Advances in transcorneal electrical stimulation: From the eye to the brain

Abstract

The mammalian brain is reported to contain about 10⁶-10⁹ neurons linked together to form complex networks. Physiologically, the neuronal networks interact in a rhythmic oscillatory pattern to coordinate the brain's functions. Neuromodulation covers a broad range of techniques that can alter neuronal network activity through the targeted delivery of electrical or chemical stimuli. Neuromodulation can be used to potentially treat medical conditions and can serve as a research tool for studying neural functions. Typically, the main method of neuromodulation is to electrically stimulate specific structures in both the central and peripheral nervous systems via surgically implanted electrodes. Therefore, it is imperative to explore novel and safer methods for altering neuronal network activity. Transcorneal electrical stimulation (TES) has rapidly emerged as a non-invasive neuromodulatory technique that can exert beneficial effects on the brain through the eyes. There is substantial evidence to show that TES can change the brain oscillations in rodents. Moreover, the molecular data clearly shows that TES can also activate non-visual brain regions. In this review, we first summarize the use of TES in the retina and then discuss its effects in the brain through the eye-brain connection. We then comprehensively review the substantial evidence from electrophysiological, behavioral, and molecular studies on the role of TES on modulating neurons in the brain. Lastly, we discuss the implications and possible future directions of the research on TES as a non-invasive tool for neuromodulation of the brain via directly stimulating the mammalian eye.

Keywords: brain neural oscillations; electrophysiology; eye-brain connection; neuromodulation; plasticity; transcorneal electrical stimulation.

Figure 1

Schematic representation of transcorneal electrical stimulation (TES). In both human and animal subjects, the stimulating electrode (blue circle) is positioned on the cornea and the other end is connected to an electrical pulse generator (EPG). Electric current pulses activate the retina and its downstream structures. Created with BioRender.com (accessed December 13, 2022).

Figure 2

Depiction of the eye-brain connection. (A) The retina contains several layers of neurons including retinal ganglion cells (RGCs), which are morphologically similar to neurons in the brain. (B) RGCs have myelinated axons that are organized to form the optic nerve. The optic nerve extends to the lateral geniculate nucleus (LGN) and superior colliculus (SC) in the brain. (C) Similar to the brain, the eye is uniquely associated with the immune system and is composed of immunoregulatory molecules. (D) The inner blood-retinal barrier, which is analogous to the blood-brain barrier, further shows the relationship between the eye and the immune system. Created with BioRender.com (accessed December 13, 2022).