Neurobiological After-Effects of Low Intensity Transcranial Electric Stimulation of the Human Nervous System: From Basic Mechanisms to Metaplasticity

Abstract

Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity, however mechanisms are still far from being elucidated. We aim to review recent results from in vitro and in vivo studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from in vitro and in vivo studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.

Keywords: neurobiological after-effects; non-invasive brain stimulation; synaptic plasiticty; transcranial alternating current stimulation; transcranial direct current stimulation.

Figure 1

Schematic representation of neurobiological after-effects of transcranial electrical stimulation (tES). tES induces intracellular Ca²⁺ increase and activation of Ca²⁺-dependent enzymes (CaM-K). Presynaptic mechanisms result in glutamate release that activates AMPA/NMDA receptors, modulates BDNF release and interaction with TrkB receptor, responsible for a cascade of intracellular events that lead to de novo protein synthesis. Electrical stimulation also modulates activation of astrocytes and neuroinflammatory response. Altogether, these mechanisms may underlie the establishment of LTP/LTD. CaBP, Ca²⁺ binding proteins; CaM-K, Ca²⁺ kinases; glu, glutamate; BDNF, brain-derived neurotrophic factor; TrkB, tyrosine kinase receptor B; LTP/LTD, long term potentiation/depression; GFAP, glial fibrillary acidic protein; TNFα, tumor necrosis factor α; IL-1β, interleukin 1β; NMDAr, N-methyl-D- aspartate receptor; AMPAr, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GABA_A, gamma amino butirric acid A receptor.