A Model of Electrically Stimulated Auditory Nerve Fiber Responses with Peripheral and Central Sites of Spike Generation

A computational model of cat auditory nerve fiber (ANF) responses to electrical stimulation is presented. The model assumes that (1) there exist at least two sites of spike generation along the ANF and (2) both an anodic (positive) and a cathodic (negative) charge in isolation can evoke a spike. A single ANF is modeled as a network of two exponential integrateand-fire point-neuron models, referred to as peripheral and central axons of the ANF. The peripheral axon is excited by the cathodic charge, inhibited by the anodic charge, and exhibits longer spike latencies than the central axon; the central axon is excited by the anodic charge, inhibited by the cathodic charge, and exhibits shorter spike latencies than the peripheral axon. The model also includes subthreshold and suprathreshold adaptive feedback loops which continuously modify the membrane potential and can account for effects of facilitation, accommodation, refractoriness, and spike-rate adaptation in ANF. Although the model is parameterized using data for either single or paired pulse stimulation with monophasic rectangular pulses, it correctly predicts effects of various stimulus pulse shapes, stimulation pulse rates, and level on the neural response statistics. The model may serve as a framework to explore the effects of different stimulus parameters on psychophysical performance measured in cochlear implant listeners

Assessment and Preservation of Auditory Nerve Integrity in the Deafened Guinea Pig

Profound hearing loss is often caused by cochlear hair cell loss. Cochlear implants (CIs) essentially replace hair cells by encoding sound and conveying the signal by means of pulsatile electrical stimulation to the spiral ganglion cells (SGCs) which form the auditory nerve. SGCs progressively degenerate following hair cell loss, as a result of lost neurotrophic signaling from the hair cells. Degeneration of the auditory nerve may compromise the ability to hear with a CI. Therefore, the first goal of this thesis was to extend the current knowledge on this degeneration process, with emphasis on changes in functionality. To this end, normal hearing and deafened guinea pigs received a CI, and the responses of the auditory nerve to electrical stimulation (electrically evoked compound action potentials; eCAPs) were recorded. Several characteristics of the eCAP correlated well with SGC survival, suggesting that eCAP recordings in human CI users, too, may be indicative of the extent of degeneration of the auditory nerve. The ability to estimate the extent of neural loss in CI users may greatly advance current research into the effect of auditory nerve degeneration on sound perception with a CI. In animal models of severe hair cell loss, treatment with exogenous neurotrophic factors such as brain-derived neurotrophic factor (BDNF) has been shown to prevent secondary SGC degeneration. However, the functionality of the SGCs rescued by the treatment has not been properly evaluated. In order to provide a comprehensive assessment of SGC functionality after neurotrophic treatment, deafened guinea pigs were chronically implanted with an intracochlear electrode array combined with a cannula, through which BDNF was slowly infused into the cochlea over a period of four weeks. Histological analysis at the end of the treatment showed almost complete survival of SGCs; eCAP recordings indicated that SGC responsiveness to electrical stimulation was often similar to that in normal-hearing controls. In order to assess clinical practicability of BDNF treatment, the long-term effects of the four-week treatment were evaluated both at the histological and at the functional level. Sustained survival of SGCs was observed both four and eight weeks after cessation of the BDNF treatment. Moreover, near-normal SGC functionality was preserved during this eight week period as well. These findings are important for translation to clinical application, since continuous administration is impractical, and may even bring risk of tumorigenesis on the long term. In summary, the experimental work described in this thesis has led to the identification of useful electrophysiological measures with which the extent of auditory nerve degeneration can be estimated. It has additionally demonstrated that, in case of auditory nerve degeneration, treatment with neurotrophic factors prevent further degeneration, preserves the nerve’s functionality, and is clinically feasible

Efficacy of a new charge-balanced biphasic electrical stimulus in the isolated sciatic nerve and the hippocampal slice

Most deep brain stimulators apply rectangular monophasic voltage pulses. By modifying the stimulus shape, it is possible to optimize stimulus efficacy and find the best compromise between clinical effect, minimal side effects and power consumption of the stimulus generator. In this study, we compared the efficacy of three types of charge-balanced biphasic pulses (CBBPs, nominal duration 100 μs) in isolated sciatic nerves and in in vitro hippocampal brain slices of the rat. Using these two models, we tested the efficacy of several stimulus shapes exclusively on axons (in the sciatic nerve) and compared the effect with that of stimuli in the more complex neuronal network of the hippocampal slice by considering the stimulus-response relation. We showed that (i) adding an interphase gap (IPG, range 100-500 μs) to the CBBP enhances stimulus efficacy in the rat sciatic nerve and (ii) that this type of stimuli (CBBP with IPG) is also more effective in hippocampal slices. This benefit was similar for both models of voltage and current stimulation. In our two models, asymmetric CBBPs were less beneficial. Therefore, CBBPs with IPG appear to be well suited for application to DBS, since they enhance efficacy, extend battery life and potentially reduce harmful side effects

The functional and morphological characteristics of sciatic nerve degeneration and regeneration after crush injury in rats

BACKGROUND: Peripheral nerve damage induces a sequence of degeneration and regeneration events with a specific time course that leads to (partial) functional recovery. Quantitative electrophysiological analysis of degeneration and recovery over time is essential to understand the process. NEW METHOD: The presented ex vivo neurophysiological method evaluates functional recovery of the propagation of the compound action potential after crush injury of the rat sciatic nerve. A 32 channel electrode array was used to monitor compound action potential propagation at time points between 1h and 35 days after semi-quantitative crush injury of the rat sciatic nerve. RESULTS: The compound action potential was characterized by four measures: the latency, the duration, the amplitude and a measure that combined time and location. These four parameters reflected the subsequent steps in early axonal degradation, the transition to rapid degeneration followed by sprouting and the long period of remyelination that accompanied regeneration. COMPARISON WITH EXISTING METHODS: The neurophysiology measures of the compound action potential were compared with the morphology of the nerve at representative time points and analysis of functional recovery of action potential propagation was compared with a behavioral test: the foot flick test. CONCLUSIONS: Our data suggests that the ex vivo electrophysiological method is complementary to the classical behavioral foot flick test in that it allows a detailed time analysis of the degeneration and early regeneration phases at a high spatial and temporal sensitivity. The results were well-matched with observations made with immunohistochemical and morphological methods

Spiral ganglion cell morphology in guinea pigs after deafening and neurotrophic treatment

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Gene expression profiling of pituitary melanotrope cells during their physiological activation

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C6 deficiency does not alter intrinsic regeneration speed after peripheral nerve crush injury

Peripheral nerve injury leads to Wallerian degeneration, followed by regeneration, in which functionality and morphology of the nerve are restored. We previously described that deficiency for complement component C6, which prevents formation of the membrane attack complex, slows down degeneration and results in an earlier recovery of sensory function after sciatic nerve injury compared to WT animals. In this study, we determine whether C6(-/-) rats have an intrinsic trait that affects sciatic nerve regeneration after injury. To study the contribution of complement activation on degeneration and regeneration with only minimal effect of complement activation, a crush injury model with only modest complement deposition was used. We compared the morphological and functional aspects of crushed nerves during degeneration and regeneration in C6(-/-) and WT animals. Morphological changes of myelin and axons showed similar degeneration and regeneration patterns in WT and C6(-/-) injured nerves. Functional degeneration and regeneration, recorded by ex vivo electrophysiology and in vivo foot flick test, showed that the timeline of the restoration of nerve conduction and sensory recovery also followed similar patterns in WT and C6(-/-) animals. Our findings suggest that C6 deficiency by itself does not alter the regrowth capacity of the peripheral nerve after crush injur