Publications using TDT

We have previously shown that neurons in primary auditory cortex (A1) of anaesthetized (ketamine/medetomidine) ferrets respond more strongly and reliably to dynamic stimuli whose statistics follow "natural" 1/f dynamics than to stimuli exhibiting pitch and amplitude modulations that are faster (1/f(0.5)) or slower (1/f(2)) than 1/f. To investigate where along the central auditory pathway this 1/f-modulation tuning arises, we have now characterized responses of neurons in the central nucleus of the inferior colliculus (ICC) and the ventral division of the mediate geniculate nucleus of the thalamus (MGV) to 1/f(γ) distributed stimuli with γ varying between 0.5 and 2.8. We found that, while the great majority of neurons recorded from the ICC showed a strong preference for the most rapidly varying (1/f(0.5) distributed) stimuli, responses from MGV neurons did not exhibit marked or systematic preferences for any particular γ exponent. Only in A1 did a majority of neurons respond with higher firing rates to stimuli in which γ takes values near 1. These results indicate that 1/f tuning emerges at forebrain levels of the ascending auditory pathway.

Generative models of neuroimaging and electrophysiological data present new opportunities for accessing hidden or latent brain states. Dynamic causal modeling (DCM) uses Bayesian model inversion and selection to infer the synaptic mechanisms underlying empirically observed brain responses. DCM for electrophysiological data, in particular, aims to estimate the relative strength of synaptic transmission at different cell types and via specific neurotransmitters. Here, we report a DCM validation study concerning inference on excitatory and inhibitory synaptic transmission, using different doses of a volatile anaesthetic agent (isoflurane) to parametrically modify excitatory and inhibitory synaptic processing while recording local field potentials (LFPs) from primary auditory cortex (A1) and the posterior auditory field (PAF) in the auditory belt region in rodents. We test whether DCM can infer, from the LFP measurements, the expected drug-induced changes in synaptic transmission mediated via fast ionotropic receptors; i.e., excitatory (glutamatergic) AMPA and inhibitory GABA(A) receptors. Cross- and auto-spectra from the two regions were used to optimise three DCMs based on biologically plausible neural mass models and specific network architectures. Consistent with known extrinsic connectivity patterns in sensory hierarchies, we found that a model comprising forward connections from A1 to PAF and backward connections from PAF to A1 outperformed a model with forward connections from PAF to A1 and backward connections from A1 to PAF and a model with reciprocal lateral connections. The parameter estimates from the most plausible model indicated that the amplitude of fast glutamatergic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) behaved as predicted by previous neurophysiological studies. Specifically, with increasing levels of anaesthesia, glutamatergic EPSPs decreased linearly, whereas fast GABAergic IPSPs displayed a nonlinear (saturating) increase. The consistency of our model-based in vivo results with experimental in vitro results lends further validity to the capacity of DCM to infer on synaptic processes using macroscopic neurophysiological data.

Non-penetrating surface electrode recording techniques are typically associated with field potential recordings, while extracellular recordings from single neurons are made using penetrating metal wire or microfabricated microelectrode arrays. Here, we report on single- and multi-unit neuronal recordings made using non-penetrating electrodes placed on the epineural surface of the dorsal root ganglia (DRG). Across four experiments in anesthetized cats, approximately 40% of the electrodes recorded single- and multi-unit spiking activity with spike-rates that covaried significantly with hindlimb movement. In two intraoperative experiments in humans, compound activity was recorded from the DRG surface in response to peripheral stimulation of the common peroneal nerve. This approach may have advantages over penetrating electrode arrays in terms of clinical acceptability and recording longevity.

In neuroprostheses that use functional electrical stimulation (FES) to restore motor function, closed-loop feedback control may compensate for muscle fatigue, perturbations and nonlinearities in the behavior of the effected muscles. Kinematic state information is naturally represented in the firing rates of primary afferent neurons, which may be recorded with multi-electrode arrays at the level of the dorsal root ganglia (DRG). Previous work in cats has shown that it is feasible to estimate the kinematic state of the hind limb with a multivariate linear regression model of the neural activity in the DRG. In this study we extend these results to estimate the limb state in real-time during intramuscular stimulation in an anesthetized cat. Furthermore, we used the limb state estimates as feedback to a finite state FES controller to generate rudimentary walking behavior. This work demonstrates the feasibility of using DRG activity in a closed-loop FES system.

The purpose was to determine the effect of hearing loss on the ability to separate competing talkers using talker differences in fundamental frequency (F0) and apparent vocal-tract length (VTL). Performance of 13 adults with hearing loss and 6 adults with normal hearing was measured using the Coordinate Response Measure. For listeners with hearing loss, the speech was amplified and filtered according to the NAL-RP hearing aid prescription. Target-to-competition ratios varied from 0 to 9 dB. The target sentence was randomly assigned to the higher or lower values of F0 or VTL on each trial. Performance improved for F0 differences up to 9 and 6 semitones for people with normal hearing and hearing loss, respectively, but only when the target talker had the higher F0. Recognition for the lower F0 target improved when trial-to-trial uncertainty was removed (9-semitone condition). Scores improved with increasing differences in VTL for the normal-hearing group. On average, hearing-impaired listeners did not benefit from VTL cues, but substantial inter-subject variability was observed. The amount of benefit from VTL cues was related to the average hearing loss in the 1–3-kHz region when the target talker had the shorter VTL.

This study tests how peripheral auditory processing and spectral dominance impact lateralization of precedence effect (PE) stimuli consisting of a pair of leading and lagging clicks. Predictions from a model whose parameters were set from established physiological results were tested with specific behavioral experiments. To generate predictions, an auditory nerve model drove a binaural, cross correlation computation whose outputs were summed across frequency using weightings derived from past physiological studies. The model predicted that lateralization (1) depends on stimulus center frequency and the inter-stimulus delay (ISD) between leading and lagging clicks for narrowband clicks and (2) changes differently with lead click level for different ISDs. Behaviorally, subjects lateralized narrowband and wideband click pairs whose stimulus parameters were chosen based on modeling results to test how peripheral processing and frequency dominance contribute to lateralization of PE stimuli. Behavioral results (including unique measures with the lead attenuated relative to the lag) suggest that peripheral interactions between leading and lagging clicks on the basilar membrane and strong weighting of cues around 750 Hz influence lateralization of paired clicks with short ISDs. When combined with auditory nerve adaptation, which emphasizes onset information, lateralization of PE click pairs with a short ISD can be well predicted.

Although high doses of sodium salicylate impair cochlear function, it paradoxically enhances sound-evoked activity in the auditory cortex (AC) and augments acoustic startle reflex responses, neural and behavioral metrics associated with hyperexcitability and hyperacusis. To explore the neural mechanisms underlying salicylate (SS)-induced hyperexcitability and "increased central gain," we examined the effects of GABA receptor agonists and antagonists on SS-induced hyperexcitability in the AC and startle reflex responses. Consistent with our previous findings, local or systemic application of SS significantly increased the amplitude of sound-evoked AC neural activity, but generally reduced spontaneous activity in the AC. Systemic injection of SS also significantly increased the acoustic startle reflex. S-baclofen or R-baclofen, GABA-B agonists, which suppressed sound-evoked AC neural firing rate and local field potentials, also suppressed the SS-induced enhancement of the AC field potential and the acoustic startle reflex. Local application of vigabatrin, which enhances GABA concentration in the brain, suppressed the SS-induced enhancement of AC firing rate. Systemic injection of vigabatrin also reduced the SS-induced enhancement of acoustic startle reflex. Collectively, these results suggest that the sound-evoked behavioral and neural hyperactivity induced by SS may arise from a SS-induced suppression of GABAergic inhibition in the AC.

Previous studies have demonstrated that single neurons in the central nucleus of the inferior colliculus (ICC) are sensitive to multiple sound localization cues. We investigated the hypothesis that ICC neurons are specialized to encode multiple sound localization cues that are aligned in space (as would naturally occur from a single broadband sound source). Sound localization cues including interaural time differences (ITDs), interaural level differences (ILDs), and spectral shapes (SSs) were measured in a marmoset monkey. Virtual space methods were used to generate stimuli with aligned and misaligned combinations of cues while recording in the ICC of the same monkey. Mutual information (MI) between spike rates and stimuli for aligned versus misaligned cues were compared. Neurons with best frequencies (BFs) less than ∼11 kHz mostly encoded information about a single sound localization cue, ITD or ILD depending on frequency, consistent with the dominance of ear acoustics by either ITD or ILD at those frequencies. Most neurons with BFs >11 kHz encoded information about multiple sound localization cues, usually ILD and SS, and were sensitive to their alignment. In some neurons MI between stimuli and spike responses was greater for aligned cues, while in others it was greater for misaligned cues. If SS cues were shifted to lower frequencies in the virtual space stimuli, a similar result was found for neurons with BFs <11 kHz, showing that the cue interaction reflects the spectra of the stimuli and not a specialization for representing SS cues. In general the results show that ICC neurons are sensitive to multiple localization cues if they are simultaneously present in the frequency response area of the neuron. However, the representation is diffuse in that there is not a specialization in the ICC for encoding aligned sound localization cues.

We examined multiunit responses to tones and to 1/3 and 2/3 octave band-pass noise (BPN) in the marmoset primary auditory cortex (A1) and the caudomedial belt (CM). In both areas, BPN was more effective than tones, evoking multiunit responses at lower intensity and across a wider frequency range. Typically, the best responses to BPN remained at the characteristic frequency. Additionally, in both areas responses to BPN tended to be of greater magnitude and shorter latency than responses to tones. These effects are consistent with the integration of more excitatory inputs driven by BPN than by tones. While it is generally thought that single units in A1 prefer narrow band sounds such as tones, we found that best responses for multi units in both A1 and CM were obtained with noises of narrow spectral bandwidths.

In the development of sensory prosthetic devices based on intracortical microstimulation (ICMS) an important objective is to optimize the stimulus waveform. However, because of the large design space such optimization is an imposing challenge. This study highlights the ability of individual rats, trained using a conditioned avoidance paradigm and performing an adaptive task, to generate highly consistent and significant data. Three experiments on the effects of phase delay, stimulus pulse rate, and waveform asymmetry were completed and revealed detailed and significant results. These results, consisting of 244 individual thresholds, were generated by one rat in 19 days.

Neural circuits are shaped by experience during periods of heightened brain plasticity in early postnatal life. Exposure to acoustic features produces age-dependent changes through largely unresolved cellular mechanisms and sites of origin. We isolated the refinement of auditory thalamocortical connectivity by in vivo recordings and day-by-day voltage-sensitive dye imaging in an acute brain slice preparation. Passive tone-rearing modified response strength and topography in mouse primary auditory cortex (A1) during a brief, 3-d window, but did not alter tonotopic maps in the thalamus. Gene-targeted deletion of a forebrain-specific cell-adhesion molecule (Icam5) accelerated plasticity in this critical period. Consistent with its normal role of slowing spinogenesis, loss of Icam5 induced precocious stubby spine maturation on pyramidal cell dendrites in neocortical layer 4 (L4), identifying a primary locus of change for the tonotopic plasticity. The evolving postnatal connectivity between thalamus and cortex in the days following hearing onset may therefore determine a critical period for auditory processing.

Hypoxia ischemia (HI; reduced blood oxygenation and/or flow to the brain) represents one of the most common injuries for both term and preterm/very low birth weight (VLBW) infants. These children experience elevated incidence of cognitive and/or sensory processing disabilities, including language based learning disabilities. Clinical data also indicate more substantial long‐term deficits for HI injured male babies as compared to HI injured females. Previously, we reported significant deficits in rapid auditory processing and spatial learning in male rats with postnatal day 1 (P1), P7, or P10 HI injury. We also showed sex differences in HI injured animals, with more severe deficits in males as compared to females. Given these findings, combined with extant clinical data, the current study sought to assess a putative role for perinatal testosterone in modulating behavioral outcome following early hypoxic‐ischemic injury in rats. Male, female, and testosterone‐propionate (TP) treated females were subjected to P7 HI or sham surgery, and subsequently (P30+) underwent a battery of auditory testing and water maze assessment. Results confirm previous reports of sex differences following HI, and add new findings of significantly worse performance in TP‐treated HI females compared to vehicle treated HI females. Post mortem anatomic analyses showed consistent effects, with significant brain weight decreases seen in HI male and TP‐treated HI females but not female HI or sham groups. Further neuromorphometric analysis of brain structures showed that HI male animals exhibited increased pathology relative to HI females as reflected in ventricular enlargement. Findings suggest that neonatal testosterone may act to enhance the deleterious consequences of early HI brain injury, as measured by both neuropathology and behavior.

The whisker-to-barrel cortex is widely used to study neurovascular coupling, but the cellular basis that underlies the perfusion changes is still largely unknown. Here, we identified neurons recruited by whisker stimulation in the rat somatosensory cortex using double immunohistochemistry for c-Fos and markers of glutamatergic and GABAergic neurons, and investigated in vivo their contribution along with that of astrocytes in the evoked perfusion response. Whisker stimulation elicited cerebral blood flow (CBF) increases concomitantly with c-Fos upregulation in pyramidal cells that coexpressed cyclooxygenase-2 (COX-2) and GABA interneurons that coexpressed vasoactive intestinal polypeptide and/or choline acetyltransferase, but not somatostatin or parvalbumin. The evoked CBF response was decreased by blockade of NMDA (MK-801, -37%), group I metabotropic glutamate (MPEP+LY367385, -40%), and GABA-A (picrotoxin, -31%) receptors, but not by GABA-B, VIP, or muscarinic receptor antagonism. Picrotoxin decreased stimulus-induced somatosensory evoked potentials and CBF responses. Combined blockade of GABA-A and NMDA receptors yielded an additive decreasing effect (-61%) of the evoked CBF compared with each antagonist alone, demonstrating cooperation of both excitatory and inhibitory systems in the hyperemic response. Blockade of prostanoid synthesis by inhibiting COX-2 (indomethacin, NS-398), expressed by ∼40% of pyramidal cells but not by astrocytes, impaired the CBF response (-50%). The hyperemic response was also reduced (-40%) after inhibition of astroglial oxidative metabolism or epoxyeicosatrienoic acids synthesis. These results demonstrate that changes in pyramidal cell activity, sculpted by specific types of inhibitory GABA interneurons, drive the CBF response to whisker stimulation and, further, that metabolically active astrocytes are also required.

Aged humans show severe difficulties in temporal auditory processing tasks (e.g., speech recognition in noise, low-frequency sound localization, gap detection). A degradation of auditory function with age is also evident in experimental animals. To investigate age-related changes in temporal processing, we compared extracellular responses to temporally variable pulse trains and human speech in the inferior colliculus of young adult (3 month) and aged (3 years) Mongolian gerbils. We observed a significant decrease of selectivity to the pulse trains in neuronal responses from aged animals. This decrease in selectivity led, on the population level, to an increase in signal correlations and therefore a decrease in heterogeneity of temporal receptive fields and a decreased efficiency in encoding of speech signals. A decrease in selectivity to temporal modulations is consistent with a downregulation of the inhibitory transmitter system in aged animals. These alterations in temporal processing could underlie declines in the aging auditory system, which are unrelated to peripheral hearing loss. These declines cannot be compensated by traditional hearing aids (that rely on amplification of sound) but may rather require pharmacological treatment.

Listeners often only have fragments of speech available to understand the intended message due to competing background noise. In order to maximize successful speech recognition, listeners must allocate their perceptual resources to the most informative acoustic properties. The speech signal contains temporally-varying acoustics in the envelope and fine structure that are present across the frequency spectrum. Understanding how listeners perceptually weigh these acoustic properties in different frequency regions during interrupted speech is essential for the design of assistive listening devices. This study measured the perceptual weighting of young normal-hearing listeners for the envelope and fine structure in each of three frequency bands for interrupted sentence materials. Perceptual weights were obtained during interruption at the syllabic rate (i.e., 4 Hz) and the periodic rate (i.e., 128 Hz) of speech. Potential interruption interactions with fundamental frequency information were investigated by shifting the natural pitch contour higher relative to the interruption rate. The availability of each acoustic property was varied independently by adding noise at different levels. Perceptual weights were determined by correlating a listener’s performance with the availability of each acoustic property on a trial-by-trial basis. Results demonstrated similar relative weights across the interruption conditions, with emphasis on the envelope in high-frequencies.

Linear predictive coding (LPC) analysis was used to create morphed natural tokens of English voiced stop consonants ranging from /b/ to /d/ and /d/ to /g/ in four vowel contexts (/i/, /æ/, /a/, /u/). Both vowel-consonant-vowel (VCV) and consonant-vowel (CV) stimuli were created. A total of 320 natural-sounding acoustic speech stimuli were created, comprising 16 stimulus series. A behavioral experiment demonstrated that the stimuli varied perceptually from /b/ to /d/ to /g/, and provided useful reference data for the ambiguity of each token. Acoustic analyses indicated that the stimuli compared favorably to standard characteristics of naturally-produced consonants, and that the LPC morphing procedure successfully modulated multiple acoustic parameters associated with place of articulation. The entire set of stimuli is freely available on the Internet (http://www.psy.cmu.edu/~lholt/php/StephensHoltStimuli.php) for use in research applications.

Neurons exhibiting on and off responses with different frequency tuning have previously been described in the primary auditory cortex (A1) of anesthetized and awake animals, but it is unknown whether other tuning properties, including sensitivity to binaural localization cues, also differ between on and off responses. We measured the sensitivity of A1 neurons in anesthetized ferrets to 1) interaural level differences (ILDs), using unmodulated broadband noise with varying ILDs and average binaural levels, and 2) interaural time delays (ITDs), using sinusoidally amplitude-modulated broadband noise with varying envelope ITDs. We also assessed fine-structure ITD sensitivity and frequency tuning, using pure-tone stimuli. Neurons most commonly responded to stimulus onset only, but purely off responses and on-off responses were also recorded. Of the units exhibiting significant binaural sensitivity nearly one-quarter showed binaural sensitivity in both on and off responses, but in almost all (∼97%) of these units the binaural tuning of the on responses differed significantly from that seen in the off responses. Moreover, averaged, normalized ILD and ITD tuning curves calculated from all units showing significant sensitivity to binaural cues indicated that on and off responses displayed different sensitivity patterns across the population. A principal component analysis of ITD response functions suggested a continuous cortical distribution of binaural sensitivity, rather than discrete response classes. Rather than reflecting a release from inhibition without any functional significance, we propose that binaural off responses may be important to cortical encoding of sound-source location.

Combined measurements of middle ear transfer function and auditory brainstem response (ABR) in live guinea pigs with middle ear effusion (MEE) are reported in this paper. The MEE model was created by injecting saline into the middle ear cavity. Vibrations of the tympanic membrane (TM), the tip of the incus, and the round window membrane (RWM) were measured with a laser vibrometer at frequencies of 0.2-40 kHz when the middle ear fluid increased from 0 to 0.2 ml (i.e., full fill of the cavity). The click and pure tone ABRs were recorded as the middle ear fluid increased. Fluid introduction reduced mobility of the TM, incus and RWM mainly at high frequencies (f > 1 kHz). The magnitude of this reduction was related to the volume of fluid. The displacement transmission ratio of the TM to incus varied with frequency and fluid level. The volume displacement ratio of the oval window to round window was approximately 1.0 over most frequencies. Elevation of ABR thresholds and prolongation of ABR latencies were observed as fluid level increased. Reduction of TM displacement correlated well with elevation of ABR threshold at 0.5-8 kHz. Alterations in the ratio of ossicular displacements before and after fluid induction are consistent with fluid-induced changes in complex ossicular motions.

Oxidative stress has been implicated broadly as a cause of cell death and neural degeneration in multiple disease conditions; however, the evidence for successful intervention with dietary antioxidant manipulations has been mixed. In this study, we investigated the potential for protection of cells in the inner ear using a dietary supplement with multiple antioxidant components, which were selected for their potential interactive effectiveness. Protection against permanent threshold shift (PTS) was observed in CBA/J mice maintained on a diet supplemented with a combination of β-carotene, vitamins C and E, and magnesium when compared with PTS in control mice maintained on a nutritionally complete control diet. Although hair cell survival was not enhanced, noise-induced loss of type II fibrocytes in the lateral wall was significantly reduced (P < 0.05), and there was a trend toward less noise-induced loss in strial cell density in animals maintained on the supplemented diet. Taken together, our data suggest that prenoise oral treatment with the high-nutrient diet can protect cells in the inner ear and reduce PTS in mice. The demonstration of functional and morphologic preservation of cells in the inner ear with oral administration of this antioxidant supplemented diet supports the possibility of translation to human patients and suggests an opportunity to evaluate antioxidant protection in mouse models of oxidative stress-related disease and pathology.

The common marmoset is a small, arboreal, New World primate that has emerged as a promising non-human model system in auditory neuroscience. A complete understanding of the neuroethology of auditory processing in marmosets will include behavioral work examining how sounds are perceived by these animals. However, there have been few studies of the marmoset's hearing and perceptual abilities and the audiogram of this species has not been measured using modern psychophysical methods. The present experiment pairs psychophysics with an operant conditioning technique to examine perception of pure tone stimuli by marmosets using an active behavioral paradigm. Subjects were trained to lick at a feeding tube when they detected a sound. Correct responses provided access to a food reward. Pure tones of varying intensities were presented to subjects using the method of constant stimuli. Behavioral thresholds were calculated for each animal based on hit rate--threshold was defined by the tone intensity that the animal correctly identified 50% of the time. Results show that marmoset hearing is comparable to that of other New World monkeys, with a hearing range extending from about 125 Hz up to 36 kHz and a sensitivity peak around 7 kHz.