Electrical Stimulation publications

The ability to localize a sound source in complex environments is essential for communication and navigation. Spatial hearing relies predominantly on the comparison of differences in the arrival time of sound between the two ears, the interaural time differences (ITDs). Hearing impairments are highly detrimental to sound localization. While cochlear implants (CIs) have been successful in restoring many crucial hearing capabilities, sound localization via ITD detection with bilateral CIs remains poor. The underlying reasons are not well understood. Neuronally, ITD sensitivity is generated by coincidence detection between excitatory and inhibitory inputs from the two ears performed by specialized brainstem neurons. Due to the lack of electrophysiological brainstem recordings during CI stimulation, it is unclear to what extent the apparent deficits are caused by the binaural comparator neurons or arise already on the input level. Here, we use a bottom-up approach to compare response features between electric and acoustic stimulation in an animal model of CI hearing. Conducting extracellular single neuron recordings in gerbils, we find severe hyper-precision and moderate hyper-entrainment of both the excitatory and inhibitory brainstem inputs to the binaural comparator neurons during electrical pulse-train stimulation. This finding establishes conclusively that the binaural processing stage must cope with highly altered input statistics during CI stimulation. To estimate the consequences of these effects on ITD sensitivity, we used a computational model of the auditory brainstem. After tuning the model parameters to match its response properties to our physiological data during either stimulation type, the model predicted that ITD sensitivity to electrical pulses is maintained even for the hyper-precise inputs. However, the model exhibits severely altered spatial sensitivity during electrical stimulation compared to acoustic: while resolution of ITDs near midline was increased, more lateralized adjacent source locations became inseparable. These results directly resemble recent findings in rodent and human CI listeners. Notably, decreasing the phase-locking precision of inputs during electrical stimulation recovered a wider range of separable ITDs. Together, our findings suggest that a central problem underlying the diminished ITD sensitivity in CI users might be the temporal hyper-precision of inputs to the binaural comparator stage induced by electrical stimulation.

We examined the effect of neonatal deafening on frequency-specific pathways for processing of interaural time differences (ITDs) in cochlear-implant stimuli. Animal studies have demonstrated differences in neural ITD sensitivity in the inferior colliculus (IC) depending on the intracochlear location of intracochlear stimulating electrodes. We used neonatally deafened (ND) rats of both sexes and recorded the responses of single neurons in the IC to electrical stimuli with ITDs delivered to the apical or basal cochlea and compared them with acutely deafened (AD) rats of both sexes with normal hearing (NH) during development. We found that neonatal deafness significantly impacted the ITD sensitivity and the ITD tuning patterns restricted to apically driven IC neurons. In ND rats, the ITD sensitivity of apically driven neurons is reduced to values similar to basally driven neurons. The prevalence of ITD-sensitive apical neurons with a peak-shaped ITD tuning curve, which may reflect predominant input from the medial superior olivary (MSO) complex, in ND rats was diminished compared with that in AD rats (67%, AD vs 40%, ND). Conversely, monotonic-type responses rarely occurred in AD rats (14%) but were approximately equally as prevalent as peak-type tuning curves in ND rats (42%). Nevertheless, in ND rats, the ITD at the maximum slope of the ITD tuning curve was still more concentrated within the physiological ITD range in apically driven than in basally driven neurons. These results indicate that the development of high ITD sensitivity processed by low-frequency pathways depends on normal auditory experience and associated biases in ITD tuning strategies.

Severe hearing loss or deafness is often caused by cochlear hair cell loss and can be mitigated by a cochlear implant (CI). CIs target the auditory nerve, consisting of spiral ganglion cells (SGCs), which degenerate gradually, following hair cell loss. In animal models, it has been established that treatment with the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) reduce SGC degeneration. In this study, we aimed to investigate whether treatment with both BDNF and NT-3 (Cocktail) is superior to treatment with each neurotrophin separately regarding cell preservation and neural responsiveness to electrical stimulation. To this end, deafened guinea pigs received neurotrophic treatment in their right ear via a gelatin sponge on the perforated round window membrane, followed by cochlear implantation 4 weeks later in the same ear for electrophysiological recordings to various stimulation paradigms. Normal-hearing and deafened untreated guinea pigs were included as positive and negative controls, respectively. Substantial SGC loss occurred in all deafened animals. Each of the neurotrophic treatments led to enhanced SGC survival mainly in the basal turn of the cochlea, gradually decreasing toward the apex. The Cocktail treatment resulted in the highest SGC survival in the treated ear, followed by BDNF, with the least protection of SGCs following NT-3 treatment. Survival of the SGC’s peripheral processes (PPs) followed the same trend in response to the treatment. However, survival of SGCs and PPs in the contralateral untreated ears was also highest in the Cocktail group. Consequently, analysis of the ratio between the treated and untreated ears showed that the BDNF group, which showed low SGC survival in the untreated ear, had the highest relative SGC survival of the three neurotrophin-treated groups. Neurotrophic treatment had positive effects in part of the electrically evoked compound action-potential recording paradigms. These effects were only observed for the BDNF or Cocktail treatment. We conclude that treatment with either BDNF or a cocktail of BDNF and NT-3 is preferred to NT-3 alone. Furthermore, since the Cocktail treatment resulted in better electrophysiological responsiveness and overall higher SGC survival than BDNF alone, we are inclined to recommend the Cocktail treatment rather than BDNF alone.

Fear and anxiety are brain states that evolved to mediate defensive responses to threat. While it is clear that the defense reaction includes multiple interacting behavioural, autonomic and endocrine adjustments, their integrative nature is poorly understood. In particular, threat has been associated with various cardiac changes, yet a clear consensus on their relevance for the integrated defense reaction is missing. We here define rapid microstates associated with specific behaviours and heart rate dynamics, both affected by long-lasting macrostates and reflecting context-dependent threat levels. In addition, we demonstrate that one of the most commonly used defensive behavioural responses, freezing measured by immobility, is part of an integrated cardio-behavioural microstate mediated by specific midbrain circuit elements. Our work puts forth a framework for systematic integration of cardiac and behavioural readouts that presents the basis for a better understanding of complex neural defensive states and their associated systemic functions.

Voluntary stream segregation was investigated in cochlear implant (CI) users and normal-hearing (NH) listeners using a segregation-promoting objective approach which evaluated the role of spectral and amplitude-modulation (AM) rate separations on stream segregation and its build-up. Sequences of 9 or 3 pairs of A and B narrowband noise (NBN) bursts were presented which differed in either center frequency of the noise band, the AM-rate, or both. In some sequences (delayed sequences), the last B burst was delayed by 35 ms from their otherwise-steady temporal position. In the other sequences (no-delay sequences), the last B bursts were temporally advanced from 0 to 10 ms. A single interval yes/no procedure was utilized to measure participants’ sensitivity ( d ′ ) in identifying delayed vs. no-delay sequences. A higher d ′ value showed the higher ability to segregate the A and B subsequences. For NH listeners, performance improved with each spectral separation. However, for CI users, performance was only significantly better for the condition with the largest spectral separation. Additionally, performance was significantly poorer for the largest AM-rate separation than for the condition with no AM-rate separation for both groups. The significant effect of sequence duration in both groups indicated that listeners made more improvement with lengthening the duration of stimulus sequences, supporting the build-up effect. The results of this study suggest that CI users are less able than NH listeners to segregate NBN bursts into different auditory streams when they are moderately separated in the spectral domain. Contrary to our hypothesis, our results indicate that AM-rate separation may interfere with the segregation of streams of NBN. Additionally, our results add evidence to the literature that CI users build up stream segregation at a rate comparable to NH listeners, when the inter-stream spectral separations are adequately large.

Aminoglycosides (AGs) are commonly used antibiotics that cause deafness through the irreversible loss of cochlear sensory hair cells (HCs). How AGs enter the cochlea and then target HCs remains unresolved. Here, we performed time-lapse multicellular imaging of cochlea in live adult hearing mice via a chemo-mechanical cochleostomy. The in vivo tracking revealed that systemically administered Texas Red–labeled gentamicin (GTTR) enters the cochlea via the stria vascularis and then HCs selectively. GTTR uptake into HCs was completely abolished in transmembrane channel-like protein 1 (TMC1) knockout mice, indicating mechanotransducer channel-dependent AG uptake. Blockage of megalin, the candidate AG transporter in the stria vascularis, by binding competitor cilastatin prevented GTTR accumulation in HCs. Furthermore, cilastatin treatment markedly reduced AG-induced HC degeneration and hearing loss in vivo. Together, our in vivo real-time tracking of megalin-dependent AG transport across the blood–labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.

Objective: To investigate the hearing protection outcomes of different drug-eluting analog electrode arrays implanted into guinea pig cochleae. Methods: Sixty guinea pigs were randomly divided into a negative control group and five experimental groups implanted separately with blank (drug carrier), dexamethasone (DXM), aracytine (Ara-C), Ara-C+DXM, and nicotinamide adenine dinucleotide (NAD+) eluting analog electrode arrays. Micro CT was used to supervise the surgical procedure. Auditory brainstem response (ABR) thresholds of the guinea pigs were measured and analyzed. Results and conclusions: Compared with the negative control, all other groups showed a significant increase in ABR threshold (p<0.001) after surgery. Among them, there was no obvious difference between the blank (0 vs 90 days: 59.70±10.57 vs 64.60±9.47 dB SPL) and the NAD+ group (0 vs 90 days: 59.90±9.87 vs 64.70±8.65 dB SPL). On the other hand, the ABR thresholds in the DXM (0 days: 58.10±10.73 dB SPL; 90 days: 51.70±9.07 dB SPL) and the Ara-C group (0 days: 59.00±10.05 dB SPL; 90 days: 51.60±8.48 dB SPL) decreased significantly compared with the former two groups (p<0.001). However, the Ara-C+DXM group showed no further benefit (p>0.05). In addition, a significantly higher survival rate of spiral ganglion neurons in cochleae was observed in the Ara-C and/or DXM groups.

The protective effect of the efferent system against acoustic trauma (AT) has been shown by several experimental approaches, including damage to one ear, sectioning of the olivocochlear bundle (OCB) in the floor of the IV ventricle, and knock-in mice overexpressing outer hair cell (OHC) cholinergic receptors, among others. Such effects have been related to changes in the regulation of the cholinergic efferent system and in cochlear amplification, which ultimately reverse upon protective hearing suppression. In addition to well-known circuits of the brainstem, the descending corticofugal pathway also regulates efferent neurons of the olivary complex. In this study, we applied our recently developed experimental paradigm of multiple sessions of electrical stimulation (ES) to activate the efferent system in combination with noise overstimulation. ABR thresholds increased 1 and 2 days after AT (8–16 kHz bandpass noise at 107 dB for 90 min) recovering at AT + 14 days. However, after multiple sessions of epidural anodal stimulation, no changes in thresholds were observed following AT. Although an inflammatory response was also observed 1 day after AT in both groups, the counts of reactive macrophages in both experimental conditions suggest decreased inflammation in the epidural stimulation group. Quantitative immunocytochemistry for choline acetyltransferase (ChAT) showed a significant decrease in the size and optical density of the efferent terminals 1 day after AT and a rebound at 14 days, suggesting depletion of the terminals followed by a long-term compensatory response. Such a synthesis recovery was significantly higher upon cortical stimulation. No significant correlation was found between ChAT optical density and size of the buttons in sham controls (SC) and ES/AT + 1day animals; however, significant negative correlations were shown in all other experimental conditions. Therefore, our comparative analysis suggests that cochleotopic cholinergic neurotransmission is also better preserved after multisession epidural stimulation.

Recent studies have shown that rats are a useful model for binaural cochlear implant (CI) research, with behavioral sensitivity to interaural time differences (ITDs) of CI stimuli which are better than those of human patients. Here, we characterize ITD tuning in the rat inferior colliculus (IC) and explore whether quality of tuning can predict behavioral performance. We recorded IC responses to stimuli of varying pulse rates and envelope types and quantified both mutual information (MI) and neural d ′ as measures of ITD sensitivity. Neural d ′ values paralleled behavioral ones, declining with increasing click rates or when envelopes changed from rectangular to Hanning windows. While MI values increased with experience, neural d ′ did not. However, neural d ′ values correlated much better with behavioral performance than MI. Thus, neural d ′ appears to be a particularly well suited to predicting how stimulus parameters will impact behavioral performance.

Hearing loss is a sensory deprivation that can affect the quality of life. Currently, only rehabilitation devices such as hearing aids and cochlear implants are used, without a definitive cure. However, in chronic hearing‐deprived patients, in whom secondary auditory neural degeneration is expected, a relatively poor rehabilitation prognosis is projected. Stem cell therapy for cochlear neural structures would be an easier and feasible strategy compared with cochlear sensory cells. Considering the highly developed cochlear implantation technology, improving cochlear neural health has significant medical and social effects. Stem cell delivery to Rosenthal’s canal in an acutely damaged mouse model has been performed and showed cell survival and the possibility of differentiation. The results of stem cell transplantation in chronic auditory neural hearing loss should be evaluated because neural stem cell replacement therapy for chronic (long‐term) sensorineural hearing loss is a major target in clinics. In the present study, we established a mouse model that mimicked chronic auditory neural hearing loss (secondary degeneration of auditory neurons after loss of sensory input). Then, mouse embryonic stem cells (mESCs) were transplanted into the scala tympani and survival and distribution of transplanted cells were compared between the acute and chronic auditory neural hearing loss models induced by ouabain or kanamycin (KM), respectively. The mESC survival was similar to the acute model, and perilymphatic distribution of cell aggregates was more predominant in the chronic model. Lastly, the effects of mESC transplantation on neural signal transduction observed in the cochlear nucleus (CN) were compared and a statistical increase was observed in the chronic model compared with other models. These results indicated that after transplantation, mESCs survived in the cochlea and increased the neural signaling toward the central auditory pathway, even in the chronic (secondary) hearing loss mouse model.

In deaf subjects using a cochlear implant (CI) for hearing restoration, the auditory nerve is subject to degeneration, which may negatively impact CI effectiveness. This nerve degeneration can be reduced by neurotrophic treatment. Here, we compare the preservative effects of the naturally occurring tyrosine receptor kinase B (TrkB) agonist brain-derived neurotrophic factor (BDNF) and the small-molecule TrkB agonist 7,8,3′-trihydroxyflavone (THF) on the auditory nerve in deafened guinea pigs. THF may be more effective than BDNF throughout the cochlea because of better pharmacokinetic properties. The neurotrophic compounds were delivered by placement of a gelatin sponge on the perforated round window membrane. To complement the histology of spiral ganglion cells (SGCs), electrically evoked compound action potential (eCAP) recordings were performed four weeks after treatment initiation. We analyzed the eCAP inter-phase gap (IPG) effect and measures derived from pulse-train evoked eCAPs, both indicative of SGC healthiness. BDNF but not THF yielded a significantly higher survival of SGCs in the basal cochlear turn than untreated controls. Regarding IPG effect and pulse-train responses, the BDNF-treated animals exhibited more normal responses than both untreated and THF-treated animals. We have thus confirmed the protective effect of BDNF, but we have not confirmed previously reported protective effects of THF with our clinically applicable delivery method.

Corticofugal modulation of auditory responses in subcortical nuclei has been extensively studied whereas corticofugal synaptic transmission must still be characterized. This study examined postsynaptic potentials of the corticocollicular system, i.e., the projections from the primary auditory cortex (AI) to the central nucleus of the inferior colliculus (ICc) of the midbrain, in anesthetized C57 mice. We used focal electrical stimulation at the microampere level to activate the AI (ESAI) and in vivo whole-cell current-clamp to record the membrane potentials of ICc neurons. Following the whole-cell patch-clamp recording of 88 ICc neurons, 42 ICc neurons showed ESAI-evoked changes in the membrane potentials. We found that the ESAI induced inhibitory postsynaptic potentials in 6 out of 42 ICc neurons but only when the stimulus current was 96 μA or higher. In the remaining 36 ICc neurons, excitatory postsynaptic potentials (EPSPs) were induced at a much lower stimulus current. The 36 ICc neurons exhibiting EPSPs were categorized into physiologically matched neurons (n = 12) when the characteristic frequencies of the stimulated AI and recorded ICc neurons were similar (≤1 kHz) and unmatched neurons (n = 24) when they were different (>1 kHz). Compared to unmatched neurons, matched neurons exhibited a significantly lower threshold of evoking noticeable EPSP, greater EPSP amplitude, and shorter EPSP latency. Our data allow us to propose that corticocollicular synaptic transmission is primarily excitatory and that synaptic efficacy is dependent on the relationship of the frequency tunings between AI and ICc neurons.

This protocol was used to collect data now published in the Journal of Neural Engineering, Sources of off-target effects of vagus nerve stimulation using the helical clinical lead in domestic pigs, see Metadata for citation. Additionally, the dataset is publicly available on Pennsieve 10.26275/qcuk-a8ty.

Nowadays, the majority of the progress in the development of implantable neuroprostheses has been achieved by improving the knowledge of brain functions so as to restore sensorial impairments. Intracortical microstimulation (ICMS) is a widely used technique to investigate site-specific cortical responses to electrical stimuli. Herein, we investigated the neural modulation induced in the primary auditory cortex (A1) by an acousto-electric transduction of ultrasonic signals using a bio-inspired intracortical microstimulator. The developed electronic system emulates the transduction of ultrasound signals in the cochlea, providing bio-inspired electrical stimuli. Firstly, we identified the receptive fields in the primary auditory cortex devoted to encoding ultrasonic waves at different frequencies, mapping each area with neurophysiological patterns. Subsequently, the activity elicited by bio-inspired ICMS in the previously identified areas, bypassing the sense organ, was investigated. The observed evoked response by microstimulation resulted as highly specific to the stimuli, and the spatiotemporal dynamics of neural oscillatory activity in the alpha, beta, and gamma waves were related to the stimuli preferred by the neurons at the stimulated site. The alpha waves modulated cortical excitability only during the activation of the specific tonotopic neuronal populations, inhibiting neural responses in unrelated areas. Greater neuronal activity in the posterior area of A1 was observed in the beta band, whereas a gamma rhythm was induced in the anterior A1. The results evidence that the proposed bio-inspired acousto-electric ICMS triggers high-frequency oscillations, encoding information about the stimulation sites and involving a large-scale integration in the brain.

In all commercial cochlear implant (CI) devices, the electric stimulation is performed with a rectangular pulse that generally has two phases of opposite polarity. To date, developing new stimulation strategies has relied on the efficacy of this shape. Here, we investigate the potential of a novel stimulation paradigm that uses biophysically-inspired electrical ramped pulses. Using electrically-evoked auditory brainstem response (eABR) recordings in mice, we found that less charge, but higher current level amplitude, is needed to evoke responses with ramped shapes that are similar in amplitude to responses obtained with rectangular shapes. The most charge-efficient pulse shape had a rising ramp over both phases, supporting findings from previous in vitro studies. This was also true for longer phase durations. Our study presents the first physiological data on CI-stimulation with ramped pulse shapes. By reducing charge consumption ramped pulses have the potential to produce more battery-efficient CIs and may open new perspectives for designing other efficient neural implants in the future.

Age-related hearing loss (ARHL) is associated with weakened inhibition in the central auditory nervous system including the cochlear nucleus. One of the main inhibitory neurons of the cochlear nucleus is the D-stellate neuron, which provides extensive glycinergic inhibition within the local neural network. It remains unclear how physiological activities of D-stellate neurons change during ARHL and what are the underlying mechanisms. Using in vitro whole-cell patch clamp technique, we studied the intrinsic membrane properties of D-stellate neurons, the changes of their firing properties, and the underlying mechanisms in CBA/CaJ mice at the ages of 3–4 months (young), 17–19 months (middle age), and 27–33 months (aged). We found that the intrinsic membrane properties of D-stellate neurons were unchanged among these three age groups. However, these neurons showed decreased firing rate with age in response to sustained auditory nerve stimulation. Further investigation showed that auditory nerve-evoked excitatory postsynaptic currents (EPSCs) were significantly reduced in strength with age. These findings suggest that D-stellate neurons receive weakened synaptic inputs from the auditory nerve and decreased sound driven activity with age, which are expected to reduce the overall inhibition and enhance the central gain in the cochlear nucleus during ARHL.

Rat auditory cortex was subjected to 0.1 mA anodal direct current in seven 10-min sessions on alternate days. Based on the well-known auditory cortex control of olivocochlear regulation through corticofugal projections, auditory brainstem responses (ABRs) were recorded as an indirect test of the effectiveness and reversibility of the multisession protocol of epidural stimulation. Increases of 20-30 dB ABR auditory thresholds shown after epidural stimulation reverted back to control levels 10 min after a single session. However, increases in thresholds revert 4 days after multisession stimulation. Less changes in wave amplitudes and threshold shifts were shown in ABR recorded contralaterally to the electrically stimulated side of the brain. To assess tissue effects of epidural electric stimulation on the brain cortex, well characterized functional anatomical markers of glial cells (GFAP/astrocytes and Iba1/microglial cells) and neurons (c-Fos) were analyzed in alternate serial sections by quantitative immunocytochemistry. Restricted astroglial and microglial reactivity was observed within the cytoarchitectural limits of the auditory cortex. However, interstitial GFAP overstaining was also observed in the ventricular surface and around blood vessels, thus supporting a potential global electrolytic stimulation of the brain. These results correlate with extensive changes in the distribution of c-Fos immunoreactive neurons among layers along sensory cortices after multisession stimulation. Quantitative immunocytochemical analysis supported this idea by showing a significant increase in the number of positive neurons in supragranular layers and a decrease in layer 6 with no quantitative changes detected in layer 5. Our data indicate that epidural stimulation of the auditory cortex induces a reversible decrease in hearing sensitivity due to local, restricted epidural stimulation. A global plastic response of the sensory cortices, also reported here, may be related to electrolytic effects of electric currents.

We proposed a piezoelectric artificial basilar membrane (ABM) composed of a microelectromechanical system cantilever array. The ABM mimics the tonotopy of the cochlea: frequency selectivity and mechanoelectric transduction. The fabricated ABM exhibits a clear tonotopy in an audible frequency range (2.92–12.6 kHz). Also, an animal model was used to verify the characteristics of the ABM as a front end for potential cochlear implant applications. For this, a signal processor was used to convert the piezoelectric output from the ABM to an electrical stimulus for auditory neurons. The electrical stimulus for auditory neurons was delivered through an implanted intra-cochlear electrode array. The amplitude of the electrical stimulus was modulated in the range of 0.15 to 3.5 V with incoming sound pressure levels (SPL) of 70.1 to 94.8 dB SPL. The electrical stimulus was used to elicit an electrically evoked auditory brainstem response (EABR) from deafened guinea pigs. EABRs were successfully measured and their magnitude increased upon application of acoustic stimuli from 75 to 95 dB SPL. The frequency selectivity of the ABM was estimated by measuring the magnitude of EABRs while applying sound pressure at the resonance and off-resonance frequencies of the corresponding cantilever of the selected channel. In this study, we demonstrated a novel piezoelectric ABM and verified its characteristics by measuring EABRs.