Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (11): 2543-2552.doi: 10.4103/1673-5374.392888

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Optimal transcorneal electrical stimulation parameters for preserving photoreceptors in a mouse model of retinitis pigmentosa

Sam Enayati1, 2, 3, 4, Karen Chang1, 3, Anton Lennikov1, 3, Menglu Yang1, Cherin Lee1, Ajay Ashok1, 3, Farris Elzaridi1, Christina Yen1, Kasim Gunes1, 5, Jia Xie1, Kin-Sang Cho1, Tor Paaske Utheim1, 2, 3, 4, Dong Feng Chen1, *#br#   

  1. 1Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; 2Institute of clinical medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; 3Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway; 4Department of Ophthalmology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway; 5Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkiye
  • Online:2024-11-15 Published:2024-03-29
  • Contact: Dong Feng Chen, MD, PhD, dongfeng_chen@meei.harvard.edu.
  • Supported by:
    This study was supported by The Norwegian Research Council; Department of Ophthalmology, Oslo University Hospital, Oslo, Norway (to TPU); Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway (to TPU); The Norwegian Association for the Blind and Partially Sighted (to TPU); The Ministry of Science and Technology of Taiwan, China MOST 105-2917-I-002-031, MOST 109-2917-I-564-032 (to KC); The Scientific and Technological Research Council of Turkiye – TUBITAK (to KG);  BrightFocus Foundation (to KSC); the Massachusetts Lions Foundation (to KSC); National Eye Institute Grant EY031696 (to DFC); Harvard NeuroDiscovery Center Grant (to DFC); Department of Defense (USA) HT9425-23-1-1045 (to DFC and AL); Core Grant for Vision Research from NIH/NEI to the Schepens Eye Research Institute (P30EY003790). South-Eastern Norway Regional Health Authority and the Norwegian Society of the Blind (to TPU).

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Abstract: Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors, leading to progressive photoreceptor loss. Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival. This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation (tcES) in mice affected by inherited retinal degeneration. Additionally, the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans. In this study, we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular, sine, and ramp waveforms. To investigate the functional effects of electrical stimulation on photoreceptors, we used human retinal explant cultures and rhodopsin knockout (Rho–/–) mice, demonstrating progressive photoreceptor degeneration with age. Human retinal explants isolated from the donors’ eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro. Photoreceptor density was evaluated by rhodopsin immunolabeling. In vivo Rho–/– mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms. Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response (OMR), respectively. Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas. Oscilloscope recordings indicated effective delivery of rectangular, sine, and ramp waveforms to the retina by transcorneal electrical stimulation, of which the ramp waveform required the lowest voltage. Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes. The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro (~0.5–1.5°C). Electrical stimulation increased photoreceptor survival in human retinal explant cultures, particularly at the ramp waveform. Transcorneal electrical stimulation (rectangular + ramp) waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results. Histology and immunolabeling demonstrated increased photoreceptor survival, improved outer nuclear layer thickness, and increased bipolar cell sprouting in Rho–/– mice. These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina, improves photoreceptor survival in both human and mouse retinas, and increases visual function in Rho–/– mice. Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion. 

Key words: bipolar cells, electrical stimulation, neuroprotection, photoreceptor degeneration, retina, retinal explants, retinitis pigmentosa, transcorneal electrical stimulation, waveform