Cellular and molecular mechanisms of action of transcranial direct current stimulation: evidence from in vitro and in vivo models

Abstract

Transcranial direct current stimulation is a noninvasive technique that has been experimentally tested for a number of psychiatric and neurological conditions. Preliminary observations suggest that this approach can indeed influence a number of cellular and molecular pathways that may be disease relevant. However, the mechanisms of action underlying its beneficial effects are largely unknown and need to be better understood to allow this therapy to be used optimally. In this review, we summarize the physiological responses observed in vitro and in vivo, with a particular emphasis on cellular and molecular cascades associated with inflammation, angiogenesis, neurogenesis, and neuroplasticity recruited by direct current stimulation, a topic that has been largely neglected in the literature. A better understanding of the neural responses to transcranial direct current stimulation is critical if this therapy is to be used in large-scale clinical trials with a view of being routinely offered to patients suffering from various conditions affecting the central nervous system.

Keywords: inflammation; long-term potentiation; neurogenesis.

© The Author 2015. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.

Putative molecular mechanisms of action of anodal transcranial direct current stimulation (tDCS). Schematic illustrating the effects of anodal tDCS on the synapses of pyramidal neurons in the primary motor cortex. Note that cathodal tDCS is not represented, as it largely generates the opposite effects of anodal tDCS, except for the mechanisms involving brain-derived neurotrophic factor (BDNF), which is described below. Anodal tDCS hyperpolarizes the membrane of the axon terminal facing the anode (Bikson et al., 2004). Despite the hyperpolarization, there is greater neurotransmitter release, which is caused by an increase in intracellular Ca2+ in response to anodal tDCS, whereas a decrease of Ca2+ leads to lower neurotransmitter release (Perret et al., 1999; Stagg et al., 2009a). Tropomyosin-receptor kinase (Trk) receptors may also be attracted to the synapse in anodal tDCS (if the presynaptic synapse faces the skull, as illustrated here) (McCaig et al., 2000; Viard et al., 2004). The activation of Trk receptors suggests a role for BDNF in anodal tDCS, which further increases the probability of synaptic vesicle docking and neurotransmitter release (Pozzo-Miller et al., 1999). Direct current electric fields (DCEFs) also directly affect the postsynaptic neuron by depolarizing (basal dendrites and soma, represented in the figure) or hyperpolarizing (apical dendrites) the membrane in anodal tDCS, or the opposite with cathodal tDCS (Kabakov et al., 2012), which further facilitates/inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-d-aspartate receptor (NMDAR)-mediated ionic changes. Overall, with long-term potentiation (LTP) responses, there is an upregulation of neurotransmitter release that facilitates the opening of AMPARs and indirectly that of NMDARs (Derkach et al., 2007). The opposite is true for long-term depression (LTD). The Ca2+ influx has been demonstrated to increase AMPAR phosphorylation and their incorporation into the membrane (Opazo et al., 2010). Ca2+ further increases the release of neurotrophic factors into the synaptic cleft and its absence decreases it (Neal and Guilarte, 2010). Once activated, postsynaptic Trk receptor induces later phase LTP (L-LTP) and favors the opening of NMDARs, which also promotes L-LTP, whereas the opposite is involved in cathodal tDCS, promoting later phase LTD (L-LTD) (Minichiello, 2009). Both L-LTP and L-LTD are dependent on modifications of gene expression (Frey et al., 1996; Smolen, 2007). PSD, postsynaptic domain; Cav; voltage-gated calcium channel.

Figure 2.

Cell types and their responses to transcranial direct current stimulation (tDCS).

Figure 3.

Putative cellular mechanisms of action of anodal transcranial direct current stimulation (tDCS). Anodal tDCS has been demonstrated to increase the amplitude and reduce the timing of glutamatergic neuronal firing (the opposite effect is observed for cathodal stimulation) (Cambiaghi et al., 2010; Hunter et al., 2013). In contrast, the firing of interneurons is decreased in both anodal and cathodal tDCS in healthy human subjects, as suggested by decreased γ-aminobutyric acid (GABA) release (Stagg et al., 2009a). Glutamate is also reduced by cathodal tDCS in healthy human subjects, whereas dopamine has been reported to be increased in normal rats with such therapy (Stagg et al., 2009a; Tanaka et al., 2013). Increases in growth associated protein-43 (GAP-43), a protein synthesized during axonal growth, and microtubule-associated protein-2 (MAP-2), involved in dendritic remodeling along with an increase in dendritic density, has been reported in stimulated brain structures in rats with ischemic lesions, which further suggests that anodal tDCS may have neuroprotective as well as neurorestorative properties (Yoon et al., 2012). There are, however, no data on their modulation by cathodal tDCS. In ischemic mice, cathodal tDCS also decreases ionized calcium-binding apater molecule-1 (Iba1+), CD45+, and caspase-3+ cell numbers, whereas the opposite is seen with anodal tDCS (Peruzzotti-Jametti et al., 2013). In a rat model of chronic stress-induced pain, tumor necrosis factor-α (TNF-α) is also downregulated by anodal tDCS, but an increase in the number of Iba1+ cells is observed in both anodal and cathodal tDCS at high intensity in normal rats (Spezia Adachi et al., 2012). Angiogenesis and increases in vascular endothelial growth factor (VEGF) levels have been reported in peripheral tissues exposed to DCEF (Bai et al., 2011). Finally, anodal tDCS in ischemic mice may also exacerbate cortical hemorrhage and provoke the disruption of the blood-brain barrier (BBB; Peruzzotti-Jametti et al., 2013). Taken together, all of this suggests that tDCS affects a number of physiological processes in both the central and peripheral nervous systems that may be relevant to its effects in disease states. AP, action potential; BDNF, brain-derived neurotrophic factor; DA, dopamine; Glu, glutamate.