Electrical Stimulation of the Retina to Produce Artificial Vision Hamed Shabani 2017-09-17

Anatomy and Structure of the Eye

Retina

Offcenter and Oncenter

Functional RGC types of the mouse retina

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

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

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

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).

Types of Retinal Prostheses

Types of Retinal Prostheses

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

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.

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

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

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

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.

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)

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

Effects of stimulus pulse duration and amplitude on RGC responses

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).

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

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.

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

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).

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

Desensitization of ganglion cell response

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)

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).

The most energy efficient stimulus pulse duration

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

RETINAL PROSTHESES UNDER DEVELOPMENT

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.