Circadian Rhythms in Conditioned Threat Extinction Reflect Time-of-Day Differences in Ventromedial Prefrontal Cortex Neural Processing.

Circadian rhythms in conditioned threat extinction emerge from a tissue-level circadian timekeeper, or local clock, in the ventromedial prefrontal cortex (vmPFC). Yet it remains unclear how this local clock contributes to extinction-dependent adaptations. Here we used single-unit and local field potential analyses to interrogate neural activity in the male rat vmPFC during repeated extinction sessions at different times of day. In association with superior recall of a remote extinction memory during the circadian active phase, vmPFC putative principal neurons exhibited phasic firing that was amplified for cue presentations and diminished at transitions in freezing behavior. Coupling of vmPFC gamma amplitude to the phase of low-frequency oscillations was greater during freezing than mobility, and this difference was augmented during the active phase, highlighting a time-of-day dependence in the organization of freezing- versus mobility-associated cell assemblies. Additionally, a greater proportion of vmPFC neurons were phase-locked to low-frequency oscillations during the active phase, consistent with heightened neural excitability at this time of day. Our results suggest that daily fluctuations in vmPFC excitability precipitate enhanced neural recruitment into extinction-based cell assemblies during the active phase, providing a potential mechanism by which the vmPFC local clock modulates circuit and behavioral plasticity during conditioned threat extinction.

Somatic Integration of Incoherent Dendritic Inputs in the Gerbil Medial Superior Olive.

The medial superior olive (MSO) is a binaural nucleus that is specialized in detecting the relative arrival times of sounds at both ears. Excitatory inputs to its neurons originating from either ear are segregated to different dendrites. To study the integration of synaptic inputs both within and between dendrites, we made juxtacellular and whole-cell recordings from the MSO in anesthetized female gerbils, while presenting a "double zwuis" stimulus, in which each ear received its own set of tones, which were chosen in a way that all second-order distortion products (DP2s) could be uniquely identified. MSO neurons phase-locked to multiple tones within the multitone stimulus, and vector strength, a measure for spike phase-locking, generally depended linearly on the size of the average subthreshold response to a tone. Subthreshold responses to tones in one ear depended little on the presence of sound in the other ear, suggesting that inputs from different ears sum linearly without a substantial role for somatic inhibition. The "double zwuis" stimulus also evoked response components in the MSO neuron that were phase-locked to DP2s. Bidendritic subthreshold DP2s were quite rare compared with bidendritic suprathreshold DP2s. We observed that in a small subset of cells, the ability to trigger spikes differed substantially between both ears, which might be explained by a dendritic axonal origin. Some neurons that were driven monaurally by only one of the two ears nevertheless showed decent binaural tuning. We conclude that MSO neurons are remarkably good in finding binaural coincidences even among uncorrelated inputs.SIGNIFICANCE STATEMENT Neurons in the medial superior olive are essential for precisely localizing low-frequency sounds in the horizontal plane. From their soma, only two dendrites emerge, which are innervated by inputs originating from different ears. Using a new sound stimulus, we studied the integration of inputs both within and between these dendrites in unprecedented detail. We found evidence that inputs from different dendrites add linearly at the soma, but that small increases in somatic potentials could lead to large increases in the probability of generating a spike. This basic scheme allowed the MSO neurons to detect the relative arrival time of inputs at both dendrites remarkably efficient, although the relative size of these inputs could differ considerably.

Just a phase? Causal probing reveals spurious phasic dependence of sustained attention.

For over a decade, electrophysiological studies have reported correlations between attention / perception and the phase of spontaneous brain oscillations. To date, these findings have been interpreted as evidence that the brain uses neural oscillations to sample and predict upcoming stimuli. Yet, evidence from simulations have shown that analysis artefacts could also lead to spurious pre-stimulus oscillations that appear to predict future brain responses. To address this discrepancy, we conducted an experiment in which visual stimuli were presented in time to specific phases of spontaneous alpha and theta oscillations. This allowed us to causally probe the role of ongoing neural activity in visual processing independent of the stimulus-evoked dynamics. Our findings did not support a causal link between spontaneous alpha / theta rhythms and behaviour. However, spurious correlations between theta phase and behaviour emerged offline using gold-standard time-frequency analyses. These findings are a reminder that care should be taken when inferring causal relationships between neural activity and behaviour using acausal analysis methods.

Chronic cannabis use alters the spontaneous and oscillatory gamma dynamics serving cognitive control.

Regular cannabis use is associated with cortex-wide changes in spontaneous and oscillatory activity, although the functional significance of such changes remains unclear. We hypothesized that regular cannabis use would suppress spontaneous gamma activity in regions serving cognitive control and scale with task performance. Participants (34 cannabis users, 33 nonusers) underwent an interview regarding their substance use history and completed the Eriksen flanker task during magnetoencephalography (MEG). MEG data were imaged in the time-frequency domain and virtual sensors were extracted from the peak voxels of the grand-averaged oscillatory interference maps to quantify spontaneous gamma activity during the pre-stimulus baseline period. We then assessed group-level differences in spontaneous and oscillatory gamma activity, and their relationship with task performance and cannabis use metrics. Both groups exhibited a significant behavioral flanker interference effect, with slower responses during incongruent relative to congruent trials. Mixed-model ANOVAs indicated significant gamma-frequency neural interference effects in the left frontal eye fields (FEF) and left temporoparietal junction (TPJ). Further, a group-by-condition interaction was detected in the left FEF, with nonusers exhibiting stronger gamma oscillations during incongruent relative to congruent trials and cannabis users showing no difference. In addition, spontaneous gamma activity was sharply suppressed in cannabis users relative to nonusers in the left FEF and TPJ. Finally, spontaneous gamma activity in the left FEF and TPJ was associated with task performance across all participants, and greater cannabis use was associated with weaker spontaneous gamma activity in the left TPJ of the cannabis users. Regular cannabis use was associated with weaker spontaneous gamma in the TPJ and FEF. Further, the degree of use may be proportionally related to the degree of suppression in spontaneous activity in the left TPJ.

Liquid Crystal Electrolyte with Lamellar Ionic Channels for All-In-One Gel Flexible Supercapacitor.

Liquid crystalline hydrogels with nanoscale order are an attractive soft material to transport ions or electrons with high efficiency. By employing noncovalent interactions between amphiphiles and solvents, defined anisotropic ordered structures can assemble that serve as interior transmissible channels. Herein, the phase behaviors of a polymerizable amphiphile of 1-vinyl-3-alkylimidazolium bromide (VCn IMBr, n = 12, 14, 16) are investigated at different concentrations in a deep eutectic solvent. The aggregation such as micelle, hexagonal, and lamellar liquid crystal phase is created. Through in-phase polymerization, the lamellar structures within an an isotropic liquid crystal can be well solidified to obtain a conductive gel electrolyte. A sandwich-structured all-in-one gel flexible supercapacitor is then built with this specific gel electrolyte. With greatly increased adhesion and minimized interfacial resistance between electrode and electrolyte, the approach will be able to create energy-storage devices with anisotropic ionic and electronic charge transportations envisioned for various electrochemical applications.

Respiratory entrainment related reverse triggering in mechanically ventilated children.

BACKGROUND: The underlying pathophysiological pathways how reverse triggering is being caused are not fully understood. Respiratory entrainment may be one of these mechanisms, but both terms are used interchangeably. We sought to characterize reverse triggering and the relationship with respiratory entrainment among mechanically ventilated children with and without acute lung injury. METHODS: We performed a secondary phyiology analysis of two previously published data sets of invasively mechanically ventilated children < 18 years with and without lung injury mechanically ventilated in a continuous or intermittent mandatory ventilation mode. Ventilator waveforms, electrical activity of the diaphragm measured with surface electromyography and oesophageal tracings were analyzed for entrained and non-entrained reverse triggered breaths. RESULTS: In total 102 measurements (3110 min) from 67 patients (median age 4.9 [1.8 ; 19,1] months) were analyzed. Entrained RT was identified in 12 (12%) and non-entrained RT in 39 (38%) recordings. Breathing variability for entrained RT breaths was lower compared to non-entrained RT breaths. We did not observe breath stacking during entrained RT. Double triggering often occurred during non-entrained RT and led to an increased tidal volume. Patients with respiratory entrainment related RT had a shorter duration of MV and length of PICU stay. CONCLUSIONS: Reverse triggering is not one entity but a clinical spectrum with different mechanisms and consequences. TRIAL REGISTRATION: Not applicable.

Dynamic signatures of the Eureka effect: an EEG study.

The Eureka effect refers to the common experience of suddenly solving a problem. Here, we study this effect in a pattern recognition paradigm that requires the segmentation of complex scenes and recognition of objects on the basis of Gestalt rules and prior knowledge. In the experiments, both sensory evidence and prior knowledge were manipulated in order to obtain trials that do or do not converge toward a perceptual solution. Subjects had to detect objects in blurred scenes and indicate recognition with manual responses. Neural dynamics were assessed with high-density Electroencephalography (EEG) recordings. The results show significant changes of neural dynamics with respect to spectral distribution, coherence, phase locking, and fractal dimensionality. The Eureka effect was associated with increased coherence of oscillations in the alpha and theta bands over widely distributed regions of the cortical mantle predominantly in the right hemisphere. This increase in coherence was associated with decreased beta power over parietal and central regions and with decreased alpha power over frontal and occipital areas. In addition, there was a right hemisphere-lateralized reduction of fractal dimensionality. We propose that the Eureka effect requires cooperation of cortical regions involved in working memory, creative thinking, and the control of attention.

Experience-dependent effects of passive auditory exposure in infants impact theta phase synchrony and predict later language.

The establishment of cortical representations critical for mounting language is supported by both ongoing neural maturation and experience-expectant plasticity as infants increasingly recognize the linguistic events that occur most often in their surrounding environment. Previous research has demonstrated that enhanced efficiency of syllabic representation and discrimination is facilitated by interactive attention-driven, nonspeech auditory experience. However, experience-dependent effects on syllable processing as a function of nonspeech, passive auditory exposure (PAE), remain unclear. As theta band-specific activity has been shown to support syllabic processing, we chose theta inter-trial phase synchrony to examine the experience-dependent effects of PAE on the processing of a syllable contrast. Results demonstrated that infants receiving PAE increased syllabic processing efficiency. Specifically, compared with controls, the group receiving PAE showed more mature, efficient processing, exhibiting less theta phase synchrony for the standard syllable at 9 months, and at 18 months, for the deviant syllable. Furthermore, the PAE modulatory effect on theta phase synchrony at 7 and 9 months was associated with language scores at 12 and 18 months. These findings confirm that supporting emerging perceptual abilities during early sensitive periods impacts syllabic processing efficiency and aligns with literature demonstrating associations between infant auditory perceptual abilities and later language outcomes.

Neural Oscillations and Multisensory Processing.

Neural oscillations play a role in sensory processing by coordinating synchronized neuronal activity. Synchronization of gamma oscillations is engaged in local computation of feedforward signals and synchronization of alpha-beta oscillations is engaged in feedback processing over long-range areas. These spatially and spectrally segregated bi-directional signals may be integrated by a mechanism of cross-frequency coupling. Synchronization of neural oscillations has also been proposed as a mechanism for information integration across multiple sensory modalities. A transient stimulus or rhythmic stimulus from one modality may lead to phase alignment of ongoing neural oscillations in multiple sensory cortices, through a mechanism of cross-modal phase reset or cross-modal neural entrainment. Synchronized activities in multiple sensory cortices are more likely to boost stronger activities in downstream areas. Compared to synchronized oscillations, asynchronized oscillations may impede signal processing, and may contribute to sensory selection by setting the oscillations in the target-related cortex and the oscillations in the distractor-related cortex to opposite phases.

Fusion of Multi-domain EEG Signatures Improves Emotion Recognition.

BACKGROUND: Affective computing has gained increasing attention in the area of the human-computer interface where electroencephalography (EEG)-based emotion recognition occupies an important position. Nevertheless, the diversity of emotions and the complexity of EEG signals result in unexplored relationships between emotion and multichannel EEG signal frequency, as well as spatial and temporal information. METHODS: Audio-video stimulus materials were used that elicited four types of emotions (sad, fearful, happy, neutral) in 32 male and female subjects (age 21-42 years) while collecting EEG signals. We developed a multidimensional analysis framework using a fusion of phase-locking value (PLV), microstates, and power spectral densities (PSDs) of EEG features to improve emotion recognition. RESULTS: An increasing trend of PSDs was observed as emotional valence increased, and connections in the prefrontal, temporal, and occipital lobes in high-frequency bands showed more differentiation between emotions. Transition probability between microstates was likely related to emotional valence. The average cross-subject classification accuracy of features fused by Discriminant Correlation Analysis achieved 64.69%, higher than that of single mode and direct-concatenated features, with an increase of more than 7%. CONCLUSIONS: Different types of EEG features have complementary properties in emotion recognition, and combining EEG data from three types of features in a correlated way, improves the performance of emotion classification.

Enhancement of phase-locking in rodents. II. An axonal recording study in chinchilla.

The trapezoid body (TB) contains axons of neurons residing in the anteroventral cochlear nucleus (AVCN) that provide excitatory and inhibitory inputs to the main monaural and binaural nuclei in the superior olivary complex (SOC). To understand the monaural and binaural response properties of neurons in the medial and lateral superior olive (MSO and LSO), it is important to characterize the temporal firing properties of these inputs. Because of its exceptional low-frequency hearing, the chinchilla (Chinchilla lanigera) is one of the widely used small animal models for studies of hearing. However, the characterization of the output of its ventral cochlear nucleus to the nuclei of the SOC is fragmentary. We obtained responses of TB axons to stimuli typically used in binaural studies and compared these responses to those of auditory nerve (AN) fibers, with a focus on temporal coding. We found enhancement of phase-locking and entrainment, i.e., the ability of a neuron to fire action potentials at a certain stimulus phase for nearly every stimulus period, in TB axons relative to AN fibers. Enhancement in phase-locking and entrainment are quantitatively more modest than in the cat but greater than in the gerbil. As in these species, these phenomena occur not only in low-frequency neurons stimulated at their characteristic frequency but also in neurons tuned to higher frequencies when stimulated with low-frequency tones, to which complex phase-locking behavior with multiple modes of firing per stimulus cycle is frequently observed.NEW & NOTEWORTHY The sensitivity of neurons to small time differences in sustained sounds to both ears is important for binaural hearing, and this sensitivity is critically dependent on phase-locking in the monaural pathways. Although studies in cat showed a marked improvement in phase-locking from the peripheral to the central auditory nervous system, the evidence in rodents is mixed. Here, we recorded from AN and TB of chinchilla and found temporal enhancement, though more limited than in cat.

Differences between children and adults in the neural encoding of voice fundamental frequency in the presence of noise and reverberation.

Environmental noise and reverberation challenge speech understanding more significantly in children than in adults. However, the neural/sensory basis for the difference is poorly understood. We evaluated the impact of noise and reverberation on the neural processing of the fundamental frequency of voice (f0 )-an important cue to tag or recognize a speaker. In a group of 39 6- to 15-year-old children and 26 adults with normal hearing, envelope following responses (EFRs) were elicited by a male-spoken /i/ in quiet, noise, reverberation, and both noise and reverberation. Due to increased resolvability of harmonics at lower than higher vowel formants that may affect susceptibility to noise and/or reverberation, the /i/ was modified to elicit two EFRs: one initiated by the low frequency first formant (F1) and the other initiated by mid to high frequency second and higher formants (F2+) with predominantly resolved and unresolved harmonics, respectively. F1 EFRs were more susceptible to noise whereas F2+ EFRs were more susceptible to reverberation. Reverberation resulted in greater attenuation of F1 EFRs in adults than children, and greater attenuation of F2+ EFRs in older than younger children. Reduced modulation depth caused by reverberation and noise explained changes in F2+ EFRs but was not the primary determinant for F1 EFRs. Experimental data paralleled modelled EFRs, especially for F1. Together, data suggest that noise or reverberation influences the robustness of f0 encoding depending on the resolvability of vowel harmonics and that maturation of processing temporal/envelope information of voice is delayed in reverberation, particularly for low frequency stimuli.

Theta:gamma phase coupling and evoked gamma activity reflect the fidelity of mental templates during memory matching in visual perception.

Top-down predictions of future events shaped by prior experience are an important control mechanism to allocate limited attentional resources more efficiently and are thought to be implemented as mental templates stored in memory. Increased evoked gamma activity and theta:gamma phase-phase coupling over parieto-occipital areas have previously been observed when mental templates meet matching visual stimuli. Here, we investigated how these signatures evolve during the formation of new mental templates and how they relate to the fidelity of such. Based on single-trial feedback, participants learned to classify target shapes as matching or mismatching with preceding cue sequences. In the end of the experiment, they were asked to freely reproduce targets as means of template fidelity. We observed fidelity-dependent increments of matching-related gamma phase locking and theta:gamma phase coupling in early visual areas around 100-200-ms poststimulus over time. Theta:gamma phase synchronization and evoked gamma activity might serve as complementary signatures of memory matching in visual perception; theta:gamma phase synchronization seemingly most important in early phases of learning and evoked gamma activity being essential for transition of mental templates into long-term memory.

Auditory nerve phase-locked response recorded from normal hearing adults using electrocochleography.

OBJECTIVE: The auditory nerve overlapped waveform response (ANOW), a new measure that can be recorded non-invasively from humans, holds promise for providing more accurate assessment of low frequency hearing thresholds than currently used objective measures. This research aims to investigate the robustness and the nature of the ANOW response in humans. DESIGN: Repeated within-session recordings of the ANOW response using low-frequency Tone Bursts (TBs) were obtained at multiple stimulus levels. ANOW's absolute amplitude and phase locking value (PLV) measures were analysed to obtain normative data and to test the reliability of the ANOW response. STUDY SAMPLE: Thirteen normal hearing adults within the age range of 25 to 40 years. RESULTS: ANOW response was obtained to both 250 Hz and 500 Hz TBs and was traced down to 30-40 dB nHL. ANOW response showed significantly higher amplitude and stronger phase locking using 250 Hz TB compared to 500 Hz TB. High degree of test retest reliability of the ANOW response was found using 250 Hz TB at presentation levels higher than 40 dB nHL. CONCLUSIONS: ANOW response is recordable noninvasively using low-frequency TBs and shows higher robustness as the stimulus frequency decreases.

Children with amblyaudia show less flexibility in auditory cortical entrainment to periodic non-speech sounds.

OBJECTIVE: We investigated auditory temporal processing in children with amblyaudia (AMB), a subtype of auditory processing disorder (APD), via cortical neural entrainment. DESIGN AND STUDY SAMPLES: Evoked responses were recorded to click-trains at slow vs. fast (8.5 vs. 14.9/s) rates in n = 14 children with AMB and n = 11 age-matched controls. Source and time-frequency analyses (TFA) decomposed EEGs into oscillations (reflecting neural entrainment) stemming from bilateral auditory cortex. RESULTS: Phase-locking strength in AMB depended critically on the speed of auditory stimuli. In contrast to age-matched peers, AMB responses were largely insensitive to rate manipulations. This rate resistance occurred regardless of the ear of presentation and in both cortical hemispheres. CONCLUSIONS: Children with AMB show less rate-related changes in auditory cortical entrainment. In addition to reduced capacity to integrate information between the ears, we identify more rigid tagging of external auditory stimuli. Our neurophysiological findings may account for domain-general temporal processing deficits commonly observed in AMB and related APDs behaviourally. More broadly, our findings may inform communication strategies and future rehabilitation programmes; increasing the rate of stimuli above a normal (slow) speech rate is likely to make stimulus processing more challenging for individuals with AMB/APD.

Selection of the Minimum Number of EEG Sensors to Guarantee Biometric Identification of Individuals.

Biometric identification uses person recognition techniques based on the extraction of some of their physical or biological properties, which make it possible to characterize and differentiate one person from another and provide irreplaceable and critical information that is suitable for application in security systems. The extraction of information from the electrical biosignal of the human brain has received a great deal of attention in recent years. Analysis of EEG signals has been widely used over the last century in medicine and as a basis for brain-machine interfaces (BMIs). In addition, the application of EEG signals for biometric recognition has recently been demonstrated. In this context, EEG-based biometric systems are often considered in two different applications: identification (one-to-many classification) and authentication (one-to-one or true/false classification). In this article, we establish a methodology for selecting and reducing the minimum number of EEG sensors necessary to carry out effective biometric identification of individuals. Two methodologies were applied, one based on principal component analysis and the other on the Wilcoxon signed-rank test in order to reduce the number of electrodes. This allowed us to identify, according to the methodology used, the areas of the cerebral cortex that would allow selection of the minimum number of electrodes necessary for the identification of individuals. The methodologies were applied to two databases, one with 13 people with self-collected recordings using low-cost EEG equipment, EMOTIV EPOC+, and another publicly available database with recordings from 109 people provided by the PhysioNet BCI.

[A study on the application of cross-frequency coupling characteristics of neural oscillation in the diagnosis of mild cognitive impairment].

In order to fully explore the neural oscillatory coupling characteristics of patients with mild cognitive impairment (MCI), this paper analyzed and compared the strength of the coupling characteristics for 28 MCI patients and 21 normal subjects under six different-frequency combinations. The results showed that the difference in the global phase synchronization index of cross-frequency coupling under δ-θ rhythm combination was statistically significant in the MCI group compared with the normal control group ( P = 0.025, d = 0.398). To further validate this coupling feature, this paper proposed an optimized convolutional neural network model that incorporated a time-frequency data enhancement module and batch normalization layers to prevent overfitting while enhancing the robustness of the model. Based on this optimized model, with the phase locking value matrix of δ-θ rhythm combination as the single input feature, the diagnostic accuracy of MCI patients was (95.49 ± 4.15)%, sensitivity and specificity were (93.71 ± 7.21)% and (97.50 ± 5.34)%, respectively. The results showed that the characteristics of the phase locking value matrix under the combination of δ-θ rhythms can adequately reflect the cognitive status of MCI patients, which is helpful to assist the diagnosis of MCI.

Memory Specific to Temporal Features of Sound Is Formed by Cue-Selective Enhancements in Temporal Coding Enabled by Inhibition of an Epigenetic Regulator.

Recent investigation of memory-related functions in the auditory system have capitalized on the use of memory-modulating molecules to probe the relationship between memory and substrates of memory in auditory system coding. For example, epigenetic mechanisms, which regulate gene expression necessary for memory consolidation, are powerful modulators of learning-induced neuroplasticity and long-term memory (LTM) formation. Inhibition of the epigenetic regulator histone deacetylase 3 (HDAC3) promotes LTM, which is highly specific for spectral features of sound. The present work demonstrates for the first time that HDAC3 inhibition also enables memory for temporal features of sound. Adult male rats trained in an amplitude modulation (AM) rate discrimination task and treated with a selective inhibitor of HDAC3 formed memory that was highly specific to the AM rate paired with reward. Sound-specific memory revealed behaviorally was associated with a signal-specific enhancement in temporal coding in the auditory system; stronger phase locking that was specific to the rewarded AM rate was revealed in both the surface-recorded frequency following response and auditory cortical multiunit activity in rats treated with the HDAC3 inhibitor. Furthermore, HDAC3 inhibition increased trial-to-trial cortical response consistency (relative to naive and trained vehicle-treated rats), which generalized across different AM rates. Stronger signal-specific phase locking correlated with individual behavioral differences in memory specificity for the AM signal. These findings support that epigenetic mechanisms regulate activity-dependent processes that enhance discriminability of sensory cues encoded into LTM in both spectral and temporal domains, which may be important for remembering spectrotemporal features of sounds, for example, as in human voices and speech.SIGNIFICANCE STATEMENT Epigenetic mechanisms have recently been implicated in memory and information processing. Here, we use a pharmacological inhibitor of HDAC3 in a sensory model of learning to reveal the ability of HDAC3 to enable precise memory for amplitude-modulated sound cues. In so doing, we uncover neural substrates for memory's specificity for temporal sound cues. Memory specificity was supported by auditory cortical changes in temporal coding, including greater response consistency and stronger phase locking. HDAC3 appears to regulate effects across domains that determine specific cue saliency for behavior. Thus, epigenetic players may gate how sensory information is stored in long-term memory and can be leveraged to reveal the neural substrates of sensory details stored in memory.

Phase-Locking Requires Efficient Ca2+ Extrusion at the Auditory Hair Cell Ribbon Synapse.

Proper perception of sounds in the environment requires auditory signals to be encoded with extraordinary temporal precision up to tens of microseconds, but how it originates from the hearing organs in the periphery is poorly understood. In particular, sound-evoked spikes in auditory afferent fibers in vivo are phase-locked to sound frequencies up to 5 kHz, but it is not clear how hair cells can handle intracellular Ca2+ changes with such high speed and efficiency. In this study, we combined patch-clamp recording and two-photon Ca2+ imaging to examine Ca2+ dynamics in hair cell ribbon synapses in the bullfrog amphibian papilla of both sexes. We found that Ca2+ clearance from single synaptic ribbons followed a double exponential function, and the weight of the fast component, but not the two time constants, was significantly reduced for prolonged stimulation, and during inhibition of the plasma membrane Ca2+ ATPase (PMCA), the mitochondrial Ca2+ uptake (MCU), or the sarcolemma/endoplasmic reticulum Ca2+ ATPase (SERCA), but not the Na+/Ca2+ exchanger (NCX). Furthermore, we found that both the basal Ca2+ level and the Ca2+ rise during sinusoidal stimulation were significantly increased by inhibition of PMCA, MCU, or SERCA. Consistently, phase-locking of synaptic vesicle releases from hair cells was also significantly reduced by blocking PMCA, MCU, or SERCA, but not NCX. We conclude that, in addition to fast diffusion mediated by mobile Ca2+ buffer, multiple Ca2+ extrusion pumps are required for phase-locking at the auditory hair cell ribbon synapse.SIGNIFICANCE STATEMENT Hair cell synapses can transmit sound-driven signals precisely in the kHz range. However, previous studies of Ca2+ handling in auditory hair cells have often been conducted in immature hair cells, with elevated extracellular Ca2+ concentration, or through steady-state stimulation that may not be physiologically relevant. Here we examine Ca2+ clearance from hair cell synaptic ribbons in a fully mature preparation at physiological concentration of external Ca2+ and at physiological temperature. By stimulating hair cells with sinusoidal voltage commands that mimic pure sound tones, we recapitulated the phase-locking of hair cell exocytosis with an in vitro approach. This allowed us to reveal the Ca2+ extrusion mechanisms that are required for phase-locking at auditory hair cell ribbon synapses.

MEG Intersubject Phase Locking of Stimulus-Driven Activity during Naturalistic Speech Listening Correlates with Musical Training.

Musical training is associated with increased structural and functional connectivity between auditory sensory areas and higher-order brain networks involved in speech and motor processing. Whether such changed connectivity patterns facilitate the cortical propagation of speech information in musicians remains poorly understood. We here used magnetoencephalography (MEG) source imaging and a novel seed-based intersubject phase-locking approach to investigate the effects of musical training on the interregional synchronization of stimulus-driven neural responses during listening to naturalistic continuous speech presented in silence. MEG data were obtained from 20 young human subjects (both sexes) with different degrees of musical training. Our data show robust bilateral patterns of stimulus-driven interregional phase synchronization between auditory cortex and frontotemporal brain regions previously associated with speech processing. Stimulus-driven phase locking was maximal in the delta band, but was also observed in the theta and alpha bands. The individual duration of musical training was positively associated with the magnitude of stimulus-driven alpha-band phase locking between auditory cortex and parts of the dorsal and ventral auditory processing streams. These findings provide evidence for a positive relationship between musical training and the propagation of speech-related information between auditory sensory areas and higher-order processing networks, even when speech is presented in silence. We suggest that the increased synchronization of higher-order cortical regions to auditory cortex may contribute to the previously described musician advantage in processing speech in background noise.SIGNIFICANCE STATEMENT Musical training has been associated with widespread structural and functional brain plasticity. It has been suggested that these changes benefit the production and perception of music but can also translate to other domains of auditory processing, such as speech. We developed a new magnetoencephalography intersubject analysis approach to study the cortical synchronization of stimulus-driven neural responses during the perception of continuous natural speech and its relationship to individual musical training. Our results provide evidence that musical training is associated with higher synchronization of stimulus-driven activity between brain regions involved in early auditory sensory and higher-order processing. We suggest that the increased synchronized propagation of speech information may contribute to the previously described musician advantage in processing speech in background noise.