elicited a single burst of spikes within 20 ms following application of the electrical stimulus, type II cells elicited a single burst of spikes with a latency greater than 37 ms, and type III cells elicited two or more bursts of spikes. The similarity of electrically evoked responses in wild-type and rd1 mouse retinas led Jensen and Rizzo to suggest that postreceptoral neurons (not photoreceptors themselves) determine the response properties of RGCs to electrical stimuli.

12.4.2.2  Activation Thresholds of RGCs

As noted above (Sect. 12.4.1), O’Hearn et al. [36] examined the thresholds for activation of RGCs in wild-type and rd1 mouse retinas with a pair of electrodes that were positioned either epiretinally or subretinally. With subretinal stimulation, the thresholds for activation of RGCs in wild-type and rd1 retinas were not statistically different. In contrast, Jensen and Rizzo [21] reported that the thresholds of RGCs in rd1 mouse retinas were 3.6-fold higher than the thresholds of RGCs in wild-type mouse retinas. The elevated thresholds occurred for all ages examined, ranging from postnatal day (P) 25 to P186. Of the three types of RGCs identified (see Sect. 12.4.2.1), type I RGC cells appeared to be particularly affected.

The discrepancy in the findings between Jensen and Rizzo [21] and O’Hearn et al. [36] may be because Jensen and Rizzo were examining the thresholds of RGCs due to indirect activation (through the network), whereas O’Hearn et al might have been examining thresholds of RGCs to direct activation, judging from the short-latency (<3 ms) responses they reported in their study.

Although Jensen and Rizzo [22] proposed that photoreceptors lower the thresholds for activation of RGCs, the reason for the higher thresholds in rd1 mouse retinas is not yet fully understood. Bipolar cells provide most of the excitatory input to RGCs. Perhaps, a greater amount of depolarizing current is needed to stimulate neurotransmitter release from these cells, either from the absence of facilitatory effects from photoreceptors or due to early structural changes in the bipolar cells themselves.

12.5  Cortical Responses to Retinal Stimulation

12.5.1  Spatial Properties Revealed by Cortical Measurements

Several studies have explored the cortical response that result from electrical stimulation of the retina. These types of studies not only confirm that elicited retinal activity is transmitted to higher visual centers, they also provide a more global view of the results of stimulation. The position of cortical electrodes can vary from surface (scalp) to penetrating: less invasive methods typically record electrically elicited cortical potentials (EECPs) – slow potentials that reflect activity of large populations of neurons. On the other hand, more invasive methods (e.g. penetrating electrodes) record brief activity (action potentials) from only a few neurons (typically one or two).

12.5.2  Local Field Potentials

Penetrating electrodes that are appropriately positioned and configured can also record local field potentials (LFPs). Whereas spiking measures neuronal output, LFPs are thought to reflect input signals to the neuron and arise from the electric currents associated with dendritic activity of a relatively large number of nearby neurons [26, 27, 32, 33]. The time course of the LFP signal contains one early and several late components; the early component reflects direct synaptic input while later components reflect later processing most likely arising from intracortical connections­ [7, 59]. By carefully positioning the recording electrodes at layer IV of visual cortex (the input layer), and looking at only the early LFP components, a measure of the input signal to the visual cortex can be obtained. Presumably this is a direct assessment of the retinal output arising from electrical stimulation.

12.5.3  Elicited Responses Are Focal

Similar to the findings of Sekirnjak et al. [49], Schanze, Wilms, Eger and colleagues [8, 43, 45, 46, 59] found that retinal stimulation from a multielectrode array elicited small focal and spatially discrete regions of cortical activity (LFPs). The average size was approximately 1.3 mm of cortex corresponding to a visual angle of 1.5° although nearly 10% of the regions were much smaller (~0.4 mm cortex/0.5° visual angle). Similar sizes (0.68° visual angle) were obtained by Cottaris and Elfar [4] in a recent study that used similar methodology. Activated regions elicited by individual stimulating electrode were topographically arranged [46, 59] confirming that electrical stimulation is transmitted retinotopically. The activated cortical regions and corresponding stimulating electrodes were not perfectly aligned however [46, 59], possibly because of limited resolution from the cortical array or possibly because electrical stimulation activated axons of distal neurons.

The width of the activated cortical region increased with the amplitude of the stimulus pulse [59]. At threshold, the width of the activated region was smallest (average ~1°) increasing by 10% in response to doubling the amplitude and by 67% in response to a tenfold increase in amplitude. These increases are smaller than might be expected since a tenfold increase in amplitude would more than double the retinal area containing activated neurons. In contrast to the increases observed by Schanze and colleagues, Cottaris and Elfar [4] observed a reduction in width with increases in stimulus strength. Cottaris and Elfar speculate that the differences may arise from the differences in pulse durations used across the two studies, perhaps because different pulse durations target different classes of retinal neurons. Further study is needed to resolve the mechanism(s) by which patches of retinal activity are transformed into patches of cortical activity.

12.5.4  Cortical Measurements Reveal Electrode Interactions

A series of papers by Schanze, Wilms, Eger and colleagues [8, 43, 45, 46, 59] found evidence of interactions between nearby electrodes. Schanze et al. [45] found that both excitatory and inhibitory interactions occur and that the sign of the interaction depended on the distance between the retinal stimulating electrodes. Specifically, they found that electrode separations of 3–4° generated excitatory interactions resulting in cortical activation regions that were larger than the sum of the two individual regions. Smaller or larger electrode separations generated the opposite effect: inhibitory interactions where the size of the activation regions was less than the sum of the individual regions.

These studies are seemingly in conflict with those of Sekirnjak et al. [49] however, there are considerable methodological differences between the studies that might underlie the observed differences. For example, while the Sekirnjak et al. study reflects the activity of a limited number of RGCs, the cortical measurements presumably reflect the activity of a large population of retinal neurons. In addition, the input activity to cortex reflects synaptic processing that occurs in the thalamus. Any of these factors might account for the electrode interactions observed in the cortical studies. Understanding these interactions will be important for effectively constructing complex spatial images from individual percepts (phosphenes).

12.5.5  Temporal Responsiveness in Cortex

The maximum spiking rate in cortical neurons is typically around 50 Hz [16, 39]; considerably slower than the maximum rate of 250 Hz generated by RGCs (Sect. 12.2.1.6). This reduction in maximum spike rate is thought to occur at the synapse between RGCs and lateral geniculate neurons. Therefore, it is important to understand how the temporal parameters of retinal stimulation translate into the temporal response patterns of cortical neurons.

To study this, Wilms et al. [59] measured the temporal properties of the LFP early component. As mentioned earlier the early component of the LFP is thought provide a representative measure of the retinal output. Rise times (10–90%) ranged from 4.8 to 8.3 ms with lower values arising from higher amplitude stimuli. A sine curve was best fit to each rise time; the resultant frequencies of 40–70 Hz were obtained by multiplying each rise time by three. More sophisticated methods of estimating the temporal responsiveness yielded similar results. This suggests that that adequate temporal resolution may be achievable with electrical stimulation of the retina. Additional findings from Wilms et al. [59] suggest that larger amplitude pulses create better temporal resolution.

Unfortunately, the large amplitude stimulus pulses that increase temporal resolution may simultaneously lower the spatial resolution. The authors suggest that in clinical use these parameters could be varied depending on whether the patient has a more