Fractal phototherapy: impact on the structure and function of the retina of rabbits with modelled retinal pigment epithelium atrophy

It is believed that in degenerative diseases of the retina, photostimulation by fractal dynamics signals activates neuroplasticity, thereby increasing the efficiency of visual rehabilitation. Previously, we showed a positive effect of fractal phototherapy (FF) on the electroretinogram (ERG) of healthy rabbits and demonstrated the safety of long-term photostimulation courses for the retina. The purpose of this work is to study the effect of FF on the functional activity and morphology of the retina in rabbits with a model of retinal pathology. Material and methods. We modelled an atrophy of retinal pigment epithelium (RPE) on both eyes of 50 rabbits. 30 days after the administration of bevacizumab, the animals were divided into two groups of 25 animals each. In the main group, photostimulation was performed using a device for FF, while in the control group incandescent lamps were used that create radiation of constant intensity. In both groups, 20-minute binocular light stimulation sessions were performed daily, five times a week. ERG and optical coherence tomography of the retina were performed before and after courses of treatment which lasted 1 week, 1 and 3 months. Results. Long-term courses of FF were shown to be safe for the morphology of the retina of animals with the RPE atrophy model. In all periods of observation, biochemical studies revealed no statistically significant changes in the content of norepinephrine and dopamine in the tear as compared with baseline values. In the main group, a slight positive effect of FF on rod and cone ERG was found after 5 FF sessions, while a significant increase in the amplitude of the transient and steady-state pattern-ERG (PERG), most pronounced after a 1-month FF course, was observed. Conclusions. A positive effect of FF on the functional activity of retinal ganglion cells (RGC) may suggest that prescribing a course of FF lasting up to 1 month (20 sessions) in diseases accompanied by a pathology of RGC is advisable, whereas for patients with a pathology of the macular region, such as AMD, an effective improvement in the activity of photoreceptors and bipolar cells could probably be achieved through a 1-week course of FF, conducted under the control of electroretinography.

1. Zhang X, Li S, Tang Y, Guo Y, Gao S. Intractable ocular diseases and treatment progress. AAPS Pharm Sci Tech. 2020 Aug 14; 21 (6): 236. doi: 10.1208/s12249-020-01774-1

2. Gilbert CD, Li W. Adult visual cortical plasticity. Neuron. 2012; 75 (2): 250–64. doi: 10.1016/j.neuron.2012.06.030

3. Pascual-Leone A, Freitas C, Oberman L, et al. Characterizing brain cortical plasticity and network dynamics across the age-span in health and disease with TMS-EEG and TMS-fMRI. Brain Topogr. 2011; 24 (3–4): 302–15. https://doi.org/10.1007/s10548-011-0196-8

4. Maya-Vetencourt J.F., Origlia N. Visual cortex plasticity: a complex interplay of genetic and environmental influences. Neural Plast. 2012; 2012: 631965. doi: 10.1155/2012/631965

5. Black JE. How a child builds its brain: some lessons from animal studies of neural plasticity. Prev Med. 1998; 27 (2): 168–71. https://doi.org/10.1006/pmed.1998.0271

6. Foehring RC, Lorenzon NM. Neuromodulation, development and synaptic plasticity.Canadian Journal of Experimental Psychology (Revue canadienne de psychologie expérimentale). 1999; 53 (1): 45–61. https://doi.org/10.1037/h0087299

7. Zueva MV. Dynamic fractal flickering as a tool in research of non-linear dynamics of the evoked activity of a visual system and the possible basis for new diagnostics and treatment of neurodegenerative diseases of the retina and brain. World Appl Sci J. 2013; 27 (4): 462–8. doi: 10.5829/idosi.wasj.2013.27.04.13657

8. Zueva MV. Fractality of sensations and the brain health: the theory linking neurodegenerative disorder with distortion of spatial and temporal scale-invariance and fractal complexity of the visible world. Front Aging Neurosci. 2015; 7: 135. https://doi.org/10.3389/fnagi.2015.00135

9. Zueva M.V., Kotelin V.I., Neroeva N.V., Fadeev V.V., Manko O.M. Problems and prospects of new methods of light stimulation in visual rehabilitation. Sensory systems. 2023; 37 (2): 93–118 (In Russ.). https://doi.org/10.31857/S0235009223020075

10. Neroeva N.V., Zueva M.V., Katargina L.A., et al. Modifying treatment for degenerative retinal diseases. Part 2: Methods of conditioning therapy and problems of maximizing retinal plasticity. Russian ophthalmological journal. 2023; 16 (3): 165–72 (In Russ.). https://doi.org/10.21516/2072-0076-2023-16-3-165-172

11. Zueva M.V., Karankevich A.I. Stimulator of complex optical signals and the method of its use. RF Patent # 2680185/2019 (In Russ.).

12. Neroev V.V., Zueva M.V., Manakhov P.A., et al. Method for improving the functional activity of the visual system using fractal phototherapy using a stereoscopic display. Patent RU # 2773684 C1, 07.06.2022 Bull. # 16 (In Russ.).

13. Neroev V.V., Zueva M.V., Neroeva N.V., et al. Device for fractal photostimulation of the visual system. Date of publication: 30.06.2022 Bull. # 19 (In Russ.).

14. Taylor RP, Spehar B, Wise JA, et al. Perceptual and physiological responses to the visual complexity of fractal patterns. Nonlinear Dynamics Psychol Life Sci. 2005; 9 (1): 89–114. doi: 10.1007/978-3-322-83487-4_4

15. Neroev V.V., Zueva M.V., Neroeva N.V., et al. Impact of fractal visual stimulation on healthy rabbit retina: functional, morphometric and biochemical studies. Russian ophthalmological journal. 2022; 15 (3): 99–111 (In Russ.). https://doi.org/10.21516/2072-0076-2022-15-3-99-111

16. Neroev VV, Zueva MV, Neroeva NV, et al. Changes in functional activity of rabbit’s retina during flicker photostimulation with scale-free dynamics. Int J Clin Med Bioeng (IJCMB). 2022; 2 (2): 1–19. https://doi.org/10.35745/ijcmb2022v02.02.0001

17. Neroeva N.V., Neroev V.V., Ilyukhin P.A., et al. Modeling the atrophy of retinal pigment epithelium. Russian ophthalmological journal. 2020; 13 (4): 58–63 (In Russ.). doi: 10.21516/2072-0076-2020-13-4-58-63

18. ARVO Statement for the Use of Animals in Ophthalmic and Visual Research. Available at: http://www.arvo.org/about_arvo/policies/statement_for_the_use_of_animals_in_ophthalmic_and_visual_research/, Accessed 30 Oct 2016

19. Principles on Good Laboratory Practice. OECD series on principles of Good Laboratory Practice and Compliance Monitoring. No 1. Available 27 November 2021 at https://www.oecd.org/chemicalsafety/testing/oecdseriesonprinciplesofgoodlaboratorypracticeglpandcompliancemonitoring.htm

20. Srinivasan K, Tikoo K, Jena GB. Good Laboratory Practice (GLP) requirements for preclinical animal studies. In: Nagarajan P, Gudde R, Srinivasan R, eds. Essentials of laboratory animal science: Principles and practices. Springer: Singapore, 2021.

21. Gjörloff K, Andréasson S, Ehinger B. Standardized full-field electroretinography in rabbits. Doc Ophthalmol. 2004; 109 (2): 163–8. doi: 10.1007/s10633-004-3924-5

22. McCulloch DL, Marmor MF, Brigell MG, et al. ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol. 2015; 130 (1): 1–12. https://doi.org/10.1007/s10633-014-9473-7

23. Zueva M.V., Neroev V.V., Tsapenko I.V., et al. Topographic diagnosis of retinal dysfunction in case of rhegmatogenous retinal detachment by the rhythmic ERG method of a wide range of frequencies. Russian ophthalmological journal. 2009; 1 (2): 18–23 (In Russ.).

24. Bach M, Brigell MG, Hawlina M, et al. ISCEV standard for clinical pattern electroretinography (PERG). Doc Ophthalmol. 2013; 126: 1–7. https://doi.org/10.1007/s10633-012-9353-y

25. Marzo A, Bai J, Otani S. Neuroplasticity regulation by noradrenaline in mammalian brain. Curr Neuropharmacol. 2009; 7 (4): 286–95. doi: 10.2174/157015909790031193

26. Polak K., Schmetterer L, Riva CE. Influence of flicker frequency on flicker-induced changes of retinal vessel diameter. Invest Ophthalmol Vis Sci. 2002; 43 (8): 2721–6.

27. Riva CE, Falsini B, Logean E. Flicker-evoked responses of human optic nerve head blood flow: luminance versus chromatic modulation. Invest Ophthalmol Vis Sci. 2001; 42 (3): 756–62.

28. Reichenbach A, Bringmann A. New functions of muller cells. Glia. 2013; 61 (5): 651–78. https://doi.org/10.1002/glia.22477

29. Falsini B, Riva CE, Logean E. Flicker-evoked changes in human optic nerve blood flow: relationship with retinal neural activity. Invest Ophthalmol Vis Sci. 2002; 43: 2309–16.

30. Riva CE, Logean E, Falsini B. Temporal dynamics and magnitude of the blood flow response at the optic disk in normal subjects during functional retinal flicker stimulation. Neurosci Lett. 2004; 356 (2): 75–8. https://doi.org/10.1016/j.neulet.2003.08.069

31. Noonan JE, Lamoureux EL, Sarossy M. Neuronal activity-dependent regulation of retinal blood flow. Clin Exp Ophthalmol. 2015; 43: 673–82. https://doi.org/10.1111/ceo.12530