Publications using TDT

Non‐human primates (NHPs) are crucial models for studies of neuronal activity. Emerging photoacoustic imaging modalities offer excellent tools for studying NHP brains with high sensitivity and high spatial resolution. In this research, a photoacoustic microscopy (PAM) device was used to provide a label‐free quantitative characterization of cerebral hemodynamic changes due to peripheral mechanical stimulation. A 5 × 5 mm area within the somatosensory cortex region of an adult squirrel monkey was imaged. A deep, fully connected neural network was characterized and applied to the PAM images of the cortex to enhance the vessel structures after mechanical stimulation on the forelimb digits. The quality of the PAM images was improved significantly with a neural network while preserving the hemodynamic responses. The functional responses to the mechanical stimulation were characterized based on the improved PAM images. This study demonstrates capability of PAM combined with machine learning for functional imaging of the NHP brain.

Background Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. Methods In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. Results Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. Conclusions These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Reward-predictive cues acquire motivating and reinforcing properties that contribute to the escalation and relapse of drug use in addiction. The ventral pallidum (VP) and ventral tegmental area (VTA) are two key nodes in brain reward circuitry implicated in addiction and cue-driven behavior. In the current study, we use in vivo fiber photometry and optogenetics to record from and manipulate VP→VTA in rats performing a discriminative stimulus task to determine the role these neurons play in invigoration and reinforcement by reward cues. We find that VP→VTA neurons are active during reward consumption and that optogenetic stimulation of these neurons biases choice behavior and is reinforcing. Critically, we find no encoding of reward-seeking vigor, and optogenetic stimulation does not enhance the probability or vigor of reward seeking in response to cues. Our results suggest that VP→VTA activity is more important for reinforcement than for invigoration of reward seeking by cues.

Speech-recognition tests are widely used in both clinical and research audiology. The purpose of this study was the development of a novel speech-recognition test that combines concepts of different speech-recognition tests to reduce training effects and allows for a large set of speech material. The new test consists of four different words per trial in a meaningful construct with a fixed structure, the so-called phrases. Various free databases were used to select the words and to determine their frequency. Highly frequent nouns were grouped into thematic categories and combined with related adjectives and infinitives. After discarding inappropriate and unnatural combinations, and eliminating duplications of (sub-)phrases, a total number of 772 phrases remained. Subsequently, the phrases were synthesized using a text-to-speech system. The synthesis significantly reduces the effort compared to recordings with a real speaker. After excluding outliers, measured speech-recognition scores for the phrases with 31 normal-hearing participants at fixed signal-to-noise ratios (SNR) revealed speech-recognition thresholds (SRT) for each phrase varying up to 4 dB. The median SRT was −9.1 dB SNR and thus comparable to existing sentence tests. The psychometric function's slope of 15 percentage points per dB is also comparable and enables efficient use in audiology. Summarizing, the principle of creating speech material in a modular system has many potential applications.

The hearing abilities of mammals are impacted by factors such as social cues, habitat, and physical characteristics. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been characterized. In this study, anatomical features are measured and auditory brainstem responses (ABRs) are used to measure auditory capabilities of prairie voles, characterizing monaural and binaural hearing and hearing range. Sexually naive male and female voles were measured to characterize differences due to sex. It was found that prairie voles show a hearing range with greatest sensitivity between 8 and 32 kHz, binaural hearing across interaural time difference ranges appropriate for their head sizes. No differences are shown between the sexes in binaural hearing or hearing range (except at 1 kHz), however, female voles have increased amplitude of peripheral ABR waves I and II and longer latency of waves III and IV compared to males. The results confirm that prairie voles have a broad hearing range, binaural hearing consistent with rodents of similar size, and differences in amplitudes and thresholds of monaural physiological measures between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in responses between sexes.

Introduction The voice and hearing can be affected to different degrees by aging, which can cause communication difficulties for elderly people. Vocal production requires effective temporal auditory processing at central levels within the nervous system, which can be compromised by the aging process. Objective To analyze the correlation between voice and temporal auditory processing in older adults. Materials and Methods A total of 40 elderly people aged 60 years or older were subdivided into 2 groups according to the presence or absence of vocal symptoms measured by the Voice Symptom Scale. All of the participants were submitted to auditory temporal tests, vocal self-assessment, and acoustic and perceptual auditory analyses of voice. Results Most of the subjects assessed had decreased voice intensity and normal variability in terms of vocal quality. The performance was normal in the Pitch Pattern Sequence test and altered in the Random Gap Detection test. In the Masking Period Pattern test, the detection thresholds for the target signal were increased in the presence of masking in different temporal target signal positions. Only pitch differed between the two groups. There were differences between the genders regarding frequency, shimmer, the overall severity of the alteration, and roughness. There was a correlation regarding temporal resolution ability and the overall severity of the alteration and roughness of the voice. Conclusion There is a central auditory impairment in temporal resolution which is correlated with vocal alterations in the elderly.

In speech audiometry, the speech-recognition threshold (SRT) is usually established by adjusting the signal-to-noise ratio (SNR) until 50% of the words or sentences are repeated correctly. However, these conditions are rarely encountered in everyday situations. Therefore, for a group of 15 young participants with normal hearing and a group of 12 older participants with hearing impairment, speech-recognition scores were determined at SRT and at four higher SNRs using several stationary and fluctuating maskers. Participants’ verbal responses were recorded, and participants were asked to self-report their listening effort on a categorical scale (self-reported listening effort, SR-LE). The responses were analyzed using an Automatic Speech Recognizer (ASR) and compared to the results of a human examiner. An intraclass correlation coefficient of r = .993 for the agreement between their corresponding speech-recognition scores was observed. As expected, speech-recognition scores increased with increasing SNR and decreased with increasing SR-LE. However, differences between speech-recognition scores for fluctuating and stationary maskers were observed as a function of SNR, but not as a function of SR-LE. The verbal response time (VRT) and the response speech rate (RSR) of the listeners’ responses were measured using an ASR. The participants with hearing impairment showed significantly lower RSRs and higher VRTs compared to the participants with normal hearing. These differences may be attributed to differences in age, hearing, or both. With increasing SR-LE, VRT increased and RSR decreased. The results show the possibility of deriving a behavioral measure, VRT, measured directly from participants’ verbal responses during speech audiometry, as a proxy for SR-LE.

Older adults with normal hearing or with age-related hearing loss face challenges when listening to speech in noisy environments. To better serve individuals with communication difficulties, precision diagnostics are needed to characterize individuals’ auditory perceptual and cognitive abilities beyond pure tone thresholds. These abilities can be heterogenous across individuals within the same population. The goal of the present study is to consider the suprathreshold variability and develop characteristic profiles for older adults with normal hearing (ONH) and with hearing loss (OHL). Auditory perceptual and cognitive abilities were tested on ONH ( n = 20) and OHL ( n = 20) on an abbreviated test battery using portable automated rapid testing. Using cluster analyses, three main profiles were revealed for each group, showing differences in auditory perceptual and cognitive abilities despite similar audiometric thresholds. Analysis of variance showed that ONH profiles differed in spatial release from masking, speech-in-babble testing, cognition, tone-in-noise, and binaural temporal processing abilities. The OHL profiles differed in spatial release from masking, speech-in-babble testing, cognition, and tolerance to background noise performance. Correlation analyses showed significant relationships between auditory and cognitive abilities in both groups. This study showed that auditory perceptual and cognitive deficits can be present to varying degrees in the presence of audiometrically normal hearing and among listeners with similar degrees of hearing loss. The results of this study inform the need for taking individual differences into consideration and developing targeted intervention options beyond pure tone thresholds and speech testing.

Cortical electro-encephalography (EEG) served as the clinical reference for monitoring unconsciousness during general anesthesia. The existing EEG-based monitors classified general anesthesia states as underdosed, adequate, or overdosed, lacking predictive power due to the absence of transition phases among these states. In response to this limitation, we undertook an analysis of the EEG signal during isoflurane-induced general anesthesia in mice. Adopting a data-driven approach, we applied signal processing techniques to track θ- and δ-band dynamics, along with iso-electric suppressions. Combining this approach with machine learning, we successfully developed an automated algorithm. The findings of our study revealed that the dampening of the δ-band occurred several minutes before the onset of significant iso-electric suppression episodes. Furthermore, a distinct γ-frequency oscillation was observed, persisting for several minutes during the recovery phase subsequent to isoflurane-induced overdose. As a result of our research, we generated a map summarizing multiple brain states and their transitions, offering a tool for predicting and preventing overdose during general anesthesia. The transition phases identified, along with the developed algorithm, have the potential to be generalized, enabling clinicians to prevent inadequate anesthesia and, consequently, tailor anesthetic regimens to individual patients.

Sleep disturbances are detrimental to our behavioral and emotional well-being. Stressful events disrupt sleep, in particular by inducing brief awakenings (microarousals, MAs), resulting in sleep fragmentation. The preoptic area of the hypothalamus (POA) is crucial for sleep control. However, how POA neurons contribute to the regulation of MAs and thereby impact sleep quality is unknown. Using fiber photometry in mice, we examine the activity of genetically defined POA subpopulations during sleep. We find that POA glutamatergic neurons are rhythmically activated in synchrony with an infraslow rhythm in the spindle band of the electroencephalogram during non-rapid eye movement sleep (NREMs) and are transiently activated during MAs. Optogenetic stimulation of these neurons promotes MAs and wakefulness. Exposure to acute social defeat stress fragments NREMs and significantly increases the number of transients in the calcium activity of POA glutamatergic neurons during NREMs. By reducing MAs, optogenetic inhibition during spontaneous sleep and after stress consolidates NREMs. Monosynaptically restricted rabies tracing reveals that POA glutamatergic neurons are innervated by brain regions regulating stress and sleep. In particular, presynaptic glutamatergic neurons in the lateral hypothalamus become activated after stress, and stimulating their projections to the POA promotes MAs and wakefulness. Our findings uncover a novel circuit mechanism by which POA excitatory neurons regulate sleep quality after stress.

Cochlear synaptopathy is a common pathology in humans associated with aging and potentially sound overexposure. Synaptopathy is widely expected to cause "hidden hearing loss," including difficulty perceiving speech in noise, but support for this hypothesis is controversial. Here in budgerigars (Melopsittacus undulatus), we evaluated the impact of long-term cochlear synaptopathy on behavioral discrimination of Gaussian noise (GN) and low-noise noise (LNN) signals processed to have a flatter envelope. Stimuli had center frequencies of 1-3kHz, 100-Hz bandwidth, and were presented at sensation levels (SLs) from 10 to 30dB. We reasoned that narrowband, low-SL stimuli of this type should minimize spread of excitation across auditory-nerve fibers, and hence might reveal synaptopathy-related defects if they exist. Cochlear synaptopathy was induced without hair-cell injury using kainic acid (KA). Behavioral threshold tracking experiments characterized the minimum stimulus duration above which animals could reliably discriminate between LNN and GN. Budgerigar thresholds for LNN-GN discrimination ranged from 40 to 60ms at 30dB SL, were similar across frequencies, and increased for lower SLs. Notably, animals with long-term 39-77% estimated synaptopathy performed similarly to controls, requiring on average a ∼7.5% shorter stimulus duration (-0.7±1.0dB; mean difference ±SE) for LNN-GN discrimination. Decision-variable correlation analyses of detailed behavioral response patterns showed that individual animals relied on envelope cues to discriminate LNN and GN, with lesser roles of FM and energy cues; no difference was found between KA-exposed and control groups. These results suggest that long-term cochlear synaptopathy does not impair discrimination of low-level signals with different envelope statistics.

The head-related transfer function (HRTF) describes the direction-dependent acoustic filtering by the head that occurs between a source signal in free-field space and the signal at the tympanic membrane. HRTFs contain information on sound source location via interaural differences of their magnitude or phase spectra and via the shapes of their magnitude spectra. The present study characterized HRTFs for source locations in the front horizontal plane for nine rabbits, which are a species commonly used in studies of the central auditory system. HRTF magnitude spectra shared several features across individuals, including a broad spectral peak at 2.6kHz that increased gain by 12 to 23dB depending on source azimuth; and a notch at 7.6kHz and peak at 9.8kHz visible for most azimuths. Overall, frequencies above 4kHz were amplified for sources ipsilateral to the ear and progressively attenuated for frontal and contralateral azimuths. The slope of the magnitude spectrum between 3 and 5kHz was found to be an unambiguous monaural cue for source azimuths ipsilateral to the ear. Average interaural level difference (ILD) between 5 and 16kHz varied monotonically with azimuth over ±31dB despite a relatively small head size. Interaural time differences (ITDs) at 0.5kHz and 1.5kHz also varied monotonically with azimuth over ±358 μs and ±260 μs, respectively. Remeasurement of HRTFs after pinna removal revealed that the large pinnae of rabbits were responsible for all spectral peaks and notches in magnitude spectra and were the main contribution to high-frequency ILDs (5-16kHz), whereas the rest of the head was the main contribution to ITDs and low-frequency ILDs (0.2-1.5kHz). Lastly, inter-individual differences in magnitude spectra were found to be small enough that deviations of individual HRTFs from an average HRTF were comparable in size to measurement error. Therefore, the average HRTF may be acceptable for use in neural or behavioral studies of rabbits implementing virtual acoustic space when measurement of individualized HRTFs is not possible.

A better understanding of the neural mechanisms of speech processing can have a major impact in the development of strategies for language learning and in addressing disorders that affect speech comprehension. Technical limitations in research with human subjects hinder a comprehensive exploration of these processes, making animal models essential for advancing the characterization of how neural circuits make speech perception possible. Here, we investigated the mouse as a model organism for studying speech processing and explored whether distinct regions of the mouse auditory cortex are sensitive to specific acoustic features of speech. We found that mice can learn to categorize frequency-shifted human speech sounds based on differences in formant transitions (FT) and voice onset time (VOT). Moreover, neurons across various auditory cortical regions were selective to these speech features, with a higher proportion of speech-selective neurons in the dorso-posterior region. Last, many of these neurons displayed mixed-selectivity for both features, an attribute that was most common in dorsal regions of the auditory cortex. Our results demonstrate that the mouse serves as a valuable model for studying the detailed mechanisms of speech feature encoding and neural plasticity during speech-sound learning.

We provide comparative data on primate audition of naturalistic sounds comprising hearing thresholds, reaction time distributions, and spectral-temporal modulation transfer functions. Our psychophysical experiments demonstrate that auditory information is primarily processed in a spectral-temporal-independent manner by both monkeys and humans. Singular value decomposition of known visual spatiotemporal contrast sensitivity, in comparison to our auditory spectral-temporal sensitivity, revealed a striking contrast in how the brain encodes natural sounds as opposed to natural images, as vision appears to be space-time inseparable.

Among the myriad of complications associated with traumatic brain injury (TBI), impairments in social behaviors and cognition have emerged as a significant area of concern. Animal models of social behavior are necessary to explore the underlying brain mechanisms contributing to chronic social impairments following brain injury. Here, we utilize large-scale brain recordings of local field potentials to identify neural signatures linked with social preference deficits following frontal brain injury. We used a controlled cortical impact model of TBI to create a severe bilateral injury centered on the prefrontal cortex. Behavior (social preference and locomotion) and brain activity (power and coherence) during a three-chamber social preference task were compared between sham and injured animals. Sham rats preferred to spend time with a social conspecific over an inanimate object. An analysis of local field oscillations showed that social preference was associated with a significant increase in coherence in gamma frequency band across widespread brain regions in these animals. Animals with a frontal TBI showed a significant reduction in this social preference, visiting an inanimate object more frequently and for more time. Reflecting these changes in social behavior, these animals also showed a significant reduction in gamma frequency (25–60 Hz) coherence associated with social preference.

Research using the model organism nematode C. elegans has greatly facilitated our understanding of sensory biology, including touch, olfaction, taste, vision and proprioception. While hearing had long been considered to be restricted to vertebrates and some arthropods, we recently discovered that C. elegans is capable of sensing and responding to airborne sound in a frequency and sound source-size-dependent manner. C. elegans auditory sensation occurs when airborne sound physically vibrates their external cuticle (skin) to activate the sound-sensitive mechanosensory FLP/PVD neurons via nicotinic acetylcholine receptors (nAChRs), triggering aversive phonotaxis behavior. Here, we report stepwise methods to characterize these three features of C. elegans auditory sensation, including sound-evoked skin vibration, neuronal activation, and behavior. This approach provides an accessible platform to investigate the cellular and molecular mechanisms underlying auditory sensation and mechanotransduction mechanisms in C. elegans.

Tinnitus is a phantom auditory sensation often accompanied by hearing loss, cognitive impairments, and psychological disturbances in various populations. Dysfunction of KCNQ2 and KCNQ3 channels—voltage-dependent potassium ion channels—in the cochlear nucleus can cause tinnitus. Despite the recognized significance of KCNQ2 and KCNQ3 channels in the auditory cortex, their precise relationship and implications in the pathogenesis of tinnitus remain areas of scientific inquiry. This study aimed to elucidate the pathological roles of KCNQ2 and KCNQ3 channels within the auditory cortex in tinnitus development and examine the therapeutic potential of mid-infrared photons for tinnitus treatment. We utilized a noise-induced tinnitus model combined with immunofluorescence, electrophysiological recording, and molecular dynamic simulation to investigate the morphological and physiological alterations after inducing tinnitus. Moreover, in vivo irradiation was administered to verify the treatment effects of infrared photons. Tinnitus was verified by deficits of the gap ratio with similar prepulse inhibition ratio and auditory brainstem response threshold. We observed an important enhancement in neuronal excitability in the auditory cortex using patch-clamp recordings, which correlated with KCNQ2 and KCNQ3 channel dysfunction. After irradiation with infrared photons, excitatory neuron firing was inhibited owing to increased KCNQ2 current resulting from structural alterations in the filter region. Meanwhile, deficits of the acoustic startle response in tinnitus animals were alleviated by infrared photons. Furthermore, infrared photons reversed the abnormal hyperexcitability of excitatory neurons in the tinnitus group. This study provided a novel method for modulating neuron excitability in the auditory cortex using KCNQ2 channels through a nonthermal effect. Infrared photons effectively mitigated tinnitus-related behaviors by suppressing abnormal neural excitability, potentially laying the groundwork for innovative therapeutic approaches for tinnitus treatment.

Recent studies have explored functional and effective neural networks in animal models; however, the dynamics of information propagation among functional modules under cognitive control remain largely unknown. Here, we addressed the issue using transfer entropy and graph theory methods on mesoscopic neural activities recorded in the dorsal premotor cortex of rhesus monkeys. We focused our study on the decision time of a Stop-signal task, looking for patterns in the network configuration that could influence motor plan maturation when the Stop signal is provided. When comparing trials with successful inhibition to those with generated movement, the nodes of the network resulted organized into four clusters, hierarchically arranged, and distinctly involved in information transfer. Interestingly, the hierarchies and the strength of information transmission between clusters varied throughout the task, distinguishing between generated movements and canceled ones and corresponding to measurable levels of network complexity. Our results suggest a putative mechanism for motor inhibition in premotor cortex: a topological reshuffle of the information exchanged among ensembles of neurons.

Chondroitin sulfate-based bioactive coating improves neuronal density and decreases biofouling and acute inflammation of neural interface devices.