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Fig. 13.3 Examples of probes for acute retinal stimulation experiments in human. (a) Polyimide stimulator used by Hornig et al. [10]. The thin and flexible polyimide device has a width of 1.6 mm. Active electrodes with diameters between 50 and 360 mm are placed at the tip of the device, the return electrodes are at the base of the device adjacent to the metal housing. (b) 17.5 Gauge steel cannula with several stimulation electrodes at the tip as used by Humayun and coauthors [12]. (c) 125 mm thin curved platinum wires for direct electrical stimulation of the retinal surface as used by Humayun and co-authors [12]
13.4 Threshold Measurements
The first approach in such settings is always the determination of thresholds at which a stimulation pulse or pulse series yields a phosphene. A two alternative forced choice method is usually applied. In such experiments threshold is commonly defined as the lowest stimulus intensity at which on 75% or more of the test repetitions the patient correctly reports a visual percept.
Also catch trials are usually employed in acute retinal stimulation testing, i.e. a stimulus is indicated, e.g., by a warning tone, but no electric pulse is given. If the subject gives a positive answer the answer is classified as false positive. Such catch trials are needed to test the reliability of a subject in this very demanding situation. Only those experiments should be analyzed in which patients do not give too many false positive responses. The criterion at which tests should not be used because of too many false positive responses should be defined for each experiment [10].
Threshold measurements were reported by Rizzo [14, 15]. In his series visual responses in patients with advanced RP could not be obtained with needle type electrodes because the charge density would exceed toxicity limits. They used
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oxidized iridium as electrode material based on a polyimide substrate. With 250 ms per phase stimulus duration threshold currents were around 1.5 mA for 400 mm electrodes in diameter. For 1 ms per phase stimulus duration the stimulus current at threshold was between 0.8 and 0.4 mA and for 16 ms per pulse phase stimulus currents at threshold were around 200 mA. Based on these experiments the rheobase was calculated as 125 mA with a chronaxie of 2.3 ms per pulse phase. When charge densities were calculated they found that for 100 mm electrodes the charge densities at threshold were between 4 and 10 mC/cm2, for 400 mm between 0.28 and 2.8 mC/cm2 which was larger than their own safety limit (1 and 0.252 mC/cm2, resp.).
In Humayun’s series nine blind RP patients were acutely stimulated with either platinum wires (25–125 mm diameter) used as electrodes or disc electrodes each 400 mm in diameter. Charges et threshold were reported between 0.2 and 2.4 mC which gives charge densities between 1 and 96 mC/cm2. The higher values were obtained for needle type electrodes [13].
13.5 Spatial Resolution and Pattern Perception
The main prerequisite for the recognition of forms and patterns is a correct retinotopical representation of the stimulus within the visual field. Humayun was able to show in his series, that stimuli were correctly identified in terms of their location within the retina resp. within the visual field. This was also confirmed by animal experiments. Spatial resolution can only be tested with electrode arrays when two electrodes or electrode clusters are stimulated simultaneously. The patient has to be asked if he sees two spots of light or two distinct patterns. In Humayun’s series he calculated a spatial resolution of 1.75° which could be achieved with epiretinal stimulation [11, 12]. These authors calculated based on simulations by Cha et al. [2] that placing a 32 × 32 array over a central field of 0.5 × 0.5 mm onto the macula surface would result in a 20/26 Snellen visual acuity. A spacing of 90 mm between each electrode would then reduce the visual acuity to 20/200. However, such electrode arrays are currently not available. Such devices are desirable when AMD treatment is supposed to be performed with such implants.
In a series of experiments in four blind subjects Rizzo and coworkers answered the question if blind patients are able to identify a stimulus pattern [15]. Only in one out of three patients more than 50% of the given patterns could be identified. Two-point discrimination was also tested in this series and only in very few experiments Rizzo’s group was able to find patient responses suggesting the perception of two separate objects. In these experiments the electrodes were 1,860 mm apart.
Acute stimulation experiments were not performed with any camera picture input. However, electrodes can be activated as if a certain pattern should be seen such as a large letter H. Humayun did such experiments in his series and he found that patients were able to detect patterned phosphenes. They used a 25 electrode array with a pattern “U” and patient reported a “H” type pattern which the authors thought to be the result of a blurring effect due to unstable positioning [13].
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13.6 Temporal Resolution
Experiments to systematically determine temporal resolution in acute tests for retinal stimulation have not been reported in detail so far for human subjects. Early results indicated that the flicker fusion frequency may be similar for electrical stimulation and for normal vision [12]. From animal experiments it should be expected that 25 frames per second could be transferred with a retinal implant [6]. It can be expected that data on temporal resolution will be extracted from the clinical trials on retinal prostheses, which are now being performed. This information is important, because useful vision elicited with prosthetic devices does not only depend on spatial characteristics but also on the time necessary to transmit a pattern from the implant to the primary visual cortex and to identify it. The type of visual sensations that can be obtained.
If patients are asked after the procedure what they have seen, the descriptions vary considerably between individuals. However, a few aspects are common. Usually the patients did not experience any unpleasant sensations. With suprathreshold stimulation patients reported dots, arcs, circles and lines of different intensity, color, and orientation. Stimulation by one electrode may not necessarily result in the perception of one single percept or phosphene but also in multiple phosphenes as reported in one volunteer by Rizzo [15]. The size of the objects does also vary with respect to the electrode size, the stimulus intensity, and duration. The characteristics of the phosphenes were reproducible; i.e. the stimulus pattern X elicits the same phosphene when it was repeated at the same retinal area. Weiland and colleagues tested two subjects before removal of the eye due to cancer. In these patients they destroyed part of the outer retina with argon green and krypton red laser photocoagulation. They stimulated normal retina and the laser treated areas with a 125 mm platinum wire electrode. The percept after stimulation of the normal retina was a dark oval shaped phosphene whereas stimulation in the krypton red treated area revealed a small white spot. Stimulation of the argon green treated area resulted in a line type of percept. Stimulus threshold at the normal retinal area in their experiments were 0.8 and 4.8 mC/cm2 respectively. The percepts being described by blind RP patients were similar to those obtained over the krypton red treated normal retinas. From a histological work-up of the stimulated retina Weiland concluded that the target for electrical stimulation with an epiretinal electrode is not the ganglion cell layer but the inner nuclear layer [19].
The shape of the percepts varied significantly with the stimulus pattern or with the orientation of the activated electrodes of the array. In Rizzo’s series circles were seen when columnar electrodes along the axon orientation were activated but also curved lines [15].
13.7 Subretinal Versus Epiretinal Stimulation
Acute retinal stimulation experiments in blind humans were only reported for epiretinal stimulation, not for subretinal stimulation. Acute tests on subretinal stimulation so far have only been reported for rabbits and pigs but not for blind
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humans [7, 16]. Therefore major assumptions as confirmed for epiretinal stimulation were so far not confirmed for subretinal stimulation scenarios.
13.8 Less Invasive Stimulation Procedures
Electrical retinal stimulation can also be performed placing electrodes outside the eye. It has been shown that even by using corneal electrodes or electrodes placed onto the scleral surface it is possible to elicit visual phosphenes. Gekeler and colleagues investigated phosphenes upon electrical stimulation via DTL electrodes placed in the fornix. They found that in some RP patients such phosphenes could not be elicited. The rheobase for RP patients was 0.69 + 0.10 mA which is 18 times higher than for normal individuals [8]. Similar experiments were performed by Delbeke and colleagues. They used corneal surface electrodes with large periorbital reference electrodes. Their estimation for rheobase varied between 2.14 and 8.16 mA and for chronaxie they found values between 0.45 and 0.87 ms whereas for healthy volunteers rheobase was 0.28 mA and the mean chronaxie was 3.07 ms [4]. In our own experience in patients with advanced stages of retinitis pigmentosa the currents necessary to obtain visual percepts with such approaches are very high and close to current with which other subjective sensations such as pain or muscle tics were evoked. Such approaches are proposed to identify patients prior to surgery who may benefit from a chronic implant. Only those patients would be selected in which phosphenes can be obtained with such non-invasive techniques. However, we learned that in RP patients even when they do not respond to external stimulation or the stimulation has to be stopped because of unpleasant somatosensory sensations the same patient may have visual sensations with a chronic implant.1 Therefore, we feel that such a test is not useful to identify good candidates for retinal implants.
13.9 Conclusions and Outlook
The available data from acute trials in electrical retinal stimulation showed that at least with epiretinal stimulation visual responses can be obtained and that the energies necessary to achieve such responses are dependent on the material of the electrodes and on their sizes and shapes. A close contact between the electrode and the retina is desirable to elicit visual responses with low stimulus intensities. A deeper knowledge of the mechanisms of retinal stimulation as well as of the phosphenes which are elicited and their role in providing vision for a blind patient is necessary. Such information can only be obtained by chronic stimulation experiments in which enough time is available to study more stimulus parameters, more electrode positions over a longer time period and to allow the patients to learn how to interpret the percepts
1Walter (2005) unpublished observation.