Publications using TDT

Hypothesis: Intracochlear pressures (P IC ) and stapes velocity (V stap ) elicited by bilaterally placed bone-anchored hearing devices (BAHD) will be systematically modulated by imposed interaural time (ITD) and level differences (ILD), demonstrating the potential for users of bilateral BAHD to access these binaural cues. Background: BAHD are traditionally implanted unilaterally under the assumption that transcranial cross-talk limits interaural differences. Recent studies have demonstrated improvements in binaural and spatial performance with bilateral BAHD; however, objective measures of binaural cues from bilateral BAHDs are lacking. Methods: Bone-conduction transducers were coupled to both mastoids of cadaveric specimens via implanted titanium abutments. P IC and V stap were measured using intracochlear pressure probes and laser Doppler vibrometry, respectively, during stimulation with pure-tone stimuli of varied frequency (250–4000 Hz) under ipsilateral, contralateral, and bilateral ITD (−1 to 1 ms) and ILD (−20 to 20 dB) conditions. Results: Bilateral stimulation produced constructive and destructive interference patterns that varied dramatically with ITD and stimulus frequency. Variation of ITD led to large variation of P IC and V stap , with opposing effects in ipsilateral and contralateral ears expected to lead to “ITD to ILD conversion.” Variation of ILD produced more straightforward (monotonic) variations of P IC and V stap , with ipsilateral-favoring ILD producing higher P IC and V stap than contralateral-favoring. Conclusion: Variation of ITDs and ILDs conveyed by BAHDs systematically modulated cochlear inputs. While transcranial cross-talk leads to complex interactions that depend on cue type and stimulus frequency, binaural disparities potentiate binaural benefit, providing a basis for improved sound localization and speech-in-noise perception.

Objective: To compare the effectiveness of current contralateral routing of signal technology (CROS) to bone-anchored implants in experienced bone-anchored implant users with unilateral severe-profound sensorineural hearing loss. Design: Prospective, within-subject repeated-measures comparison study. Setting: Tertiary referral center. Patients: Adult, English-speaking patients (n = 12) with severe-profound unilateral sensorineural hearing loss implanted with a bone-anchored implant for the indication of single-sided deafness. Intervention: Subjects were fitted with contralateral routing of signal amplification and tested for speech in noise performance and localization error. Outcome Measures: Speech perception in noise was assessed using the BKB-SIN test materials. Localization was assessed using narrow band noises centered at 500 and 4000 Hz, as well as a broadband speech stimulus presented at random to the front hemifield by 19 speakers spatially separated by 10 degrees. Results: There was no improvement in localization ability in the aided condition and no significant difference in performance with CROS versus bone-anchored implants (BAI). There was a significant improvement in speech in noise performance for monaural listeners in the aided condition for speech poorer ear/noise better ear, speech front/noise front, and speech front/noise back. No significant difference was observed on performance with CROS versus BAI subjects. Conclusion: Contrary to earlier studies suggesting improved performance of BAIs over CROS, the current study found no difference in performance in BAI over CROS devices. Both CROS and BAI provide significant benefit for monaural listeners. The results suggest that noninvasive CROS solutions can successfully rehabilitate certain monaural listening deficits, provide improved hearing outcomes, and expand the reach of treatment in this population.

In a complex auditory scene, signals of interest can be distinguished from masking sounds by differences in source location [spatial release from masking (SRM)] and by differences between masker-alone and masker-plus-signal envelopes. This study investigated interactions between those factors in release of masking of 700-Hz tones in an open sound field. Signal and masker sources were colocated in front of the listener, or the signal source was shifted 90° to the side. In Experiment 1, the masker contained a 25-Hz-wide on-signal band plus flanking bands having envelopes that were either mutually uncorrelated or were comodulated. Comodulation masking release (CMR) was largely independent of signal location at a higher masker sound level, but at a lower level CMR was reduced for the lateral signal location. In Experiment 2, a brief signal was positioned at the envelope maximum (peak) or minimum (dip) of a 50-Hz-wide on-signal masker. Masking was released in dip more than in peak conditions only for the 90° signal. Overall, open-field SRM was greater in magnitude than binaural masking release reported in comparable closed-field studies, and envelope-related release was somewhat weaker. Mutual enhancement of masking release by spatial and envelope-related effects tended to increase with increasing masker level.

The morphology of the head and pinna shape the spatial and frequency dependence of sound propagation that give rise to the acoustic cues to sound source location. During early development, the physical dimensions of the head and pinna increase rapidly. Thus, the binaural (interaural time and level differences, ITD and ILD) and monaural (spectral shape) cues are also hypothesized to change rapidly. Complex interactions between the size and shape of the head and pinna limit the accuracy of simple acoustical models (e.g. spherical) and necessitate empirical measurements. Here, we measured the cues to location in the developing guinea pig, a precocial species commonly used for studies of the auditory system. We measured directional transfer functions (DTFs) and the dimensions of the head and pinna in guinea pigs from birth (P0) through adulthood. Dimensions of the head and pinna increased by 87% and 48%, respectively, reaching adult values by ∼8 weeks (P56). The monaural acoustic gain produced by the head and pinna increased with frequency and age, with maximum gains at higher frequencies (>8 kHz) reaching values of 10-21 dB for all ages. The center frequency of monaural spectral notches also decreased with age, from higher frequencies (∼17 kHz) at P0 to lower frequencies (∼12 kHz) in adults. In all animals, ILDs and ITDs were dependent on both frequency and spatial location. Over development, the maximum ILD magnitude increased from ∼15 dB at P0 to ∼30 dB in adults (at frequencies >8 kHz), while the maximum low frequency ITDs increased from ∼185 μs at P0 to ∼300 μs in adults. These results demonstrate that the changes in the acoustical cues are directly related to changes in head and pinna morphology.

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2'-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Spike sorting is an essential first step in most analyses of extracellular in vivo electrophysiological recordings. Here we show that spike-sorting success depends critically on characteristics of coordinated population activity that can differ between anesthetic states. In tetrode recordings from mouse auditory cortex, spike sorting was significantly less successful under ketamine/medetomidine (ket/med) than urethane anesthesia. Surprisingly, this difficulty with sorting under ket/med anesthesia did not appear to result from either greater millisecond-scale burstiness of neural activity or increased coordination of activity among neighboring neurons. Rather, the key factor affecting sorting success appeared to be the amount of coordinated population activity at long time intervals and across large cortical distances. We propose that spike-sorting success is directly dependent on overall coordination of activity, and is most disrupted by large-scale fluctuations in cortical population activity. Reliability of single-unit recording may therefore differ not only between urethane-anesthetized and ket/med-anesthetized states as demonstrated here, but also between synchronized and desynchronized states, asleep and awake states, or inattentive and attentive states in unanesthetized animals.

The mechanisms underlying multi-sensory interactions are still poorly understood despite considerable progress made since the first neurophysiological recordings of multi-sensory neurons. While the majority of single-cell neurophysiology has been performed in anesthetized or passive-awake laboratory animals, the vast majority of behavioral data stems from studies with human subjects. Interpretation of neurophysiological data implicitly assumes that laboratory animals exhibit perceptual phenomena comparable or identical to those observed in human subjects. To explicitly test this underlying assumption, we here characterized how two rhesus macaques and four humans detect changes in intensity of auditory, visual, and audio-visual stimuli. These intensity changes consisted of a gradual envelope modulation for the sound, and a luminance step for the LED. Subjects had to detect any perceived intensity change as fast as possible. By comparing the monkeys' results with those obtained from the human subjects we found that (1) unimodal reaction times differed across modality, acoustic modulation frequency, and species, (2) the largest facilitation of reaction times with the audio-visual stimuli was observed when stimulus onset asynchronies were such that the unimodal reactions would occur at the same time (response, rather than physical synchrony), and (3) the largest audio-visual reaction-time facilitation was observed when unimodal auditory stimuli were difficult to detect, i.e., at slow unimodal reaction times. We conclude that despite marked unimodal heterogeneity, similar multisensory rules applied to both species. Single-cell neurophysiology in the rhesus macaque may therefore yield valuable insights into the mechanisms governing audio-visual integration that may be informative of the processes taking place in the human brain.

The subthalamic nucleus is a key site controlling motor function in humans. Deep brain stimulation of the subthalamic nucleus can improve movements in patients with Parkinson's disease; however, for unclear reasons, it can also have cognitive effects. Here, we show that the human subthalamic nucleus is monosynaptically connected with cognitive brain areas such as the prefrontal cortex. Single neurons and field potentials in the subthalamic nucleus are modulated during cognitive processing and are coherent with 4-Hz oscillations in medial prefrontal cortex. These data predict that low-frequency deep brain stimulation may alleviate cognitive deficits in Parkinson's disease patients. In line with this idea, we found that novel 4-Hz deep brain stimulation of the subthalamic nucleus improved cognitive performance. These data support a role for the human hyperdirect pathway in cognitive control, which could have relevance for brain-stimulation therapies aimed at cognitive symptoms of human brain disease.awx300media15660002226001.

Sleep is a dynamic process comprising multiple stages, each associated with distinct electrophysiological properties and potentially serving different functions. While these phenomena are well described in vertebrates, it is unclear if invertebrates have distinct sleep stages. We perform local field potential (LFP) recordings on flies spontaneously sleeping, and compare their brain activity to flies induced to sleep using either genetic activation of sleep-promoting circuitry or the GABA A agonist Gaboxadol. We find a transitional sleep stage associated with a 7–10 Hz oscillation in the central brain during spontaneous sleep. Oscillatory activity is also evident when we acutely activate sleep-promoting neurons in the dorsal fan-shaped body (dFB) of Drosophila . In contrast, sleep following Gaboxadol exposure is characterized by low-amplitude LFPs, during which dFB-induced effects are suppressed. Sleep in flies thus appears to involve at least two distinct stages: increased oscillatory activity, particularly during sleep induction, followed by desynchronized or decreased brain activity.

Panx1 forms plasma membrane channels in brain and several other organs, including the inner ear. Biophysical properties, activation mechanisms and modulators of Panx1 channels have been characterized in detail, however the impact of Panx1 on auditory function is unclear due to conflicts in published results. To address this issue, hearing performance and cochlear function of the Panx1-/- mouse strain, the first with a reported global ablation of Panx1, were scrutinized. Male and female homozygous (Panx1-/-), hemizygous (Panx1+/-) and their wild type (WT) siblings (Panx1+/+) were used for this study. Successful ablation of Panx1 was confirmed by RT-PCR and Western immunoblotting in the cochlea and brain of Panx1-/- mice. Furthermore, a previously validated Panx1-selective antibody revealed strong immunoreactivity in WT but not in Panx1-/- cochleae. Hearing sensitivity, outer hair cell-based "cochlear amplifier" and cochlear nerve function, analyzed by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings, were normal in Panx1+/- and Panx1-/- mice. In addition, we determined that global deletion of Panx1 impacts neither on connexin expression, nor on gap-junction coupling in the developing organ of Corti. Finally, spontaneous intercellular Ca2+ signal (ICS) activity in organotypic cochlear cultures, which is key to postnatal development of the organ of Corti and essential for hearing acquisition, was not affected by Panx1 ablation. Therefore, our results provide strong evidence that, in mice, Panx1 is dispensable for hearing acquisition and auditory function.

Background: Despite advances in sophisticated robotic hands, intuitive control of and sensory feedback from these prostheses has been limited to only 3-degrees-of-freedom (DOF) with 2 sensory percepts in closed-loop control. A Utah Slanted Electrode Array (USEA) has been used in the past to provide up to 81 sensory percepts for human amputees. Here, we report on the advanced capabilities of multiple USEAs implanted in the residual peripheral arm nerves of human amputees for restoring control of 5 DOF and sensation of up to 131 proprioceptive and cutaneous hand sensory percepts. We also demonstrate that USEA-restored sensory percepts provide a useful source of feedback during closed-loop virtual prosthetic hand control. Methods: Two 100-channel USEAs were implanted for 4-5 weeks, one each in the median and ulnar arm nerves of two human subjects with prior long-duration upper-arm amputations. Intended finger and wrist positions were decoded from neuronal firing patterns via a modified Kalman filter, allowing subjects to control many movements of a virtual prosthetic hand. Additionally, USEA microstimulation was used to evoke numerous sensory percepts spanning the phantom hand. Closed-loop control was achieved by stimulating via an electrode of the ulnar-nerve USEA while recording and decoding movement via the median-nerve USEA. Results: Subjects controlled up to 12 degrees-of-freedom during informal, 'freeform' online movement decode sessions, and experienced up to 131 USEA-evoked proprioceptive and cutaneous sensations spanning the phantom hand. Independent control was achieved for a 5-DOF real-time decode that included flexion/extension of the thumb, index, middle, and ring fingers, and the wrist. Proportional control was achieved for a 4-DOF real-time decode. One subject used a USEA-evoked hand sensation as feedback to complete a 1-DOF closed-loop virtual-hand movement task. There were no observed long-term functional deficits due to the USEA implants. Conclusions: Implantation of high-channel-count USEAs enables multi-degree-of-freedom control of virtual prosthetic hand movement and restoration of a rich selection of both proprioceptive and cutaneous sensory percepts spanning the hand during the short 4-5 week post-implant period. Future USEA use in longer-term implants and in closed-loop may enable restoration of many of the capabilities of an intact hand while contributing to a meaningful embodiment of the prosthesis.

Short-term memory load can impair attentional control, but prior work shows that the extent of the effect ranges from being very general to very specific. One factor for the mixed results may be reliance on point estimates of memory load effects on attention. Here we used auditory attention gradients as an analog measure to map-out the impact of short-term memory load over space. Verbal or spatial information was maintained during an auditory spatial attention task and compared to no-load. Stimuli were presented from five virtual locations in the frontal azimuth plane, and subjects focused on the midline. Reaction times progressively increased for lateral stimuli, indicating an attention gradient. Spatial load further slowed responses at lateral locations, particularly in the left hemispace, but had little effect at midline. Verbal memory load had no (Experiment 1), or a minimal (Experiment 2) influence on reaction times. Spatial and verbal load increased switch costs between memory encoding and attention tasks relative to the no load condition. The findings show that short-term memory influences the distribution of auditory attention over space; and that the specific pattern depends on the type of information in short-term memory.

Approximately 15% of American adults report some degree of difficulty hearing in a noisy environment or have auditory filtering difficulties. There are objective clinical tests of auditory filtering, yet few tests exist for mouse models that do not rely on extensive training. We have used reflex modification audiometry (RMA) and developed exclusion criteria for the mouse model. This RMA based test makes use of the acoustic startle response (ASR) and the ability of prepulses to inhibit the ASR [i.e., prepulse inhibition (PPI)] to assess the mouse's ability to detect prepulse signals presented in quiet or embedded in masking noise. We have studied PPI behavior across four inbred mouse strains with normal cochlear function and developed pre-testing exclusion criteria and test/retest reliability measures. Moreover, because both the medial (MOC) and the lateral (LOC) olivocochlear efferent feedback systems have been proposed to improve auditory behavior performance, especially in noisy backgrounds, we have examined PPI abilities in mice (with their littermate controls) either lacking the MOC receptor subunit α9 nicotinic acetylcholine receptor [α9 nAChR (-/-)] or expressing an overactive receptor [Ld'T mutation in α9 nAChR KI], or lacking an LOC efferent neuropeptide, alpha calcitonin gene-related peptide [αCGRP (-/-)] only in the CNS. Because CGRP receptor formation has been shown to mature from juvenile to adult ages, we also studied if this maturation would be reflected in PPI behavioral responses in juvenile and adult (+/+) controls and in adult αCGRP (-/-) animals. We show that 50% PPI response thresholds (sound level with 50% correct responses) in quiet are decreased in the (-/-) α9 nAChR animals, and 50% PPI responses are increased for mice with an overactive receptor (α9 nAChR KI) and are increased in adult mice lacking αCGRP (-/-). However, in background noise, only mice lacking αCGRP exhibited increased 50% PPI response thresholds, as there were no significant differences between α9 nAChR adult mouse lines and their littermate controls. These findings suggest that MOC and LOC olivocochlear neurotransmission work in tandem to improve behavioral responses to sound. These experiments further pave the way for rapid behavioral hearing assessments in other mouse models.

Introduction Resting‐state connectivity patterns have been observed in humans and other mammal species, and can be recorded using a variety of different technologies. Functional connectivity has been previously compared between species using resting‐state fMRI , but not in electrophysiological studies. Methods We compared connectivity with implanted electrodes in humans (electrocorticography) to macaques and sheep (microelectrocorticography), which are capable of recording neural data at high frequencies with spatial precision. We specifically examined synchrony, implicated in functional integration between regions. Results We found that connectivity strength was overwhelmingly similar in humans and monkeys for pairs of two different brain regions (prefrontal, motor, premotor, parietal), but differed more often within single brain regions. The two connectivity measures, correlation and phase locking value, were similar in most comparisons. Connectivity strength agreed more often between the species at higher frequencies. Where the species differed, monkey synchrony was stronger than human in all but one case. In contrast, human and sheep connectivity within somatosensory cortex diverged in almost all frequencies, with human connectivity stronger than sheep. Discussion Our findings imply greater heterogeneity within regions in humans than in monkeys, but comparable functional interactions between regions in the two species. This suggests that monkeys may be effectively used to probe resting‐state connectivity in humans, and that such findings can then be validated in humans. Although the discrepancy between humans and sheep is larger, we suggest that findings from sheep in highly invasive studies may be used to provide guidance for studies in other species.

Cisplatin chemotherapy causes permanent hearing loss in 40–80% of treated patients. It is unclear whether the cochlea has unique sensitivity to cisplatin or is exposed to higher levels of the drug. Here we use inductively coupled plasma mass spectrometry (ICP-MS) to examine cisplatin pharmacokinetics in the cochleae of mice and humans. In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans. Using laser ablation coupled to ICP-MS, we map cisplatin distribution within the human cochlea. Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph. Our results demonstrate long-term retention of cisplatin in the human cochlea, and they point to the stria vascularis as an important therapeutic target for preventing cisplatin ototoxicity.

The hippocampus is known as a neuronal structure involved in learning, memory and spatial navigation using multi-sensory cues. However, the basic features of its response to acoustic stimuli without any behavioral tasks (conditioning) remains poorly studied. Here, we investigated the CA3 response to auditory stimuli using in vivo loose-patch recordings in awake and anesthetized C57 mice. Different acoustic stimuli in addition to broadband noise such as click, FM sound and pure tone were applied to test the response of CA3 in awake animals. It was found that the wakefulness of the animal is important for the recorded neurons to respond. The CA3 neurons showed a stronger response to broadband noise rather than the other type of stimuli which suggested that auditory information arrived at CA3 via broadband pathways. Finally, we investigated the excitatory and inhibitory inputs to CA3 neurons by using in vivo whole-cell voltage-clamp techniques with the membrane potential holding at -70 and 0 mV, respectively. In awake animals, the excitatory and inhibitory inputs CA3 neurons receive induced by noise are balanced by showing stable intervals and proportional changes of their latencies and peak amplitudes as a function of the stimulation intensities.

Today, the standard method to predict output levels of active middle ear implants (AMEIs) before clinical data are available is stapes vibration measurement in human cadaveric ears, according to ASTM standard F2504-05. Although this procedure is well established, the validity of the predicted output levels has never been demonstrated clinically. Furthermore, this procedure requires a mobile and visually accessible stapes and an AMEI stimulating the ossicular chain. Thus, an alternative method is needed to quantify the output level of AMEIs in all other stimulation modes, e.g. reverse stimulation of the round window. Intracochlear pressure difference (ICPD) is a good candidate for such a method as it correlates with evoked potentials in animals and it is measurable in cadaveric ears. To validate this method we correlated AMEI output levels calculated from ICPD and from stapes vibration in cadaveric ears with outputs levels determined from clinical data. Output levels calculated from ICPD were similar to output levels calculated from stapes vibration and almost identical to clinical data. Our results demonstrate that both ICPD and stapes vibration can be used as a measure to predict AMEI clinical output levels in cadaveric ears and that ICPD as reference provided even more accurate results.

Learning to recognize a stimulus category requires experience with its many natural variations. However, the mechanisms that allow a category's sensorineural representation to be updated after experiencing new exemplars are not well understood, particularly at the molecular level. Here we investigate how a natural vocal category induces expression in the auditory system of a key synaptic plasticity effector immediate early gene, Arc/Arg3.1 , which is required for memory consolidation. We use the ultrasonic communication system between mouse pups and adult females to study whether prior familiarity with pup vocalizations alters how Arc is engaged in the core auditory cortex after playback of novel exemplars from the pup vocal category. A computerized, 3D surface-assisted cellular compartmental analysis, validated against manual cell counts, demonstrates significant changes in the recruitment of neurons expressing Arc in pup-experienced animals (mothers and virgin females “cocaring” for pups) compared with pup-inexperienced animals (pup-naïve virgins), especially when listening to more familiar, natural calls compared to less familiar but similarly recognized tonal model calls. Our data support the hypothesis that the kinetics of Arc induction to refine cortical representations of sensory categories is sensitive to the familiarity of the sensory experience.

Despite decades of microelectrode recordings, fundamental questions remain about how auditory cortex represents sound-source location. Here, we used in vivo 2-photon calcium imaging to measure the sensitivity of layer II/III neurons in mouse primary auditory cortex (A1) to interaural level differences (ILDs), the principal spatial cue in this species. Although most ILD-sensitive neurons preferred ILDs favoring the contralateral ear, neurons with either midline or ipsilateral preferences were also present. An opponent-channel decoder accurately classified ILDs using the difference in responses between populations of neurons that preferred contralateral-ear-greater and ipsilateral-ear-greater stimuli. We also examined the spatial organization of binaural tuning properties across the imaged neurons with unprecedented resolution. Neurons driven exclusively by contralateral ear stimuli or by binaural stimulation occasionally formed local clusters, but their binaural categories and ILD preferences were not spatially organized on a more global scale. In contrast, the sound frequency preferences of most neurons within local cortical regions fell within a restricted frequency range, and a tonotopic gradient was observed across the cortical surface of individual mice. These results indicate that the representation of ILDs in mouse A1 is comparable to that of most other mammalian species, and appears to lack systematic or consistent spatial order.

The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat.