Research ArticleRETINAL PROSTHESES

Improving the spatial resolution of epiretinal implants by increasing stimulus pulse duration

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Science Translational Medicine  16 Dec 2015:
Vol. 7, Issue 318, pp. 318ra203
DOI: 10.1126/scitranslmed.aac4877
  • Fig. 1. Effects of stimulus pulse duration on RGC responses to electrical stimulation.

    Electrode size (200-μm diameter) is the same as the Argus II retinal implant. (A) Burst stimulation with 0.4-ms pulses activated a streak of RGCs extending from the transparent stimulating electrode (green circle) to the edge of the retina. Left: Fluorescence image mosaic of the GCaMP5G-labeled retina before stimulation. Right: Background-subtracted GCaMP5G responses to electrical stimulation. (B) Spatial threshold maps. The stimulating electrode is drawn as a black circle. Each colored dot represents the average threshold charge density (log2 scale) needed to stimulate cells at its location. Unfilled gray dots indicate areas containing cells that did not respond to stimulation. Small, medium, and large dots specify one to two, three to four, and five or more cells, respectively. Maps are oriented such that the optic disc lies to the left of the image, with axons running horizontally toward their originating somata on the right [same orientation as (A)]. Each map contains data from three or four retinas (table S2). (C) Threshold as a function of displacement from electrode center for 100-ms pulses (n = 344 RGCs). (D) Change in RGC stimulation threshold as a function of pulse width in the presence of synaptic blockers [CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), d-APV (d-aminophosphovalerate), l-APB (l-aminophosphonobutyrate), strychnine, and picrotoxin]. Pulses longer than 8 ms did not evoke responses in the presence of blockers. Thresholds for all pulse widths except 0.06 ms rose significantly once blockers were applied (**P < 0.001 compared to the no-blocker condition with paired t tests). Error bars indicate SEM. Data were fit with an inverse sigmoid: y = − a ln[b/(xc) − 1] + d.

  • Fig. 2. Comparison of 20-Hz sine and square wave stimulation.

    Electrode diameter is 200 μm. Sine wave thresholds are specified in zero-to-peak amplitude. (A) Spatial threshold maps (as in Fig. 1B). The sine wave map (top) contains data from three retinas (table S2). Of the 344 cells that we imaged far (≥225 μm) to the right of the electrode perimeter, only 5 were stimulated antidromically. On the basis of the maximum stimulus amplitude delivered, the minimum selectivity ratio (see the Supplementary Materials) for 20-Hz sine waves was 16.7. The square wave map (bottom) is the same one shown in Fig. 1B for 25-ms pulses, except that the color scale has been changed. (B) Individual RGC thresholds for 20-Hz sine and square waves. Each data point represents a different cell (n = 121). Data were combined from two retinas. Square wave thresholds were 22.8 ± 35.5% higher than sine wave thresholds (P < 0.001, generalized estimating equations comparing means adjusted for repeated measures; percent change calculated from raw means).

  • Fig. 3. Effects of RD (top row) and electrode size (subsequent rows) on RGC responses to electrical stimulation.

    Spatial threshold maps for three pulse durations that cover the gamut of response types: direct RGC stimulation (0.06 ms, left column), combined ganglion and bipolar cell stimulation (1 ms, middle column), and bipolar cell stimulation (25 ms, right column) in RD and wild-type (WT) rats. Each map contains data from three or four retinas (table S2). In all cases, 0.06-ms pulses provided good selectivity for local somata over passing axons, 1-ms pulses provided poor selectivity (fig. S1), and 25-ms pulses produced focal responses. The bottom row shows background-subtracted GCaMP5G responses to suprathreshold stimuli for 30-μm-diameter electrodes (red circles). Images from each retina were transformed into the same reference frame and averaged.

  • Fig. 4. Patterns resulting from multielectrode stimulation of RGCs.

    (A) Line stimulation with four 30-μm-diameter electrodes (red circles) on a 75-μm pitch. Electrodes are oriented transverse (top and middle rows) and parallel (bottom row) to axon bundles. Leftmost images show local ganglion cell layer anatomy as revealed by Alexa Fluor 594 fluorescence (see Materials and Methods). Subsequent images show background-subtracted GCaMP5G responses to stimulation at different amplitudes [minimum current (Imin) is slightly above threshold]. Responses generally become stronger with increasing amplitude. Top row: Pulse width is 0.1 ms. Middle and bottom rows: Pulse width is 25 ms. (B) Left: Letters patterned onto a single retina with transparent 75-μm-diameter electrodes (green circles) on a 150-μm pitch. Pulse width is 25 ms. The letters conform to the definition of Snellen optotype, which requires a critical detail size (stroke and gap width) that subtends one-fifth of the total height. Right: The word LIFT spelled by combining the letters L, F, and T with a line pattern from (A). The image shows the actual size of the word at typical reading distance (40 cm).

  • Fig. 5. Effect of stimulus pulse duration on phosphene shape in a retinal prosthesis subject.

    (A) Stimulus waveform, a train of either 0.45-ms-per-phase (red) or 25-ms-per-phase (blue) pulses, each applied at 20 Hz for a duration of 500 ms. Twenty-five–millisecond pulses were presented as sinusoids to increase the likelihood of staying within electrochemical safety limits (see Fig. 2). Pseudosinusoids were used because the implant hardware does not permit stimulation with true sine waves. (B) Subject’s drawings of phosphenes elicited from stimulation with electrode C4 (top row) and C3 (bottom row). Plots show the average percept drawn across up to five trials (see table S4). The electrode diameter is 520 μm (top row) or 260 μm (bottom row).

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/318/318ra203/DC1

    Results

    Fig. S1. Selectivity ratios (mean axon threshold divided by mean soma threshold) for different stimulus pulse durations.

    Fig. S2. Strength-duration curves for 200-μm-diameter electrodes.

    Fig. S3. Multielectrode stimulation of RGCs with synchronous pulses.

    Fig. S4. Multielectrode stimulation of RGCs with temporally interleaved pulses.

    Fig. S5. Charge injection limits for short and long pulses.

    Table S1. Electrical stimulation parameters used in the single-electrode calcium imaging experiments.

    Table S2. Number of retinas and RGCs that make up each threshold map.

    Table S3. Comparison of thresholds in wild-type and RD retinas for three pulse widths.

    Table S4. Effect of stimulus pulse duration on phosphene elongation in a retinal prosthesis subject.

    Movie S1. Single-electrode stimulation with 1-ms pulses.

    Movie S2. Multielectrode stimulation with 25-ms pulses.

    Reference (50)

  • Supplementary Material for:

    Improving the spatial resolution of epiretinal implants by increasing stimulus pulse duration

    Andrew C. Weitz, Devyani Nanduri, Matthew R. Behrend, Alejandra Gonzalez-Calle, Robert J. Greenberg, Mark S. Humayun, Robert H. Chow,* James D. Weiland*

    *Corresponding author. E-mail: jweiland{at}med.usc.edu (J.D.W.); rchow{at}med.usc.edu (R.H.C.)

    Published 16 December 2015, Sci. Transl. Med. 7, 318ra203 (2015)
    DOI: 10.1126/scitranslmed.aac4877

    This PDF file includes:

    • Results
    • Fig. S1. Selectivity ratios (mean axon threshold divided by mean soma threshold) for different stimulus pulse durations.
    • Fig. S2. Strength-duration curves for 200-μm-diameter electrodes.
    • Fig. S3. Multielectrode stimulation of RGCs with synchronous pulses.
    • Fig. S4. Multielectrode stimulation of RGCs with temporally interleaved pulses.
    • Fig. S5. Charge injection limits for short and long pulses.
    • Table S1. Electrical stimulation parameters used in the single-electrode calcium imaging experiments.
    • Table S2. Number of retinas and RGCs that make up each threshold map.
    • Table S3. Comparison of thresholds in wild-type and RD retinas for three pulse widths.
    • Table S4. Effect of stimulus pulse duration on phosphene elongation in a retinal prosthesis subject.
    • Legends for movies S1 and S2
    • Reference (50)

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1. (.mov format). Single-electrode stimulation with 1-ms pulses.
    • Movie S2 Multielectrode stimulation with 25-ms pulses.

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