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According to the predictive processing framework, perception emerges fromthe reciprocal exchange of predictions and prediction errors (PEs) between hierarchically organized neural circuits. The nonlemniscal division of the inferior colliculus (IC) is the earliest source of auditory PE signals, but their neuronal generators, properties, and functional relevance have remained mostly undefined. We recorded single-unitmismatch responses to auditory oddball stimulation at different intensities, together with activity evoked by two sequences of alternating tones to control frequency-specific effects. Our results reveal a differential treatment of the unpredictable "many-standards" control and the predictable "cascade" control by lemniscal and nonlemniscal IC neurons that is not present in the auditory thalamus or cortex. Furthermore, we found that frequency response areas of nonlemniscal IC neurons reflect their role in subcortical predictive processing, distinguishing three hierarchical levels: (1) nonlemniscal neurons with sharply tuned receptive fields exhibitmild repetition suppression without signaling PEs, thereby constituting the input level of the local predictive processing circuitry. (2) Neurons with broadly tuned receptive fields formthemain, "spectral" PE signaling system, which provides dynamic gain compensation to near-threshold unexpected sounds. This early enhancement of saliency reliant on spectral features was not observed in the auditory thalamus or cortex. (3) Untuned neurons form an accessory, "nonspectral" PE signaling system, which reports all surprising auditory deviances in a robust and consistentmanner, resembling nonlemniscal neurons in the auditory cortex. These nonlemniscal IC neurons show unstructured and unstable receptive fields that could result from inhibitory input controlled by corticofugal projections conveying top-down predictions. [ABSTRACT FROM AUTHOR]

Most current methods for neuromodulation target the cortex. Approaches for inducing plasticity in subcortical motor pathways, such as the reticulospinal tract, could help to boost recovery after damage (e.g., stroke). In this study, we paired loud acoustic stimulation (LAS) with transcranial magnetic stimulation (TMS) over the motor cortex in male and female healthy humans. LAS activates the reticular formation; TMS activates descending systems, including corticoreticular fibers. Two hundred paired stimuli were used, with 50ms interstimulus interval at which LAS suppresses TMS responses. Before and after stimulus pairing, responses in the contralateral biceps muscle to TMS alone were measured. Ten, 20, and 30min after stimulus pairing ended, TMS responses were enhanced, indicating the induction of LTP. No long-term changes were seen in control experiments which used 200 unpaired TMS or LAS, indicating the importance of associative stimulation. Following paired stimulation, no changes were seen in responses to direct corticospinal stimulation at the level of the medulla, or in the extent of reaction time shortening by a loud sound (StartReact effect), suggesting that plasticity did not occur in corticospinal or reticulospinal synapses. Direct measurements in female monkeys undergoing a similar paired protocol revealed no enhancement of corticospinal volleys after paired stimulation, suggesting no changes occurred in intracortical connections. The most likely substrate for the plastic changes, consistent with all our measurements, is an increase in the efficacy of corticoreticular connections. This new protocol may find utility, as it seems to target different motor circuits compared with other available paradigms. [ABSTRACT FROM AUTHOR]

In the presence of temporally organized stimuli, there is a tendency to entrain to the beat, even at the neurological level. Previous research has shown that when adults listen to rhythmic stimuli and are asked to imagine the beat, their neural responses are the same as when the beat is physically accented. The current study explores the neural processing of simple beat structures where the beat is physically accented or inferred from a previously presented physically accented beat structure in a passive listening context. We further explore the associations of these neural correlates with behavioral and self-reported measures of musicality. Fifty-seven participants completed a passive listening EEG paradigm, a behavioral rhythm discrimination task, and a self-reported musicality questionnaire. Our findings suggest that when the beat is physically accented, individuals demonstrate distinct neural responses to the beat in the beta (13-23 Hz) and gamma (24-50 Hz) frequency bands. We further find that the neural marker in the beta band is associated with individuals' self-reported musical perceptual abilities. Overall, this study provides insights into the neural correlates of spontaneous beat processing and its connections with musicality., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Scartozzi et al.)

Previous physiological and psychophysical studies have explored whether feedback to the cochlea from the efferent system influences forward masking. The present work proposes that the limited growth-of-masking (GOM) observed in auditory nerve (AN) fibers may have been misunderstood; namely, that this limitation may be due to the influence of anesthesia on the efferent system. Building on the premise that the unanesthetized AN may exhibit GOM similar to more central nuclei, the present computational modeling study demonstrates that feedback from the medial olivocochlear (MOC) efferents may contribute to GOM observed physiologically in onset-type neurons in both the cochlear nucleus and inferior colliculus (IC). Additionally, the computational model of MOC efferents used here generates a decrease in masking with longer masker-signal delays similar to that observed in IC physiology and in psychophysical studies. An advantage of this explanation over alternative physiological explanations (e.g., that forward masking requires inhibition from the superior paraolivary nucleus) is that this theory can explain forward masking observed in the brainstem, early in the ascending pathway. For explaining psychoacoustic results, one strength of this model is that it can account for the lack of elevation in thresholds observed when masker level is randomly varied from interval-to-interval, a result that is difficult to explain using the conventional temporal window model of psychophysical forward masking. Future directions for evaluating the efferent mechanism as a contributing mechanism for psychoacoustic results are discussed., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Maxwell et al.)

Musicians can have better abilities to understand speech in adverse condition such as background noise than non-musicians. However, the neural mechanisms behind such enhanced behavioral performances remain largely unclear. Studies have found that the subcortical frequency-following response to the fundamental frequency of speech and its higher harmonics (speech-FFR) may be involved since it is larger in people with musical training than in those without. Recent research has shown that the speech-FFR consists of a cortical contribution in addition to the subcortical sources. Both the subcortical and the cortical contribution are modulated by selective attention to one of two competing speakers. However, it is unknown whether the strength of the cortical contribution to the speech-FFR, or its attention modulation, is influenced by musical training. Here we investigate these issues through magnetoencephalographic (MEG) recordings of 52 subjects (18 musicians, 25 non-musicians, and 9 neutral participants) listening to two competing male speakers while selectively attending one of them. The speech-in-noise comprehension abilities of the participants were not assessed. We find that musicians and non-musicians display comparable cortical speech-FFRs and additionally exhibit similar subject-to-subject variability in the response. Furthermore, we also do not observe a difference in the modulation of the neural response through selective attention between musicians and non-musicians. Moreover, when assessing whether the cortical speech-FFRs are influenced by particular aspects of musical training, no significant effects emerged. Taken together, we did not find any effect of musical training on the cortical speech-FFR., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Riegel et al.)

Sensory processing disruptions are a core symptom of autism spectrum disorder (ASD) and other neurological disorders. The acoustic startle response and prepulse inhibition (PPI) are common metrics used to assess disruptions in sensory processing and sensorimotor gating in clinical studies and animal models. However, often there are inconsistent findings on ASD-related PPI deficits across different studies. Here, we used a novel method for assessing changes in startle and PPI in rodents, using the Cntnap2 knock-out (KO) rat model for neurodevelopmental disorder/ASD that has consistently shown PPI disruptions in past studies. We discovered that not only sex and prepulse intensity but also the intensity of the startle stimulus profoundly impacts whether PPI deficits are evident in the Cntnap2 KO rat or not. We show that rats do not universally exhibit a PPI deficit; instead, impaired PPI is contingent on specific testing conditions. Notably, at lower startle stimulus intensities, Cntnap2 KO rats not only demonstrated intact PPI but also exhibited evidence of enhanced PPI compared with their wild-type counterparts. This finding emphasizes the importance of considering specific testing conditions when evaluating startle and PPI in the context of ASD and other neuropsychiatric conditions and might explain some of the inconsistencies between different studies., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Doornaert et al.)

Reverberation, a ubiquitous feature of real-world acoustic environments, exhibits statistical regularities that human listeners leverage to self-orient, facilitate auditory perception, and understand their environment. Despite the extensive research on sound source representation in the auditory system, it remains unclear how the brain represents real-world reverberant environments. Here, we characterized the neural response to reverberation of varying realism by applying multivariate pattern analysis to electroencephalographic (EEG) brain signals. Human listeners (12 males and 8 females) heard speech samples convolved with real-world and synthetic reverberant impulse responses and judged whether the speech samples were in a "real" or "fake" environment, focusing on the reverberant background rather than the properties of speech itself. Participants distinguished real from synthetic reverberation with ∼75% accuracy; EEG decoding reveals a multistage decoding time course, with dissociable components early in the stimulus presentation and later in the perioffset stage. The early component predominantly occurred in temporal electrode clusters, while the later component was prominent in centroparietal clusters. These findings suggest distinct neural stages in perceiving natural acoustic environments, likely reflecting sensory encoding and higher-level perceptual decision-making processes. Overall, our findings provide evidence that reverberation, rather than being largely suppressed as a noise-like signal, carries relevant environmental information and gains representation along the auditory system. This understanding also offers various applications; it provides insights for including reverberation as a cue to aid navigation for blind and visually impaired people. It also helps to enhance realism perception in immersive virtual reality settings, gaming, music, and film production., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 García-Lázaro and Teng.)

Older listeners often report difficulties understanding speech in noisy environments. It is important to identify where in the auditory pathway hearing-in-noise deficits arise to develop appropriate therapies. We tested how encoding of sounds is affected by masking noise at early stages of the auditory pathway by recording responses of principal cells in the anteroventral cochlear nucleus (AVCN) of aging CBA/CaJ and C57BL/6J mice in vivo. Previous work indicated that masking noise shifts the dynamic range of single auditory nerve fibers (ANFs), leading to elevated tone thresholds. We hypothesized that such threshold shifts could contribute to increased hearing-in-noise deficits with age if susceptibility to masking increased in AVCN units. We tested this by recording the responses of AVCN principal neurons to tones in the presence and absence of masking noise. Surprisingly, we found that masker-induced threshold shifts decreased with age in primary-like units and did not change in choppers. In addition, spontaneous activity decreased in primary-like and chopper units of old mice, with no change in dynamic range or tuning precision. In C57 mice, which undergo early-onset hearing loss, units showed similar changes in threshold and spontaneous rate at younger ages, suggesting they were related to hearing loss and not simply aging. These findings suggest that sound information carried by AVCN principal cells remains largely unchanged with age. Therefore, hearing-in-noise deficits may result from other changes during aging, such as distorted across-channel input from the cochlea and changes in sound coding at later stages of the auditory pathway., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Postolache et al.)

The zebrafish, a widely used model in neurobiology, relies on hearing in aquatic environments. Unfortunately, its auditory pathways have mainly been studied in larvae. In this study, we examined the involvement of the anterior tuberal nucleus (AT) in auditory processing in adult zebrafish. Our tract-tracing experiments revealed that the dorsal subdivision of AT is strongly bidirectionally connected to the central nucleus of the torus semicircularis (TSc), a major auditory nucleus in fishes. Immunohistochemical visualization of the ribosomal protein S6 (pS6) phosphorylation to map neural activity in response to auditory stimulation substantiated this finding: the dorsal but not the ventral part of AT responded strongly to auditory stimulation. A similar response to auditory stimulation was present in the TSc but not in the nucleus isthmi, a visual region, which we used as a control for testing if the pS6 activation was specific to the auditory stimulation. We also measured the time course of pS6 phosphorylation, which was previously unreported in teleost fish. After auditory stimulation, we found that pS6 phosphorylation peaked between 100 and 130 min and returned to baseline levels after 190 min. This information will be valuable for the design of future pS6 experiments. Our results suggest an anatomical and functional subdivision of AT, where only the dorsal part connects to the auditory network and processes auditory information., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Corrales Parada et al.)

The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, noninvasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in the human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants (13 males, 7 females). All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under a placebo. The GABA A receptor-agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA blocker memantine. Our findings indicate that the 40 Hz ASSR in the auditory cortex involves synaptic (and likely intracortical) inhibition via the GABA A receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Toso et al.)

This study compared the impact of spectral and temporal degradation on vocoded speech recognition between early-blind and sighted subjects. The participants included 25 early-blind subjects (30.32 ± 4.88 years; male:female, 14:11) and 25 age- and sex-matched sighted subjects. Tests included monosyllable recognition in noise at various signal-to-noise ratios (-18 to -4 dB), matrix sentence-in-noise recognition, and vocoded speech recognition with different numbers of channels (4, 8, 16, and 32) and temporal envelope cutoff frequencies (50 vs 500 Hz). Cortical-evoked potentials (N2 and P3b) were measured in response to spectrally and temporally degraded stimuli. The early-blind subjects displayed superior monosyllable and sentence recognition than sighted subjects (all p  < 0.01). In the vocoded speech recognition test, a three-way repeated-measure analysis of variance (two groups × four channels × two cutoff frequencies) revealed significant main effects of group, channel, and cutoff frequency (all p  < 0.001). Early-blind subjects showed increased sensitivity to spectral degradation for speech recognition, evident in the significant interaction between group and channel ( p  = 0.007). N2 responses in early-blind subjects exhibited shorter latency and greater amplitude in the 8-channel ( p  = 0.022 and 0.034, respectively) and shorter latency in the 16-channel ( p  = 0.049) compared with sighted subjects. In conclusion, early-blind subjects demonstrated speech recognition advantages over sighted subjects, even in the presence of spectral and temporal degradation. Spectral degradation had a greater impact on speech recognition in early-blind subjects, while the effect of temporal degradation was similar in both groups., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Choi et al.)

Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca 2+ imaging in FMR1 ( fragile X messenger ribonucleoprotein 1 ) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1 week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC network activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Wadle et al.)

More and more patients worldwide are diagnosed with dementia, which emphasizes the urgent need for early detection markers. In this study, we built on the auditory hypersensitivity theory of a previous study-which postulated that responses to auditory input in the subcortex as well as cortex are enhanced in cognitive decline-and examined auditory encoding of natural continuous speech at both neural levels for its indicative potential for cognitive decline. We recruited study participants aged 60 years and older, who were divided into two groups based on the Montreal Cognitive Assessment, one group with low scores ( n  = 19, participants with signs of cognitive decline) and a control group ( n  = 25). Participants completed an audiometric assessment and then we recorded their electroencephalography while they listened to an audiobook and click sounds. We derived temporal response functions and evoked potentials from the data and examined response amplitudes for their potential to predict cognitive decline, controlling for hearing ability and age. Contrary to our expectations, no evidence of auditory hypersensitivity was observed in participants with signs of cognitive decline; response amplitudes were comparable in both cognitive groups. Moreover, the combination of response amplitudes showed no predictive value for cognitive decline. These results challenge the proposed hypothesis and emphasize the need for further research to identify reliable auditory markers for the early detection of cognitive decline., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Bolt and Giroud.)

Cortical oscillations have been proposed to play a functional role in speech and music perception, attentional selection, and working memory, via the mechanism of neural entrainment. One of the properties of neural entrainment that is often taken for granted is that its modulatory effect on ongoing oscillations outlasts rhythmic stimulation. We tested the existence of this phenomenon by studying cortical neural oscillations during and after presentation of melodic stimuli in a passive perception paradigm. Melodies were composed of; 60 and; 80 Hz tones embedded in a 2.5 Hz stream. Using intracranial and surface recordings in male and female humans, we reveal persistent oscillatory activity in the high-c band in response to the tones throughout the cortex, well beyond auditory regions. By contrast, in response to the 2.5 Hz stream, no persistent activity in any frequency band was observed. We further show that our data are well captured by a model of damped harmonic oscillator and can be classified into three classes of neural dynamics, with distinct damping properties and eigenfrequencies. This model provides a mechanistic and quantitative explanation of the frequency selectivity of auditory neural entrainment in the human cortex. [ABSTRACT FROM AUTHOR]

At any given moment our sensory systems receive multiple, often rhythmic, inputs from the environment. Processing of temporally structured events in one sensory modality can guide both behavioral and neural processing of events in other sensory modalities, but whether this occurs remains unclear. Here, we used human electroencephalography (EEG) to test the crossmodal influences of a continuous auditory frequency-modulated (FM) sound on visual perception and visual cortical activity. We report systematic fluctuations in perceptual discrimination of brief visual stimuli in line with the phase of the FM-sound. We further show that this rhythmic modulation in visual perception is related to an accompanying rhythmic modulation of neural activity recorded over visual areas. Importantly, in our task, perceptual and neural visual modulations occurred without any abrupt and salient onsets in the energy of the auditory stimulation and without any rhythmic structure in the visual stimulus. As such, the results provide a critical validation for the existence and functional role of cross-modal entrainment and demonstrates its utility for organizing the perception of multisensory stimulation in the natural environment. [ABSTRACT FROM AUTHOR]

Existing non-invasive stimulation protocols can generate plasticity in the motor cortex and its corticospinal projections; techniques for inducing plasticity in subcortical circuits and alternative descending pathways such as the reticulospinal tract (RST) are less well developed. One possible approach developed by this laboratory pairs electrical muscle stimulation with auditory clicks, using a wearable device to deliver stimuli during normal daily activities. In this study, we applied a variety of electrophysiological assessments to male and female healthy human volunteers during a morning and evening laboratory visit. In the intervening time (;6 h), subjects wore the stimulation device, receiving three different protocols, in which clicks and stimulation of the biceps muscle were paired at either low or high rate, or delivered at random. Paired stimulation: (1) increased the extent of reaction time shortening by a loud sound (the StartReact effect); (2) decreased the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; (3) enhanced muscle responses elicited by a TMS coil oriented to induce anterior-posterior (AP) current, but not posterior-anterior (PA) current, in the brain. These measurements have all been suggested to be sensitive to subcortical, possibly reticulospinal, activity. Changes were similar for either of the two paired stimulus rates tested, but absent after unpaired (control) stimulation. Taken together, these results suggest that pairing clicks and muscle stimulation for long periods does indeed induce plasticity in subcortical systems such as the RST. [ABSTRACT FROM AUTHOR]

Sensory stimulation is often accompanied by fluctuations at high frequencies (>30 Hz) in brain signals. These could be "narrowband" oscillations in the gamma band (30-70 Hz) or nonoscillatory "broadband" high-gamma (70-150 Hz) activity. Narrowband gamma oscillations, which are induced by presenting some visual stimuli such as gratings and have been shown to weaken with healthy aging and the onset of Alzheimer's disease, hold promise as potential biomarkers. However, since delivering visual stimuli is cumbersome as it requires head stabilization for eye tracking, an equivalent auditory paradigm could be useful. Although simple auditory stimuli have been shown to produce high-gamma activity, whether specific auditory stimuli can also produce narrowband gamma oscillations is unknown. We tested whether auditory ripple stimuli, which are considered an analog to visual gratings, could elicit narrowband oscillations in auditory areas. We recorded 64-channel electroencephalogram from male and female (18 each) subjects while they either fixated on the monitor while passively viewing static visual gratings or listened to stationary and moving ripples, played using loudspeakers, with their eyes open or closed. We found that while visual gratings induced narrowband gamma oscillations with suppression in the alpha band (8-12 Hz), auditory ripples did not produce narrowband gamma but instead elicited very strong broadband high-gamma response and suppression in the beta band (14-26 Hz). Even though we used equivalent stimuli in both modalities, our findings indicate that the underlying neuronal circuitry may not share ubiquitous strategies for stimulus processing., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Gulati and Ray.)

Pure-tone audiograms often poorly predict elderly humans' ability to communicate in everyday complex acoustic scenes. Binaural processing is crucial for discriminating sound sources in such complex acoustic scenes. The compromised perception of communication signals presented above hearing threshold has been linked to both peripheral and central age-related changes in the auditory system. Investigating young and old Mongolian gerbils of both sexes, an established model for human hearing, we demonstrate age-related supra-threshold deficits in binaural hearing using behavioral, electrophysiological, anatomical, and imaging methods. Binaural processing ability was measured as the binaural masking level difference (BMLD), an established measure in human psychophysics. We tested gerbils behaviorally with "virtual headphones," recorded single-unit responses in the auditory midbrain and evaluated gross midbrain and cortical responses using positron emission tomography (PET) imaging. Furthermore, we obtained additional measures of auditory function based on auditory brainstem responses, auditory-nerve synapse counts, and evidence for central inhibitory processing revealed by PET. BMLD deteriorates already in middle-aged animals having normal audiometric thresholds and is even worse in old animals with hearing loss. The magnitude of auditory brainstem response measures related to auditory-nerve function and binaural processing in the auditory brainstem also deteriorate. Furthermore, central GABAergic inhibition is affected by age. Because the number of synapses in the apical turn of the inner ear was not reduced in middle-aged animals, we conclude that peripheral synaptopathy contributes little to binaural processing deficits. Exploratory analyses suggest increased hearing thresholds, altered binaural processing in the brainstem and changed central GABAergic inhibition as potential contributors., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Real-world listening settings often consist of multiple concurrent sound streams. To limit perceptual interference during selective listening, the auditory system segregates and filters the relevant sensory input. Previous work provided evidence that the auditory cortex is critically involved in this process and selectively gates attended input toward subsequent processing stages. We studied at which level of auditory cortex processing this filtering of attended information occurs using functional magnetic resonance imaging (fMRI) and a naturalistic selective listening task. Forty-five human listeners (of either sex) attended to one of two continuous speech streams, presented either concurrently or in isolation. Functional data were analyzed using an inter-subject analysis to assess stimulus-specific components of ongoing auditory cortex activity. Our results suggest that stimulus-related activity in the primary auditory cortex and the adjacent planum temporale are hardly affected by attention, whereas brain responses at higher stages of the auditory cortex processing hierarchy become progressively more selective for the attended input. Consistent with these findings, a complementary analysis of stimulus-driven functional connectivity further demonstrated that information on the to-be-ignored speech stream is shared between the primary auditory cortex and the planum temporale but largely fails to reach higher processing stages. Our findings suggest that the neural processing of ignored speech cannot be effectively suppressed at the level of early cortical processing of acoustic features but is gradually attenuated once the competing speech streams are fully segregated., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Networks are a useful mathematical tool for capturing the complexity of the world. In a previous behavioral study, we showed that human adults were sensitive to the high-level network structure underlying auditory sequences, even when presented with incomplete information. Their performance was best explained by a mathematical model compatible with associative learning principles, based on the integration of the transition probabilities between adjacent and nonadjacent elements with a memory decay. In the present study, we explored the neural correlates of this hypothesis via magnetoencephalography (MEG). Participants ( N  = 23, 16 females) passively listened to sequences of tones organized in a sparse community network structure comprising two communities. An early difference (∼150 ms) was observed in the brain responses to tone transitions with similar transition probability but occurring either within or between communities. This result implies a rapid and automatic encoding of the sequence structure. Using time-resolved decoding, we estimated the duration and overlap of the representation of each tone. The decoding performance exhibited exponential decay, resulting in a significant overlap between the representations of successive tones. Based on this extended decay profile, we estimated a long-horizon associative learning novelty index for each transition and found a correlation of this measure with the MEG signal. Overall, our study sheds light on the neural mechanisms underlying human sensitivity to network structures and highlights the potential role of Hebbian-like mechanisms in supporting learning at various temporal scales., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium, NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recorded in vivo awake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly in females. Behaviorally, we trained birds using operant conditioning and tested their ability to detect songs in scenes after administering FAD orally or injected bilaterally into NCM. Oral FAD increased response bias and decreased correct rejections in females, but not in males. FAD in NCM did not affect performance. Thus, FAD in the NCM impaired neuronal ASA but that did not lead to behavioral disruption suggesting the existence of resilience or compensatory responses. Moreover, impaired performance after systemic FAD suggests involvement of other aromatase-rich networks outside the auditory pathway in ASA. This work highlights how transient estrogen synthesis disruption can modulate higher-order processing in an animal model of vocal communication., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Fernández-Vargas et al.)

Neurons in the mouse auditory cortex are strongly influenced by behavior, including both suppression and enhancement of sound-evoked responses during movement. The mouse auditory cortex comprises multiple fields with different roles in sound processing and distinct connectivity to movement-related centers of the brain. Here, we asked whether movement-related modulation in male mice might differ across auditory cortical fields, thereby contributing to the heterogeneity of movement-related modulation at the single-cell level. We used wide-field calcium imaging to identify distinct cortical fields and cellular-resolution two-photon calcium imaging to visualize the activity of layer 2/3 excitatory neurons within each field. We measured each neuron's responses to three sound categories (pure tones, chirps, and amplitude-modulated white noise) as mice rested and ran on a non-motorized treadmill. We found that individual neurons in each cortical field typically respond to just one sound category. Some neurons are only active during rest and others during locomotion, and those that are responsive across conditions retain their sound-category tuning. The effects of locomotion on sound-evoked responses vary at the single-cell level, with both suppression and enhancement of neural responses, and the net modulatory effect of locomotion is largely conserved across cortical fields. Movement-related modulation in auditory cortex also reflects more complex behavioral patterns, including instantaneous running speed and nonlocomotor movements such as grooming and postural adjustments, with similar patterns seen across all auditory cortical fields. Our findings underscore the complexity of movement-related modulation throughout the mouse auditory cortex and indicate that movement-related modulation is a widespread phenomenon., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Luminance-independent changes in pupil diameter (PD) during wakefulness influence and are influenced by neuromodulatory, neuronal, and behavioral responses. However, it is unclear whether changes in neuromodulatory activity in a specific brain area are necessary for the associated changes in PD or whether some different mechanisms cause parallel fluctuations in both PD and neuromodulation. To answer this question, we simultaneously recorded PD and cortical neuronal activity in male and female mice. Namely, we measured PD and neuronal activity during adaptation to sound contrast, which is a well-described adaptation conserved in many species and brain areas. In the primary auditory cortex (A1), increases in the variability of sound level (contrast) induce a decrease in the slope of the neuronal input-output relationship, neuronal gain, which depends on cortical neuromodulatory zinc signaling. We found a previously unknown modulation of PD by changes in background sensory context: high stimulus contrast sounds evoke larger increases in evoked PD compared with low-contrast sounds. To explore whether these changes in evoked PD are controlled by cortical neuromodulatory zinc signaling, we imaged single-cell neural activity in A1, manipulated zinc signaling in the cortex, and assessed PD in the same awake mouse. We found that cortical synaptic zinc signaling is necessary for increases in PD during high-contrast background sounds compared with low-contrast sounds. This finding advances our knowledge about how cortical neuromodulatory activity affects PD changes and thus advances our understanding of the brain states, circuits, and neuromodulatory mechanisms that can be inferred from pupil size fluctuations., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

During communication in real-life settings, our brain often needs to integrate auditory and visual information and at the same time actively focus on the relevant sources of information, while ignoring interference from irrelevant events. The interaction between integration and attention processes remains poorly understood. Here, we use rapid invisible frequency tagging and magnetoencephalography to investigate how attention affects auditory and visual information processing and integration, during multimodal communication. We presented human participants (male and female) with videos of an actress uttering action verbs (auditory; tagged at 58 Hz) accompanied by two movie clips of hand gestures on both sides of fixation (attended stimulus tagged at 65 Hz; unattended stimulus tagged at 63 Hz). Integration difficulty was manipulated by a lower-order auditory factor (clear/degraded speech) and a higher-order visual semantic factor (matching/mismatching gesture). We observed an enhanced neural response to the attended visual information during degraded speech compared to clear speech. For the unattended information, the neural response to mismatching gestures was enhanced compared to matching gestures. Furthermore, signal power at the intermodulation frequencies of the frequency tags, indexing nonlinear signal interactions, was enhanced in the left frontotemporal and frontal regions. Focusing on the left inferior frontal gyrus, this enhancement was specific for the attended information, for those trials that benefitted from integration with a matching gesture. Together, our results suggest that attention modulates audiovisual processing and interaction, depending on the congruence and quality of the sensory input., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The neural mechanisms underlying the exogenous coding and neural entrainment to repetitive auditory stimuli have seen a recent surge of interest. However, few studies have characterized how parametric changes in stimulus presentation alter entrained responses. We examined the degree to which the brain entrains to repeated speech (i.e., /ba/) and nonspeech (i.e., click) sounds using phase-locking value (PLV) analysis applied to multichannel human electroencephalogram (EEG) data. Passive cortico-acoustic tracking was investigated in N  = 24 normal young adults utilizing EEG source analyses that isolated neural activity stemming from both auditory temporal cortices. We parametrically manipulated the rate and periodicity of repetitive, continuous speech and click stimuli to investigate how speed and jitter in ongoing sound streams affect oscillatory entrainment. Neuronal synchronization to speech was enhanced at 4.5 Hz (the putative universal rate of speech) and showed a differential pattern to that of clicks, particularly at higher rates. PLV to speech decreased with increasing jitter but remained superior to clicks. Surprisingly, PLV entrainment to clicks was invariant to periodicity manipulations. Our findings provide evidence that the brain's neural entrainment to complex sounds is enhanced and more sensitized when processing speech-like stimuli, even at the syllable level, relative to nonspeech sounds. The fact that this specialization is apparent even under passive listening suggests a priority of the auditory system for synchronizing to behaviorally relevant signals., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Momtaz and Bidelman.)

Layer 5 pyramidal neurons of sensory cortices project "corticofugal" axons to myriad sub-cortical targets, thereby broadcasting high-level signals important for perception and learning. Recent studies suggest dendritic Ca 2+ spikes as key biophysical mechanisms supporting corticofugal neuron function: these long-lasting events drive burst firing, thereby initiating uniquely powerful signals to modulate sub-cortical representations and trigger learning-related plasticity. However, the behavioral relevance of corticofugal dendritic spikes is poorly understood. We shed light on this issue using 2-photon Ca 2+ imaging of auditory corticofugal dendrites as mice of either sex engage in a GO/NO-GO sound-discrimination task. Unexpectedly, only a minority of dendritic spikes were triggered by behaviorally relevant sounds under our conditions. Task related dendritic activity instead mostly followed sound cue termination and co-occurred with mice's instrumental licking during the answer period of behavioral trials, irrespective of reward consumption. Temporally selective, optogenetic silencing of corticofugal neurons during the trial answer period impaired auditory discrimination learning. Thus, auditory corticofugal systems' contribution to learning and plasticity may be partially nonsensory in nature., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Temporal orienting improves sensory processing, akin to other top- down biases. However, it is unknown whether these improvements reflect increased neural gain to any stimuli presented at expected time points, or specific tuning to task-relevant stimulus aspects. Furthermore, while other top- down biases are selective, the extent of trade-offs across time is less well characterized. Here, we tested whether gain and/or tuning of auditory frequency processing in humans is modulated by rhythmic temporal expectations, and whether these modulations are specific to time points relevant for task performance. Healthy participants (N = 23) of either sex performed an auditory discrimination task while their brain activity was measured using magnetoencephalography/electroencephalography (M/EEG). Acoustic stimulation consisted of sequences of brief distractors interspersed with targets, presented in a rhythmic or jittered way. Target rhythmicity not only improved behavioral discrimination accuracy and M/EEG-based decoding of targets, but also of irrelevant distractors preceding these targets. To explain this finding in terms of increased sensitivity and/or sharpened tuning to auditory frequency, we estimated tuning curves based on M/EEG decoding results, with separate parameters describing gain and sharpness. The effect of rhythmic expectation on distractor decoding was linked to gain increase only, suggesting increased neural sensitivity to any stimuli presented at relevant time points. [ABSTRACT FROM AUTHOR]

Reading acquisition involves the integration of auditory and visual stimuli. Thus, low-level audiovisual multisensory integration might contribute to disrupted reading in developmental dyslexia. Although dyslexia is more frequently diagnosed in males and emerging evidence indicates that the neural basis of dyslexia might differ between sexes, previous studies examining multisensory integration did not evaluate potential sex differences nor tested its neural correlates. In the current study on 88 adolescents and young adults, we found that only males with dyslexia showed a deficit in multisensory integration of simple nonlinguistic stimuli. At the neural level, both females and males with dyslexia presented smaller differences in response to multisensory compared to those in response to unisensory conditions in the N1 and N2 components (early components of event-related potentials associated with sensory processing) than the control group. Additionally, in a subsample of 80 participants matched for nonverbal IQ, only males with dyslexia exhibited smaller differences in the left hemisphere in response to multisensory compared to those in response to unisensory conditions in the N1 component. Our study indicates that deficits of multisensory integration seem to be more severe in males than females with dyslexia. This provides important insights into sex-modulated cognitive processes that might confer vulnerability to reading difficulties., (Copyright © 2024 the authors.)

Interaural time differences (ITDs) are a major cue for sound localization and change with increasing head size. Since the barn owl's head width more than doubles in the month after hatching, we hypothesized that the development of their ITD detection circuit might be modified by experience. To test this, we raised owls with unilateral ear inserts that delayed and attenuated the acoustic signal, and then measured the ITD representation in the brainstem nucleus laminaris (NL) when they were adults. The ITD circuit is composed of delay line inputs to coincidence detectors, and we predicted that plastic changes would lead to shorter delays in the axons from the manipulated ear, and complementary shifts in ITD representation on the two sides. In owls that received ear inserts starting around P14, the maps of ITD shifted in the predicted direction, but only on the ipsilateral side, and only in those tonotopic regions that had not experienced auditory stimulation prior to insertion. The contralateral map did not change. Thus, experience-dependent plasticity of the ITD circuit occurs in NL, and our data suggest that ipsilateral and contralateral delays are independently regulated. As a result, altered auditory input during development leads to long-lasting changes in the representation of ITD. Significance Statement The early life of barn owls is marked by increasing sensitivity to sound, and by increasing ITDs. Their prolonged post-hatch development allowed us to examine the role of altered auditory experience in the development of ITD detection circuits. We raised owls with a unilateral ear insert and found that their maps of ITD were altered by experience, but only in those tonotopic regions ipsilateral to the occluded ear that had not experienced auditory stimulation prior to insertion. This experience-induced plasticity allows the sound localization circuits to be customized to individual characteristics, such as the size of the head, and potentially to compensate for imbalanced hearing sensitivities between the left and right ears., (Copyright © 2023 the authors.)

The key assumption of the predictive coding framework is that internal representations are used to generate predictions on how the sensory input will look like in the immediate future. These predictions are tested against the actual input by the so-called prediction error units, which encode the residuals of the predictions. What happens to prediction errors, however, if predictions drawn by different stages of the sensory hierarchy contradict each other? To answer this question, we conducted two fMRI experiments while female and male human participants listened to sequences of sounds: pure tones in the first experiment and frequency-modulated sweeps in the second experiment. In both experiments, we used repetition to induce predictions based on stimulus statistics (stats-informed predictions) and abstract rules disclosed in the task instructions to induce an orthogonal set of (task-informed) predictions. We tested three alternative scenarios: neural responses in the auditory sensory pathway encode prediction error with respect to (1) the stats-informed predictions, (2) the task-informed predictions, or (3) a combination of both. Results showed that neural populations in all recorded regions (bilateral inferior colliculus, medial geniculate body, and primary and secondary auditory cortices) encode prediction error with respect to a combination of the two orthogonal sets of predictions. The findings suggest that predictive coding exploits the non-linear architecture of the auditory pathway for the transmission of predictions. Such non-linear transmission of predictions might be crucial for the predictive coding of complex auditory signals like speech. Significance Statement Sensory systems exploit our subjective expectations to make sense of an overwhelming influx of sensory signals. It is still unclear how expectations at each stage of the processing pipeline are used to predict the representations at the other stages. The current view is that this transmission is hierarchical and linear. Here we measured fMRI responses in auditory cortex, sensory thalamus, and midbrain while we induced two sets of mutually inconsistent expectations on the sensory input, each putatively encoded at a different stage. We show that responses at all stages are concurrently shaped by both sets of expectations. The results challenge the hypothesis that expectations are transmitted linearly and provide for a normative explanation of the non-linear physiology of the corticofugal sensory system., (Copyright © 2023 the authors.)

Spontaneous speech is produced in chunks called intonation units (IUs). IUs are defined by a set of prosodic cues and presumably occur in all human languages. Recent work has shown that across different grammatical and sociocultural conditions IUs form rhythms of ∼1 unit per second. Linguistic theory suggests that IUs pace the flow of information in the discourse. As a result, IUs provide a promising and hitherto unexplored theoretical framework for studying the neural mechanisms of communication. In this article, we identify a neural response unique to the boundary defined by the IU. We measured the EEG of human participants (of either sex), who listened to different speakers recounting an emotional life event. We analyzed the speech stimuli linguistically and modeled the EEG response at word offset using a GLM approach. We find that the EEG response to IU-final words differs from the response to IU-nonfinal words even when equating acoustic boundary strength. Finally, we relate our findings to the body of research on rhythmic brain mechanisms in speech processing. We study the unique contribution of IUs and acoustic boundary strength in predicting delta-band EEG. This analysis suggests that IU-related neural activity, which is tightly linked to the classic Closure Positive Shift (CPS), could be a time-locked component that captures the previously characterized delta-band neural speech tracking. SIGNIFICANCE STATEMENT Linguistic communication is central to human experience, and its neural underpinnings are a topic of much research in recent years. Neuroscientific research has benefited from studying human behavior in naturalistic settings, an endeavor that requires explicit models of complex behavior. Usage-based linguistic theory suggests that spoken language is prosodically structured in intonation units. We reveal that the neural system is attuned to intonation units by explicitly modeling their impact on the EEG response beyond mere acoustics. To our understanding, this is the first time this is demonstrated in spontaneous speech under naturalistic conditions and under a theoretical framework that connects the prosodic chunking of speech, on the one hand, with the flow of information during communication, on the other., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 the authors.)

Selective attention to one of several competing speakers is required for comprehending a target speaker among other voices and for successful communication with them. It moreover has been found to involve the neural tracking of low-frequency speech rhythms in the auditory cortex. Effects of selective attention have also been found in subcortical neural activities, in particular regarding the frequency-following response related to the fundamental frequency of speech (speech-FFR). Recent investigations have, however, shown that the speech-FFR contains cortical contributions as well. It remains unclear whether these are also modulated by selective attention. Here we used magnetoencephalography to assess the attentional modulation of the cortical contributions to the speech-FFR. We presented both male and female participants with two competing speech signals and analyzed the cortical responses during attentional switching between the two speakers. Our findings revealed robust attentional modulation of the cortical contribution to the speech-FFR: the neural responses were higher when the speaker was attended than when they were ignored. We also found that, regardless of attention, a voice with a lower fundamental frequency elicited a larger cortical contribution to the speech-FFR than a voice with a higher fundamental frequency. Our results show that the attentional modulation of the speech-FFR does not only occur subcortically but extends to the auditory cortex as well. SIGNIFICANCE STATEMENT Understanding speech in noise requires attention to a target speaker. One of the speech features that a listener can use to identify a target voice among others and attend it is the fundamental frequency, together with its higher harmonics. The fundamental frequency arises from the opening and closing of the vocal folds and is tracked by high-frequency neural activity in the auditory brainstem and in the cortex. Previous investigations showed that the subcortical neural tracking is modulated by selective attention. Here we show that attention affects the cortical tracking of the fundamental frequency as well: it is stronger when a particular voice is attended than when it is ignored., (Copyright © 2023 the authors.)

The auditory system relies on both local and summary representations; acoustic local features exceeding system constraints are compacted into a set of summary statistics. Such compression is pivotal for sound-object recognition. Here, we assessed whether computations subtending local and statistical representations of sounds could be distinguished at the neural level. A computational auditory model was employed to extract auditory statistics from natural sound textures (i.e., fire, rain) and to generate synthetic exemplars where local and statistical properties were controlled. Twenty-four human participants were passively exposed to auditory streams while the electroencephalography (EEG) was recorded. Each stream could consist of short, medium, or long sounds to vary the amount of acoustic information. Short and long sounds were expected to engage local or summary statistics representations, respectively. Data revealed a clear dissociation. Compared with summary-based ones, auditory-evoked responses based on local information were selectively greater in magnitude in short sounds. Opposite patterns emerged for longer sounds. Neural oscillations revealed that local features and summary statistics rely on neural activity occurring at different temporal scales, faster (beta) or slower (theta-alpha). These dissociations emerged automatically without explicit engagement in a discrimination task. Overall, this study demonstrates that the auditory system developed distinct coding mechanisms to discriminate changes in the acoustic environment based on fine structure and summary representations., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Berto et al.)

The acoustic environment an animal experiences early in life shapes the structure and function of its auditory system. This process of experience-dependent development is thought to be primarily orchestrated by potentiation and depression of synapses, but plasticity of intrinsic voltage dynamics may also contribute. Here, we show that in juvenile male and female zebra finches, neurons in a cortical-level auditory area, the caudal mesopallium (CM), can rapidly change their firing dynamics. This plasticity was only observed in birds that were reared in a complex acoustic and social environment, which also caused increased expression of the low-threshold potassium channel K v 1.1 in the plasma membrane and endoplasmic reticulum (ER). Intrinsic plasticity depended on activity, was reversed by blocking low-threshold potassium currents, and was prevented by blocking intracellular calcium signaling. Taken together, these results suggest that K v 1.1 is rapidly mobilized to the plasma membrane by activity-dependent elevation of intracellular calcium. This produces a shift in the excitability and temporal integration of CM neurons that may be permissive for auditory learning in complex acoustic environments during a crucial period for the development of vocal perception and production. SIGNIFICANCE STATEMENT Neurons can change not only the strength of their connections to other neurons, but also how they integrate synaptic currents to produce patterns of action potentials. In contrast to synaptic plasticity, the mechanisms and functional roles of intrinisic plasticity remain poorly understood. We found that neurons in the zebra finch auditory cortex can rapidly shift their spiking dynamics within a few minutes in response to intracellular stimulation. This plasticity involves increased conductance of a low-threshold potassium current associated with the K v 1.1 channel, but it only occurs in birds reared in a rich acoustic environment. Thus, auditory experience regulates a mechanism of neural plasticity that allows neurons to rapidly adapt their firing dynamics to stimulation., (Copyright © 2023 the authors.)

Communication difficulties are one of the core criteria in diagnosing autism spectrum disorder (ASD), and are often characterized by speech reception difficulties, whose biological underpinnings are not yet identified. This deficit could denote atypical neuronal ensemble activity, as reflected by neural oscillations. Atypical cross-frequency oscillation coupling, in particular, could disrupt the joint tracking and prediction of dynamic acoustic stimuli, a dual process that is essential for speech comprehension. Whether such oscillatory anomalies already exist in very young children with ASD, and with what specificity they relate to individual language reception capacity is unknown. We collected neural activity data using electroencephalography (EEG) in 64 very young children with and without ASD (mean age 3; 17 females, 47 males) while they were exposed to naturalistic-continuous speech. EEG power of frequency bands typically associated with phrase-level chunking (δ, 1-3 Hz), phonemic encoding (low-γ, 25-35 Hz), and top-down control (β, 12-20 Hz) were markedly reduced in ASD relative to typically developing (TD) children. Speech neural tracking by δ and θ (4-8 Hz) oscillations was also weaker in ASD compared with TD children. After controlling gaze-pattern differences, we found that the classical θ/γ coupling was replaced by an atypical β/γ coupling in children with ASD. This anomaly was the single most specific predictor of individual speech reception difficulties in ASD children. These findings suggest that early interventions (e.g., neurostimulation) targeting the disruption of β/γ coupling and the upregulation of θ/γ coupling could improve speech processing coordination in young children with ASD and help them engage in oral interactions. SIGNIFICANCE STATEMENT Very young children already present marked alterations of neural oscillatory activity in response to natural speech at the time of autism spectrum disorder (ASD) diagnosis. Hierarchical processing of phonemic-range and syllabic-range information (θ/γ coupling) is disrupted in ASD children. Abnormal bottom-up (low-γ) and top-down (low-β) coordination specifically predicts speech reception deficits in very young ASD children, and no other cognitive deficit., (Copyright © 2023 Wang et al.)

Rhythmic entrainment echoes-rhythmic brain responses that outlast rhythmic stimulation-can demonstrate endogenous neural oscillations entrained by the stimulus rhythm. Here, we tested for such echoes in auditory perception. Participants detected a pure tone target, presented at a variable delay after another pure tone that was rhythmically modulated in amplitude. In four experiments involving 154 human (female and male) participants, we tested (1) which stimulus rate produces the strongest entrainment echo and, inspired by the tonotopical organization of the auditory system and findings in nonhuman primates, (2) whether these are organized according to sound frequency. We found the strongest entrainment echoes after 6 and 8 Hz stimulation, respectively. The best moments for target detection (in phase or antiphase with the preceding rhythm) depended on whether sound frequencies of entraining and target stimuli matched, which is in line with a tonotopical organization. However, for the same experimental condition, best moments were not always consistent across experiments. We provide a speculative explanation for these differences that relies on the notion that neural entrainment and repetition-related adaptation might exercise competing opposite influences on perception. Together, we find rhythmic echoes in auditory perception that seem more complex than those predicted from initial theories of neural entrainment. SIGNIFICANCE STATEMENT Rhythmic entrainment echoes are rhythmic brain responses that are produced by a rhythmic stimulus and persist after its offset. These echoes play an important role for the identification of endogenous brain oscillations, entrained by rhythmic stimulation, and give us insights into whether and how participants predict the timing of events. In four independent experiments involving >150 participants, we examined entrainment echoes in auditory perception. We found that entrainment echoes have a preferred rate (between 6 and 8 Hz) and seem to follow the tonotopic organization of the auditory system. Although speculative, we also found evidence that several, potentially competing processes might interact to produce such echoes, a notion that might need to be considered for future experimental design., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 the authors.)

The inferior colliculus (IC) is a midbrain hub critical for perceiving complex sounds, such as speech. In addition to processing ascending inputs from most auditory brainstem nuclei, the IC receives descending inputs from auditory cortex that control IC neuron feature selectivity, plasticity, and certain forms of perceptual learning. Although corticofugal synapses primarily release the excitatory transmitter glutamate, many physiology studies show that auditory cortical activity has a net inhibitory effect on IC neuron spiking. Perplexingly, anatomy studies imply that corticofugal axons primarily target glutamatergic IC neurons while only sparsely innervating IC GABA neurons. Corticofugal inhibition of the IC may thus occur largely independently of feedforward activation of local GABA neurons. We shed light on this paradox using in vitro electrophysiology in acute IC slices from fluorescent reporter mice of either sex. Using optogenetic stimulation of corticofugal axons, we find that excitation evoked with single light flashes is indeed stronger in presumptive glutamatergic neurons compared with GABAergic neurons. However, many IC GABA neurons fire tonically at rest, such that sparse and weak excitation suffices to significantly increase their spike rates. Furthermore, a subset of glutamatergic IC neurons fire spikes during repetitive corticofugal activity, leading to polysynaptic excitation in IC GABA neurons owing to a dense intracollicular connectivity. Consequently, recurrent excitation amplifies corticofugal activity, drives spikes in IC GABA neurons, and generates substantial local inhibition in the IC. Thus, descending signals engage intracollicular inhibitory circuits despite apparent constraints of monosynaptic connectivity between auditory cortex and IC GABA neurons. SIGNIFICANCE STATEMENT Descending "corticofugal" projections are ubiquitous across mammalian sensory systems, and enable the neocortex to control subcortical activity in a predictive or feedback manner. Although corticofugal neurons are glutamatergic, neocortical activity often inhibits subcortical neuron spiking. How does an excitatory pathway generate inhibition? Here we study the corticofugal pathway from auditory cortex to inferior colliculus (IC), a midbrain hub important for complex sound perception. Surprisingly, cortico-collicular transmission was stronger onto IC glutamatergic compared with GABAergic neurons. However, corticofugal activity triggered spikes in IC glutamate neurons with local axons, thereby generating strong polysynaptic excitation and feedforward spiking of GABAergic neurons. Our results thus reveal a novel mechanism that recruits local inhibition despite limited monosynaptic convergence onto inhibitory networks., (Copyright © 2023 the authors.)