Publications using TDT

Objective The goal of this work is to establish a new dual‐modal brain‐mapping technique based on diffuse optical tomography ( DOT ) and electroencephalographic source localization ( ESL ) that can chronically/intracranially record optical/electroencephalography ( EEG ) data to precisely map seizures and localize the seizure‐onset zone and associated epileptic brain network. Methods The dual‐modal imaging system was employed to image seizures in an experimental acute bicuculline methiodide rat model of focal epilepsy. Depth information derived from DOT was used as constraint in ESL to enhance the image reconstruction. Groups of animals were compared based on localization of seizure foci, either at different positions or at different depths. Results This novel imaging technique successfully localized the seizure‐onset zone in rat induced by bicuculline methiodide injected at a depth of 1, 2, and 3 mm, respectively. The results demonstrated that the incorporation of the depth information from DOT into the ESL image reconstruction resulted in more accurate and reliable ESL images. Although the ESL images showed a horizontal shift of the source localization, the DOT identified the seizure focus accurately. In one case, when the bicuculline methiodide (BMI) was injected at a site outside the field of view ( FOV ) of the DOT / ESL interface, ESL gave false‐positive detection of the focus, while DOT showed negative detection. Significance This study represents the first to identify seizure‐onset zone using implantable DOT . In addition, the combination of DOT / ESL has never been documented in neuroscience and epilepsy imaging. This technology will enable us to precisely measure the neural activity and hemodynamic response at exactly the same tissue site and at both cortical and subcortical levels.

While the timing of neuronal activity in the olfactory bulb (OB) relative to sniffing has been the object of many studies, the behavioral relevance of timing information generated by patterned activation within the bulbar response has not been explored. Here we show, using sniff-triggered, dynamic, 2-D, optogenetic stimulation of mitral/tufted cells, that virtual odors that differ by as little as 13 ms are distinguishable by mice. Further, mice are capable of discriminating a virtual odor movie based on an optically imaged OB odor response versus the same virtual odor devoid of temporal dynamics-independently of the sniff-phase. Together with studies showing the behavioral relevance of graded glomerular responses and the response timing relative to odor sampling, these results imply that the mammalian olfactory system is capable of very high transient information transmission rates.

The interaural level difference (ILD) cue to sound location is first encoded in the lateral superior olive (LSO). ILD sensitivity results because the LSO receives excitatory input from the ipsilateral cochlear nucleus and inhibitory input indirectly from the contralateral cochlear nucleus via glycinergic neurons of the ipsilateral medial nucleus of the trapezoid body (MNTB). It is hypothesized that in order for LSO neurons to encode ILDs, the sound spectra at both ears must be accurately encoded via spike rate by their afferents. This spectral-coding hypothesis has not been directly tested in MNTB, likely because MNTB neurons have been mostly described and studied recently in regards to their abilities to encode temporal aspects of sounds, not spectral. Here, we test the hypothesis that MNTB neurons and their inputs from the cochlear nucleus and auditory nerve code sound spectra via discharge rate. The Random Spectral Shape (RSS) method was used to estimate how the levels of 100-ms duration spectrally stationary stimuli were weighted, both linearly and non-linearly, across a wide band of frequencies. In general, MNTB neurons, and their globular bushy cell inputs, were found to be well-modeled by a linear weighting of spectra demonstrating that the pathways through the MNTB can accurately encode sound spectra including those resulting from the acoustical cues to sound location provided by head-related directional transfer functions (DTFs). Together with the anatomical and biophysical specializations for timing in the MNTB-LSO complex, these mechanisms may allow ILDs to be computed for complex stimuli with rapid spectrotemporally-modulated envelopes such as speech and animal vocalizations and moving sound sources.

Mice that carry a mutation in a calcium binding domain of Otoferlin, the putative calcium sensor at hair cell synapses, have normal distortion product otoacoustic emissions (DPOAEs), but auditory brain stem responses (ABRs) are absent. In mutant mice mechanotransduction is normal but transmission of acoustic information to the auditory pathway is blocked even before the onset of hearing. The cross-sectional area of the auditory nerve of mutant mice is reduced by 54%, and the volume of ventral cochlear nuclei is reduced by 46% relative to hearing control mice. While the tonotopic organization was not detectably changed in mutant mice, the axons to end bulbs of Held and the end bulbs themselves were smaller. In mutant mice bushy cells in the anteroventral cochlear nucleus (aVCN) have the electrophysiological hallmarks of control cells. Spontaneous miniature excitatory postsynaptic currents (EPSCs) occur with similar frequencies and have similar shapes in deaf as in hearing animals, but they are 24% larger in deaf mice. Bushy cells in deaf mutant mice are contacted by ∼2.6 auditory nerve fibers compared with ∼2.0 in hearing control mice. Furthermore, each fiber delivers more synaptic current, on average 4.8 nA compared with 3.4 nA, in deaf versus hearing control mice. The quantal content of evoked EPSCs is not different between mutant and control mice; the increase in synaptic current delivered in mutant mice is accounted for by the increased response to the size of the quanta. Although responses to shocks presented at long intervals are larger in mutant mice, they depress more rapidly than in hearing control mice.

Assemblies of vertically connected neurons in the cerebral cortex form information processing units (columns) that participate in the distribution and segregation of sensory signals. Despite well-accepted models of columnar architecture, functional mechanisms of inter-laminar communication remain poorly understood. Hence, the purpose of the present investigation was to examine the effects of sensory information features on columnar response properties. Using acute recording techniques, extracellular response activity was collected from the right hemisphere of eight mature cats (felis catus). Recordings were conducted with multichannel electrodes that permitted the simultaneous acquisition of neuronal activity within primary auditory cortex columns. Neuronal responses to simple (pure tones), complex (noise burst and frequency modulated sweeps), and ecologically relevant (con-specific vocalizations) acoustic signals were measured. Collectively, the present investigation demonstrates that despite consistencies in neuronal tuning (characteristic frequency), irregularities in discharge activity between neurons of individual A1 columns increase as a function of spectral (signal complexity) and temporal (duration) acoustic variations.

Music perception builds on expectancy in harmony, melody, and rhythm. Neural responses to the violations of such expectations are observed in event-related potentials (ERPs) measured using electroencephalography. Most previous ERP studies demonstrating sensitivity to musical violations used stimuli that were temporally regular and musically structured, with less-frequent deviant events that differed from a specific expectation in some feature such as pitch, harmony, or rhythm. Here, we asked whether expectancies about Western musical scale are strong enough to elicit ERP deviance components. Specifically, we explored whether pitches inconsistent with an established scale context elicit deviant components even though equally rare pitches that fit into the established context do not, and even when their timing is unpredictable. We used Markov chains to create temporally irregular pseudo-random sequences of notes chosen from one of two diatonic scales. The Markov pitch-transition probabilities resulted in sequences that favored notes within the scale, but that lacked clear melodic, harmonic, or rhythmic structure. At the random positions, the sequence contained probe tones that were either within the established scale or were out of key. Our subjects ignored the note sequences, watching a self-selected silent movie with subtitles. Compared to the in-key probes, the out-of-key probes elicited a significantly larger P2 ERP component. Results show that random note sequences establish expectations of the "first-order" statistical property of musical key, even in listeners not actively monitoring the sequences.

Objective: The dorsal root ganglion is an attractive target for implanting neural electrode arrays that restore sensory function or provide therapy via stimulation. However, penetrating microelectrodes designed for these applications are small and deliver low currents. For long-term performance of microstimulation devices, novel coating materials are needed in part to decrease impedance values at the electrode-tissue interface and to increase charge storage capacity. Approach: Conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) and multi-wall carbon nanotubes (CNTs) were coated on the electrode surface and doped with the anti-inflammatory drug, dexamethasone. Electrode characteristics and the tissue reaction around neural electrodes as a result of stimulation, coating and drug release were characterized. Hematoxylin and eosin staining along with antibodies recognizing Iba1 (microglia/macrophages), NF200 (neuronal axons), NeuN (neurons), vimentin (fibroblasts), caspase-3 (cell death) and L1 (neural cell adhesion molecule) were used. Quantitative image analyses were performed using MATLAB. Main results: Our results indicate that coated microelectrodes have lower in vitro and in vivo impedance values. Significantly less neuronal death/damage was observed with coated electrodes as compared to non-coated controls. The inflammatory response with the PEDOT/CNT-coated electrodes was also reduced. Significance: This study is the first to report on the utility of these coatings in stimulation applications. Our results indicate PEDOT/CNT coatings may be valuable additions to implantable electrodes used as therapeutic modalities.

Various cochlear pathologies, such as acoustic trauma, ototoxicity and age-related degeneration, cause hearing loss. These pre-existing hearing losses can alter cochlear responses to subsequent acoustic overstimulation. So far, the knowledge on the impacts of pre-existing hearing loss caused by genetic alteration of cochlear genes is limited. Prestin is the motor protein expressed exclusively in outer hair cells in the mammalian cochlea. This motor protein contributes to outer hair cell motility. At present, it is not clear how the interference of prestin function affects cochlear responses to acoustic overstimulation. To address this question, a genetic model of prestin dysfunction in mice was created by inserting an internal ribosome entry site (IRES)-CreERT2-FRT-Neo-FRT cassette into the prestin locus after the stop codon. Homozygous mice exhibit a threshold elevation of auditory brainstem responses with large individual variation. These mice also display a threshold elevation and a shift of the input/output function of the distortion product otoacoustic emission, suggesting a reduction in outer hair cell function. The disruption of prestin function reduces the threshold shifts caused by exposure to a loud noise at 120 dB (sound pressure level) for 1 h. This reduction is positively correlated with the level of pre-noise cochlear dysfunction and is accompanied by a reduced change in Cdh1 expression, suggesting a reduction in molecular responses to the acoustic overstimulation. Together, these results suggest that prestin interference reduces cochlear stress responses to acoustic overstimulation.

Processing of complex signals in the hearing organ remains poorly understood. This paper aims to contribute to this topic by presenting investigations on the mechanical and neuronal response of the hearing organ of the tropical bushcricket species Mecopoda elongata to simple pure tone signals as well as to the conspecific song as a complex acoustic signal. The high-frequency hearing organ of bushcrickets, the crista acustica (CA), is tonotopically tuned to frequencies between about 4 and 70 kHz. Laser Doppler vibrometer measurements revealed a strong and dominant low-frequency-induced motion of the CA when stimulated with either pure tone or complex stimuli. Consequently, the high-frequency distal area of the CA is more strongly deflected by low-frequency-induced waves than by high-frequency-induced waves. This low-frequency dominance will have strong effects on the processing of complex signals. Therefore, we additionally studied the neuronal response of the CA to native and frequency-manipulated chirps. Again, we found a dominant influence of low-frequency components within the conspecific song, indicating that the mechanical vibration pattern highly determines the neuronal response of the sensory cells. Thus, we conclude that the encoding of communication signals is modulated by ear mechanics.

Biases such as the preference of a particular response for no obvious reason, are an integral part of psychophysics. Such biases have been reported in the common two-alternative forced choice (2AFC) experiments, where participants are instructed to compare two consecutively presented stimuli. However, the principles underlying these biases are largely unknown and previous studies have typically used ad-hoc explanations to account for them. Here we consider human performance in the 2AFC tone frequency discrimination task, utilizing two standard protocols. In both protocols, each trial contains a reference stimulus. In one (Reference-Lower protocol), the frequency of the reference stimulus is always lower than that of the comparison stimulus, whereas in the other (Reference protocol), the frequency of the reference stimulus is either lower or higher than that of the comparison stimulus. We find substantial interval biases. Namely, participants perform better when the reference is in a specific interval. Surprisingly, the biases in the two experiments are opposite: performance is better when the reference is in the first interval in the Reference protocol, but is better when the reference is second in the Reference-Lower protocol. This inconsistency refutes previous accounts of the interval bias, and is resolved when experiments statistics is considered. Viewing perception as incorporation of sensory input with prior knowledge accumulated during the experiment accounts for the seemingly contradictory biases both qualitatively and quantitatively. The success of this account implies that even simple discriminations reflect a combination of sensory limitations, memory limitations, and the ability to utilize stimuli statistics.

Isolation calls produced by dependent young are a fundamental form of communication. For species in which vocal signals remain important to adult communication, the function and social context of vocal behavior changes dramatically with the onset of sexual maturity. The ontogenetic relationship between these distinct forms of acoustic communication is surprisingly under-studied. We conducted a detailed analysis of vocal development in sister species of Neotropical singing mice, Scotinomys teguina and S. xerampelinus. Adult singing mice are remarkable for their advertisement songs, rapidly articulated trills used in long-distance communication; the vocal behavior of pups was previously undescribed. We recorded 30 S. teguina and 15 S. xerampelinus pups daily, from birth to weaning; 23 S. teguina and 11 S. xerampelinus were recorded until sexual maturity. Like other rodent species with poikilothermic young, singing mice were highly vocal during the first weeks of life and stopped vocalizing before weaning. Production of first advertisement songs coincided with the onset of sexual maturity after a silent period of ≧2 weeks. Species differences in vocal behavior emerged early in ontogeny and notes that comprise adult song were produced from birth. However, the organization and relative abundance of distinct note types was very different between pups and adults. Notably, the structure, note repetition rate, and intra-individual repeatability of pup vocalizations did not become more adult-like with age; the highly stereotyped structure of adult song appeared de novo in the first songs of young adults. We conclude that, while the basic elements of adult song are available from birth, distinct selection pressures during maternal dependency, dispersal, and territorial establishment favor major shifts in the structure and prevalence of acoustic signals. This study provides insight into how an evolutionarily conserved form of acoustic signaling provides the raw material for adult vocalizations that are highly species specific.

Mice are a commonly used model in hearing research, yet little is known about how they perceive conspecific ultrasonic vocalizations (USVs). Humans and birds can distinguish partial versions of a communication signal, and discrimination is superior when the beginning of the signal is present compared to the end of the signal. Since these effects occur in both humans and birds, it was hypothesized that mice would display similar facilitative effects with the initial portions of their USVs. Laboratory mice were tested on a discrimination task using operant conditioning procedures. The mice were required to discriminate incomplete versions of a USV target from a repeating background containing the whole USV. The results showed that the mice had difficulty discriminating incomplete USVs from whole USVs, especially when the beginning of the USVs were presented. This finding suggests that the mice perceive the initial portions of a USV as more similar to the whole USV than the latter parts of the USV, similar to results from humans and birds.

Temporal variation in listeners' sensitivity to interaural time and level differences (ITD and ILD, respectively) was measured for sounds of different carrier frequency using the temporal weighting function (TWF) paradigm [Stecker and Hafter (2002) J. Acoust. Soc. Am. 112,1046–1057]. Listeners made lateralization judgments following brief trains of filtered impulses (Gabor clicks) presented over headphones with overall ITD and/or ILD ranging from ±500 μs ITD and/or ±5 dB ILD across trials. Individual clicks within each train varied by an additional ±100 μs ITD or ±2 dB ILD to allow TWF calculation by multiple regression. In separate conditions, TWFs were measured for carrier frequencies of 1, 2, 4, and 8 kHz. Consistent with past studies, TWFs demonstrated high weight on the first click for stimuli with short interclick interval (ICI = 2 ms), but flatter weighting for longer ICI (5–10 ms). Some conditions additionally demonstrated greater weight for clicks near the offset than near the middle of the train. Results support a primary role of the auditory periphery in emphasizing onset and offset cues in rapidly modulated low-frequency sounds. For slower modulations, sensitivity to ongoing high-frequency ILD and low-frequency ITD cues appears subject to recency effects consistent with the effects of leaky temporal integration of binaural information.

C57BL/6 inbred mice are frequently used as models in auditory research, mostly the C57BL/6J and C57BL/6N substrains. Genetic variation and phenotypic disparities between these two substrains have been extensively investigated, but conflicting information exists about differences in their auditory and vestibular phenotypes. Literature-based comparisons are rendered difficult or impossible because most auditory publications do not designate the substrain used. We therefore evaluated commercial C57BL/6N and C57BL/6J mice for their baseline auditory brainstem response (ABR) thresholds at 3 months of age as well as their susceptibility to noise exposure and aminoglycoside antibiotics. Both substrains have similar thresholds at 4 and 12 kHz, but C57BL/6N show significantly higher baseline thresholds at 24 and 32 kHz. Because of these elevated thresholds, the N substrain is unsuitable as a model for drug ototoxicity, which primarily affects high frequencies. Exposure to 2-20 kHz broadband noise for 2 h at 110 dB produced significantly higher threshold shifts in the J substrain. These results suggest caution in the selection of C57BL/6 substrains for auditory research and indicate the need to specify substrains, age and the breeding source in all publications.

Chronic implantation of microelectrodes into the cortex has been shown to lead to inflammatory gliosis and neuronal loss in the microenvironment immediately surrounding the probe, a hypothesized cause of neural recording failure. Caspase-1 (aka Interleukin 1β converting enzyme) is known to play a key role in both inflammation and programmed cell death, particularly in stroke and neurodegenerative diseases. Caspase-1 knockout (KO) mice are resistant to apoptosis and these mice have preserved neurologic function by reducing ischemia-induced brain injury in stroke models. Local ischemic injury can occur following neural probe insertion and thus in this study we investigated the hypothesis that caspase-1 KO mice would have less ischemic injury surrounding the neural probe. In this study, caspase-1 KO mice were implanted with chronic single shank 3 mm Michigan probes into V1m cortex. Electrophysiology recording showed significantly improved single-unit recording performance (yield and signal to noise ratio) of caspase-1 KO mice compared to wild type C57B6 (WT) mice over the course of up to 6 months for the majority of the depth. The higher yield is supported by the improved neuronal survival in the caspase-1 KO mice. Impedance fluctuates over time but appears to be steadier in the caspase-1 KO especially at longer time points, suggesting milder glia scarring. These findings show that caspase-1 is a promising target for pharmacologic interventions.

Background: Silver nanoparticles (AgNPs) displayed strong activities in anti-bacterial, anti-viral, and anti-fungal studies and was reportedly efficient in treating otitis media .The potential impact of AgNPs on the inner ear was missing. Objective: Attempted to evaluate the potential toxicity of AgNPs in the inner ear, middle ear, and external ear canal after transtympanic injection in rats. Results: In in vitro studies, the IC50 for AgNPs in neutral red uptake assay was lower than that in NAD(P)H-dependent cellular oxidoreductase enzyme assay (WST-1) and higher than that in total cellular ATP and nuclear membrane integrity (propidium iodide) assessments. In in vivo experiments, magnetic resonance imaging (MRI) showed that significant changes in the permeability of biological barriers occurred in the middle ear mucosa, the skin of the external ear canal, and the inner ear at 5 h post-transtympanic injection of AgNPs at concentrations ranging from 20 μg/ml to 4000 μg/ml. The alterations in permeability showed a dosage-response relationship, and were reversible. The auditory brainstem response showed that 4000 μg/ml AgNPs induced hearing loss with partial recovery at 7 d, whereas 20 μg/ml caused reversible hearing loss. The functional change in auditory system was in line with the histology results. In general, the BALB/c 3T3 cell line is more than 1000 times more sensitive than the in vivo studies. Impairment of the mitochondrial function was indicated to be the mechanism of toxicity of AgNPs. Conclusion: These results suggest that AgNPs caused significant, dose-dependent changes in the permeability of biological barriers in the middle ear mucosa, the skin of the external ear canal, and the inner ear. In general, the BALB/c 3T3 cell line is more than 1000 times more sensitive than the in vivo studies. The rat ear model might be expended to other engineered nanomaterials in nanotoxicology study.

Purpose Gap detection and the temporal modulation transfer function (TMTF) are 2 common methods to obtain behavioral estimates of auditory temporal acuity. However, the agreement between the 2 measures is not clear. This study compares results from these 2 methods and their dependencies on listener age and hearing status. Method Gap detection thresholds and the parameters that describe the TMTF (sensitivity and cutoff frequency) were estimated for young and older listeners who were naive to the experimental tasks. Stimuli were 800-Hz-wide noises with upper frequency limits of 2400 Hz, presented at 85 dB SPL. A 2-track procedure (Shen & Richards, 2013) was used for the efficient estimation of the TMTF. Results No significant correlation was found between gap detection threshold and the sensitivity or the cutoff frequency of the TMTF. No significant effect of age and hearing loss on either the gap detection threshold or the TMTF cutoff frequency was found, while the TMTF sensitivity improved with increasing hearing threshold and worsened with increasing age. Conclusion Estimates of temporal acuity using gap detection and TMTF paradigms do not seem to provide a consistent description of the effects of listener age and hearing status on temporal envelope processing.

This work is part of a study of the interaction of sound pressure in the ear canal (EC) with tympanic membrane (TM) surface displacement. Sound pressures were measured with 0.5–2 mm spacing at three locations within the shortened natural EC or an artificial EC in human temporal bones: near the TM surface, within the tympanic ring plane, and in a plane transverse to the long axis of the EC. Sound pressure was also measured at 2-mm intervals along the long EC axis. The sound field is described well by the size and direction of planar sound pressure gradients, the location and orientation of standing-wave nodal lines, and the location of longitudinal standing waves along the EC axis. Standing-wave nodal lines perpendicular to the long EC axis are present on the TM surface >11–16 kHz in the natural or artificial EC. The range of sound pressures was larger in the tympanic ring plane than at the TM surface or in the transverse EC plane. Longitudinal standing-wave patterns were stretched. The tympanic-ring sound field is a useful approximation of the TM sound field, and the artificial EC approximates the natural EC.

Sensory neuron input to the olfactory bulb (OB) was activated precisely for different durations with blue light in mice expressing channelrhodopsin-2 in olfactory sensory neurons. Behaviorally the mice discriminated differences of 10 ms in duration of direct glomerular activation. In addition, a subset of mitral/tufted cells in the OB of awake mice responded tonically therefore conveying information on stimulus duration. Our study provides evidence that duration of the input to glomeruli not synchronized to sniffing is detected. This potent cue may be used to obtain information on puffs in odor plumes.

Cortical reorganization following sensory deprivation is characterized by alterations in the connectivity between neurons encoding spared and deprived cortical inputs. The extent to which this alteration depends on Spike Timing Dependent Plasticity (STDP), however, is largely unknown. We quantified changes in the functional connectivity between layer V neurons in the vibrissal primary somatosensory cortex (vSI) (barrel cortex) of rats following sensory deprivation. One week after chronic implantation of a microelectrode array in vSI, sensory-evoked activity resulting from mechanical deflections of individual whiskers was recorded (control data) after which two whiskers on the contralateral side were paired by sparing them while trimming all other whiskers on the rat's mystacial pad. The rats' environment was then enriched by placing novel objects in the cages to encourage exploratory behavior with the spared whiskers. Sensory-evoked activity in response to individual stimulation of spared whiskers and adjacent re-grown whiskers was then recorded under anesthesia 1-2 days and 6-7 days post-trimming (plasticity data). We analyzed spike trains within 100 ms of stimulus onset and confirmed previously published reports documenting changes in receptive field sizes in the spared whisker barrels. We analyzed the same data using Dynamic Bayesian Networks (DBNs) to infer the functional connectivity between the recorded neurons. We found that DBNs inferred from population responses to stimulation of each of the spared whiskers exhibited graded increase in similarity that was proportional to the pairing duration. A significant early increase in network similarity in the spared-whisker barrels was detected 1-2 days post pairing, but not when single neuron responses were examined during the same period. These results suggest that rapid reorganization of cortical neurons following sensory deprivation may be mediated by an STDP mechanism.