Intracortical Microstimulation Modulates Cortical Induced Responses

Abstract

Recent advances in cortical prosthetics relied on intracortical microstimulation (ICMS) to activate the cortical neural network and convey information to the brain. Here we show that activity elicited by low-current ICMS modulates induced cortical responses to a sensory stimulus in the primary auditory cortex (A1). A1 processes sensory stimuli in a stereotyped manner, encompassing two types of activity: evoked activity (phase-locked to the stimulus) and induced activity (non-phase-locked to the stimulus). Time-frequency analyses of extracellular potentials recorded from all layers and the surface of the auditory cortex of anesthetized guinea pigs of both sexes showed that ICMS during the processing of a transient acoustic stimulus differentially affected the evoked and induced response. Specifically, ICMS enhanced the long-latency-induced component, mimicking physiological gain increasing top-down feedback processes. Furthermore, the phase of the local field potential at the time of stimulation was predictive of the response amplitude for acoustic stimulation, ICMS, as well as combined acoustic and electric stimulation. Together, this was interpreted as a sign that the response to electrical stimulation was integrated into the ongoing cortical processes in contrast to substituting them. Consequently, ICMS modulated the cortical response to a sensory stimulus. We propose such targeted modulation of cortical activity (as opposed to a stimulation that substitutes the ongoing processes) as an alternative approach for cortical prostheses.SIGNIFICANCE STATEMENT Intracortical microstimulation (ICMS) is commonly used to activate a specific subset of cortical neurons, without taking into account the ongoing activity at the time of stimulation. Here, we found that a low-current ICMS pulse modulated the way the auditory cortex processed a peripheral stimulus, by supra-additively combining the response to the ICMS with the cortical processing of the peripheral stimulus. This artificial modulation mimicked natural modulations of response magnitude such as attention or expectation. In contrast to what was implied in earlier studies, this shows that the response to electrical stimulation is not substituting ongoing cortical activity but is integrated into the natural processes.

Keywords: auditory cortex; cortical implant; hearing; neuroprosthetic; oscillation.

Figure 1.

Methodology. A, Photograph showing the exposed cortex and the recording electrode arrangement. The double shank recording/stimulation electrode array was inserted through a hole in the substrate of the rectangular 16-channel surface electrode array placed on A1. PSS, Pseudo-sylvian sulcus. B, Recording/stimulation channel parameters. The first 16 channels (Shank 1) of the depth electrode array could be connected to a dedicated current source. Cortical layers have been assigned to single electrodes according to literature (Wallace and Palmer, 2008) and current source density profiles (Voigt et al., 2017). C, Schematic of the stimulus combination used. Auditory (condensation click, 50 μs, 40 dB above ABR hearing threshold) and electric stimuli (biphasic, 200 μs/phase, cathodic-leading, ∼3 μA) have been presented either alone or in combination. In combined conditions the auditory stimulus was always leading the electric stimulus with a delay (Δt) of 5, 15, or 25 ms of the electric stimulus.

Figure 2.

Response of A1 to transient acoustic stimulation. A, Example of multiunit activity elicited by acoustic click stimuli. In the raster plot of the first 16 channels (top), as well as the collapsed peristimulus time histogram (bottom) a strong primary excitation (evoked response) is visible, followed by a weaker secondary excitation (induced response). In the raster plot (top), each dot marks one action potential. The horizontal lines separate the data from different electrodes. For each electrode the response to each of 30 stimulus repetitions is shown stacked. B, Whereas the evoked response is visible in the trial-averaged LFP response, the induced response is more difficult to distinguish from background activity. C, Grand mean time-frequency representation (baseline-corrected, total power) showed the strong early response component, as well as a longer-latency response in the 100–300 ms time window (vertical dashed lines). Horizontal dashed lines show borders of the frequency band definition used herein (α < 15 Hz, 16 < β < 30 Hz, 31< γ_low < 60 Hz, γ_high > 60 Hz).

Figure 3.

Quantification of the response of A1 to transient acoustic stimulation. A, Grand average of the intertrial phase coherence averaged over the electrodes of Shank 1. B, Collapse of the phase-locking factor over all frequencies (dark green line = mean, shaded area = SD) shows that during the first 100 ms the intertrial phase coherence drops below the critical value for statistical significance, i.e., the early response is evoked (= phase-locked to the stimulus) and the long-latency response is induced (= non-phase-locked). C–F, Amplitude of the evoked response (C, E) and induced response (D, F) as a function of cortical layer (C, D) and frequency band (E, F) for Shank 1 (left) and Shank 2 (right) *p < 0.05, **p < 0.01. G, Amplitude of the evoked response (left) and induced response (right) calculated from the time-frequency response of 16 surface electrodes. H, Example trace of the low-pass filtered ECoG signal (ECoG-LFP) in response to acoustic stimulation showing the same time course as depth recordings. I, Spatial plots of ECoG-LFP amplitude at different time points. The click stimulus evoked a widespread biphasic response between 10 and 35 ms after the stimulation, followed by a slow negative component and a weaker, spatially more inhomogeneous long-latency positive component.

Figure 4.

Response of A1 to intracortical microstimulation. A, Grand average of total power (Shank 1) for electrical stimulation in each cortical layer. B, Grand average of intertrial phase coherence (Shank 1) for electrical stimulation in each cortical layer. C, Cluster-based permutation test for statistically significant differences between responses to acoustic stimulation and electric stimulation in each layer (black contour = statistically significant clusters, p < 0.05). Warm colors (yellow/orange) signify more power in the auditory condition; cool colors (blue) signify more power in the electric condition. D, Single example of the time-frequency representation of activity evoked by electric-only stimulation with 45 μA. Data from a separate animal, recording electrode in layer 2, ICMS in layer 1. E, Evoked response amplitude (mean ± SEM) as a function of recorded layers for electrodes on Shank 1 (left) and Shank 2 (right). See F for color code. F, Evoked response amplitude (mean ± SEM) as a function of frequency band for Shank 1 (left) and Shank 2 (right). Different shades of orange mark different stimulated layers. G, Example trace of the ECoG-LFP signal in response to ICMS. Only the early evoked response is visible. H, Spatial plots of the grand mean of ECoG-LFP response amplitude at different time points (x = approximate position of the stimulation electrode). I, Spatial plot of the grand mean of peak ECoG-LFP response in the 50 ms poststimulation for ICMS in each cortical layer. J, Quantification of peak evoked response amplitude (mean ± SEM) for stimulation in each layer. K, Approximation of observed ECoG amplitudes (a.u.) for stimulation in different cortical depths as the sum of a linear and nonlinear model equation with arbitrarily chosen parameters, representing the distance of a dipole from the surface and the effectivity of ICMS as a function of cortical depth respectively (for a detailed explanation, see Results).

Figure 5.

Response of A1 to combined acoustic and electric stimulation. A, Example of total power, average of the supragranular electrodes of Shank 1, for combined auditory and electric stimulation (A&E, left), acoustic stimulation alone (A, middle left), electric stimulation alone (E, middle right), and the difference between those (right), calculated as A&E − (A + E). B, Grand mean of phase-locking factor for combined stimulation, average of all electrodes of Shank 1 and all stimulated layers at Δt = 5 ms. C, Phase-locking factor collapsed over frequencies. Responses up to 100 ms poststimulation were statistically phase-locked (= evoked, dark orange line = mean, shaded area = SD). D, Evoked response amplitude (mean ± SEM) for combined stimulation as a function of stimulated layer for electrodes of Shank 1 (left), Shank 2 (middle), and from the surface (ECoG, right). Different colored lines mark different time delays between acoustic and electrical stimulus. E, Evoked response amplitude (mean ± SEM) as a function of frequency band for electrodes of Shank 1. For color code see D. F, Peak of induced response of the calculated difference for a delay of 5 ms (left) and auditory only stimulation (middle). Each dot represents a single experiment (blue = super-additive, dark gray = neutral). Stacked bar chart showing the percentage of experiments classified as super-additive (right).

Figure 6.

Combined acoustic and electric stimulation shows supra-additive enhancement of long-latency induced responses. A, Grand mean of the difference (supragranular recording electrodes, supra-additive experiments) for stimulation in each cortical layer with a delay of 5 ms, for Shank 1 (top row), and Shank 2 (bottom row). B, Same as A, but for Δt = 15 ms. C, Same as A, but for Δt = 25 ms. D–F, Peak induced difference (supragranular electrodes, Shank 1) as a function of stimulation delay (D), stimulated layer (E; Δt = 5 ms), and frequency band (F; Δt = 5 ms). Each dot represents a single experiment (blue = super-additive, dark gray = neutral). *p < 0.05 for one-sample t tests showing statistically significant differences from 0.

Figure 7.

Influence of trial-to-trial prestimulus phase on response amplitudes. A, Example LFP in response to acoustic only stimulation, colored according to the instantaneous phase of the signal (8 bins, −π to π). The dashed green line marks the time of acoustic stimulation and the dotted orange lines mark the possible time points at which in combined stimulation an electrical stimulus was presented. The delays (Δt) of 5, 15, and 25 ms ensured that the electric pulse was applied in three different phase bins. Δϕ denotes the time relative to stimulus onset. B, Evoked LFP response amplitude (z-scored) for single trials, acoustic only stimulation, as a function of LFP phase at Δϕ = −300 ms (left) and Δϕ = 0 ms (right) for an example electrode. Data of all experiments (n = 9) and all trials (n = 30) were pooled. Each dot marks one trial. The modulation index (MI) was calculated as the maximal minus the minimal bin average (8 bins, −π to π, mean ± SD). C, Same as B for electric only stimulation, at Δϕ = −300 ms (left) and Δϕ = −5 ms (right). D, MI calculated for instantaneous phase at different prestimulus time points (Δϕ) in acoustic only stimulation. E, Same as D for electric only stimulation. Different shades of orange mark different stimulated layers. Mean ± SEM. F, Modulation index for auditory only stimulation calculated with phase at Δϕ = −300 ms (left) and Δϕ = 0 ms (right), as a function of recorded layer. Light green, Shank 1; dark green, Shank 2. Each dot represents a single electrode. G, Same as F for electric only stimulation. Different shades of orange mark different stimulated layers. H, Same as G for combined stimulation (evoked response, Δt = 5 ms) calculated for the single-trial amplitude of low-gamma (30–60 Hz) activity. I, Same as D for combined stimulation (induced response, Δt = 5 ms). Different shades of orange mark different stimulated layers. Mean ± SEM J, Same as H but for the low-gamma activity amplitude in the induced response time-window.