Preserved Auditory Steady State Response and Envelope-Following Response in Severe Brainstem Dysfunction Highlight the Need for Cross-Checking.

OBJECTIVES: Commercially available auditory steady state response (ASSR) systems are widely used to obtain hearing thresholds in the pediatric population objectively. Children are often examined during natural or induced sleep so that the recorded ASSRs are of subcortical origin, the inferior colliculus being often designated as the main ASSR contributor in these conditions. This report presents data from a battery of auditory neurophysiological objective tests obtained in 3 cases of severe brainstem dysfunction in sleeping children. In addition to ASSRs, envelope-following response (EFR) recordings designed to distinguish peripheral (cochlear nerve) from central (brainstem) were recorded to document the effect of brainstem dysfunction on the two types of phase-locked responses. DESIGN: Results obtained in the 3 children with severe brainstem dysfunctions were compared with those of age-matched controls. The cases were identified as posterior fossa tumor, undiagnosed (UD), and Pelizaeus-Merzbacher-Like Disease. The standard audiological objective tests comprised tympanograms, distortion product otoacoustic emissions, click-evoked auditory brainstem responses (ABRs), and ASSRs. EFRs were recorded using horizontal (EFR-H) and vertical (EFR-V) channels and a stimulus phase rotation technique allowing isolation of the EFR waveforms in the time domain to obtain direct latency measurements. RESULTS: The brainstem dysfunctions of the 3 children were revealed as abnormal (weak, absent, or delayed) ABRs central waves with a normal wave I. In addition, they all presented a summating and cochlear microphonic potential in their ABRs, coupled with a normal wave I, which implies normal cochlear and cochlear nerve function. EFR-H and EFR-V waveforms were identified in the two cases in whom they were recorded. The EFR-Hs onset latencies, response durations, and phase-locking values did not differ from their respective age-matched control values, indicating normal cochlear nerve EFRs. In contrast, the EFR-V phase-locking value and onset latency varied from their control values. Both patients had abnormal but identifiable and significantly phase-locked brainstem EFRs, even in a case with severely distorted ABR central waves. ASSR objective audiograms were recorded in two cases. They showed normal or slightly elevated (explained by a slight transmission loss) thresholds that do not yield any clue about their brainstem dysfunction, revealing the method's lack of sensitivity to severe brainstem dysfunction. CONCLUSIONS: The present study, performed on 3 sleeping children with severe brainstem dysfunction but normal cochlear responses (cochlear microphonic potential, summating potential, and ABR wave I), revealed the differential sensitivity of three auditory electrophysiological techniques. Estimated thresholds obtained by standard ASSR recordings (cases UD and Pelizaeus-Merzbacher-Like Disease) provided no clue to the brainstem dysfunction clearly revealed by the click-evoked ABR. EFR recordings (cases posterior fossa tumor and UD) showed preserved central responses with abnormal latencies and low phase-locking values, whereas the peripheral EFR attributed to the cochlear nerve was normal. The one case (UD) for which the three techniques could be performed confirms this sensitivity gradient, emphasizing the need for applying the Cross-Check Principle by avoiding resorting to ASSR recording alone. The entirely normal EFR-H recordings observed in two cases further strengthen the hypothesis of its cochlear nerve origin in sleeping children.

Seizure evolution can be characterized as path through synaptic gain space of a neural mass model.

Physiologically based models could facilitate better understanding of mechanisms underlying epileptic seizures. In this paper, we attempt to reveal the dynamic evolution of intracranial EEG activity during epileptic seizures based on synaptic gain identification procedure of a neural mass model. The distribution of average excitatory, slow and fast inhibitory synaptic gain in the parameter space and their temporal evolution, i.e., the path through the model parameter space, were analyzed in thirty seizures from ten temporal lobe epileptic patients. Results showed that the synaptic gain values located roughly on a plane before seizure onset, dispersed during seizure and returned to the plane when seizure terminated. Cluster analysis was performed on seizure paths and demonstrated consistency in synaptic gain evolution across different seizures from the individual patient. Furthermore, two patient groups were identified, each one corresponding to a specific synaptic gain evolution in the parameter space during a seizure. Results were validated by a bootstrapping approach based on comparison with random paths. The differences in the path revealed variations in EEG dynamics for patients despite showing identical seizure onset pattern. Our approach may have the potential to classify the epileptic patients into subgroups based on different mechanisms revealed by subtle changes in synaptic gains and further enable more robust decisions regarding treatment strategy.

Dynamics underlying interictal to ictal transition in temporal lobe epilepsy: insights from a neural mass model.

We propose an approach that combines a neural mass model and clinical intracranial electroencephalographic (iEEG) recordings to explore the potential pathophysiological mechanisms (at the neuronal population level) of ictogenesis. Thirty iEEG recordings from 10 temporal lobe epilepsy (TLE) patients around seizure onset were investigated. Physiologically meaningful parameters [average excitatory (Ae ), slow (B), and fast (G) inhibitory synaptic gain] were identified during interictal to ictal transition. Four ratios (Ae /G, Ae /B, Ae /(B + G), and B/G) were derived from these parameters, and their evolution over time was analyzed. The excitation/inhibition ratio increased around seizure onset and decreased before seizure offset, indicating the impairment and re-emergence of excitation/inhibition balance around seizure onset and before seizure offset, respectively. Moreover, the slow inhibition may have an earlier effect on excitation/inhibition imbalance. We confirm the decrease in excitation/inhibition ratio upon seizure termination in human temporal lobe epilepsy, as revealed by optogenetic approaches both in vivo in animal models and in vitro. The increase in excitation/inhibition ratio around seizure occurrence could be an indicator to detect seizures.

Generalization of the primary tone phase variation method: An exclusive way of isolating the frequency-following response components.

The primary tone phase variation (PTPV) technique combines selective sub-averaging with systematic variation of the phases of multitone stimuli. Each response component having a known phase relationship with the stimulus components phases can be isolated in the time domain. The method was generalized to the frequency-following response (FFR) evoked by a two-tone (f 1 and f 2) stimulus comprising both linear and non-linear, as well as transient components. The generalized PTPV technique isolated each spectral component present in the FFR, including those sharing the same frequency, allowing comparison of their latencies. After isolation of the envelope component f 2 - f 1 from its harmonic distortion 2f 2 - 2f 1 and from the transient auditory brainstem response, a computerized analysis of instantaneous amplitudes and phases was applied in order to objectively determine the onset and offset latencies of the response components. The successive activation of two generators separated by 3.7 ms could be detected in all (N = 12) awake adult normal subjects, but in none (N = 10) of the sleeping/sedated children with normal hearing thresholds. The method offers an unprecedented way of disentangling the various FFR subcomponents. These results open the way for renewed investigations of the FFR components in both human and animal research as well as for clinical applications.

Subcortical neural generators of the envelope-following response in sleeping children: A transfer function analysis.

Multiple auditory structures, from cochlea to cortex, phase-lock to the envelope of complex stimuli. The relative contributions of these structures to the human surface-recorded envelope-following response (EFR) are still uncertain. Identification of the active contributor(s) is complicated by the fact that even the simplest two-tone (f1&f2) stimulus, targeting its (f2-f1) envelope, evokes additional linear (f1&f2) and non-linear (2f1-f2) phase-locked components as well as a transient auditory brainstem response (ABR). Here, we took advantage of the generalized primary tone phase variation method to isolate each predictable component in the time domain, allowing direct measurements of onset latency, duration and phase discontinuity values from which the involved generators were inferred. Targeting several envelope frequencies (0.22-1 kHz), we derived the EFR transfer functions along a vertical vertex-to-neck and a horizontal earlobe-to-earlobe recording channels, yielding respectively EFR-V and EFR-H waveforms. Subjects (N= 30) were sleeping children with normal electrophysiological thresholds and normal oto-acoustic emissions. Both EFR-H and EFR-V phase-locking values (PLV) transfer functions had a low-pass profile, EFR-V showing a lower cut-off frequency than EFR-H. We also computed the frequency-latency relationships of both EFRs onset latencies. EFR-H data fitted a power-law function incorporating a frequency-dependent traveling wave delay and a fixed one amounting to 1.2 ms. The fitted function nicely fell within five published estimations of the latency-frequency function of the ABR wave-I, thus pointing to a cochlear nerve origin. The absence of phase discontinuity and overall response durations that were equal to that of the stimulus indicated no contribution from a later generator. The recording of an entirely similar EFR-H response in a patient who had severe brainstem encephalitis with a normal, isolated, ABR wave-I but complete absence of later waves, further substantiated a cochlear nerve origin. Modeling of the EFR-V latency-frequency functions indicated a fixed transport time of 2 ms with respect to EFR-H onset, suggesting a cochlear nucleus (CN) origin, here also, without indication for multiple generators. Other features of the EFR-V response pointing to the CN were, at least for the EFR frequency below the cut-off values of the transfer functions, higher PLVs coupled with increased harmonic distortion. Such a behavior has been described in the so-called highly-synchronized neurons of the ventral cochlear nucleus (VCN). The present study compellingly demonstrated the advantage of isolating the EFR in the temporal domain so as to extract detailed spectro-temporal parameters that, combined with orthogonal recording channels, shed new light on the involved neural generators.

Automated epileptic seizure detection based on break of excitation/inhibition balance.

Physiological models are attractive for seizure detection, as their parameters are related to physiological meanings. We propose an algorithm to early detect epileptic seizures based on automatic estimation of average synaptic gains (excitatory Ae, slow and fast inhibitory B and G) by combining clinical data with a neural mass model. Three indices (Ae/B, Ae/G and Ae/(B + G)), all related to excitation/inhibition balance, were calculated and used as cues to detect seizures. A simple thresholding method was employed. We evaluated the algorithm against the manual scoring of a human expert on intracranial EEG samples from 23 patients suffering from different types of epilepsy. Best performance was achieved using Ae/(B + G) as a cue, i.e. excitation/(slow + fast) inhibition, on temporal lobe epilepsy (TLE) patients. A leave-one-out cross-validation showed that the algorithm achieved 92.98% sensitivity for TLE patients. The median false positive rate was 0.16 per hour, and median detection delay was 14.5 s. Of interest, the threshold values determined by a leave-one-out cross-validation did nearly not vary among TLE patients, suggesting a general excitation/inhibition balance baseline in TLE patients. The same approach could be used with other types of epilepsy by adapting the neural mass model to these types.

Implant survival rate in calvarial bone grafts: A retrospective clinical study with 10 year follow-up.

BACKGROUND: In this study, we present medium- and long-term data on implant survival in a cohort of patients with severe maxillary atrophy rehabilitated using reconstructive implant site development with calvarial bone grafts. MATERIALS AND METHODS: We obtained clinical records from patients treated with implant rehabilitation supported by calvaria bone grafts in the Oral Surgery Department of IRCSS San Raffaele (Milan, Italy). Implant and prosthetic survival and success rates were retrospectively evaluated. Graft survival and postoperative complications were also assessed. RESULTS: A total of 207 implants placed in 32 patients were evaluated for a mean period of 10.0 years from loading. After 10 years, the cumulative survival rate was 97.10%, the implant success rate was 92.75%, and the prosthetic complication rate was 9.76%. A graft survival percentage of 96.88% was observed, and postoperative complications occurred in 28.13% of cases. CONCLUSIONS: The 10-year survival rate and prosthetic complications for patients treated with implant rehabilitation supported by calvarial bone grafts are excellent, as implant loss was relatively rare, although limited subjects were available for the 10-year follow-up.