Effects of location and timing of co-activated neurons in the auditory midbrain on cortical activity: implications for a new central auditory prosthesis

Abstract

Objective: An increasing number of deaf individuals are being implanted with central auditory prostheses, but their performance has generally been poorer than for cochlear implant users. The goal of this study is to investigate stimulation strategies for improving hearing performance with a new auditory midbrain implant (AMI). Previous studies have shown that repeated electrical stimulation of a single site in each isofrequency lamina of the central nucleus of the inferior colliculus (ICC) causes strong suppressive effects in elicited responses within the primary auditory cortex (A1). Here we investigate if improved cortical activity can be achieved by co-activating neurons with different timing and locations across an ICC lamina and if this cortical activity varies across A1.

Approach: We electrically stimulated two sites at different locations across an isofrequency ICC lamina using varying delays in ketamine-anesthetized guinea pigs. We recorded and analyzed spike activity and local field potentials across different layers and locations of A1.

Results: Co-activating two sites within an isofrequency lamina with short inter-pulse intervals (<5 ms) could elicit cortical activity that is enhanced beyond a linear summation of activity elicited by the individual sites. A significantly greater extent of normalized cortical activity was observed for stimulation of the rostral-lateral region of an ICC lamina compared to the caudal-medial region. We did not identify any location trends across A1, but the most cortical enhancement was observed in supragranular layers, suggesting further integration of the stimuli through the cortical layers.

Significance: The topographic organization identified by this study provides further evidence for the presence of functional zones across an ICC lamina with locations consistent with those identified by previous studies. Clinically, these results suggest that co-activating different neural populations in the rostral-lateral ICC rather than the caudal-medial ICC using the AMI may improve or elicit different types of hearing capabilities.

Figure 1.

(a) The A1 recording locations, overlaid on a typical guinea pig cortex, with color representing the BF for each location averaged across layers I–V. Only sites that were BF-matched to ICC pairs were included and analyzed. (b) The midbrain and array placements were reconstructed in three dimensions and normalized onto a single brain. Green shanks correspond to ICC placements which were electrically stimulated (in pairs). Black and red shanks are placements on the border of or outside the ICC, as determined by FRMs along the shank (see Results). The 10 kHz isofrequency lamina was approximated by a plane at a depth which corresponds to neurons with 10 kHz BF, the average BF of the stimulated ICC sites. (c) The locations of the stimulated sites in the ICC were plotted along with the border and outside ICC sites across the 10 kHz lamina. (d) Analysis of the location effects across an ICC lamina was performed by determining the midpoint between each stimulated pair of ICC neurons. Scale bars are 1 mm. A1, primary auditory cortex; BF, best frequency; ICC, central nucleus of the inferior colliculus; SC, superior colliculus; IC, inferior colliculus; D, dorsal; C, caudal; L, lateral; R, rostral.

Figure 2.

A comparison of LFP and spiking responses measured simultaneously across different layers of a single A1 shank for one stimulation case within one animal in response to one stimulation level. While greater responses at shorter IPIs were observed at all layers, the most enhancement for both LFPs and DSRs was observed in layer I/II. (a) Recorded in layers I/II (top), III/IV (middle) and V (bottom) of A1, LFPs increase in response to DSS as IPIs decrease from 8 to 0 ms (right to left columns). (b) PSTHs recorded in layers I/II and III/IV of A1 in response to DSS at IPIs from 0 to 8 ms. (c) LFP areas and DSRs were calculated for each layer of A1. (d) For the different layers, IPI curves were created by normalizing cortical responses to the sum of responses to individual pulses. The normalization factor 1 is indicated by the dashed line. Electrical artifacts were removed in A and B. Time is relative to initial stimulus onset. DSR, driven spike rate; LFP, local field potential; IPI, inter-pulse interval; PSTH, post-stimulus time histogram.

Figure 3.

The effects of different stimulation levels on the normalized LFP (a) and DSR (b) responses recorded in layer III/IV of A1 in response to DSS applied at a single ICC pair. One ICC site from the pair was stimulated at the level indicated in each plot while the other ICC site was stimulated at a constant level. The IPI curves were averaged across the stimulation levels to calculate the IPI-a curves, shown in black in each panel. Only levels that were above threshold and below saturation were analyzed. Though some differences could be observed between curves across levels, there were no obvious or consistent trends across levels for either the normalized LFP or DSR data.

Figure 4.

Summary of LFP (a) and DSR (b) responses across A1 layers, averaged across all stimulation cases and animals (N = number of stimulation cases). For IPIs between 0–4 ms for LFP areas and 0–8 ms for DSRs, activity in layer I/II was significantly increased above the deeper layers (marked by asterisks; see text for P-values).

Figure 5.

A case example of how stimulating different locations across an ICC isofrequency lamina alters IPI and IPI-a curves recorded in one cortical location from a single animal. (a) The midpoint locations of four pairs of ICC sites stimulated across the ICC lamina are shown with other ICC midpoint locations for reference. Elicited activity was recorded in one cortical location in layer III/IV. (b) For pair #2–4, we found stimulation levels that elicited similar cortical activity at the 8 ms IPI and found that LFP areas increased more at shorter IPIs with more rostral–lateral stimulation locations. Stimulating pair #1 did not result in reliable LFP areas for this cortical location within the threshold bounds of our electrode arrays. (c) When averaged across stimulation levels, the IPI-a curves confirm that more rostral locations reveal higher levels of cortical activity. Error bars are standard deviations across levels. The scale bar is 1 mm.

Figure 6.

DSS in rostral–lateral ICC elicits greater normalized LFP areas across cortical layers than caudal–medial regions. (a) The amount of elicited normalized LFP area (color) is shown for the midpoint location between each pair of stimulated ICC sites (dots) at the 0 ms IPI. Cortical activity was averaged across A1 locations within a specific layer if multiple locations recorded activity elicited from one pair of sites. Using multiple linear regression to fit the cortical activity as a function of the ICC midpoint location, the steepest gradient axis (line) was found. The angle of the steepest gradient is shown, where 0 would indicate alignment with the medial to lateral axis and 90° would indicate alignment with the caudal to rostral axis. The scale bar is 1 mm. (b) Normalized LFP area is shown as a function of midpoint location along the steepest gradient axis, where 0 is the most caudal–medial location and 1 is the most rostral–lateral location. SGA: steepest gradient axis.

Figure 7.

(a) Normalized DSRs (color) recorded in supragranular and granular layers of the cortex are shown for the midpoint between each stimulation location. (b) Normalized DSR is plotted as a function of the midpoint location across the steepest gradient axis ((a) black line). Similar to figure 6, DSS of rostral–lateral areas results in greater normalized DSR activity than caudal–medial areas. The scale bar is 1 mm.

Figure 8.

The ICC lamina was split into caudal–medial versus rostral–lateral regions (a) by the line perpendicular to the average steepest gradient axis, which is the average direction where cortical activity varies the most for the 0 and 0.5 ms IPI. The midpoint between each stimulation pair was determined to originate from one of those two regions. The A1 locations, overlaid on the cortex with BF values (b), recorded activity elicited from the caudal–medial region similar to those of the rostral–lateral region (c). The scale bars are 1 mm. Note that panels with A1 locations are boxed while ICC locations are open.

Figure 9.

The location of sites across A1 does not have a clear impact on the amount of normalized LFP area (top) or DSRs (bottom) recorded across different layers (columns). Indicated by color (no units), the normalized cortical activity for each location was averaged across stimulated locations in the ICC. The scale bars are 1 mm.

Figure 10.

Histograms of FSLs for all stimulation cases recorded in layer III/IV (a) and layer I/II (b) at the 0 ms IPI. When comparing sites recorded from the same A1 location, FSLs recorded in layer I/II were on average ~3 ms longer than those in layer III/IV at the 0 ms IPI (c) as well as all IPIs from 0–8 ms (d).

Figure 11.

Comparisons across different experiments show that caudal–medial regions exhibit different response properties than rostral–lateral ICC regions in locations which, when electrically stimulated, elicit different cortical responses. (a) Normalized LFPs recorded in layer I/II (color) were typically smaller in the caudal–medial region and enhanced in rostral–lateral region across the 10 kHz isofrequency lamina of the ICC. (b) In response to 10 kHz pure tones (0.5 ms), the duration of PSTHs were longer in the caudal–medial region and shorter in the rostral–lateral region across the 10 kHz isofrequency lamina of the ICCs (data originally presented in Straka et al [20]). (c) A1 stimulation caused excitatory responses in the caudal–medial but not the rostral–lateral region of the ICC for sites with BFs of 10–16 kHz (data originally presented in Markovitz et al [80]). These excitatory responses could be present across a few or many frequency laminae (i.e., broadly tuned (BT) or narrowly tuned (NT), respectively). Locations from (a), (b), and (c) were normalized in the same standard brain and locations were taken across the 10 kHz lamina.