Changes across time in the temporal responses of auditory nerve fibers stimulated by electric pulse trains

Abstract

Most auditory prostheses use modulated electric pulse trains to excite the auditory nerve. There are, however, scant data regarding the effects of pulse trains on auditory nerve fiber (ANF) responses across the duration of such stimuli. We examined how temporal ANF properties changed with level and pulse rate across 300-ms pulse trains. Four measures were examined: (1) first-spike latency, (2) interspike interval (ISI), (3) vector strength (VS), and (4) Fano factor (FF, an index of the temporal variability of responsiveness). Data were obtained using 250-, 1,000-, and 5,000-pulse/s stimuli. First-spike latency decreased with increasing spike rate, with relatively small decrements observed for 5,000-pulse/s trains, presumably reflecting integration. ISIs to low-rate (250 pulse/s) trains were strongly locked to the stimuli, whereas ISIs evoked with 5,000-pulse/s trains were dominated by refractory and adaptation effects. Across time, VS decreased for low-rate trains but not for 5,000-pulse/s stimuli. At relatively high spike rates (>200 spike/s), VS values for 5,000-pulse/s trains were lower than those obtained with 250-pulse/s stimuli (even after accounting for the smaller periods of the 5,000-pulse/s stimuli), indicating a desynchronizing effect of high-rate stimuli. FF measures also indicated a desynchronizing effect of high-rate trains. Across a wide range of response rates, FF underwent relatively fast increases (i.e., within 100 ms) for 5,000-pulse/s stimuli. With a few exceptions, ISI, VS, and FF measures approached asymptotic values within the 300-ms duration of the low- and high-rate trains. These findings may have implications for designs of cochlear implant stimulus protocols, understanding electrically evoked compound action potentials, and interpretation of neural measures obtained at central nuclei, which depend on understanding the output of the auditory nerve.

Figures

FIG. 1

Examples IHs obtained from one ANF stimulated at three pulse rates (columns) and four levels (rows). In each of the three columns and for each level, three IHs are shown, corresponding to three temporal analysis windows (as labeled near the top of each column in italic print). Stimulus levels are indicated at the top left of each of the 12 panels. Comparisons across IHs for the three analysis windows reveal effects of adaptation that occur across the duration of each pulse train. Unique, two-peaked IHs can be seen for the three higher-level IHs produced by the 5,000-pulse/s stimuli over the “onset” (0–12 ms) response epoch. In all cases, bin width was 50 μs.

FIG. 2

Examples of spikes evoked by 5,000-pulse/s trains from three fibers of three cats. Superimposed responses to the first 10 ms of repeated pulse trains are shown. In the spikes shown in the left column, two distinctly different ISIs are evident in response to the two highest stimulus levels, consistent with a two-peaked IH. Spikes from a second fiber (middle column) demonstrate somewhat different timing, with smaller differences between the first and second ISIs. That fiber also demonstrates a cumulative effect of increasing temporal variation within successive volleys of spikes. That pattern should not be interpreted simply as increased “jitter” but also as greater uncertainty in the stimulus pulse number that causes spike initiation. In the case of fiber D58-7-1 (right column), two-stage artifact reduction (box-car filtering followed by template subtraction) was required to reduce the impact of a relatively large ECAP potential that occurred across the first 1.5 ms of each trace. The ECAP subtraction resulted in distorted first spikes; specifically, those spikes had a large preceding negative peak (single asterisk) and a narrowed action potential (double asterisks). In this case of poor artifact subtraction, the occurrence of spike failures (i.e., relatively flat lines over the 0–1.5-ms epoch) reinforce the fact that the distorted spikes are, indeed, action potentials.

FIG. 3

The effect of pulse rate and response rate on first-spike latency. Mean first-spike latencies from individual ANFs are plotted using gray symbols and dotted lines, whereas across-fiber median values are plotted using larger, open symbols and solid lines. Response rates were computed by averaging spike activity across the entire 300-ms duration of the pulse-train stimuli (A 5,000-pulse/s, B 1,000-pulse/s, and C 250-pulse/s stimuli). The median values were computed using analysis windows centered at 50, 150, 250, 350, and 450 spike/s. The median data of A, B, and C, are replotted together in D to facilitate comparison of pulse-rate effects.

FIG. 4

Further examination of mean first-spike latencies. In contrast to the data of Figure 3, mean first-spike latencies from eight representative ANFs (from eight cats) are plotted vs. stimulus level (A–H). Data obtained with low-rate (250 pulse/s) stimuli are plotted using open circles, whereas data obtained using 5,000-pulse/s trains are plotted using filled triangles. Stimulus level is expressed in decibels relative to each subject’s ECAP threshold level. The scaling of each ordinate axis is identical.

FIG. 5

Summary plots demonstrating how ISI, VS, and FF vary over the duration of the 300-ms stimuli for low, 250-pulses/s stimuli (left panels) and high, 5,000-pulse/s stimuli (right panels). The several plots within each panel demonstrate response-rate effects. Data from all fibers were grouped according to “onset spike rate” (computed over the first 12-ms epoch) to facilitate across-ANF comparison of spike-rate effects. The spike-rate ranges were chosen so that the median values of each plot were similar for the low- and high-rate responses (e.g., plots with the same symbol type can be compared across the pulse rates). All plots report median values computed across fibers. The temporal analysis windows are shown, using gray rectangles, along the bottom abscissae. Note that different ordinate scales are used to plot the VS data for the two pulse rates. The dotted lines in the upper left panel indicate integer multiples of the stimulus period.

FIG. 6

“Steady state” values ISI, VS, and FF plotted as a function of onset spike rate. Data for low-rate (250 pulse/s) and high-rate (5,000 pulse/s) pulse trains are plotted using open circles and filled triangles, respectively. Group (across-fiber) values of each measure were computed for spike activity occurring within the final (200–300 ms) response epoch. “Onset spike rate” was computed over the initial (0–12 ms) response epoch. These data were derived from the plots of Figure 5 to more clearly demonstrate the effects of response rate on the measures assessed in the final response epoch.

FIG. 7

The effects of stimulus level and response rate on ISIs for ANF excited by 5,000-pulse/s trains. The effect of stimulus level on IH mode for 16 ANFs is plotted in A, whereas the effect of onset spike rate on IH mode for the same fibers is plotted in B. Systematic differences in IH mode can be seen across this group of fibers. In C are plotted IH modes for 78 ANFs as a function of response rate. Three sets of data are included in this graph, covering three response epochs. IH mode vs. spike rate are plotted for (1) the onset (0–12 ms) window, (2) the subsequent 12–24-ms window, and (3) the final (200–300 ms) response window. The hyperbola indicates the IH mode expected for ANFs firing at a constant rate. For response rates >200 spike/s, most data cluster near the hyperbola, with the exception of a subset of responses assessed over the onset (0–12 ms) epoch.

FIG. 8

Summary of a method used to compare VS values obtained at three pulse rates. The small, filled symbols of A, C, and D show VS values obtained from 37 ANFs at stimulus rates of 250, 1,000, and 5,000 pulse/s, respectively. Across-pulse-rate VS comparisons require accounting for the effect of different pulse periods on VS. This effect is shown in B, where simulated distributions of spike times were used to relate VS and jitter for the three pulse rates. Multiple symbols for fixed jitter and pulse rate reflect multiple simulations; smooth curves connect these points. These curves provided a means of predicting VS (for 1,000- and 5,000-pulse/s rates) under the assumption that an ANF’s jitter is not affected by stimulus rate. The predicted (constant jitter) VS values are plotted in C and D using filled diamond symbols. In the case of 5,000-pulse/s stimuli, all experimental data lie below the prediction curve for response rates greater than 200 spike/s, indicating spike desynchronization.

FIG. 9

Summary of the effects of (1) response rate, (2) stimulus rate, and (3) time after stimulus onset on FF. In A and B, FFs for all ANFs are plotted vs. response rate. The gray background regions in these graphs indicate the expected region (within 99% of cases) of FFs for a Poisson process with a 2-ms dead time (i.e., a refractory-driven process). In A, FFs computed over an early response epoch (4–50 ms) are plotted for each fiber and the three stimulus rates. In B, FFs are plotted for spikes occurring in the “steady state” (200–300 ms) response epoch. In C, median FFs – computed across fibers and several ranges of response rates – are plotted for 250- and 5,000-pulse/s stimuli, again computed over the “steady state” (200–300 ms) response epoch. Consistent symbol types are used across the three panels. The small numbers appearing above selected data in C indicate the ratios of FF obtained at 5,000 and 250 pulse/s, demonstrating increased stochasticity for the high-rate responses.