Neuromodulation in the developing visual cortex after long-term monocular deprivation.

Neural dynamics are altered in the primary visual cortex (V1) during critical period monocular deprivation (MD). Synchronization of neural oscillations is pertinent to physiological functioning of the brain. Previous studies have reported chronic disruption of V1 functional properties such as ocular dominance, spatial acuity, and binocular matching after long-term monocular deprivation (LTMD). However, the possible neuromodulation and neural synchrony has been less explored. Here, we investigated the difference between juvenile and adult experience-dependent plasticity in mice from intracellular calcium signals with fluorescent indicators. We also studied alterations in local field potentials power bands and phase-amplitude coupling (PAC) of specific brain oscillations. Our results showed that LTMD in juveniles causes higher neuromodulatory changes as seen by high-intensity fluorescent signals from the non-deprived eye (NDE). Meanwhile, adult mice showed a greater response from the deprived eye (DE). LTMD in juvenile mice triggered alterations in the power of delta, theta, and gamma oscillations, followed by enhancement of delta-gamma PAC in the NDE. However, LTMD in adult mice caused alterations in the power of delta oscillations and enhancement of delta-gamma PAC in the DE. These markers are intrinsic to cortical neuronal processing during LTMD and apply to a wide range of nested oscillatory markers.

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

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.

Transcorneal Electrical Stimulation Induces Long-Lasting Enhancement of Brain Functional and Directional Connectivity in Retinal Degeneration Mice.

To investigate neuromodulation of functional and directional connectivity features in both visual and non-visual brain cortices after short-term and long-term retinal electrical stimulation in retinal degeneration mice. We performed spontaneous electrocorticography (ECoG) in retinal degeneration (rd) mice following prolonged transcorneal electrical stimulation (pTES) at varying currents (400, 500 and 600 µA) and different time points (transient or day 1 post-stimulation, 1-week post-stimulation and 2-weeks post-stimulation). We also set up a sham control group of rd mice which did not receive any electrical stimulation. Subsequently we analyzed alterations in cross-frequency coupling (CFC), coherence and directional connectivity of the primary visual cortex and the prefrontal cortex. It was observed that the sham control group did not display any significant changes in brain connectivity across all stages of electrical stimulation. For the stimulated groups, we observed that transient electrical stimulation of the retina did not significantly alter brain coherence and connectivity. However, for 1-week post-stimulation, we identified enhanced increase in theta-gamma CFC. Meanwhile, enhanced coherence and directional connectivity appeared predominantly in theta, alpha and beta oscillations. These alterations occurred in both visual and non-visual brain regions and were dependent on the current amplitude of stimulation. Interestingly, 2-weeks post-stimulation demonstrated long-lasting enhancement in network coherence and connectivity patterns at the level of cross-oscillatory interaction, functional connectivity and directional inter-regional communication between the primary visual cortex and prefrontal cortex. Application of electrical stimulation to the retina evidently neuromodulates brain coherence and connectivity of visual and non-visual cortices in retinal degeneration mice and the observed alterations are largely maintained. pTES holds strong possibility of modulating higher cortical functions including pathways of cognition, awareness, emotion and memory.

ECoG Power Alterations Across Stages of Prolonged Transcorneal Electrical Stimulation in the Blind Mice.

Transcorneal electrical stimulation (TES) is a noninvasive approach for activating the retina and its downstream components through the application of electric current on the cornea. Although previous studies have demonstrated the clinical relevance of TES for modulating neurons with improvements in visual evoked potentials (VEPs) and electroretinograms (ERGs), there are still huge gaps in knowledge of its effect on the brain structures. To determine the short-term impact as well as the aftereffects of TES on neural oscillatory power in retinal degeneration mice, we performed electrocorticography (ECoG) recording in the prefrontal and primary visual cortices at different stages of prolonged TES [transient stage, following prolonged stimulation (post-stimulation stage 1) and long after the end of the retinal stimulation (post-stimulation stage 2)]) under varying stimulation current amplitudes (400 µA, 500 µA and 600 µA). The results revealed asymmetric differences between short-term and long-term pTES under different stimulation current amplitudes. Specifically, in post-stimulation stage 1 we observed significant increase in ECoG power of theta, alpha and beta oscillations respectively compared with baseline pre-stimulation results. These effects were dependent on the stimulation current amplitude and stimulation stage. Transient TES was not sufficient to cause significant changes in the ECoG power of all accessed oscillations except in medium, high and ultra-gamma oscillations which significantly decreased in 400 µA and 500 µA stimulation groups respectively compared with pre-stimulation results. Regarding long-term stimulation, the increase in ECoG power of theta, alpha and beta oscillations observed in post-stimulation stage 1 was significantly maintained in post-stimulation stage 2.Clinical Relevance- These results could be of core importance for human TES protocols suggesting that following pTES and long after the end of the stimulation, TES current amplitudes could have relatively different impacts on the power/activity of cortical oscillations. For example, by increasing the activity of oscillations that have been reported to inhibit irrelevant neural processes and enable the brain to focus on more relevant neural processes thus, inducing better coordination in the cortex.

Spontaneous Feedforward Connectivity in Electrically Stimulated Retinal Degeneration Mice.

Retinal degeneration (Rd) is a neurodegenerative disorder primarily associated with the degeneration of the retina neurons and culminates in the eventual loss of visual perception or blindness. Decrease in fronto-, parietal and occipital brain connectivity have been reported in a number of neurodegeneration diseases involving cognitive decline. However, cortical communication in the brain of retinal degeneration patients remains largely unknown and strategies to remediate observed dysfunctional brain connectivity in such instance have not be thoroughly investigated. We used rd10 mice as a model to study brain connectivity in the human retinal degeneration disease, retinitis pigmentosa. Rd10 mice with sham matched controls were electrically stimulated at varying stimulation frequencies and the consequent perturbations in feedforward brain connectivity were studied in the visual cortex and pre-frontal cortex using electrocorticography (ECoG) and normalized symbolic transfer entropy (NSTE). Contra Vcx - contra PFx feed forward connectivity significantly (p<0.05) increased in theta, alpha and beta oscillatory bands of 2 Hz and 10 Hz stimulated rd10 respectively in comparison with sham group. Also, this increase was significantly maintained even after the end of the stimulation period.

Excitation of the Pre-frontal and Primary Visual Cortex in Response to Transcorneal Electrical Stimulation in Retinal Degeneration Mice.

Retinal degeneration (rd) is one of the leading causes of blindness in the modern world today. Various strategies including electrical stimulation are being researched for the restoration of partial or complete vision. Previous studies have demonstrated that the effectiveness of electrical stimulation in somatosensory, frontal and visual cortices is dependent on stimulation parameters including stimulation frequency and brain states. The aim of the study is to investigate the effect of applying a prolonged electrical stimulation on the eye of rd mice with various stimulation frequencies, in awake and anesthetized brain states. We recorded spontaneous electrocorticogram (ECoG) neural activity in prefrontal cortex and primary visual cortex in a mouse model of retinitis pigmentosa (RP) after prolonged (5-day) transcorneal electrical stimulation (pTES) at various frequencies (2, 10, and 20 Hz). We evaluated the absolute power and coherence of spontaneous ECoG neural activities in contralateral primary visual cortex (contra Vcx) and contralateral pre-frontal cortex (contra PFx). Under the awake state, the absolute power of theta, alpha and beta oscillations in contra Vcx, at 10 Hz stimulation, was higher than in the sham group. Under the anesthetized state, the absolute power of medium-, high-, and ultra-high gamma oscillations in the contra PFx, at 2 Hz stimulation, was higher than in the sham group. We also observed that the ultra-high gamma band coherence in contra Vcx-contra PFx was higher than in the sham group, with both 10 and 20 Hz stimulation frequencies. Our results showed that pTES modulates rd brain oscillations in a frequency and brain state-dependent manner. These findings suggest that non-invasive electrical stimulation of retina changes patterns of neural oscillations in the brain circuitry. This also provides a starting point for investigating the sustained effect of electrical stimulation of the retina to brain activities.