Publications using TDT

Behavioral and neural responses to auditory stimuli are profoundly influenced by recent sounds, yet how this occurs is not known. Here, the authors show in the auditory cortex of awake mice that the quality of history-dependent effects is diverse and related to cell type, response latency, firing rates, and receptive field bandwidth. In a cortical model, differences in excitatory-inhibitory balance can produce this diversity, providing the cortex with multiple ways of representing temporally complex information.

The ability to detect and discriminate sounds in background noise is critical for our ability to communicate. The neural basis of robust perceptual performance in noise is not well understood. We identified neuronal populations in core auditory cortex of squirrel monkeys that differ in how they process foreground signals in background noise and that may contribute to robust signal representation and discrimination in acoustic environments with prominent background noise.

Hypoxic-ischemic (HI) brain injury is recognized as a significant problem in the perinatal period, contributing to life-long language-learning and other cognitive impairments. Central auditory processing deficits are common in infants with hypoxic-ischemic encephalopathy and have been shown to predict language learning deficits in other at risk infant populations. Inter-alpha inhibitor proteins (IAIPs) are a family of structurally related plasma proteins that modulate the systemic inflammatory response to infection and have been shown to attenuate cell death and improve learning outcomes after neonatal brain injury in rats. Here, we show that systemic administration of IAIPs during the early HI injury cascade ameliorates complex auditory discrimination deficits as compared to untreated HI injured subjects, despite reductions in brain weight. These findings have significant clinical implications for improving central auditory processing deficits linked to language learning in neonates with HI related brain injury.

Blasts exposures often produce hearing difficulties. Although cochlear damage typically occurs, the downstream effects on central auditory processing are less clear. Moreover, outcomes were compared between individuals exposed to the blast pressure wave vs. those who experienced the blast noise without the pressure wave. It was found that a single blast exposure produced changes at all stages of the ascending auditory path at least 4 wk postblast, whereas blast noise alone produced largely transient changes.

Neurons within fMRI-defined face patches of the macaque brain exhibit shared categorical responses to flashed images but diverge in their responses under more natural viewing conditions. Here we investigate functional diversity among neurons in the anterior fundus (AF) face patch, combining whole-brain fMRI with longitudinal single-unit recordings in a local population (<1 mm3). For each cell, we computed a whole-brain correlation map based on its shared time course with voxels throughout the brain during naturalistic movie viewing. Based on this mapping, neighboring neurons showed markedly different affiliation with distant visually responsive areas and fell coarsely into subpopulations. Of these, only one subpopulation (∼16% of neurons) yielded similar correlation maps to the local fMRI signal. The results employ the readout of large-scale fMRI networks and, by indicating multiple functional domains within a single voxel, present a new view of functional diversity within a local neural population.

Behavioral studies reveal listeners exploit intrinsic differences in voice fundamental frequency (F0) to segregate concurrent speech sounds-the so-called "F0-benefit." More favorable signal-to-noise ratio (SNR) in the environment, an extrinsic acoustic factor, similarly benefits the parsing of simultaneous speech. Here, we examined the neurobiological substrates of these two cues in the perceptual segregation of concurrent speech mixtures. We recorded event-related brain potentials (ERPs) while listeners performed a speeded double-vowel identification task. Listeners heard two concurrent vowels whose F0 differed by zero or four semitones presented in either clean (no noise) or noise-degraded (+5 dB SNR) conditions. Behaviorally, listeners were more accurate in correctly identifying both vowels for larger F0 separations but F0-benefit was more pronounced at more favorable SNRs (i.e., pitch × SNR interaction). Analysis of the ERPs revealed that only the P2 wave (∼200 ms) showed a similar F0 x SNR interaction as behavior and was correlated with listeners' perceptual F0-benefit. Neural classifiers applied to the ERPs further suggested that speech sounds are segregated neurally within 200 ms based on SNR whereas segregation based on pitch occurs later in time (400-700 ms). The earlier timing of extrinsic SNR compared to intrinsic F0-based segregation implies that the cortical extraction of speech from noise is more efficient than differentiating speech based on pitch cues alone, which may recruit additional cortical processes. Findings indicate that noise and pitch differences interact relatively early in cerebral cortex and that the brain arrives at the identities of concurrent speech mixtures as early as ∼200 ms.

Cannabinoid receptors (CBRs) are widely distributed in the brain, including the inferior colliculus (IC). Here, we aim to study whether endocannabinoids influence a specific type of neuronal adaptation, namely, stimulus-specific adaptation (SSA) found in some IC neurons. SSA is important because it has been found as early as the level of the midbrain and therefore it may be a neuronal correlate of early indices of deviance detection. Furthermore, recent studies have demonstrated a direct link between SSA and MMN, that is widely used as an outcome measure in a variety of human neurodegenerative disorders. SSA is considered a form of short-term plasticity, and CBRs have been shown to play a role in short-term neural plasticity. Therefore, it is reasonable to hypothesize that endocannabinoids may play a role in the generation or modulation of SSA. We recorded single units in the IC under an oddball paradigm stimulation. The results demonstrate that cannabinoid agonists lead to a reduction in the neuronal adaptation. This change is due to a differential increase of the neuronal firing rate to the standard tone alone. Furthermore, we show that the effect is mediated by the cannabinoid receptor 1 (CBR1). Thus, cannabinoid agonists down-modulate SSA in IC neurons.

Hypothesis: Acoustic stimulation generates measurable sound pressure levels in the semicircular canals. Background: High-intensity acoustic stimuli can cause hearing loss and balance disruptions. To examine the propagation of acoustic stimuli to the vestibular end-organs, we simultaneously measured fluid pressure in the cochlea and semicircular canals during both air- and bone-conducted sound presentation. Methods: Five full-cephalic human cadaveric heads were prepared bilaterally with a mastoidectomy and extended facial recess. Vestibular pressures were measured within the superior, lateral, and posterior semicircular canals, and referenced to intracochlear pressure within the scala vestibuli with fiber-optic pressure probes. Pressures were measured concurrently with laser Doppler vibrometry measurements of stapes velocity during stimulation with both air- and bone-conduction. Stimuli were pure tones between 100 Hz and 14 kHz presented with custom closed-field loudspeakers for air-conducted sounds and via commercially available bone-anchored device for bone-conducted sounds. Results: Pressures recorded in the superior, lateral, and posterior semicircular canals in response to sound stimulation were equal to or greater in magnitude than those recorded in the scala vestibuli (up to 20 dB higher). The pressure magnitudes varied across canals in a frequency-dependent manner. Conclusion: High sound pressure levels were recorded in the semicircular canals with sound stimulation, suggesting that similar acoustical energy is transmitted to the semicircular canals and the cochlea. Since these intralabyrinthine pressures exceed intracochlear pressure levels, our results suggest that the vestibular end-organs may also be at risk for injury during exposure to high-intensity acoustic stimuli known to cause trauma in the auditory system.

Hypothesis: Drilling on the incus produces intracochlear pressure changes comparable to pressures created by high-intensity acoustic stimuli. Background: New-onset sensorineural hearing loss (SNHL) following mastoid surgery can occur secondary to inadvertent drilling on the ossicular chain. To investigate this, we test the hypothesis that high sound pressure levels are generated when a high-speed drill contacts the incus. Methods: Human cadaveric heads underwent mastoidectomy, and fiber-optic sensors were placed in scala tympani and vestibuli to measure intracochlear pressures ( P IC ). Stapes velocities ( V stap ) were measured using single-axis laser Doppler vibrometry. P IC and V stap were measured while drilling on the incus. Four-millimeter diamond and cutting burrs were used at drill speeds of 20k, 50k, and 80k Hz. Results: No differences in peak equivalent ear canal noise exposures (134–165 dB SPL) were seen between drill speeds or burr types. Root-mean-square P IC amplitude calculated in third-octave bandwidths around 0.5, 1, 2, 4, and 8 kHz revealed equivalent ear canal (EAC) pressures up to 110 to 112 dB SPL. A statistically significant trend toward increasing noise exposure with decreasing drill speed was seen. No significant differences were noted between burr types. Calculations of equivalent EAC pressure from V stap were significantly higher at 101 to 116 dB SPL. Conclusion: Our results suggest that incidental drilling on the ossicular chain can generate P IC comparable to high-intensity acoustic stimulation. Drill speed, but not burr type, significantly affected the magnitude of P IC . Inadvertent drilling on the ossicular chain produces intense cochlear stimulation that could cause SNHL.

By recording in visual cortex in unanesthetized infant rats, we show that neural activity attributable to retinal waves is specifically suppressed when pups spontaneously awaken or are experimentally aroused. These findings suggest that the relatively abundant sleep of early development plays a permissive functional role for the visual system. It follows, then, that biological or environmental factors that disrupt sleep may interfere with the development of these neural networks.

Children with autism spectrum disorder (ASD) are a heterogeneous group, some with hyperacusis and some without. Our research shows that hyperacusis can be estimated in children with ASD by using medial olivocochlear (MOC) reflex measurements. By establishing that an objective measure correlates with attributes of hyperacusis, our results enable future work to enable subtyping of children with ASD to provide improved individualized treatments to at-risk children and those without adequate language to describe their hyperacusis symptoms.

Plasticity of myelination represents a mechanism to tune the flow of information by balancing functional requirements with metabolic and spatial constraints. The auditory system is heavily myelinated and operates at the upper limits of action potential generation frequency and speed observed in the mammalian CNS. This study aimed to characterize the development of myelin within the trapezoid body, a central auditory fiber tract, and determine the influence sensory experience has on this process in mice of both sexes. We find that in vitro conduction speed doubles following hearing onset and the ability to support high-frequency firing increases concurrently. Also in this time, the diameter of trapezoid body axons and the thickness of myelin double, reaching mature-like thickness between 25 and 35 d of age. Earplugs were used to induce ∼50 dB elevation in auditory thresholds. If introduced at hearing onset, trapezoid body fibers developed thinner axons and myelin than age-matched controls. If plugged during adulthood, the thickest trapezoid body fibers also showed a decrease in myelin. These data demonstrate the need for sensory activity in both development and maintenance of myelin and have important implications in the study of myelin plasticity and how this could relate to sensorineural hearing loss following peripheral impairment.SIGNIFICANCE STATEMENT The auditory system has many mechanisms to maximize the dynamic range of its afferent fibers, which operate at the physiological limit of action potential generation, precision, and speed. In this study we demonstrate for the first time that changes in peripheral activity modifies the thickness of myelin in sensory neurons, not only in development but also in mature animals. The current study suggests that changes in CNS myelination occur as a downstream mechanism following peripheral deficit. Given the required submillisecond temporal precision for binaural auditory processing, reduced myelination might augment sensorineural hearing impairment.

Conventional microscopy has limitations in viewing the cochlear microstructures due to three-dimensional spiral structure and the overlying bone. But these issues can be overcome by imaging the cochlea in vitro with intravital multiphoton microscopy (MPM). By using near-infrared lasers for multiphoton excitation, intravital MPM can detect endogenous fluorescence and second harmonic generation of tissues. In this study, we used intravital MPM to visualize various cochlear microstructures without any staining and non-invasively analyze the volume changes of the scala media (SM) without removing the overlying cochlear bone. The intravital MPM images revealed various tissue types, ranging from thin membranes to dense bone, as well as the spiral ganglion beneath the cochlear bone. The two-dimensional, cross-sectional, and serial z-stack intravital MPM images also revealed the spatial dilation of the SM in the temporal bone of pendrin-deficient mice. These findings suggest that intravital MPM might serve as a new method for obtaining microanatomical information regarding the cochlea, similar to standard histopathological analyses in the animal study for the cochlea. Given the capability of intravital MPM for detecting an increase in the volume of the SM in pendrin-deficient mice, it might be a promising new tool for assessing the pathophysiology of hearing loss in the future.

There is evidence that the contribution of a given harmonic in a complex tone to residue pitch is influenced by the accuracy with which the frequency of that harmonic is encoded. The present study investigated whether listeners adjust the weights assigned to individual harmonics based on acquired knowledge of the reliability of the frequency estimates of those harmonics. In a two-interval forced-choice task, seven listeners indicated which of two 12-harmonic complex tones had the higher overall pitch. In context trials (60 % of all trials), the fundamental frequency (F0) was 200 Hz in one interval and 200 + ΔF0 Hz in the other. In different (blocked) conditions, either the 3rd or the 4th harmonic (plus the 7th, 9th, and 12th harmonics), were replaced by narrowband noises that were identical in the two intervals. Feedback was provided. In randomly interspersed test trials (40 % of all trials), the fundamental frequency was 200 + ΔF0/2 Hz in both intervals; in the second interval, either the third or the fourth harmonic was shifted slightly up or down in frequency with equal probability. There were no narrowband noises. Feedback was not provided. The results showed that substitution of a harmonic by noise in context trials reduced the contribution of that harmonic to pitch judgements in the test trials by a small but significant amount. This is consistent with the notion that listeners give smaller weight to a harmonic or frequency region when they have learned that this frequency region does not provide reliable information for a given task.

Defects in the biosynthesis of phospholipids and neutral lipids are associated with cell membrane dysfunction, disrupted energy metabolism, and diseases including lipodystrophy. In these pathways, the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) enzymes transfer a fatty acid to the sn-2 carbon of sn-1-acylglycerol-3-phosphate (lysophosphatidic acid) to form sn-1, 2-acylglycerol-3-phosphate [phosphatidic acid (PA)]. PA is a precursor for key phospholipids and diacylglycerol. AGPAT1 and AGPAT2 are highly homologous isoenzymes that are both expressed in adipocytes. Genetic defects in AGPAT2 cause congenital generalized lipodystrophy, indicating that AGPAT1 cannot compensate for loss of AGPAT2 in adipocytes. To further explore the physiology of AGPAT1, we characterized a loss-of-function mouse model (Agpat1-/-). The majority of Agpat1-/- mice died before weaning and had low body weight and low plasma glucose levels, independent of plasma insulin and glucagon levels, with reduced percentage of body fat but not generalized lipodystrophy. These mice also had decreased hepatic messenger RNA expression of Igf-1 and Foxo1, suggesting a decrease in gluconeogenesis. In male mice, sperm development was impaired, with a late meiotic arrest near the onset of round spermatid production, and gonadotropins were elevated. Female mice showed oligoanovulation yet retained responsiveness to gonadotropins. Agpat1-/- mice also demonstrated abnormal hippocampal neuron development and developed audiogenic seizures. In summary, Agpat1-/- mice developed widespread disturbances of metabolism, sperm development, and neurologic function resulting from disrupted phospholipid homeostasis. AGPAT1 appears to serve important functions in the physiology of multiple organ systems. The Agpat1-deficient mouse provides an important model in which to study the contribution of phospholipid and triacylglycerol synthesis to physiology and diseases.

Electrode arrays interfacing with peripheral nerves are essential for neuromodulation devices targeting peripheral organs to relieve symptoms. To modulate (i.e., single-unit recording and stimulating) individual peripheral nerve axons remains a technical challenge. Here, we report an in vitro setup to allow simultaneous single-unit recordings from multiple mouse sciatic nerve axons. The sciatic nerve (~30 mm) was harvested and transferred to a tissue chamber, the ~5mm distal end pulled into an adjacent recording chamber filled with paraffin oil. A custom-built multi-wire electrode array was used to interface with split fine nerve filaments. Single-unit action potentials were evoked by electrical stimulation and recorded from 186 axons, of which 49.5% were classed A-type with conduction velocities (CV) greater than 1 m/s and 50.5% were C-type (CV < 1 m/s). The single-unit recordings had no apparent bias towards A- or C-type axons, were robust and repeatable for over 60 minutes, and thus an ideal opportunity to assess different neuromodulation strategies targeting peripheral nerves. For instance, ultrasonic modulation of action potential transmission was assessed using the setup, indicating increased nerve conduction velocity following ultrasound stimulus. This setup can also be used to objectively assess the design of next-generation electrode arrays interfacing with peripheral nerves.

Auditory neuropathy (AN) is a hearing disorder characterized by normal cochlear amplification to sound but poor temporal processing and auditory perception in noisy backgrounds. These deficits likely result from impairments in auditory neural synchrony; such dyssynchrony of the neural responses has been linked to demyelination of auditory nerve fibers. However, no appropriate animal models are currently available that mimic this pathology. In this study, Cre-inducible diphtheria toxin receptor ( iDTR +/+ ) mice were cross-mated with mice containing Cre ( Bhlhb5-Cre +/− ) specific to spiral ganglion neurons (SGNs). In double-positive offspring mice, the injection of diphtheria toxin (DT) led to a 30–40% rate of death for SGNs, but no hair cell damage. Demyelination types of pathologies were observed around the surviving SGNs and their fibers, many of which were distorted in shape. Correspondingly, a significant reduction in response synchrony to amplitude modulation was observed in this group of animals compared to the controls, which had a Cre − genotype. Taken together, our results suggest that SGN damage following the injection of DT in mice with Bhlhb5-Cre +/− and iDTR +/− is likely to be a good AN model of demyelination.

Closed-loop brain stimulation is a promising alternative to treat drug-resistant epilepsies. In contrast to optogenetic interventions, transcranial electrical stimulation (TES) does not require cellular modification of neurons to be effective, and it is less invasive compared to deep brain stimulation. Furthermore, on-demand TES of targeted brain regions allows the potential for normal function of these networks during interictal periods, a possibility that is eliminated by resective surgical treatment approaches. To further explore the translation of closed-loop TES for treatment of epilepsy, we show here for the first time that unsupervised closed-loop TES in rats can consistently interrupt seizures for 6 weeks and has the potential to control seizure activity up to 4 months (longest periods examined). On-demand TES significantly reduced the time spent in seizure and the individual seizure duration, although significantly higher seizure rate was observed during the treatment. The 6 week long stimulation had no residual adverse effects on the electrophysiologic characteristics of the brain after the termination of the treatment and did not induce glial remodelling in the brain. Our findings demonstrate the safety and effectiveness of minimally invasive, potentially lifelong TES treatment of epilepsy either alone or as a complement to drug treatments.

The most widespread measures of human brain activity are the blood-oxygen-level dependent (BOLD) signal and surface field potential. Prior studies report a variety of relationships between these signals. To develop an understanding of how to interpret these signals and the relationship between them, we developed a model of (a) neuronal population responses and (b) transformations from neuronal responses into the functional magnetic resonance imaging (fMRI) BOLD signal and electrocorticographic (ECoG) field potential. Rather than seeking a transformation between the two measures directly, this approach interprets each measure with respect to the underlying neuronal population responses. This model accounts for the relationship between BOLD and ECoG data from human visual cortex in V1, V2, and V3, with the model predictions and data matching in three ways: across stimuli, the BOLD amplitude and ECoG broadband power were positively correlated, the BOLD amplitude and alpha power (8-13 Hz) were negatively correlated, and the BOLD amplitude and narrowband gamma power (30-80 Hz) were uncorrelated. The two measures provide complementary information about human brain activity, and we infer that features of the field potential that are uncorrelated with BOLD arise largely from changes in synchrony, rather than level, of neuronal activity.

The auditory brainstem response (ABR) in tinnitus subjects has been extensively investigated over the last decade with the hopes of finding possible abnormalities related to the pathology. Despite this effort, the use of the ABR for tinnitus diagnosis or as an outcome measure is under debate. The present study reviewed published literature on ABR and tinnitus. The authors searched PubMed, MedLine, Embase, PsycINFO, and CINAHL, and identified additional records through manually searching reference lists and gray literature. There were 4,566 articles identified through database searching and 151 additional studies through the manual search (4,717 total): 2,128 articles were removed as duplicates, and 2,567 records did not meet eligibility criteria. From the final 22 articles that were included, ABR results from 1,240 tinnitus subjects and 664 control subjects were compiled and summarized with a focus on three main areas: the participant characteristics, the methodology used, and the outcome measures of amplitude and/or latency of waves I, III, and V. The results indicate a high level of heterogeneity between the studies for all the assessed areas. Amplitude and latency differences between tinnitus and controls were not consistent between studies. Nevertheless, the longer latency and reduced amplitude of wave I for the tinnitus group with normal hearing compared to matched controls was the most consistent finding across studies. These results support the need for greater stratification of the tinnitus population and the importance of a standardized ABR method to make comparisons between studies possible.