In vivo Conditions Induce Faithful Encoding of Stimuli by Reducing Nonlinear Synchronization in Vestibular Sensory Neurons

Previous studies have shown that neurons within the vestibular nuclei (VN) can faithfully encode the time course of sensory input through changes in firing rate in vivo. However, studies performed in vitro have shown that these same VN neurons often display nonlinear synchronization (i.e. phase locking) in their spiking activity to the local maxima of sensory input, thereby severely limiting their capacity for faithful encoding of said input through changes in firing rate. We investigated this apparent discrepancy by studying the effects of in vivo conditions on VN neuron activity in vitro using a simple, physiologically based, model of cellular dynamics. We found that membrane potential oscillations were evoked both in response to step and zap current injection for a wide range of channel conductance values. These oscillations gave rise to a resonance in the spiking activity that causes synchronization to sinusoidal current injection at frequencies below 25 Hz. We hypothesized that the apparent discrepancy between VN response dynamics measured in in vitro conditions (i.e., consistent with our modeling results) and the dynamics measured in vivo conditions could be explained by an increase in trial-to-trial variability under in vivo vs. in vitro conditions. Accordingly, we mimicked more physiologically realistic conditions in our model by introducing a noise current to match the levels of resting discharge variability seen in vivo as quantified by the coefficient of variation (CV). While low noise intensities corresponding to CV values in the range 0.04–0.24 only eliminated synchronization for low (<8 Hz) frequency stimulation but not high (>12 Hz) frequency stimulation, higher noise intensities corresponding to CV values in the range 0.5–0.7 almost completely eliminated synchronization for all frequencies. Our results thus predict that, under natural (i.e. in vivo) conditions, the vestibular system uses increased variability to promote fidelity of encoding by single neurons. This prediction can be tested experimentally in vitro

Noise and vestibular perception of passive self-motion

Noise defined as random disturbances is ubiquitous in both the external environment and the nervous system. Depending on the context, noise can degrade or improve information processing and performance. In all cases, it contributes to neural systems dynamics. We review some effects of various sources of noise on the neural processing of self-motion signals at different stages of the vestibular pathways and the resulting perceptual responses. Hair cells in the inner ear reduce the impact of noise by means of mechanical and neural filtering. Hair cells synapse on regular and irregular afferents. Variability of discharge (noise) is low in regular afferents and high in irregular units. The high variability of irregular units provides information about the envelope of naturalistic head motion stimuli. A subset of neurons in the vestibular nuclei and thalamus are optimally tuned to noisy motion stimuli that reproduce the statistics of naturalistic head movements. In the thalamus, variability of neural discharge increases with increasing motion amplitude but saturates at high amplitudes, accounting for behavioral violation of Weber’s law. In general, the precision of individual vestibular neurons in encoding head motion is worse than the perceptual precision measured behaviorally. However, the global precision predicted by neural population codes matches the high behavioral precision. The latter is estimated by means of psychometric functions for detection or discrimination of whole-body displacements. Vestibular motion thresholds (inverse of precision) reflect the contribution of intrinsic and extrinsic noise to perception. Vestibular motion thresholds tend to deteriorate progressively after the age of 40 years, possibly due to oxidative stress resulting from high discharge rates and metabolic loads of vestibular afferents. In the elderly, vestibular thresholds correlate with postural stability: the higher the threshold, the greater is the postural imbalance and risk of falling. Experimental application of optimal levels of either galvanic noise or whole-body oscillations can ameliorate vestibular function with a mechanism reminiscent of stochastic resonance. Assessment of vestibular thresholds is diagnostic in several types of vestibulopathies, and vestibular stimulation might be useful in vestibular rehabilitation

Advances in Clinical Neurophysiology

Including some of the newest advances in the field of neurophysiology, this book can be considered as one of the treasures that interested scientists would like to collect. It discusses many disciplines of clinical neurophysiology that are, currently, crucial in the practice as they explain methods and findings of techniques that help to improve diagnosis and to ensure better treatment. While trying to rely on evidence-based facts, this book presents some new ideas to be applied and tested in the clinical practice. Advances in Clinical Neurophysiology is important not only for the neurophysiologists but also for clinicians interested or working in wide range of specialties such as neurology, neurosurgery, intensive care units, pediatrics and so on. Generally, this book is written and designed to all those involved in, interpreting or requesting neurophysiologic tests

29th Annual Computational Neuroscience Meeting: CNS*2020

Meeting abstracts This publication was funded by OCNS. The Supplement Editors declare that they have no competing interests. Virtual | 18-22 July 202

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

Influence of the dentritic morphology on electrophysiological responses of thalamocortical neurons

Les neurones thalamiques de relai ont un rôle exclusif dans la transformation et de transfert de presque toute l'information sensorielle dans le cortex. L'intégration synaptique et la réponse électrophysiologique des neurones thalamiques de relai sont déterminées non seulement par l’état du réseau impliqué, mais ils sont également contrôlés par leurs propriétés intrinsèques tels les divers canaux ioniques voltage-dépendants ainsi que l’arborisation dendritique élaboré. Par conséquent, investiguer sur le profil complexe de morphologie dendritique et sur les propriétés dendritiques actives révèle des renseignements importants sur la fonction d'entrée-sortie de neurones thalamiques de relai. Dans cette étude, nous avons reconstruit huit neurones thalamocorticaux (TC) du noyau VPL de chat adulte. En se basant sur ces données morphologiques complètes, nous avons développé plusieurs modèles multicompartimentaux afin de trouver un rôle potentiellement important des arbres dendritiques des neurones de TC dans l'intégration synaptique et l’intégration neuronale. L'analyse des caractéristiques morphologiques des neurones TC accordent des valeurs précises à des paramètres géométriques semblables ou différents de ceux publiés antérieurement. En outre, cette analyse fait ressortir de tous nouveaux renseignements concernant le patron de connectivité entre les sections dendritiques telles que l'index de l'asymétrie et la longueur de parcours moyen (c'est-à-dire, les paramètres topologiques). Nous avons confirmé l’étendue des valeurs rapportée antérieurement pour plusieurs paramètres géométriques tels que la zone somatique (2956.24±918.89 m2), la longueur dendritique totale (168017.49±4364.64 m) et le nombre de sous-arbres (8.3±1.5) pour huit neurones TC. Cependant, contrairement aux données rapportées antérieurement, le patron de ramification dendritique (avec des cas de bifurcation 98 %) ne suit pas la règle de puissance de Rall 3/2 pour le ratio géométrique (GR), et la valeur moyenne de GR pour un signal de propagation est 2,5 fois plus grande que pour un signal rétropropagé. Nous avons également démontré une variabilité significative dans l'index de symétrie entre les sous-arbres de neurones TC, mais la longueur du parcours moyen n'a pas montré une grande variation à travers les ramifications dendritiques des différents neurones. Nous avons examiné la conséquence d’une distribution non-uniforme des canaux T le long de l'arbre dendritique sur la réponse électrophysiologique émergeante, soit le potentiel Ca 2+ à seuil bas (low-threshold calcium spike, LTS) des neurones TC. En appliquant l'hypothèse du «coût minimal métabolique», nous avons constaté que le neurone modélisé nécessite un nombre minimal de canaux-T pour générer un LTS, lorsque les canaux-T sont situés dans les dendrites proximales. Dans la prochaine étude, notre modèle informatique a illustré l'étendue d'une rétropropagation du potentiel d'action et de l'efficacité de la propagation vers des PPSEs générés aux branches dendritiques distales. Nous avons démontré que la propagation dendritique des signaux électriques est fortement contrôlée par les paramètres morphologiques comme illustré par les différents paliers de polarisation obtenus par un neurone à équidistance de soma pendant la propagation et la rétropropagation des signaux électriques. Nos résultats ont révélé que les propriétés géométriques (c.-à-d. diamètre, GR) ont un impact plus fort sur la propagation du signal électrique que les propriétés topologiques. Nous concluons que (1) la diversité dans les propriétés morphologiques entre les sous-arbres d'un seul neurone TC donne une capacité spécifique pour l'intégration synaptique et l’intégration neuronale des différents dendrites, (2) le paramètre géométrique d'un arbre dendritique fournissent une influence plus élevée sur le contrôle de l'efficacité synaptique et l'étendue du potentiel d'action rétropropagé que les propriétés topologiques, (3) neurones TC suivent le principe d’optimisation pour la distribution de la conductance voltage-dépendant sur les arbres dendritiques.Thalamic relay neurons have an exclusive role in processing and transferring nearly all sensory information into the cortex. The synaptic integration and the electrophysiological response of thalamic relay neurons are determined not only by a state of the involved network, but they are also controlled by their intrinsic properties; such as diverse voltage-dependent ionic channels as well as by elaborated dendritic arborization. Therefore, investigating the complex pattern of dendritic morphology and dendritic active properties reveals important information on the input-output function of thalamic relay neurons. In this study, we reconstructed eight thalamocortical (TC) neurons from the VPL nucleus of adult cats. Based on these complete morphological data, we developed several multi-compartment models in order to find a potentially important role for dendritic trees of TC neurons in the synaptic integration and neuronal computation. The analysis of morphological features of TC neurons yield precise values of geometrical parameters either similar or different from those previously reported. In addition, this analysis extracted new information regarding the pattern of connectivity between dendritic sections such as asymmetry index and mean path length (i.e., topological parameters). We confirmed the same range of previously reported value for several geometric parameters such as the somatic area (2956.24±918.89 m2), the total dendritic length (168017.49±4364.64 m) and the number of subtrees (8.3±1.5) for eight TC neurons. However, contrary to previously reported data, the dendritic branching pattern (with 98% bifurcation cases) does not follow Rall’s 3/2 power rule for the geometrical ratio (GR), and the average GR value for a forward propagation signal was 2.5 times bigger than for a backward propagating signal. We also demonstrated a significant variability in the symmetry index between subtrees of TC neurons, but the mean path length did not show a large variation through the dendritic arborizations of different neurons. We examined the consequence of non-uniform distribution of T-channels along the dendritic tree on the prominent electrophysiological response, the low-threshold Ca2+ spike (LTS) of TC neurons. By applying the hypothesis of “minimizing metabolic cost”, we found that the modeled neuron needed a minimum number of T-channels to generate low-threshold Ca2+ spike (LTS), when T-channels were located in proximal dendrites. In the next study, our computational model illustrated the extent of an action potential back propagation and the efficacy of forward propagation of EPSPs arriving at the distal dendritic branches. We demonstrated that dendritic propagation of electrical signals is strongly controlled by morphological parameters as shown by different levels of polarization achieved by a neuron at equidistance from the soma during back and forward propagation of electrical signals. Our results revealed that geometrical properties (i.e. diameter, GR) have a stronger impact on the electrical signal propagation than topological properties. We conclude that (1) diversity in the morphological properties between subtrees of a single TC neuron lead to a specific ability for synaptic integration and neuronal computation of different dendrites, (2) geometrical parameter of a dendritic tree provide higher influence on the control of synaptic efficacy and the extent of the back propagating action potential than topological properties, (3) TC neurons follow the optimized principle for distribution of voltage-dependent conductance on dendritic trees

An alternative approach for assessing drug induced seizures, using non-protected larval zebrafish

As many as 9% of epileptic seizures occur as a result of drug toxicity. Identifying compounds with seizurogenic side effects is imperative for assessing compound safety during drug development, however, multiple marketed drugs still have clinical associations with seizures. Moreover, current approaches for assessing seizurogenicity, namely rodent EEG and behavioural studies, are highly resource intensive. This being the case, alternative approaches have been postulated for assessing compound seizurogenicity, including in vitro, in vivo, and in silico methods. In this thesis, experimental work is presented supporting the use of larval zebrafish as a candidate model organism for developing new seizure liability screening approaches. Larval zebrafish are translucent, meaning they are highly amenable to imaging approaches while offering a more ethical alternative to mammalian research. Zebrafish are furthermore highly fecund facilitating capacity for both high replication and high throughput. The primary goal of this thesis was to identify biomarkers in larval zebrafish, both behavioural and physiological, of compounds that increase seizure liability. The efficacy of this model organism for seizure liability testing was assessed through exposure of larval zebrafish to a mechanistically diverse array of compounds, selected for their varying degrees of seizurogenicity. Their central nervous systems were monitored using a variety of different techniques including light sheet microscopy, local field potential recordings, and behavioural monitoring. Data acquired from these measurements were then analysed using a variety of techniques including frequency domain analysis, clustering, functional connectivity, regression, and graph theory. Much of this analysis was exploratory in nature and is reflective of the infancy of the field. Experimental findings suggest that larval zebrafish are indeed sensitive to a wide range of pharmacological mechanisms of action and that drug actions are reflected by behavioural and direct measurements of brain activity. For example, local field potential recordings revealed electrographic responses akin to pre-ictal, inter-ictal and ictal events identified in humans. Ca2+ imaging using light sheet microscopy found global increases in fluorescent intensity and functional connectivity due to seizurogenic drug administration. In addition, [2] further functional connectivity and graph analysis revealed macroscale network changes correlated with drug seizurogenicity and mechanism of action. Finally, analysis of swimming behaviour revealed a strong correlation between high speed swimming behaviours and administration of convulsant compounds. In conclusion, presented herein are data demonstrating the power of functional brain imaging, LFP recordings, and behavioral monitoring in larval zebrafish for assessing the action of neuroactive drugs in a highly relevant vertebrate model. These data help us to understand the relevance of the 4 dpf larval zebrafish for neuropharmacological studies and reveal that even at this early developmental stage, these animals are highly responsive to a wide range of neuroactive compounds across multiple primary mechanisms of action. This represents compelling evidence of the potential utility of larval zebrafish as a model organism for seizure liability testing

Treatise on Hearing: The Temporal Auditory Imaging Theory Inspired by Optics and Communication

A new theory of mammalian hearing is presented, which accounts for the auditory image in the midbrain (inferior colliculus) of objects in the acoustical environment of the listener. It is shown that the ear is a temporal imaging system that comprises three transformations of the envelope functions: cochlear group-delay dispersion, cochlear time lensing, and neural group-delay dispersion. These elements are analogous to the optical transformations in vision of diffraction between the object and the eye, spatial lensing by the lens, and second diffraction between the lens and the retina. Unlike the eye, it is established that the human auditory system is naturally defocused, so that coherent stimuli do not react to the defocus, whereas completely incoherent stimuli are impacted by it and may be blurred by design. It is argued that the auditory system can use this differential focusing to enhance or degrade the images of real-world acoustical objects that are partially coherent. The theory is founded on coherence and temporal imaging theories that were adopted from optics. In addition to the imaging transformations, the corresponding inverse-domain modulation transfer functions are derived and interpreted with consideration to the nonuniform neural sampling operation of the auditory nerve. These ideas are used to rigorously initiate the concepts of sharpness and blur in auditory imaging, auditory aberrations, and auditory depth of field. In parallel, ideas from communication theory are used to show that the organ of Corti functions as a multichannel phase-locked loop (PLL) that constitutes the point of entry for auditory phase locking and hence conserves the signal coherence. It provides an anchor for a dual coherent and noncoherent auditory detection in the auditory brain that culminates in auditory accommodation. Implications on hearing impairments are discussed as well.Comment: 603 pages, 131 figures, 13 tables, 1570 reference

Auf einem menschlichen Gehörmodell basierende Elektrodenstimulationsstrategie für Cochleaimplantate

Cochleaimplantate (CI), verbunden mit einer professionellen Rehabilitation, haben mehreren hunderttausenden Hörgeschädigten die verbale Kommunikation wieder ermöglicht. Betrachtet man jedoch die Rehabilitationserfolge, so haben CI-Systeme inzwischen ihre Grenzen erreicht. Die Tatsache, dass die meisten CI-Träger nicht in der Lage sind, Musik zu genießen oder einer Konversation in geräuschvoller Umgebung zu folgen, zeigt, dass es noch Raum für Verbesserungen gibt.Diese Dissertation stellt die neue CI-Signalverarbeitungsstrategie Stimulation based on Auditory Modeling (SAM) vor, die vollständig auf einem Computermodell des menschlichen peripheren Hörsystems beruht.Im Rahmen der vorliegenden Arbeit wurde die SAM Strategie dreifach evaluiert: mit vereinfachten Wahrnehmungsmodellen von CI-Nutzern, mit fünf CI-Nutzern, und mit 27 Normalhörenden mittels eines akustischen Modells der CI-Wahrnehmung. Die Evaluationsergebnisse wurden stets mit Ergebnissen, die durch die Verwendung der Advanced Combination Encoder (ACE) Strategie ermittelt wurden, verglichen. ACE stellt die zurzeit verbreitetste Strategie dar. Erste Simulationen zeigten, dass die Sprachverständlichkeit mit SAM genauso gut wie mit ACE ist. Weiterhin lieferte SAM genauere binaurale Merkmale, was potentiell zu einer Verbesserung der Schallquellenlokalisierungfähigkeit führen kann. Die Simulationen zeigten ebenfalls einen erhöhten Anteil an zeitlichen Pitchinformationen, welche von SAM bereitgestellt wurden. Die Ergebnisse der nachfolgenden Pilotstudie mit fünf CI-Nutzern zeigten mehrere Vorteile von SAM auf. Erstens war eine signifikante Verbesserung der Tonhöhenunterscheidung bei Sinustönen und gesungenen Vokalen zu erkennen. Zweitens bestätigten CI-Nutzer, die kontralateral mit einem Hörgerät versorgt waren, eine natürlicheren Klangeindruck. Als ein sehr bedeutender Vorteil stellte sich drittens heraus, dass sich alle Testpersonen in sehr kurzer Zeit (ca. 10 bis 30 Minuten) an SAM gewöhnen konnten. Dies ist besonders wichtig, da typischerweise Wochen oder Monate nötig sind. Tests mit Normalhörenden lieferten weitere Nachweise für die verbesserte Tonhöhenunterscheidung mit SAM.Obwohl SAM noch keine marktreife Alternative ist, versucht sie den Weg für zukünftige Strategien, die auf Gehörmodellen beruhen, zu ebnen und ist somit ein erfolgversprechender Kandidat für weitere Forschungsarbeiten.Cochlear implants (CIs) combined with professional rehabilitation have enabled several hundreds of thousands of hearing-impaired individuals to re-enter the world of verbal communication. Though very successful, current CI systems seem to have reached their peak potential. The fact that most recipients claim not to enjoy listening to music and are not capable of carrying on a conversation in noisy or reverberative environments shows that there is still room for improvement.This dissertation presents a new cochlear implant signal processing strategy called Stimulation based on Auditory Modeling (SAM), which is completely based on a computational model of the human peripheral auditory system.SAM has been evaluated through simplified models of CI listeners, with five cochlear implant users, and with 27 normal-hearing subjects using an acoustic model of CI perception. Results have always been compared to those acquired using Advanced Combination Encoder (ACE), which is today’s most prevalent CI strategy. First simulations showed that speech intelligibility of CI users fitted with SAM should be just as good as that of CI listeners fitted with ACE. Furthermore, it has been shown that SAM provides more accurate binaural cues, which can potentially enhance the sound source localization ability of bilaterally fitted implantees. Simulations have also revealed an increased amount of temporal pitch information provided by SAM. The subsequent pilot study, which ran smoothly, revealed several benefits of using SAM. First, there was a significant improvement in pitch discrimination of pure tones and sung vowels. Second, CI users fitted with a contralateral hearing aid reported a more natural sound of both speech and music. Third, all subjects were accustomed to SAM in a very short period of time (in the order of 10 to 30 minutes), which is particularly important given that a successful CI strategy change typically takes weeks to months. An additional test with 27 normal-hearing listeners using an acoustic model of CI perception delivered further evidence for improved pitch discrimination ability with SAM as compared to ACE.Although SAM is not yet a market-ready alternative, it strives to pave the way for future strategies based on auditory models and it is a promising candidate for further research and investigation