Age-related Changes in Auditory Cortex Without Detectable Peripheral Alterations: A Multi-level Study in Sprague-Dawley Rats.

Aging is often considered to affect both the peripheral (i.e. the cochlea) and central (brainstem and thalamus-cortex) auditory systems. We investigated the effects of aging on the cochlea, brainstem and cortex of female Sprague-Dawley rats. The auditory nerve threshold remained stable between the ages of nine and 21 months, as did distortion product otoacoustic emissions and the number of ribbon synapses between inner hair cells and nerve fibers. The first clear signs of aging appeared in the brainstem, in which response amplitude decreased, with thresholds remaining stable until the age of 15 months, and increasing slightly thereafter. The responses of primary auditory cortex neurons revealed specific effects of aging: at 21 months, receptive fields were spectrally narrower and the temporal reliability of responses to communication sounds was lower. However, aging had a null or even positive effect on neuronal responses in the presence of background noise, responses to amplitude-modulated sounds, and responses in gap-detection protocols. Overall, inter-animal variability remained high relative to the variability across groups of different ages, for all parameters tested. Behavioral performance for the modulation depth of amplitude modulation noise was worse in 21-month old animals than in other animals. Age-related alterations of cortical and behavioral responses were thus observed in animals displaying no signs of aging at the peripheral level. These results suggest that intrinsic, central aging effects can affect the perception of acoustic stimuli independently of the effects of aging on peripheral receptors.

Sound Coding in the Auditory Nerve: From Single Fiber Activity to Cochlear Mass Potentials in Gerbils.

Auditory nerve fibers (ANFs) convey acoustic information from the sensory cells to the brainstem using an elaborated neural code based on both spike timing and rate. As the stimulus tone frequency increases, time coding fades and ceases, resulting in high-frequency tone encoding that relies mostly on the spike discharge rate. Here, we recapitulated our recent single-unit data from gerbil's auditory nerve to highlight the most relevant mode of coding (spike timing versus spike rate) in tone-in-noise. We report that high-spontaneous rate (SR) fibers driven by low-frequency tones in noise are able to phase lock ∼30 dB below the level that evoked a significant elevation of the discharge rate, whereas medium- and low-SR fibers switch their preferential mode of coding from rate coding in quiet, to time coding in noise. For high-frequency tone, the low-threshold/high-SR fibers reach their maximum discharge rate in noise and do not respond to tones, whereas medium- and low-SR fibers are still able to respond to tones making them more resistant to background noise. Based on these findings, we first discuss the ecological function of the ANF distribution according to their spontaneous discharge rate. Then, we point out the poor synchronization of the low-SR ANFs, accounting for the discrepancy between ANF number and the amplitude of the compound action potential of the of the auditory nerve. Finally, we proposed a new diagnostic tool to assess low-SR fibers, which does not rely on the onset response of the ANFs.

Prevention of trauma-induced cochlear fibrosis using intracochlear application of anti-inflammatory and antiproliferative drugs.

Cochlear fibrosis is a common finding following cochlear implantation. Evidence suggests that cochlear fibrosis could be triggered by inflammation and epithelial-to-mesenchymal cell transition (EMT). In this study, we investigate the mechanisms of cochlear fibrosis and the risk/benefit ratio of local administration of the anti-inflammatory drug dexamethasone (DEX) and antimitotic drug aracytine (Ara-C). Cochlear fibrosis was evaluated in cochlear fibrosis models of rat cochlear slices in vitro and in KLH-induced immune labyrinthitis and platinum wire cochlear implantation-induced fibrosis in vivo. Cochleae were invaded with tissue containing fibroblastic cells expressing α-SMA (alpha smooth muscle actin), which along with collagen I, fibronectin, and laminin in the extracellular matrix, suggests the involvement of a fibrotic process triggered by EMT in vitro and in vivo. After perilymphatic injection of an adenoviral vector expressing GFP in vivo, we demonstrated that the fibroblastic cells derived from the mesothelial cells of the scalae tympani and vestibuli. Activation of inflammatory and EMT pathways was further assessed by ELISA analysis of the expression of IL-1ß and TGF-ß1. Both markers were elevated in vitro and in vivo, and DEX and Ara-C were able to reduce IL-1ß and TGF-ß1 production. After 5days of culture in vitro, quantification of calcein-positive cells revealed that Ara-C was 30-fold more efficient in preventing fibrosis, and provoked less sensory hair cell loss, than DEX. In KLH-induced immune labyrinthitis and platinum wire-implanted models, Ara-C was more efficient in preventing proliferation of fibrosis with less side effects on hair cells and neurons than DEX. In conclusion, DEX and Ara-C both prevent fibrosis in the cochlea. Analysis of the risk/benefit ratio favors the use of Ara-C for preventing cochlear fibrosis.

A computational model of the primary auditory neuron activity.

Sound translation into neural message at the first auditory synapse is of prime importance for providing organism with sound environment. Here, we compiled experimental features of the primary auditory neurons into a computational model, composed of two distinct compartments (i.e., afferent bouton and axon). Simulation of the model closely reproduces the whole biophysical properties of both excitatory post-synaptic currents and action potentials firing. This simple model provides a powerful tool to understand the synaptic disorders on the sound neural coding at the first auditory synapse.

Detection of synchronized firings in multivariate neural spike trains during motor tasks.

This paper describes and compares two classical methods for the detection of neuron groups which exhibit synchronized firings in multivariate spike trains. These methods were compared on experimental and randomized data corresponding to the firing activity of 104 neurons located in motor, premotor, and parietal cortices in a monkey during movement tasks. Both methods exhibited high false positive rates in randomized data, but results showed that this rate can be advantageously reduced with a simple postprocessing. Otherwise, one method permitted to detect a significant number of synchronized groups of neurons related to the behavioral task.

Comparison of three spike detectors dedicated to single unit action potentials of the auditory nerve.

This paper compares three methods for the detection of single unit action potentials in auditory nerve. The detector structures are similar consisting of a filtering procedure in the first stage and a decision rule in the second stage. The detection accuracy of each detector is characterized by the couple probability of a true detection vs. rates of false detection with synthetic data. The performance comparison between detectors shows that the detector using a band-pass finite-impulse-response filter with complex coefficients offers the best performance. This observation was especially evident for low signal to noise ratios. This finding is confirmed with real data and leads us to revise the protocol of spike detection in auditory nerve.

A method to identify reproducible subsets of co-activated structures during interictal spikes. Application to intracerebral EEG in temporal lobe epilepsy.

OBJECTIVE: We present a novel quantitative method to statistically analyze the distribution of multichannel intracerebral interictal spikes (multi-IIS) in stereoelectroencephalographic (SEEG) recordings. The method automatically extracts groups of brain structures conjointly and frequently involved in the generation of interictal activity. These groups are referred to as 'subsets of co-activated structures' (SCAS). We applied the method to long duration interictal recordings in patients with mesial temporal lobe epilepsy (MTLE) and analyzed the reproducibility of subsets of structures involved in the generation of multi-IIS for each patient and among patients. METHODS: Fifteen patients underwent long-term intracerebral EEG recording (SEEG technique) using depth electrodes. A 1 h period of continuous interictal EEG recording was selected for each patient with precautions regarding the time after anesthesia pre-SEEG, the temporal distance with respect to seizures, the vigilance state of the patient, and the anti-epileptic drug withdrawal. A research of SCAS was conducted on each recording using the developed method that includes 3 steps: (i) automatic detection of monochannel intracerebral interictal spikes (mono-IIS), (ii) formation of multi-IIS using a temporal sliding window, and (iii) extraction of SCAS. In the third step, statistical tests are used to evaluate the frequency of multi-IIS as well as their significance (with respect to the 'random distribution of mono-IIS' case). RESULTS: In each patient, several thousands of multi-IIS (mean+/-SD, 3322+/-2190) were formed and several SCAS (mean+/-SD, 3.80+/-1.47) were automatically extracted. Results show that reproducible subsets of brain structures are involved in the generation of interictal activity. Although SCAS were found to be variable from one patient to another, some invariant information was pointed up. In all patients, multi-IIS distribute over two distinct groups of structures: mesial structures (15/15) and lateral structures (7/15). Moreover, two particular structures, the internal temporal pole and the temporo-basal cortex, may be conjointly involved with either the first or the second group. Finally, some extracted SCAS seem to match well-defined anatomo-functional circuits of the temporal lobe. CONCLUSIONS AND SIGNIFICANCE: During interictal activity in MTLE, similar subsets of temporal lobe structures are involved in the generation of spikes. This paper brings statistical evidence for the existence of these subsets and presents a method to automatically extract them from SEEG recordings. Interictal activity is spatially organized in the temporal lobe and preferentially involves two functional systems of the temporal lobe (either mesial or lateral).

Epileptic fast intracerebral EEG activity: evidence for spatial decorrelation at seizure onset.

Low-voltage rapid discharges (or fast EEG ictal activity) constitute a characteristic electrophysiological pattern in focal seizures of human epilepsy. They are characterized by a decrease of signal voltage with a marked increase of signal frequency (typically beyond 25 Hz). They have long been observed in stereoelectroencephalographic (SEEG) signals recorded with intra-cerebral electrodes, generally occurring at seizure onset and simultaneously involving distinct brain regions. Spectral properties of rapid ictal discharges as well as spatial correlations measured between SEEG signals generated from distant sites before, during and after these discharges were studied. Cross-correlation estimates within typical EEG sub-bands and statistical tests performed in 10 patients suffering from partial epilepsy (frontal, temporal or fronto-temporal) reveal that SEEG signals are significantly de-correlated during the discharge period compared with periods that precede and follow this discharge. These results can be interpreted as a functional decoupling of distant brain sites at seizure onset followed by an abnormally high re-coupling when the seizure develops. They lead to the concept of 'disruption' that is complementary of that of 'activation' (revealed by significantly high correlations between signals recorded during seizures), both giving insights into our understanding of pathophysiological processes involved in human partial epilepsies as well as in the interpretation of clinical semiology.