Mouse auditory cortex sub-fields receive neuronal projections from MGB subdivisions independently.

Mouse auditory cortex is composed of six sub-fields: primary auditory field (AI), secondary auditory field (AII), anterior auditory field (AAF), insular auditory field (IAF), ultrasonic field (UF) and dorsoposterior field (DP). Previous studies have examined thalamo-cortical connections in the mice auditory system and learned that AI, AAF, and IAF receive inputs from the ventral division of the medial geniculate body (MGB). However, the functional and thalamo-cortical connections between nonprimary auditory cortex (AII, UF, and DP) is unclear. In this study, we examined the locations of neurons projecting to these three cortical sub-fields in the MGB, and addressed the question whether these cortical sub-fields receive inputs from different subsets of MGB neurons or common. To examine the distributions of projecting neurons in the MGB, retrograde tracers were injected into the AII, UF, DP, after identifying these areas by the method of Optical Imaging. Our results indicated that neuron cells which in ventral part of dorsal MGB (MGd) and that of ventral MGB (MGv) projecting to UF and AII with less overlap. And DP only received neuron projecting from MGd. Interestingly, these three cortical areas received input from distinct part of MGd and MGv in an independent manner. Based on our foundings these three auditory cortical sub-fields in mice may independently process auditory information.

Superior Attentional Efficiency of Auditory Cue via the Ventral Auditory-thalamic Pathway.

Auditory commands are often executed more efficiently than visual commands. However, empirical evidence on the underlying behavioral and neural mechanisms remains scarce. In two experiments, we manipulated the delivery modality of informative cues and the prediction violation effect and found consistently enhanced RT benefits for the matched auditory cues compared with the matched visual cues. At the neural level, when the bottom-up perceptual input matched the prior prediction induced by the auditory cue, the auditory-thalamic pathway was significantly activated. Moreover, the stronger the auditory-thalamic connectivity, the higher the behavioral benefits of the matched auditory cue. When the bottom-up input violated the prior prediction induced by the auditory cue, the ventral auditory pathway was specifically involved. Moreover, the stronger the ventral auditory-prefrontal connectivity, the larger the behavioral costs caused by the violation of the auditory cue. In addition, the dorsal frontoparietal network showed a supramodal function in reacting to the violation of informative cues irrespective of the delivery modality of the cue. Taken together, the results reveal novel behavioral and neural evidence that the superior efficiency of the auditory cue is twofold: The auditory-thalamic pathway is associated with improvements in task performance when the bottom-up input matches the auditory cue, whereas the ventral auditory-prefrontal pathway is involved when the auditory cue is violated.

Microglia induce auditory dysfunction after status epilepticus in mice.

Auditory dysfunction and increased neuronal activity in the auditory pathways have been reported in patients with temporal lobe epilepsy, but the cellular mechanisms involved are unknown. Here, we report that microglia play a role in the disinhibition of auditory pathways after status epilepticus in mice. We found that neuronal activity in the auditory pathways, including the primary auditory cortex and the medial geniculate body (MGB), was increased and auditory discrimination was impaired after status epilepticus. We further demonstrated that microglia reduced inhibitory synapses on MGB relay neurons over an 8-week period after status epilepticus, resulting in auditory pathway hyperactivity. In addition, we found that local removal of microglia from the MGB attenuated the increase in c-Fos+ relay neurons and improved auditory discrimination. These findings reveal that thalamic microglia are involved in auditory dysfunction in epilepsy.

The Interaural Time Difference for High-Pass Filtered Noise and Its Relationship With Brainstem Dysfunction and Disability in Multiple Sclerosis.

PURPOSE: Just noticeable difference for interaural time difference (JND-ITD) is a sensitive test to detect silent lesions and neural asynchrony along the auditory pathways among individuals with multiple sclerosis (MS), but it has not been studied with brainstem functional system scores (BFSS) and expanded disability status scale (EDSS). The study aims to assess the usefulness of JND-ITD thresholds in individuals with MS and relate to brainstem magnetic resonance imaging (MRI) lesions, BFSS, and disability (EDSS). METHOD: Standard group comparison design was adapted to compare the JND-ITD thresholds between individuals with MS (n = 45) and age and gender-matched healthy participants (n = 45). All participants underwent case history, neurological examination including BFSS and EDSS scoring, MRI brain imaging, minimental state examination, routine audiological evaluation, and ITD testing for high-pass filtered noise stimuli. RESULTS: Of the 36 MS participants with abnormal JND-ITD thresholds, 22 (48.9%) participants could not identify maximum JND-ITD values (1,280 µs) in the ITD task. Abnormal JND-ITDs thresholds (139-1,280 µs) were obtained in 14 (31.11%) participants with MS. The JND-ITD thresholds were significantly different between the healthy and MS group. No significant association was found between the presence of ITD abnormality with the presence of brainstem lesions (MRI) and brainstem dysfunction (BFSS). Also, this study did not find any relationship between JND-ITD thresholds with disability (EDSS). CONCLUSIONS: This study supports the findings that JND-ITD for high-pass filtered noise is a sensitive test to detect lesions along the auditory system. Even though JND-ITD thresholds did not relate with BFSS and EDSS scores, JND-ITD abnormalities can be of great value in identifying lesions along the auditory system, especially in the early stages of MS, when clinical neurological examination does not show any signs of brainstem dysfunction, disability, and MRI without any lesions in the brain.

Medial-lateral organization of primary auditory cortex and the question of sound localization.

Pandya made many important contributions to the understanding of the anatomy of the cortical auditory pathways beginning with his publication in 1969. This review focuses on the observation in that article on the transcallosal connections of the primary auditory cortex. The medial part of the cortex has such connections, but the lateral part does not. Pandya and colleagues speculated that this might have something to do with spatial localization of sound. Review of the subsequent literature shows that the primary auditory cortex anatomy is complex, but the original observation is likely correct. However, the physiological speculation was not.

Alterations of sensory cell activity in the thalamic reticular nucleus by prefrontal cortex activation in anesthetized rats.

The thalamic reticular nucleus (TRN), receiving excitatory inputs from thalamic nuclei and cortical areas, regulates thalamic sensory processing through its inhibitory projections to thalamic nuclei. Higher cognitive function has been shown to affect this regulation from the prefrontal cortex (PFC). The present study examined how activation of the PFC modulates auditory or visual responses of single TRN cells in anesthetized rats, using juxta-cellular recording and labelling techniques. Electrical microstimulation of the medial PFC did not evoke cell activities in the TRN, but it altered sensory responses in the majority of auditory (40/43) and visual cells (19/20) with regard to response magnitude, latency and/or burst spiking. Alterations in response magnitude were bidirectional, either facilitation or attenuation, including induction of de novo cell activity and nullification of sensory response. Response modulation was observed in early (onset) and/or recurrent late responses. PFC stimulation, either before or after early response, affected late response. Alterations occurred in the two types of cells projecting to the first- and higher-order thalamic nuclei. Further, auditory cells projecting to the somatosensory thalamic nuclei were affected. Facilitation was induced at relatively high incidences as compared with that in the sub-threshold intra- or cross-modal sensory interplay in the TRN where attenuation is predominated in bidirectional modulation. Highly complex cooperative and/or competitive interactions between the top-down influence from the PFC and bottom-up sensory inputs are assumed to take place in the TRN to adjust attention and perception depending on the weights of external sensory signals and internal demands of higher cognitive function.

Highly branched and complementary distributions of layer 5 and layer 6 auditory corticofugal axons in mouse.

The auditory cortex exerts a powerful, yet heterogeneous, effect on subcortical targets. Auditory corticofugal projections emanate from layers 5 and 6 and have complementary physiological properties. While several studies suggested that layer 5 corticofugal projections branch widely, others suggested that multiple independent projections exist. Less is known about layer 6; no studies have examined whether the various layer 6 corticofugal projections are independent. Therefore, we examined branching patterns of layers 5 and 6 auditory corticofugal neurons, using the corticocollicular system as an index, using traditional and novel approaches. We confirmed that dual retrograde injections into the mouse inferior colliculus and auditory thalamus co-labeled subpopulations of layers 5 and 6 auditory cortex neurons. We then used an intersectional approach to relabel layer 5 or 6 corticocollicular somata and found that both layers sent extensive branches to multiple subcortical structures. Using a novel approach to separately label layers 5 and 6 axons in individual mice, we found that layers 5 and 6 terminal distributions partially spatially overlapped and that giant terminals were only found in layer 5-derived axons. Overall, the high degree of branching and complementarity in layers 5 and 6 axonal distributions suggest that corticofugal projections should be considered as 2 widespread systems, rather than collections of individual projections.

[Auditory response of the reticular nucleus of thalamus in awake mice].

This study aims to explore the auditory response characteristics of the thalamic reticular nucleus (TRN) in awake mice during auditory information processing, so as to deepen the understanding of TRN and explore its role in the auditory system. By in vivo electrophysiological single cell attached recording of TRN neurons in 18 SPF C57BL/6J mice, we observed the responses of 314 recorded neurons to two kinds of auditory stimuli, noise and tone, applied to mice. The results showed that TRN received projections from layer six of the primary auditory cortex (A1). Among 314 TRN neurons, 56.05% responded silently, 21.02% responded only to noise and 22.93% responded to both noise and tone. The neurons with noise response can be divided into three patterns according to their response time: onset, sustain and long-lasting, accounting for 73.19%, 14.49% and 12.32%, respectively. The response threshold of the sustain pattern neurons was lower than those of the other two types. Under noise stimulation, compared with A1 layer six, TRN neurons showed unstable auditory response (P < 0.001), higher spontaneous firing rate (P < 0.001), and longer response latency (P < 0.001). Under tone stimulation, TRN's response continuity was poor, and the frequency tuning was greatly different from that of A1 layer six (P < 0.001), but their sensitivity to tone was similar (P > 0.05), and TRN's tone response threshold was much higher than that of A1 layer six (P < 0.001). The above results demonstrate that TRN mainly undertakes the task of information transmission in the auditory system. The noise response of TRN is more extensive than the tone response. Generally, TRN prefers high-intensity acoustic stimulation.

Incorporating models of subcortical processing improves the ability to predict EEG responses to natural speech.

The goal of describing how the human brain responds to complex acoustic stimuli has driven auditory neuroscience research for decades. Often, a systems-based approach has been taken, in which neurophysiological responses are modeled based on features of the presented stimulus. This includes a wealth of work modeling electroencephalogram (EEG) responses to complex acoustic stimuli such as speech. Examples of the acoustic features used in such modeling include the amplitude envelope and spectrogram of speech. These models implicitly assume a direct mapping from stimulus representation to cortical activity. However, in reality, the representation of sound is transformed as it passes through early stages of the auditory pathway, such that inputs to the cortex are fundamentally different from the raw audio signal that was presented. Thus, it could be valuable to account for the transformations taking place in lower-order auditory areas, such as the auditory nerve, cochlear nucleus, and inferior colliculus (IC) when predicting cortical responses to complex sounds. Specifically, because IC responses are more similar to cortical inputs than acoustic features derived directly from the audio signal, we hypothesized that linear mappings (temporal response functions; TRFs) fit to the outputs of an IC model would better predict EEG responses to speech stimuli. To this end, we modeled responses to the acoustic stimuli as they passed through the auditory nerve, cochlear nucleus, and inferior colliculus before fitting a TRF to the output of the modeled IC responses. Results showed that using model-IC responses in traditional systems analyzes resulted in better predictions of EEG activity than using the envelope or spectrogram of a speech stimulus. Further, it was revealed that model-IC derived TRFs predict different aspects of the EEG than acoustic-feature TRFs, and combining both types of TRF models provides a more accurate prediction of the EEG response.

[Tinnitus]. / Tinnitus.

Tinnitus is a highly prevalent symptom and a common reason for seeing an otolaryngologist. Since tinnitus can go hand in hand with hearing loss, the step-by-step clarification of hearing loss is one of the essential ENT examinations for tinnitus sufferers. The anamnesis and medical history are relevant, since a multidimensional interaction with the tinnitus can be important for the treatment, especially in the case of a psychological comorbidity. In the vast majority of patients, no causal factor can be found. In the absence of external stimuli, phantom perceptions of tones or noises are held responsible for subjective tinnitus, which probably arises from pathological changes of the auditory pathway, but also in non-auditory cortical structures. In the case of acute tinnitus, a comprehensive audiological assessment is needed, and if the hearing threshold is normal, counseling is the priority. The patient must be informed about the nature of these benign symptoms. So far, there is no acute therapy that has been proven to increase the probability of healing, i.e. the disappearance of the acute tinnitus. Only if the hearing threshold descended, for instance in case of sudden idiopathic hearing loss, therapy of the underlying disease can also lead to improvement or healing of the acute tinnitus. Counseling for chronic tinnitus with high burden is also about reducing exaggerated expectations of healing that cannot be fulfilled. The training of habituation strategies is important. The standard of therapy for chronic tinnitus with psychological strain represents cognitive behavioral therapy for dealing with the tinnitus in a beneficial way. Tinnitus is a symptom of a very heterogeneous group of patients. In the future, it is to be hoped that digital applications and interventions in particular will be evaluated in quality-controlled clinical studies in order to be able to further personalize patient therapy.

The neural representations underlying asymmetric cross-modal prediction of words.

Cross-modal prediction serves a crucial adaptive role in the multisensory world, yet the neural mechanisms underlying this prediction are poorly understood. The present study addressed this important question by combining a novel audiovisual sequence memory task, functional magnetic resonance imaging (fMRI), and multivariate neural representational analyses. Our behavioral results revealed a reliable asymmetric cross-modal predictive effect, with a stronger prediction from visual to auditory (VA) modality than auditory to visual (AV) modality. Mirroring the behavioral pattern, we found the superior parietal lobe (SPL) showed higher pattern similarity for VA than AV pairs, and the strength of the predictive coding in the SPL was positively correlated with the behavioral predictive effect in the VA condition. Representational connectivity analyses further revealed that the SPL mediated the neural pathway from the visual to the auditory cortex in the VA condition but was not involved in the auditory to visual cortex pathway in the AV condition. Direct neural pathways within the unimodal regions were found for the visual-to-visual and auditory-to-auditory predictions. Together, these results provide novel insights into the neural mechanisms underlying cross-modal sequence prediction.

Convergence of bilateral auditory midbrain inputs on neurons in the auditory thalamus of chicken.

In the avian ascending auditory pathway, the nucleus mesencephalicus lateralis pars dorsalis (MLd; the auditory midbrain center) receives inputs from virtually all lower brainstem auditory nuclei and sends outputs bilaterally to the nucleus ovoidalis (Ov; the auditory thalamic nucleus). Axons from part of the MLd terminate in a particular domain of Ov, thereby suggesting a formation of segregated pathways point-to-point from lower brainstem nuclei via MLd to the thalamus. However, it has not yet been demonstrated whether any spatial clustering of thalamic neurons that receive inputs from specific domains of MLd exists. Ov neurons receive input from bilateral MLds; however, the degree of laterality has not been reported yet. In this study, we injected a recombinant avian adeno-associated virus, a transsynaptic anterograde vector into the MLd of the chick, and analyzed the distribution of labeled postsynaptic neurons on both sides of the Ov. We found that fluorescent protein-labeled neurons on both sides of the Ov were clustered in domains corresponding to subregions of the MLd. The laterality of projections was calculated as the ratio of neurons labeled by comparing ipsilateral to contralateral projections from the MLd, and it was 1.86 on average, thereby indicating a slight ipsilateral projection dominance. Bilateral inputs from different subdomains of the MLd converged on several single Ov neurons, thereby implying a possibility of a de novo binaural processing of the auditory information in the Ov.

Evaluation of auditory pathway excitability using a pre-operative trans-tympanic electrically evoked auditory brainstem response under local anesthesia in cochlear implant candidates.

OBJECTIVE: Subjective promontory stimulation is used to evaluate cochlear implant (CI) candidacy, but the test reliability is low. Electrically evoked auditory brainstem response (EABR) can verify the function of the auditory system objectively. This study's procedure uses a trans-tympanic rounded bent-tip electrode to perform pre-operative EABR under local anaesthesia (LA-TT-EABR) using MED-EL Software and Hardware. This study aimed to determine usability and effectiveness for CI candidates. DESIGN: We hypothesised that LA-TT-EABR waveforms of good quality would be related to successful hearing outcomes. We assumed that the duration of hearing loss/deafness was a confounding factor to study outcomes. STUDY SAMPLE: 19 borderline CI candidates. RESULTS: Positive LA-TT-EABR results were confirmed in 14 patients. LA-TT-EABR's mean latency was 2.05 ± 0.31 ms (eII/eIII) and 4.24 ± 0.39 ms (eIV/eV). Latencies weren't statistically different from intra-operative EABR elicited by basal CI contacts. All positive LA-TT-EABR patients benefitted from CI and speech performance improved one year after implantation. One patient with negative LA-TT-EABR was cochlear-implanted and had no hearing sensation. CONCLUSIONS: LA-TT-EABR is a tool in the frame of pre-operative objective testing the auditory pathway. It seems useful for clinical testing CI candidacy. Based on this study's outcomes, LA-TT-EABR should be recommended for uncertain CI candidates.

Auditory response of the reticular nucleus of thalamus in awake mice / 生理学报

This study aims to explore the auditory response characteristics of the thalamic reticular nucleus (TRN) in awake mice during auditory information processing, so as to deepen the understanding of TRN and explore its role in the auditory system. By in vivo electrophysiological single cell attached recording of TRN neurons in 18 SPF C57BL/6J mice, we observed the responses of 314 recorded neurons to two kinds of auditory stimuli, noise and tone, applied to mice. The results showed that TRN received projections from layer six of the primary auditory cortex (A1). Among 314 TRN neurons, 56.05% responded silently, 21.02% responded only to noise and 22.93% responded to both noise and tone. The neurons with noise response can be divided into three patterns according to their response time: onset, sustain and long-lasting, accounting for 73.19%, 14.49% and 12.32%, respectively. The response threshold of the sustain pattern neurons was lower than those of the other two types. Under noise stimulation, compared with A1 layer six, TRN neurons showed unstable auditory response (P < 0.001), higher spontaneous firing rate (P < 0.001), and longer response latency (P < 0.001). Under tone stimulation, TRN's response continuity was poor, and the frequency tuning was greatly different from that of A1 layer six (P < 0.001), but their sensitivity to tone was similar (P > 0.05), and TRN's tone response threshold was much higher than that of A1 layer six (P < 0.001). The above results demonstrate that TRN mainly undertakes the task of information transmission in the auditory system. The noise response of TRN is more extensive than the tone response. Generally, TRN prefers high-intensity acoustic stimulation.

Selective corticofugal modulation on sound processing in auditory thalamus of awake marmosets.

Cortical feedback has long been considered crucial for the modulation of sensory perception and recognition. However, previous studies have shown varying modulatory effects of the primary auditory cortex (A1) on the auditory response of subcortical neurons, which complicate interpretations regarding the function of A1 in sound perception and recognition. This has been further complicated by studies conducted under different brain states. In the current study, we used cryo-inactivation in A1 to examine the role of corticothalamic feedback on medial geniculate body (MGB) neurons in awake marmosets. The primary effects of A1 inactivation were a frequency-specific decrease in the auditory response of most MGB neurons coupled with an increased spontaneous firing rate, which together resulted in a decrease in the signal-to-noise ratio. In addition, we report for the first time that A1 robustly modulated the long-lasting sustained response of MGB neurons, which changed the frequency tuning after A1 inactivation, e.g. some neurons are sharper with corticofugal feedback and some get broader. Taken together, our results demonstrate that corticothalamic modulation in awake marmosets serves to enhance sensory processing in a manner similar to center-surround models proposed in visual and somatosensory systems, a finding which supports common principles of corticothalamic processing across sensory systems.

Left frontal eye field encodes sound locations during passive listening.

Previous studies reported that auditory cortices (AC) were mostly activated by sounds coming from the contralateral hemifield. As a result, sound locations could be encoded by integrating opposite activations from both sides of AC ("opponent hemifield coding"). However, human auditory "where" pathway also includes a series of parietal and prefrontal regions. It was unknown how sound locations were represented in those high-level regions during passive listening. Here, we investigated the neural representation of sound locations in high-level regions by voxel-level tuning analysis, regions-of-interest-level (ROI-level) laterality analysis, and ROI-level multivariate pattern analysis. Functional magnetic resonance imaging data were collected while participants listened passively to sounds from various horizontal locations. We found that opponent hemifield coding of sound locations not only existed in AC, but also spanned over intraparietal sulcus, superior parietal lobule, and frontal eye field (FEF). Furthermore, multivariate pattern representation of sound locations in both hemifields could be observed in left AC, right AC, and left FEF. Overall, our results demonstrate that left FEF, a high-level region along the auditory "where" pathway, encodes sound locations during passive listening in two ways: a univariate opponent hemifield activation representation and a multivariate full-field activation pattern representation.

Visual Deprivation Selectively Reduces Thalamic Reticular Nucleus-Mediated Inhibition of the Auditory Thalamus in Adults.

Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher-order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes in which cross-modal plasticity occurs even earlier in the sensory-processing pathway at the level of the thalamus in a modality-selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory synaptic transmission from the primary visual cortex to dLGN or TRN and A1 to MGBv, which suggests that the visual deprivation-induced plasticity occurs predominantly at the level of thalamic inhibition. We provide evidence that visual deprivation-induced change in the short-term depression of TRN inhibition to MGBv involves endocannabinoid CB1 receptors. TRN inhibition is considered critical for sensory gating, selective attention, and multimodal performances; hence, its plasticity has implications for sensory processing. Our results suggest that selective disinhibition and altered short-term dynamics of TRN inhibition in the spared thalamic nucleus support cross-modal plasticity in the adult brain.SIGNIFICANCE STATEMENT Losing vision triggers adaptation of the brain to enhance the processing of the remaining senses, which can be observed as better auditory performance in blind subjects. We previously found that depriving vision of adult rodents produces widespread circuit reorganization in the primary auditory cortex and enhances auditory processing at a neural level. Here we report that visual deprivation-induced plasticity in adults occurs much earlier in the auditory pathway, at the level of thalamic inhibition. Sensory processing is largely gated at the level of the thalamus via strong cortical feedback inhibition mediated through the thalamic reticular nucleus (TRN). We found that TRN inhibition of the auditory thalamus is selectively reduced by visual deprivation, thus playing a role in adult cross-modal plasticity.

Neural tracking as a diagnostic tool to assess the auditory pathway.

When a person listens to sound, the brain time-locks to specific aspects of the sound. This is called neural tracking and it can be investigated by analysing neural responses (e.g., measured by electroencephalography) to continuous natural speech. Measures of neural tracking allow for an objective investigation of a range of auditory and linguistic processes in the brain during natural speech perception. This approach is more ecologically valid than traditional auditory evoked responses and has great potential for research and clinical applications. This article reviews the neural tracking framework and highlights three prominent examples of neural tracking analyses: neural tracking of the fundamental frequency of the voice (f0), the speech envelope and linguistic features. Each of these analyses provides a unique point of view into the human brain's hierarchical stages of speech processing. F0-tracking assesses the encoding of fine temporal information in the early stages of the auditory pathway, i.e., from the auditory periphery up to early processing in the primary auditory cortex. Envelope tracking reflects bottom-up and top-down speech-related processes in the auditory cortex and is likely necessary but not sufficient for speech intelligibility. Linguistic feature tracking (e.g. word or phoneme surprisal) relates to neural processes more directly related to speech intelligibility. Together these analyses form a multi-faceted objective assessment of an individual's auditory and linguistic processing.

Corticofugal regulation of predictive coding.

Sensory systems must account for both contextual factors and prior experience to adaptively engage with the dynamic external environment. In the central auditory system, neurons modulate their responses to sounds based on statistical context. These response modulations can be understood through a hierarchical predictive coding lens: responses to repeated stimuli are progressively decreased, in a process known as repetition suppression, whereas unexpected stimuli produce a prediction error signal. Prediction error incrementally increases along the auditory hierarchy from the inferior colliculus (IC) to the auditory cortex (AC), suggesting that these regions may engage in hierarchical predictive coding. A potential substrate for top-down predictive cues is the massive set of descending projections from the AC to subcortical structures, although the role of this system in predictive processing has never been directly assessed. We tested the effect of optogenetic inactivation of the auditory cortico-collicular feedback in awake mice on responses of IC neurons to stimuli designed to test prediction error and repetition suppression. Inactivation of the cortico-collicular pathway led to a decrease in prediction error in IC. Repetition suppression was unaffected by cortico-collicular inactivation, suggesting that this metric may reflect fatigue of bottom-up sensory inputs rather than predictive processing. We also discovered populations of IC units that exhibit repetition enhancement, a sequential increase in firing with stimulus repetition. Cortico-collicular inactivation led to a decrease in repetition enhancement in the central nucleus of IC, suggesting that it is a top-down phenomenon. Negative prediction error, a stronger response to a tone in a predictable rather than unpredictable sequence, was suppressed in shell IC units during cortico-collicular inactivation. These changes in predictive coding metrics arose from bidirectional modulations in the response to the standard and deviant contexts, such that the units in IC responded more similarly to each context in the absence of cortical input. We also investigated how these metrics compare between the anesthetized and awake states by recording from the same units under both conditions. We found that metrics of predictive coding and deviance detection differ depending on the anesthetic state of the animal, with negative prediction error emerging in the central IC and repetition enhancement and prediction error being more prevalent in the absence of anesthesia. Overall, our results demonstrate that the AC provides cues about the statistical context of sound to subcortical brain regions via direct feedback, regulating processing of both prediction and repetition.

Hearing abnormalities in multiple sclerosis: clinical semiology and pathophysiologic mechanisms.

Auditory manifestations from multiple sclerosis (MS) are not as common as the well-recognized sentinel exacerbations of optic neuritis, partial myelitis, motor weakness, vertiginous episodes, heat intolerance, and eye movement abnormalities. This paper discusses four cases of auditory changes, secondary to MS, and describes the first case, to our knowledge, of palinacousis, the perseveration of hearing, despite cessation of the sound stimulus. For each we characterize the initial complaint, the diagnostic work up, and ultimately, underscore the individualized treatment interventions, that allowed us to achieve a remission in all four cases. Individually codifying the treatment regimens served to mitigate, if not to abolish, the clinical derangements in hearing. Special attention is focused upon examination of the clinical manifestations and the pathophysiologic mechanisms which are responsible for them. We further emphasize the differential diagnostic considerations, and physical exam findings, along with the results of laboratory testing, neuro-imaging sequences, and lesion localization. Taken together, such information is germane to organizing cogently coherent strategic treatment plan(s). We believe that this small case series represents a clinically pragmatic example of 'precision medicine'; a principal theme and goal throughout this paper, the achievement of such in MS, but also as an illustration for the assessment and management schema for neuroimmunologic disorders in general.