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BackgroundSpatial hearing remains one of the major challenges for bilateral cochlear implant (biCI) users, and early deaf patients in particular are often completely insensitive to interaural time differences (ITDs) delivered through biCIs. One popular hypothesis is that this may be due to a lack of early binaural experience. However, we have recently shown that neonatally deafened rats fitted with biCIs in adulthood quickly learn to discriminate ITDs as well as their normal hearing litter mates, and perform an order of magnitude better than human biCI users.MethodsOur unique behaving biCI rat model allows us to investigate other possible limiting factors of prosthetic binaural hearing, such as the effect of stimulus pulse rate and envelope shape. Previous work has indicated that ITD sensitivity may decline substantially at the high pulse rates often used in clinical practice. We therefore measured behavioral ITD thresholds in neonatally deafened, adult implanted biCI rats to pulse trains of 50, 300, 900 and 1800 pulses per second (pps), with either rectangular or Hanning window envelopes.ResultsOur rats exhibited very high sensitivity to ITDs at pulse rates up to 900 pps for both envelope shapes, similar to those in common clinical use. However, ITD sensitivity declined to near zero at 1800 pps, for both Hanning and rectangular windowed pulse trains.ConclusionsCurrent clinical cochlear implant (CI) processors are often set to pulse rates ≥900 pps, but ITD sensitivity in human CI listeners has been reported to decline sharply above ∼300 pps. Our results suggest that the relatively poor ITD sensitivity seen at >300 pps in human CI users may not reflect the hard upper limit of biCI ITD performance in the mammalian auditory pathway. Perhaps with training or better CI strategies good binaural hearing may be achievable at pulse rates high enough to allow good sampling of speech envelopes while delivering usable ITDs.

Cochlear implants (CIs) are widely used neural prostheses to restore hearing in hearing impaired patients. The implant's platinum electrodes are comparable to microelectrodes typically used in bio- and chemo-sensors. We show how advanced electrochemical protocols can be used to turn CI electrodes into electrochemical sensors, e.g. for oxygen. The overall goal is to measure the implant's microenvironment and characterize electrode degradation in order to improve implant function and life-time. For the first time, we characterized the performance of CI electrodes as chemical sensors and demonstrated the in vivo measurement of intracochlear oxygen levels with a CI in an animal model.

An important challenge of neuroscience research and future brain machine interfacing is the reliable assignment of spikes to putative neurons. By means of extracellular recordings, researchers try to match different types action potentials with their putative neuronal source and timing. Unfortunately, this procedure is by far not standardized and reliable, leading to many different suggestions and as many differing results. It appears that sharing of data is thus hampered by different processing pipelines in different labs, thus playing along the reproducibility crisis in neurosciences. To systematically shed light on this issue, we present preliminary results of several easy event detection schemes on one data set, meant to illustrate the inconsistencies arising from different processing pipelines already in its initial step. The results indicate that thresholding choices alter findings due to a lack of a ground truth for spike sorting. We suggest to increase reliability in findings by only accepting and further processing events accepted by more than one processing pipeline.

For deaf patients cochlear implants (CIs) can restore substantial amounts of functional hearing. However, binaural hearing, and in particular, the perception of interaural time differences (ITDs) with current CIs has been found to be notoriously poor, especially in the event of early hearing loss. One popular hypothesis for these deficits posits that a lack of early binaural experience may be a principal cause of poor ITD perception in pre-lingually deaf CI patients. This is supported by previous electrophysiological studies done in neonatally deafened, bilateral CI-stimulated animals showing reduced ITD sensitivity. However, we have recently demonstrated that neonatally deafened CI rats can quickly learn to discriminate microsecond ITDs under optimized stimulation conditions which suggests that the inability of human CI users to make use of ITDs is not due to lack of binaural hearing experience during development. In the study presented here, we characterized ITD sensitivity and tuning of inferior colliculus neurons under bilateral CI stimulation of neonatally deafened and hearing experienced rats. The hearing experienced rats were not deafened prior to implantation. Both cohorts were implanted bilaterally between postnatal days 64-77 and recorded immediately following surgery. Both groups showed comparably large proportions of ITD sensitive multi-units in the inferior colliculus (Deaf: 84.8%, Hearing: 82.5%), and the strength of ITD tuning, quantified as mutual information between response and stimulus ITD, was independent of hearing experience. However, the shapes of tuning curves differed substantially between both groups. We observed four main clusters of tuning curves - trough, contralateral, central, and ipsilateral tuning. Interestingly, over 90% of multi-units for hearing experienced rats showed predominantly contralateral tuning, whereas as many as 50% of multi-units in neonatally deafened rats were centrally tuned. However, when we computed neural d' scores to predict likely limits on performance in sound lateralization tasks, we did not find that these differences in tuning shapes predicted worse psychoacoustic performance for the neonatally deafened animals. We conclude that, at least in rats, substantial amounts of highly precise, "innate" ITD sensitivity can be found even after profound hearing loss throughout infancy. However, ITD tuning curve shapes appear to be strongly influenced by auditory experience although substantial lateralization encoding is present even in its absence.

Cochlear implants are the most successful neural prostheses worldwide and routinely restore sensorineural hearing loss by direct electrical stimulation of the auditory nerve. Enhancing this standard implant by chemical sensor functionality opens up new possibilities, ranging from access to the biochemical microenvironment of the implanted electrode array to the long-term study of the electrode status. We developed an electrochemical method to turn the platinum stimulation microelectrodes of cochlear implants into electrochemical sensors. The electrodes showed excellent and stable chemical sensor properties, as demonstrated by in vitro characterizations with combined amperometric and active potentiometric dissolved oxygen and hydrogen peroxide measurements. Linear, stable and highly reproducible sensor responses within the relevant concentration ranges with negligible offset were shown. This approach was successfully applied in vivo in an animal model. Intracochlear oxygen dynamics in rats upon breathing pure oxygen were reproducibly and precisely measured in real-time from the perilymph. At the same time, correct implant placement and its functionality was verified by measurements of electrically evoked auditory brainstem responses with clearly distinguishable peaks. Acute measurements indicated no adverse influence of electrical stimulation on electrochemical measurements and vice versa. Our work is ground-breaking towards advanced implant functionality, future implant lifetime monitoring, and implant-life-long in situ investigation of electrode degradation in cochlear implant patients.

Neural implants that electrically stimulate neural tissue such as deep brain stimulators, cochlear implants (CI), and vagal nerve stimulators are becoming the routine treatment options for various diseases. Optimizing electrical stimulation paradigms requires closed-loop stimulation using simultaneous recordings of evoked neural activity in real time. Stimulus-evoked artifacts at the recording site are generally orders of magnitude larger than the neural signals, which challenge the interpretation of evoked neural activity. We developed a generalized artifact removal algorithm that can be applied in a variety of neural recording modalities. The procedure leverages known electrical stimulation currents to derive optimal filters that are used to predict and remove artifacts. We validated the procedure using paired recordings and electrical stimulation from sciatic nerve axons, high-rate bilateral CI stimulation, and concurrent multichannel stimulation in auditory midbrain and recordings in auditory cortex. We demonstrate a vast enhancement in the quality of recording even for high-throughput multi-site stimulation with typical improvements in the signal-to-noise ratio between 20-40 dB. The algorithm is efficient, can be scaled to arbitrary number of sites, and is applicable in range of recording modalities. It has numerous benefits over existing approaches and thus should be valuable for emerging neural recording and stimulation technologies.

Currently, there is controversy around whether rats can use interaural time differences (ITDs) to localize sound. Here, naturalistic pulse train stimuli were used to evaluate the rat's sensitivity to onset and ongoing ITDs using a two-alternative forced choice sound lateralization task. Pulse rates between 50 Hz and 4.8 kHz with rectangular or Hanning windows were delivered with ITDs between ±175 μs over a near-field acoustic setup. Similar to other mammals, rats performed with 75% accuracy at ∼50 μs ITD, demonstrating that rats are highly sensitive to envelope ITDs.

Aim of this study was to induce a single-sided deafness (SSD) in rats before hearing onset. Rats were operated at postnatal day 10 by approaching the tympanic cavity along a retroauricular path without manipulating ossicles or tympanic membrane. The ototoxic aminoglycoside neomycin was injected intracochlearly through the round window membrane on one side. When the animals have reached young adult stages, their hearing threshold was determined by their auditory brainstem response (ABR). Monaural deafening was considered successful when the hearing threshold was at least 95 dB above the threshold of the normal hearing ear. Growing up with one non-functional ear, rats developed a striking anatomical asymmetry of their cochlear nuclei (CN). The CN from age-matched normal hearing brains and from both sides of single-sided deaf brains were cut into series of frontal sections and their volumes calculated. No difference was detected between the volume of the normal hearing CN and the contralateral CN in SSD rats. By contrast, growth retardation was found for the ventral CN on the deaf side to result in a volume of only 57% compared to the normal hearing side. Marginal growth retardation was also observed for the dorsal CN on the deaf side. Thus, loss of sensory activation leads mainly, but not exclusively, to a reduction of tissue volume in the ventral CN of the deaf side, leaving the contralateral side apparently unaffected.

Worldwide, almost 500 million people are hearing impaired, making hearing loss the most common sensory impairment among humans. For people with single-sided deafness (SSD), cochlear implants (CIs) can be enormously beneficial by providing binaural information. However, binaural benefits in CI users have been only incompletely realized. Overcoming these limitations requires a better knowledge of how neuronal circuits adapt to SSD and how unilateral CI stimulation can compensate a deaf ear. We investigated effects of neonatal SSD on auditory brainstem circuitry using acoustic (AS), electric (ES), or acoustic stimulation on one ear and electric stimulation on the other ear (AS + ES). The molecular marker Fos was used to investigate changes in interneuronal communication due to SSD. To induce SSD, neonatal rats obtained a unilateral intracochlear injection of neomycin. In adulthood, rats were acutely stimulated by AS, ES, or AS + ES. AS and ES were applied correspondingly in terms of intracochlear stimulation side and intensity resulting in bilaterally comparable Fos expression in hearing rats. In contrast, SSD rats showed a loss of tonotopic order along the deafened pathway, indicated by a massive increase and spread of Fos expressing neurons. We report three major results: First, AS of the hearing ear of SSD rats resulted in bilateral activation of neurons in the cochlear nucleus (CN). Second, ES of the deaf ear did not activate contralateral CN. Third, AS + ES of SSD rats resulted in bilateral reduced Fos expression in the auditory brainstem compared to monaural stimulations. These findings indicate changes in inhibitory interactions among neuronal networks as a result of monaural deafness.

Neuron–glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron–glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

In this study we investigated the pattern of c-Fos expression in anteroventral (AVCN) and dorsal cochlear nucleus (DCN) and central inferior colliculus (CIC) following electrical intracochlear stimulation (EIS) of anesthetized adult rats that were neonatally deafened. The animals never experienced acoustic sensations as their hair cells were destroyed by daily kanamycin injections between postnatal days 10 to 20, resulting in a rise of hearing threshold by about 90 dB. Unilateral EIS was applied through a cochlear implant inserted into the medial turn of the left cochlea and lasted for 45 or 73 min, 2, 3:15, or 5h. Following EIS at 50Hz, a high number of c-Fos positive nuclei were observed showing only marginal tonotopic order in ipsilateral AVCN, in DCN bilaterally, and in contralateral CIC. Quantifying the number of c-Fos positive nuclei in ipsilateral AVCN, we found a steady increase with stimulation time. By contrast, the population of neurons expressing c-Fos in DCN and CIC revealed a transient maximum at 73 min. A direct comparison with our previous study (Rosskothen-Kuhl, N., Illing, R.-B., 2010. Nonlinear development of the populations of neurons expressing c-Fos under sustained electrical intracochlear stimulation in the rat auditory brainstem. Brain Res. 1347, 33-41) reveals that absence of hearing experience has far-reaching consequences for the interneuronal communication within networks of the auditory brainstem. When hearing fails, EIS entails expression of c-Fos in populations of neurons that are much larger than normally, essentially disregard tonotopic order, and lack much of spatio-temporal variations seen in hearing-experienced rats.

Objective: It has been debated for decades if and to what extent the mature central nervous system of mammals is capable to respond to altered sensory use and function with changes of structure and function. We attempted to shed new light on the neuroplastic potential of the central auditory system, using light and electron microscopic techniques to explore it on the levels of cells (both neurons and glia), synapses, selected molecular components of the tissue, and the spatiotemporal relationship among these following the induction of changed patterns of sensory activity. Study Design: Working in an animal model, we induced two modifications to normal auditory signalling in the adult rat brain. Through unilateral cochleotomy, we caused a total primary deafferentation in the cochlear nucleus and abolished all sensory input through the ear. By electrical intracochlear stimulation (EIS) we substituted normal sensory signalling by an artificial input that was under complete temporal control. Results: ...

Expression of the immediate-early gene fos (also known as c-fos) and phosphorylation of the product of the early response gene atf2 (pATF2) in the adult auditory brainstem can be modulated by electrical intracochlear stimulation. The Fos and pATF2 proteins are competitive monomers of the heterodimeric activator protein-1 (AP-1) transcription factor that triggers the expression of genes related to neural plasticity. Our previous findings showed that the stimulation-induced spatio-temporal pattern of Fos expression in the adult auditory system depends on hearing experience. In this study, we aimed to identify a possible correlation of pATF2 and Fos expression. Adult normal hearing and neonatally deafened rats were unilaterally stimulated with a cochlear implant (CI) for 45 min, 73 min, or 2h. The numbers of Fos- and pATF2-positive neurons in the anteroventral cochlear nucleus (AVCN), the lateral superior olive (LSO), and the central inferior colliculus (CIC) were evaluated. Following stimulation, an increased Fos expression was demonstrated in all these regions in hearing and deaf rats. However, in neonatally deafened rats, significantly more Fos-positive neurons emerged that did not obey a tonotopic order. Independent of hearing experience, Fos expression correlated with a locally matching decrease of pATF2 expression in AVCN and LSO, but not in CIC. We suggest that these changes in gene expression result in a shift of AP-1 dimer composition from ATF2:Jun to Fos:Jun. This change in AP-1 constellation is expected to invoke different transcriptional cascades leading to distinct modes of tissue reorganization and plasticity responses in the mature central auditory system under stimulation.

Specific sensory activity such as sustained acoustical or Electrical Intracochlear Stimulation (EIS) elicits electrical responses and molecular changes in neuronal subpopulations of the auditory brainstem. One of the first molecular changes observed is the expression of the immediate early gene Fos. Its protein functions as a monomer of the transcription factor Activator Protein-1 (AP-1) which triggers cascades of protein synthesis that play a crucial role in neuroplastic remodeling. We investigated the pattern of Fos expression in Anteroventral (AVCN) and Dorsal Cochlear Nucleus (DCN) and Central Inferior Colliculus (CIC) following 2 h of unilateral EIS at 1.6, 50, and 400 Hz in anesthetized untreated and nimodipine-treated rats. Our data indicate that with increasing stimulation frequency the population of cells expressing Fos changed in composition and size in AVCN, DCN, and CIC. In all investigated auditory regions, systemic nimodipine treatment, an antagonist of L-type calcium channels, resulted in a significant increase in the number of neurons expressing Fos upon EIS compared to non-treated rats at the same stimulation parameters. Apparently, antagonizing L-type calcium channels enhances the responsiveness of neurons, and thus their readiness to respond with functional changes to sensory activity, in the auditory brainstem with little influence on the tonotopic precision of the response.

Learning is the essence of life. Throughout evolution, all species learn to adapt to a particular environment. As a consequence, organs are formed and reformed, and cellular function extends to respond to a broadening spectrum of types of energy and chemical compounds and focuses on particular stimulus configurations to respond to them in ever subtler ways. In ontogeny, chemical and spatial orientation is essential for the cells of an embryo so that it can grow all parts at the right time and at the right location. Postnatally, the radius from which an organism needs to learn expands from itself to the world surrounding it. For mammals, there appear to be two distinctly different phases of learning from the environment: early in life, or approximately before sexual maturity, and later in life, or post puberty. It has been a remarkable neuroscientific discovery that the molecular machinery employed by organism during their development is subtly but effectively modified to provide neuroplasticity later in life.