Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression

Abstract

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

Keywords: TES; antidepressant; depression; neuromodulation; neuroprotection; transcorneal electrical stimulation.

Figure 1

Connections between the visual and emotional systems. The diagram illustrates the major cortical (red arrows) and subcortical (blue arrows) pathways connecting brain regions involved in vision and emotion. In the cortical routes, visual inputs originating from the retina are transmitted to the VC via the thalamic relay station LGN. The VC further projects dorsally to PPC or ventrally to ITC, where they interconnect to the PFC and limbic structures, including Amy and Hipp, which are involved in emotional regulation. Alternatively, visual signals can be conveyed subcortically to Amy via SC and Pul in the thalamus. Amy, Hipp, and PFC can further interchange information directly or indirectly through various relay structures. The less significant intermediate structures and connections in these pathways are not shown to simplify the diagram. Amy: amygdala; Hipp: hippocampus; ITC: inferior temporal cortex; LGN: lateral geniculate nuclei; PFC: prefrontal cortex; PPC: posterior parietal cortex; Pul: pulvinar; SC: superior colliculus; VC: visual cortex. Created with BioRender.com (accessed on 28 August 2021).

Figure 2

Potential mechanisms of the action of TES. The diagram shows the enlarged structures in retinal layers associated with several proposed mechanisms underlying the neuroprotective effects of TES. Overall, TES increases the survival of neurons and preserves their functions by promoting the expression of neurotrophins in Müller cells, reducing inflammation by inhibiting microglial activation, and preventing apoptotic cell death. TES administration was reported to enhance activities in the VC and PFC, possibly through repeated activation of the visual pathway leading to strengthened synaptic function and neuronal synchronization from the retina to the VC or to the PFC via cortical or subcortical routes. Additionally, TES was reported to rescue cells from glutamate-induced excitotoxicity by enhancing the release of glutamine synthetase from Müller cells. Increasing chorioretinal blood flow through vasodilation is proposed to underlie the protective effects of TES. Bax: Bcl-2-associated X protein; Bcl2: B-cell lymphoma 2; BDNF: brain-derived neurotrophic factor; CNTF: ciliary nerve trophic factor; COX2: cyclooxygenase-2; EEG: electroencephalogram; Glu: glutamate; Gln: glutamine; GS: glutamine synthetase; IGF-1: insulin-like growth factor 1; IL: interleukin; L-VDCC: L-type voltage-dependent calcium channel; NF-kB: nuclear factor κB; PFC: prefrontal cortex; TES: transcorneal electrical stimulation; TNF-α: tumour necrosis factor-α; Tnfrsf12a: TNF receptor superfamily member 12a; VC: visual cortex. Created with BioRender.com (accessed on 28 August 2021).