Disentangling Temporal and Rate Codes in the Primate Somatosensory Cortex.

Millisecond-scale temporal spiking patterns encode sensory information in the periphery, but their role in the neocortex remains controversial. The sense of touch provides a window into temporal coding because tactile neurons often exhibit precise, repeatable, and informative temporal spiking patterns. In the somatosensory cortex (S1), responses to skin vibrations exhibit phase locking that faithfully carries information about vibratory frequency. However, the respective roles of spike timing and rate in frequency coding are confounded because vibratory frequency shapes both the timing and rates of responses. To disentangle the contributions of these two neural features, we measured S1 responses as rhesus macaques performed frequency discrimination tasks in which differences in frequency were accompanied by orthogonal variations in amplitude. We assessed the degree to which the strength and timing of responses could account for animal performance. First, we showed that animals can discriminate frequency, but their performance is biased by amplitude variations. Second, rate-based representations of frequency are susceptible to changes in amplitude but in ways that are inconsistent with the animals' behavioral biases, calling into question a rate-based neural code for frequency. In contrast, timing-based representations are highly informative about frequency but impervious to changes in amplitude, which is also inconsistent with the animals' behavior. We account for the animals' behavior with a model wherein frequency coding relies on a temporal code, but frequency judgments are biased by perceived magnitude. We conclude that information about vibratory frequency is not encoded in S1 firing rates but primarily in temporal patterning on millisecond timescales.

Different time courses of maturation for learning and generalization following auditory training in children.

OBJECTIVE: We recently demonstrated that learning abilities among school-age children vary following frequency discrimination (FD) training, with some exhibiting mature adult-like learning while others performing poorly (non-adult-like learners). This study tested the hypothesis that children's post-training generalisation is related to their learning maturity. Additionally, it investigated how training duration influences children's generalisation, considering the observed decrease with increased training in adults. DESIGN: Generalisation to the untrained ear and untrained 2000 Hz frequency was assessed following single-session or nine-session 1000 Hz FD training, using an adaptive forced-choice procedure. Two additional groups served as controls for the untrained frequency. STUDY SAMPLE: Fifty-four children aged 7-9 years and 59 adults aged 18-30 years. RESULTS: (1) Only adult-like learners generalised their learning gains across frequency or ear, albeit less efficiently than adults; (2) As training duration increased children experienced reduced generalisation, similar to adults; (3) Children's performance in the untrained tasks correlated strongly with their trained task performance after the first training session. CONCLUSIONS: Auditory skill learning and its generalisation do not necessarily mature contemporaneously, although mature learning is a prerequisite for mature generalisation. Furthermore, in children, as in adults, more practice makes rather specific experts. These findings should be considered when designing training programs.

Multiplexing intensity and frequency sensations for artificial touch by modulating temporal features of electrical pulse trains.

In neural prostheses, intensity modulation of a single channel (i.e., through a single stimulating electrode) has been achieved by increasing the magnitude or width of each stimulation pulse, which risks eliciting pain or paraesthesia; and by changing the stimulation rate, which leads to concurrent changes in perceived frequency. In this study, we sought to render a perception of tactile intensity and frequency independently, by means of temporal pulse train patterns of fixed magnitude, delivered non-invasively. Our psychophysical study exploits a previously discovered frequency coding mechanism, where the perceived frequency of stimulus pulses grouped into periodic bursts depends on the duration of the inter-burst interval, rather than the mean pulse rate or periodicity. When electrical stimulus pulses were organised into bursts, perceived intensity was influenced by the number of pulses within a burst, while perceived frequency was determined by the time between the end of one burst envelope and the start of the next. The perceived amplitude was modulated by 1.6× while perceived frequency was varied independently by 2× within the tested range (20-40 Hz). Thus, the sensation of intensity might be controlled independently from frequency through a single stimulation channel without having to vary the injected electrical current. This can form the basis for improving strategies in delivering more complex and natural sensations for prosthetic hand users.

Frequency-Selective, Multi-Channel, Self-Powered Artificial Basilar Membrane Sensor with a Spiral Shape and 24 Critical Bands Inspired by the Human Cochlea.

A spiral-artificial basilar membrane (S-ABM) sensor is reported that mimics the basilar membrane (BM) of the human cochlea and can detect sound by separating it into 24 sensing channels based on the frequency band. For this, an analytical function is proposed to design the width of the BM so that the frequency bands are linearly located along the length of the BM. To fabricate the S-ABM sensor, a spiral-shaped polyimide film is used as a vibrating membrane, with maximum displacement at locations corresponding to specific frequency bands of sound, and attach piezoelectric sensor modules made of poly(vinylidene fluoride-trifluoroethylene) film on top of the polyimide film to measure the vibration amplitude at each channel location. As the result, the S-ABM sensor implements a characteristic frequency band of 96-12,821 Hz and 24-independent critical bands. Using real-time signals from discriminate channels, it is demonstrated that the sensor can rapidly identify the operational noises from equipment processes as well as vehicle sounds from environmental noises on the road. The sensor can be used in a variety of applications, including speech recognition, dangerous situation recognition, hearing aids, and cochlear implants, and more.

Differential representation of sensory information and behavioral choice across layers of the mouse auditory cortex.

The activity of neurons in sensory areas sometimes covaries with upcoming choices in decision-making tasks. However, the prevalence, causal origin, and functional role of choice-related activity remain controversial. Understanding the circuit-logic of decision signals in sensory areas will require understanding their laminar specificity, but simultaneous recordings of neural activity across the cortical layers in forced-choice discrimination tasks have not yet been performed. Here, we describe neural activity from such recordings in the auditory cortex of mice during a frequency discrimination task with delayed report, which, as we show, requires the auditory cortex. Stimulus-related information was widely distributed across layers but disappeared very quickly after stimulus offset. Choice selectivity emerged toward the end of the delay period-suggesting a top-down origin-but only in the deep layers. Early stimulus-selective and late choice-selective deep neural ensembles were correlated, suggesting that the choice-selective signal fed back to the auditory cortex is not just action specific but develops as a consequence of the sensory-motor contingency imposed by the task.

Variability in auditory processing performance is associated with reading difficulties rather than with history of otitis media.

The nature and cause of auditory processing deficits in dyslexic individuals have been debated for decades. Auditory processing deficits were argued to be the first step in a causal chain of difficulties, leading to difficulties in speech perception and thereby phonological processing and literacy difficulties. More recently, it has been argued that auditory processing difficulties may not be causally related to language and literacy difficulties. This study compares two groups who have phonological processing impairments for different reasons: dyslexia and a history of otitis media (OM). We compared their discrimination thresholds and response variability to chronological age- and reading age-matched controls, across three auditory processing tasks: frequency discrimination, rise-time discrimination and speech perception. Dyslexic children showed raised frequency discrimination thresholds in comparison with age-matched controls but did not differ from reading age-matched controls or individuals with a history of OM. There were no group differences on speech perception or rise-time tasks. For the dyslexic children, there was an association between phonological awareness and frequency discrimination response variability, but no association with thresholds. These findings are not consistent with a 'causal chain' explanation but could be accounted for within a multiple deficits view of literacy difficulties.

The use of non-invasive brain stimulation in auditory perceptual learning: A review.

Auditory perceptual learning is an experience-dependent form of auditory learning that can improve substantially throughout adulthood with practice. A key mechanism associated with perceptual learning is synaptic plasticity. In the last decades, an increasingly better understanding has formed about the neural mechanisms related to auditory perceptual learning. Research in animal models found an association between the functional organization of the primary auditory cortex and frequency discrimination ability. Several studies observed an increase in the area of representation to be associated with improved frequency discrimination. Non-invasive brain stimulation techniques have been related to the promotion of plasticity. Despite its popularity in other fields, non-invasive brain stimulation has not been used much in auditory perceptual learning. The present review has discussed the application of non-invasive brain stimulation methods in auditory perceptual learning by discussing the mechanisms, current evidence and challenges, and future directions.

Frequency detection, frequency discrimination, and spectro-temporal pattern perception in older and younger typically hearing adults.

Elderly adults often experience difficulties in speech understanding, possibly due to age-related deficits in frequency perception. It is unclear whether age-related deficits in frequency perception differ between the apical or basal regions of the cochlea. It is also unclear how aging might differently affect frequency discrimination or detection of a change in frequency within a stimulus. In the present study, pure-tone frequency thresholds were measured in 19 older (61-74 years) and 20 younger (22-28 years) typically hearing adults. Participants were asked to discriminate between reference and probe frequencies or to detect changes in frequency within a probe stimulus. Broadband spectro-temporal pattern perception was also measured using the spectro-temporal modulated ripple test (SMRT). Frequency thresholds were significantly poorer in the basal than in the apical region of the cochlea; the deficit in the basal region was 2 times larger for the older than for the younger group. Frequency thresholds were significantly poorer in the older group, especially in the basal region where frequency detection thresholds were 3.9 times poorer for the older than for the younger group. SMRT thresholds were 1.5 times better for the younger than for the older group. Significant age effects were observed for SMRT thresholds and for frequency thresholds only in the basal region. SMRT thresholds were significantly correlated with frequency thresholds only in the older group. The poorer frequency and spectro-temporal pattern perception may contribute to age-related deficits in speech perception, even when audiometric thresholds are nearly normal.

Corticostriatal Neurons in the Anterior Auditory Field Regulate Frequency Discrimination Behavior.

The anterior auditory field (AAF) is a core region of the auditory cortex and plays a vital role in discrimination tasks. However, the role of the AAF corticostriatal neurons in frequency discrimination remains unclear. Here, we used c-Fos staining, fiber photometry recording, and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task. c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task. Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination. In addition, histological results revealed that AAF pyramidal neurons send strong projections to the striatum. Moreover, pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination. Collectively, our findings show that AAF pyramidal neurons, particularly the AAF-striatum projections, play a crucial role in frequency discrimination behavior.

Training allows switching from limited-capacity manipulations to large-capacity perceptual processing.

In contrast to perceptual tasks, which enable concurrent processing of many stimuli, working memory (WM) tasks have a very small capacity, limiting cognitive skills. Training on WM tasks often yields substantial improvement, suggesting that training might increase the general WM capacity. To understand the underlying processes, we trained a test group with a newly designed tone manipulation WM task and a control group with a challenging perceptual task of pitch pattern discrimination. Functional magnetic resonance imaging (fMRI) scans confirmed that pretraining, manipulation was associated with a dorsal fronto-parietal WM network, while pitch comparison was associated with activation of ventral auditory regions. Training induced improvement in each group, which was limited to the trained task. Analyzing the behavior of the group trained with tone manipulation revealed that participants learned to replace active manipulation with a perceptual verification of the position of a single salient tone in the sequence presented as a tentative reply. Posttraining fMRI scans revealed modifications in ventral activation of both groups. Successful WMtrained participants learned to utilize auditory regions for the trained task. These observations suggest that the huge task-specific enhancement of WM capacity stems from a task-specific switch to perceptual routines, implemented in perceptual regions.

Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals.

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in vivo evidence that regional identity in the embryonic cochlea acts as a framework upon which tonotopy-specific properties essential for frequency selectivity in the mature cochlea develop. We found that follistatin (FST) is required for the maintenance of apical cochlear identity, but dispensable for its initial induction. In a fate-mapping analysis, we found that FST promotes expansion of apical cochlear cells, contributing to the formation of the apical cochlear domain. SHH, in contrast, is required both for the induction and maintenance of apical identity. In the absence of FST or SHH, mice produce a short cochlea lacking its apical domain. This results in the loss of apex-specific anatomical and molecular properties and low-frequency-specific hearing loss.

Corticostriatal Neurons in the Anterior Auditory Field Regulate Frequency Discrimination Behavior / 神经科学通报·英文版

The anterior auditory field (AAF) is a core region of the auditory cortex and plays a vital role in discrimination tasks. However, the role of the AAF corticostriatal neurons in frequency discrimination remains unclear. Here, we used c-Fos staining, fiber photometry recording, and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task. c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task. Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination. In addition, histological results revealed that AAF pyramidal neurons send strong projections to the striatum. Moreover, pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination. Collectively, our findings show that AAF pyramidal neurons, particularly the AAF-striatum projections, play a crucial role in frequency discrimination behavior.

Genetic Hearing Loss Affects Cochlear Processing.

The relationship between speech recognition and hereditary hearing loss is not straightforward. Underlying genetic defects might determine an impaired cochlear processing of sound. We obtained data from nine groups of patients with a specific type of genetic hearing loss. For each group, the affected cochlear site-of-lesion was determined based on previously published animal studies. Retrospectively obtained speech recognition scores in noise were related to several aspects of supra-threshold cochlear processing as assessed by psychophysical measurements. The differences in speech perception in noise between these patient groups could be explained by these factors and partially by the hypothesized affected structure of the cochlea, suggesting that speech recognition in noise was associated with a genetics-related malfunctioning of the cochlea. In particular, regression models indicate that loudness growth and spectral resolution best describe the cochlear distortions and are thus a good biomarker for speech understanding in noise.

Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

Cortical potentials evoked by tone frequency changes can predict speech perception in noise.

Accurate and objective assessment of higher order auditory processing is challenging and mainly relies on evaluations that require a subjects' active participation in tests such as frequency discrimination or speech perception in noise. This study investigates the value of cortical auditory evoked potentials (CAEPs) evoked in response to auditory change stimuli, known as acoustic change complexes (ACCs), as an objective measurement of auditory performance in hearing impairment. Secondary objectives were to assess the effect of hearing loss and non-professional musical experience on the ACC, and compare the ACC to the 'conventional' CAEP evoked in response to stimulus onset. In 24 normal-hearing subjects, consisting of 12 musicians and 12 non-musicians, and 13 age-matched hearing-impaired subjects ACCs were recorded in response to 12% frequency increases at four base frequencies (0.5, 1, 2 and 4 kHz). ACC amplitudes and latencies were compared to frequency discrimination thresholds at each base frequency, and to speech perception in noise. Frequency discrimination and speech perception in noise were significantly better for larger ACC N1-P2 amplitudes and shorter N1 latencies, whereas both frequency discrimination and speech perception did not correlate with onset CAEP amplitude or latency. Multiple regression analysis for prediction of speech perception in noise revealed that the strongest model was obtained by averaging over three frequencies (1, 2 and 4 kHz) with two significant predictors: hearing loss (R2 = 0.52) and ACC latency (R2 = 0.35). Thus, explaining 87% of the variance, this model indicates that subjects with longer ACC latencies have worse speech perception in noise than subjects with comparable hearing thresholds and shorter ACC latencies. If hearing loss was removed from this model, the combination of ACC amplitude and latency over those three frequencies explained 74% of the total variance in speech perception in noise. There were no differences in frequency discrimination, speech perception, CAEP, or ACC between recreational musicians and non-musicians. We conclude that the objective ACC N1 latency is a good predictor of speech perception in noise. When confirmed in validation studies with larger numbers of subjects, it can aid clinicians in their evaluation of auditory performance and higher order processing, in particular when behavioral testing is unreliable.

Effect of Frequency Discrimination Training on Tinnitus in Individuals with Flat Sensorineural Hearing loss.

Tinnitus is associated with sensorineural hearing loss irrespective of its severity and configuration. Frequency discrimination training is a contemporary method used for the treatment of tinnitus. However, its efficacy in treating tinnitus associated with flat sensorineural hearing loss is not studied yet. The objectives were to assess (a) treatment effect across sessions on tinnitus percept using subjective questionnaires (b) association in the severity and handicap of tinnitus before and after FDT treatment. A total of 16 participants with mean age of 56 years, who had subjective tinnitus and flat sensorineural hearing loss ranging from mild to moderate were included in the study. However, only 11 participants completed the treatment regime. Each participant was provided FDT in a game format for 15 days. The Quantitative (tinnitus pitch and loudness in each session) and qualitative measurements (THI and TFI) were assessed in each participant. Friedman test revealed a significant reduction in handicap from tinnitus as reflected in THI and reduced functionality impairment from tinnitus as reflected in TFI across sessions. Besides, a significant association was observed in the Chi-square test in severity and handicap of tinnitus before and after therapy. A change in pitch and reduced loudness was noted in eight of 11 participants. Three of them had no tinnitus perception at the end of the treatment regime. The current study findings demonstrate the efficacy of FDT using a game module in treating tinnitus associated with flat sensorineural hearing loss. The perceived severity and handicap of tinnitus reduces as a function of treatment.

Reduced Learning of Sound Categories in Dyslexia Is Associated with Reduced Regularity-Induced Auditory Cortex Adaptation.

A main characteristic of dyslexia is poor use of sound categories. We now studied within-session learning of new sound categories in dyslexia, behaviorally and neurally, using fMRI. Human participants (males and females) with and without dyslexia were asked to discriminate which of two serially-presented tones had a higher pitch. The task was administered in two protocols, with and without a repeated reference frequency. The reference condition introduces regularity, and enhances frequency sensitivity in typically developing (TD) individuals. Enhanced sensitivity facilitates the formation of "high" and "low" pitch categories above and below this reference, respectively. We found that in TDs, learning was paralleled by a gradual decrease in activation of the primary auditory cortex (PAC), and reduced activation of the superior temporal gyrus (STG) and left posterior parietal cortex (PPC), which are important for using sensory history. No such sensitivity was found among individuals with dyslexia (IDDs). Rather, IDDs showed reduced behavioral learning of stimulus regularities and no regularity-associated adaptation in the auditory cortex or in higher-level regions. We propose that IDDs' reduced cortical adaptation, associated with reduced behavioral learning of sound regularities, underlies their impoverished use of stimulus history, and consequently impedes their formation of rich sound categories.SIGNIFICANCE STATEMENT Reading difficulties in dyslexia are often attributed to poor use of phonological categories. To test whether poor category use could result from poor learning of new sound categories in general, we administered an auditory discrimination task that examined the learning of new pitch categories above and below a repeated reference sound. Individuals with dyslexia (IDDs) learned categories slower than typically developing (TD) individuals. TD individuals showed adaptation to the repeated sounds that paralleled the category learning in their primary auditory cortex (PAC) and other higher-level regions. In dyslexia, no brain region showed such adaptation. We suggest that poor learning of sound statistics in sensory regions may underlie the poor representations of both speech and nonspeech categories in dyslexia.

The Influence of the Psychophysical Assessment Paradigm on Pitch Discrimination for Adults (and a Pilot Sample of Children).

Pitch discrimination ability has been of research interest due to its potential relationship to language and literacy. However, assessment protocols for pitch discrimination have varied widely. Prior studies with both children and adults have produced conflicting performance findings across different pitch discrimination research paradigms, though they have consistently shown that discrimination accuracy is based on the psychophysical assessment method applied. In the present study, we examined pitch discrimination performance among convenience samples of 19 adult women and ten female children across six different adaptive psychophysical measurement conditions. We found pitch discrimination performance in both groups to be impacted by the measurement paradigm such that, while adults exhibited significantly better discrimination thresholds than did children, the pattern of performance across the six conditions was similar for both the adults and the children.

Ephrin-A3 is required for tonotopic map precision and auditory functions in the mouse auditory brainstem.

Tonotopy is a prominent feature of the vertebrate auditory system and forms the basis for sound discrimination, but the molecular mechanism that underlies its formation remains largely elusive. Ephrin/Eph signaling is known to play important roles in axon guidance during topographic mapping in other sensory systems, so we investigated its possible role in the establishment of tonotopy in the mouse cochlear nucleus. We found that ephrin-A3 molecules are differentially expressed along the tonotopic axis in the cochlear nucleus during innervation. Ephrin-A3 forward signaling is sufficient to repel auditory nerve fibers in a developmental stage-dependent manner. In mice lacking ephrin-A3, the tonotopic map is degraded and isofrequency bands of neuronal activation upon pure tone exposure become imprecise in the anteroventral cochlear nucleus. Ephrin-A3 mutant mice also exhibit a delayed second wave in auditory brainstem responses upon sound stimuli and impaired detection of sound frequency changes. Our findings establish an essential role for ephrin-A3 in forming precise tonotopy in the auditory brainstem to ensure accurate sound discrimination.

Unilateral auditory deprivation in humans: Effects on frequency discrimination and auditory memory span in the normal ear.

Hearing with one ear is associated with auditory deprivation leading to cortical neuronal reorganization. Despite evidence for substantial effects of unilateral input on cortical and sub-cortical structures, the functional consequences of such alterations on human hearing is underexplored. Unilateral hearing impairment offers a unique model to study the perceptual consequences of cortical reorganization. The present study provides evidence for larger (poorer) difference limens for frequency for sounds heard by the normal ear of listeners with unilateral hearing loss relative to bilaterally normal-hearing controls. This difference in frequency discrimination ability was observed for the low (250 Hz), but not for the high-frequency tone (4000 Hz). Besides auditory perceptual effects, we also found reduced working memory capacity as revealed by forward and backward digit span measures. Contrary to the expectation, there was no significant association between frequency discrimination and working memory capacity in listeners with unilateral hearing loss. Auditory deprivation associated with unilateral hearing impairment affects low-frequency (pitch) discrimination and working memory capacity despite normal hearing in the intact ear. Such deficits in basic auditory processes and memory span for sounds heard by the normal ear may contribute to the hearing and communication difficulties experienced by listeners with unilateral or single-sided deafness.