis have shown microglial activation can occur after anodal or cathodal stimulation at 0.5 mA for 15 minutes (Rueger et al, 2012) (c.f.…”

“…(Liebetanz et al, 2009). Microglial changes in morphology associated with neurodegeneration after anodal tDCS have been reported at current intensities as low as 0.4 mA (31.8 A/m 2 electrode current density) (Gellner et al, 2016). …”

“…Indeed, computational current models notably show brain current density is not simply a function of the electrode current density, but also anatomy and details of electrode size and position (Datta et al, 2009a, Miranda et al, 2009, Datta et al, 2012, Saturnino et al, 2015). Therefore, animal models of tDCS safety can benefit from being updated in regards to: 1) variation of stimulation polarity/dose (anodal vs. cathodal); 2) alternative indications of injury (Wachter et al, 2011, Rueger et al, 2012, Wong et al, 2014, Gellner et al, 2016); and 3) the suitability of electrode parameters to set a safety threshold given computational current models show brain current density is not a simple, linear function of the applied current or electrode current density (Datta et al, 2009a, Miranda et al, 2009, Datta et al, 2012, Saturnino et al, 2015). …”