1. Electrical Stimulation of the Retina to Produce Artificial Vision
Hamed Shabani

2. Anatomy and Structure of the Eye

3. Retina

4. Offcenter and Oncenter

5. Functional RGC types of the mouse retina

6. Eye disorders
Retinitis Pigmentosa (RP)
degeneration of photoreceptors
RP is an inherited disorder that results from harmful changes in any one of more than 50 genes
Age related Macular Degeneration(AMD).
photoreceptor degeneration in AMD begins in the macula
In severe end-stage RP, approximately 95% of photoreceptors, 20% of bipolar cells, and 70% of ganglion cells degenerate

7. Treatments
Gene therapy–based solutions for RP are currently being validated in animal models
A potential impediment for gene therapies is that there are many genetic mutations that cause RP, each of which would require a unique gene therapy solution
Another RP treatment under development uses optogenetics, which aims to impart light sensitivity to the remaining retinal neurons by introducing photovoltaic molecules or transmembrane proteins
Electronic retinal prostheses represent another RP therapy

8. Retinal Prostheses First attempt in 1929 (Foerster)
application of electric current to the occipital lobe was found to evoke a perception of light in patients
In 1968 (Brindley& Lewin 1968)
development of an 80-electrode implantable cortical visual prosthesis that proved capable of evoking visual percepts in a blind patient

9. cortical prostheses advantage of cortical prostheses
their effectiveness is largely independent of ocular health.
challenges for cortical prostheses
long-term stability of the electrode–tissue interface and the complexity of creating visual percepts.
It was later demonstrated that electrodes placed on the retina surface could evoke percepts via electrical stimulation in patients suffering from photoreceptor degeneration (Humayun et al. 1996).

10. Types of Retinal Prostheses

11. Types of Retinal Prostheses

12. Types of Retinal Prostheses
Epiretinal prosthesis arrays are placed on the ganglion cell surface within the vitreous space.
Subretinal prosthesis arrays are placed between bipolar cells and the retinal pigmented epithelium.
Suprachoroidal prosthesis arrays are either placed between the choroid and sclera or contained within the sclera

13. Bipolar cells and ganglion cells are the main targets of electrical stimulation.
Bipolar cells are interneurons that convey signals from photoreceptors to ganglion cells.
Ganglion cells are the output neurons of the retina whose axons exit the eye carrying imaging-forming input to the brain.

14. direct and indirect stimulation
Somatic Stimulation
Somatic stimulation refers to the direct activation of ganglion cell somas or axon initial segments that are located in the immediate vicinity of the stimulating electrode
Axonal Stimulation
Axonal stimulation refers to the activation of peripheral ganglion cell axons that pass beneath the stimulating electrode
indirect stimulation
Indirect stimulation refers to the activation of inner retinal neurons that in turn synaptically modulate postsynaptic ganglion cell activity

15. Direct Stimulation
activate ganglion cells with high temporal precision
during retinal degeneration, there is significant rewiring of the synaptic connections in the inner retina
This reorganization affects the baseline activity in ganglion cells causing them to rhythmically fire action potentials at a rate of 5 to 10 Hz in rd1 and rd10 mouse retina
increase the background noise carried from ganglion cells to the brain

16. Direct Stimulation
A prosthesis coupled with an encoder can stimulate ganglion cells directly in accordance to the predicted patterns
some encoders include the flexibility to iteratively tune stimulus parameters with patient feedback

17. Ganglion cell response
ON–OFF direction-selective and ON direction-selective ganglion cells follow up to approximately 200 pps.
local edge detector ganglion cells can follow up to 100 pps (Higher amplitude).
2,000-pps stimulation at 25 μA
activated brisk-transient ganglion cells
but only slightly activated direction-selective ganglion cells (Cai et al. 2013).
2,000- pps stimulation at 75 μA
activated these ganglion cells subclasses in the opposite manner.
This paradigm demonstrates a potential method to selectively stimulate different groups of ganglion.

18. Ganglion cell response
The location on ganglion cells with the lowest threshold to extracellular electrical stimulation is the axon initial segment because it contains a high density of voltage-gated sodium channels
In the retina, photoreceptor degeneration alters the input to ganglion cells, which could lead to modulation of the axon initial segment.
Disruption of the axon initial segment has been shown to limit the ability of ganglion cells to sustain high action-potential firing rates (Van Wart & Matthews 2006)

19. Axonal stimulation
Axonal activation occurs when axons of ganglion cells are depolarized by the electrical stimulus.

20. Effects of stimulus pulse duration and amplitude on RGC responses

21. Axonal stimulation
Achieving high spatial resolution is made difficult by axonal stimulation
to avoid axonal stimulation
short-duration (≤100-μs) pulses
an approximately twofold threshold dynamic range
frequency encoding can also modulate percept brightness
Long-duration (25-ms) pulses or low-frequency (<25-Hz) sinusoid stimulation can avoid axonal activation and provide focal activation of ganglion cells (Freeman et al. 2010; Weitz et al. 2013, 2015).

22. Indirect Stimulation
stimulating bipolar cells that in turn activate postsynaptic ganglion cells
The rationale for using indirect stimulation is that the stimulus will be processed and refined by the remaining retinal circuitry
produce a more natural ganglion cell output
Subretinal prostheses

23. Bipolar cell response
bipolar cells are known to respond to increments in light intensity with proportional changes in membrane potential
The spikes are mediated by voltage-gated calcium channels or voltage-gated sodium channels
At low stimulus amplitudes, sodium currents depolarize bipolar cells, but at sufficiently high amplitudes, bipolar cells hyperpolarize in response to the stimulus.

24. Ganglion cell response (Indirect Stimulation)
naturalistic output in ganglion
Freeman et al. (2010) found that low-frequency (5–25 Hz) sinusoids could activate bipolar cells while avoiding activation of underlying ganglion cell axons.
calcium-imaging studies examining indirect stimulation with long-duration (e.g., 25-ms) square pulses demonstrated that activated ganglion cells are local to the electrode
prosthesis patients reported generation of focal percepts in response to stimulation with long-duration pulses (Nanduri 2011)
Stimulation with the same electrode and shorter pulse durations evoked elongated percepts, suggesting an activation of ganglion cell axons (Nanduri et al. 2012).
supports the notion that selectively stimulation

25. Advantages and disadvantages of indirect method
Selectively stimulating the inner retina in human subjects may avoid axonal activation and generate focal percepts.
Disadvantages of using long-duration pulses
limit the maximal stimulation rate and require more charge (Geddes 2004).

26. spatial resolution attainable through indirect stimulation
The area of activated ganglion cells stimulated indirectly will reach a point where it stops shrinking significantly with further reduction in electrode size

27. Desensitization of ganglion cell response

28. Fading of electrically evoked percepts.
If the microsaccades are actively suppressed and fixation is stable about a point, perception of visual targets quickly fades (Coppola & Purves 1996, Martinez-Conde et al. 2006, Riggs et al. 1953)
Argus II epiretinal prosthesis
the majority of patients reported seeing an initially bright percept that faded over time (P´erez Fornos et al. 2012).
The fading occurred in less than 0.5 s for some patients and in 2–5 s for others. The kinetics of percept fading were similar in response to pulse rates of 5, 20, and 60 pps
Alpha IMS subretinal implant
percepts faded in 2 s for 2-pps stimulation, and in 0.5 s for 10-pps stimulation (Zrenner et al. 2011)

29. Fading of electrically evoked percepts.
A potential explanation for the persistent fading despite utilizing microsaccades is that the electrical stimulus from a single electrode may affect such a large region that shifting the stimulus to adjacent electrodes does not significantly change the activated neurons (Behrend et al. 2011).

30. The most energy efficient stimulus pulse duration

31. The most energy efficient stimulus pulse duration
The most energy efficient stimulus pulse duration for activating the neuron can be determined from the rheobase current (Geddes 2004).
This pulse duration is known as chronaxie and it corresponds to the stimulus duration found at twice the rheobase current along the strength- duration curve
ganglion cells having shorter membrane time constants than neurons of the inner retina (Ranck 1975).
Suggests that ganglion cells are able to integrate charge from the electrical stimulus only over a narrow time window in comparison to inner retinal neurons.
For ganglion cells, chronaxie has been measured to be between 0.08 and 0.6 ms

32. RETINAL PROSTHESES UNDER DEVELOPMENT

33. SUMMARY POINTS
1. Retinal prostheses use microelectrode arrays positioned near the retina to provide useful visual information to individuals blinded by retinitis pigmentosa.
2. Direct stimulation activates ganglion cells directly, whereas indirect stimulation activates ganglion cells by first activating inner retinal neurons that then synaptically drive ganglion cells.
3. Axonal activation results in antidromic activation of peripheral ganglion cells that is perceived by patients as an elongated percept, which may reduce the quality of the perception.
4. Short (<0.1-ms) and long (>25-ms) pulse durations may be best suited to avoid axonal activation and activate ganglion cells focally with respect to the stimulating electrode location while allowing for a large dynamic range of stimulation amplitudes before passing axons are activated.
5. Ganglion cells can respond faithfully to high rates of direct stimulation, but their response to indirect stimulation attenuates at high frequencies. This may contribute to percept fading noted in implant patients.