Publications using TDT

Accurate localization of complex sounds involves combining interaural information across frequencies to produce a single location percept. Interaural level differences (ILDs) are highly frequency dependent and it is unclear how the auditory system combines differing ILDs across frequency. Therefore, ILD just noticeable differences (JNDs) and intracranial lateralization were measured in young normal-hearing listeners using single- and multi-band stimuli. The bands were 300-ms, 10-Hz narrowband noises; the multi-band condition had three bands; they started and ended synchronously; they were located around three different frequency regions (750, 2000, or 4000 Hz); they had five different frequency separations that ranged from unresolved to resolved; the bands were dichotic with the same non-zero ILD (targets) or were diotic with zero ILD (interferers). Results showed single-band ILD JNDs were marginally frequency dependent. If unresolved diotic interferers were added, ILD JNDs increased greatly because of interaural decorrelation. If well-resolved diotic interferers were added, ILD JNDs were frequency dependent and the worst performance occurred when targets were near 1000 or 4000 Hz. This frequency dependence might be partially explained by ILD vs azimuth non-monotonicities for free-field sound sources in this frequency region. These results suggest that binaural processing models need revision for the processing of complex sounds.

To better understand how object recognition can be triggered independently of the sensory channel through which information is acquired, we devised a task in which rats judged the orientation of a raised, black and white grating. They learned to recognize two categories of orientation: 0° ± 45° ("horizontal") and 90° ± 45° ("vertical"). Each trial required a visual (V), a tactile (T), or a visual-tactile (VT) discrimination; VT performance was better than that predicted by optimal linear combination of V and T signals, indicating synergy between sensory channels. We examined posterior parietal cortex (PPC) and uncovered key neuronal correlates of the behavioral findings: PPC carried both graded information about object orientation and categorical information about the rat's upcoming choice; single neurons exhibited identical responses under the three modality conditions. Finally, a linear classifier of neuronal population firing replicated the behavioral findings. Taken together, these findings suggest that PPC is involved in the supramodal processing of shape.

How and where in the brain audio-visual signals are bound to create multimodal objects remains unknown. One hypothesis is that temporal coherence between dynamic multisensory signals provides a mechanism for binding stimulus features across sensory modalities. Here, we report that when the luminance of a visual stimulus is temporally coherent with the amplitude fluctuations of one sound in a mixture, the representation of that sound is enhanced in auditory cortex. Critically, this enhancement extends to include both binding and non-binding features of the sound. We demonstrate that visual information conveyed from visual cortex via the phase of the local field potential is combined with auditory information within auditory cortex. These data provide evidence that early cross-sensory binding provides a bottom-up mechanism for the formation of cross-sensory objects and that one role for multisensory binding in auditory cortex is to support auditory scene analysis.

Age-related hearing loss is experienced by one-third of individuals aged 65 years and older and can be socially debilitating. Historically, there has been poor correlation between age-related threshold changes, loss of speech understanding, and loss of cochlear hair cells. We examined changes in ribbon synapse number at four different ages in Fisher Brown Norway rats, an extensively studied rat model of aging. In contrast to previous work in mice/Wistar rats, we found minimal ribbon synapse loss before 20 months, with significant differences in 24- and 28-month-old rats at 4 kHz. Significant outer HC loss was observed at 24 and 28 months in low- to mid-frequency regions. Age-related reductions in auditory brainstem response wave I amplitude and increases in threshold were strongly correlated with ribbon synapse loss. Wave V/I ratios increased across age for click, 2, 4, and 24 kHz. Together, we find that ribbon synapses in the Fisher Brown Norway rat cochlea show resistance to aging until ∼60% of their life span, suggesting species/strain differences may underpin decreased peripheral input into the aging central processor.

This study explored the extent to which informational masking of speech depends on the frequency region and number of extraneous formants in an interferer. Target formants—monotonized three-formant (F1+F2+F3) analogues of natural sentences—were presented monaurally, with target ear assigned randomly on each trial. Interferers were presented contralaterally. In experiment 1, single-formant interferers were created using the time-reversed F2 frequency contour and constant amplitude, root-mean-square (RMS)-matched to F2. Interferer center frequency was matched to that of F1, F2, or F3, while maintaining the extent of formant-frequency variation (depth) on a log scale. Adding an interferer lowered intelligibility; the effect of frequency region was small and broadly tuned around F2. In experiment 2, interferers comprised either one formant (F1, the most intense) or all three, created using the time-reversed frequency contours of the corresponding targets and RMS-matched constant amplitudes. Interferer formant-frequency variation was scaled to 0%, 50%, or 100% of the original depth. Increasing the depth of formant-frequency variation and number of formants in the interferer had independent and additive effects. These findings suggest that the impact on intelligibility depends primarily on the overall extent of frequency variation in each interfering formant (up to ∼100% depth) and the number of extraneous formants.

Objective . Direct electrical stimulation (DES) is a clinical gold standard for human brain mapping and readily evokes conscious percepts, yet the neurophysiological changes underlying these percepts are not well understood. Approach . To determine the neural correlates of DES, we stimulated the somatosensory cortex of ten human participants at frequency-amplitude combinations that both elicited and failed to elicit conscious percepts, meanwhile recording neural activity directly surrounding the stimulation site. We then compared the neural activity of perceived trials to that of non-perceived trials. Main results . We found that stimulation evokes distributed high gamma activity, which correlates with conscious perception better than stimulation parameters themselves. Significance . Our findings suggest that high gamma activity is a reliable biomarker for perception evoked by both natural and electrical stimuli.

Mutations in the GJB2 gene [which encodes connexin 26 (Cx26)] are the most common causes of hereditary hearing loss in humans, and previous studies showed postnatal development arrest of the organ of Corti in different Cx26-null mouse models. To explore the pathological changes and the mechanism behind the cochlear abnormalities in these mice further, we established transgenic mouse models by conditional knockdown of cochlear Cx26 at postnatal day (P) 0 and P8. Auditory brainstem responses were recorded and the morphological features in the organ of Corti were analyzed 18 days after Cx26 knockdown. Mice in the P0 knockdown group displayed severe hearing loss at all frequencies, whereas mice in the P8 knockdown group showed nearly normal hearing. In the P8 knockdown group, the organ of Corti displayed normal architecture, and no ultrastructural changes were observed. In the P0 knockdown group, the phalangeal processes of Deiter's cells did not develop into finger-like structures, and the formation of microtubules in the pillar cells was significantly reduced; moreover, the amount of acetylated α-tubulin was reduced in pillar cells. Our results indicate that Gjb2 participates in postnatal development of the cytoskeleton in pillar cells during structural maturation of the organ of Corti. In P0 knockdown mice, the reduction in microtubules in pillar cells might be responsible for the failure of the tunnel of Corti to open, and the malformed phalangeal processes might negatively affect the supporting framework of the organ of Corti, which would be a new mechanism of Gjb2-related hearing loss.

Real-world value often depends on subtle, continuously variable visual cues specific to particular object categories, like the tailoring of a suit, the condition of an automobile, or the construction of a house. Here, we used microelectrode recording in behaving monkeys to test two possible mechanisms for category-specific value-cue processing: (1) previous findings suggest that prefrontal cortex (PFC) identifies object categories, and based on category identity, PFC could use top-down attentional modulation to enhance visual processing of category-specific value cues, providing signals to PFC for calculating value, and (2) a faster mechanism would be first-pass visual processing of category-specific value cues, immediately providing the necessary visual information to PFC. This, however, would require learned mechanisms for processing the appropriate cues in a given object category. To test these hypotheses, we trained monkeys to discriminate value in four letter-like stimulus categories. Each category had a different, continuously variable shape cue that signified value (liquid reward amount) as well as other cues that were irrelevant. Monkeys chose between stimuli of different reward values. Consistent with the first-pass hypothesis, we found early signals for category-specific value cues in area TE (the final stage in monkey ventral visual pathway) beginning 81 ms after stimulus onset-essentially at the start of TE responses. Task-related activity emerged in lateral PFC approximately 40 ms later and consisted mainly of category-invariant value tuning. Our results show that, for familiar, behaviorally relevant object categories, high-level ventral pathway cortex can implement rapid, first-pass processing of category-specific value cues.

The ability to identify who is talking is an important aspect of communication in social situations and, while empirical data are limited, it is possible that a disruption to this ability contributes to the difficulties experienced by listeners with hearing loss. In this study, talker identification was examined under both quiet and masked conditions. Subjects were grouped by hearing status (normal hearing/sensorineural hearing loss) and age (younger/older adults). Listeners first learned to identify the voices of four same-sex talkers in quiet, and then talker identification was assessed (1) in quiet, (2) in speech-shaped, steady-state noise, and (3) in the presence of a single, unfamiliar same-sex talker. Both younger and older adults with hearing loss, as well as older adults with normal hearing, generally performed more poorly than younger adults with normal hearing, although large individual differences were observed in all conditions. Regression analyses indicated that both age and hearing loss were predictors of performance in quiet, and there was some evidence for an additional contribution of hearing loss in the presence of masking. These findings suggest that both hearing loss and age may affect the ability to identify talkers in “cocktail party” situations.

Sound onsets dominate spatial judgments of many types of periodic sound. Conversely, ongoing cues often dominate in spatial judgments of aperiodic noise. This study quantified onset dominance as a function of both the bandwidth and the temporal regularity of stimuli by measuring temporal weighting functions (TWF) from Stecker, Ostreicher, and Brown [(2013) J. Acoust. Soc. Am. 134, 1242–1252] for lateralization of periodic and aperiodic noise-burst trains. Stimuli consisted of 16 noise bursts (1 ms each) repeating at an interval of 2 or 5 ms. TWFs were calculated by multiple regression of lateralization judgments onto interaural time and level differences, which varied independently (±100 μs, ±2 dB) across bursts. Noise tokens were either refreshed on each burst (aperiodic) or repeated across sets of 2, 4, 8, or 16 bursts. TWFs revealed strong onset dominance for periodic noise-burst trains (16 repeats per token), which was markedly reduced in aperiodic trains. A second experiment measured TWFs for periodic but sinusoidally amplitude-modulated noise burst trains, revealing greater weight on the earliest and least intense bursts of the rising envelope slope. The results support the view that envelope fluctuations drive access to binaural information in both periodic and aperiodic sounds.

There is, at present, no curative treatment for genetic hearing loss. We have previously reported that transuterine gene transfer of wild type CONNEXIN30 (CX30) genes into otocysts in CX30-deleted mice could restore hearing. Cell transplantation therapy might be another therapeutic option, although it is still unknown whether stem cell-derived progenitor cells could migrate into mouse otocysts. Here, we show successful cell transplantation of progenitors of outer sulcus cell-like cells derived from human-derived induced pluripotent stem cells into mouse otocysts on embryonic day 11.5. The delivered cells engrafted more frequently in the non-sensory region in the inner ear of CX30-deleted mice than in wild type mice and survived for up to 1 week after transplantation. Some of the engrafted cells expressed CX30 proteins in the non-sensory region. This is the first report that demonstrates successful engraftment of exogenous cells in prenatal developing otocysts in mice. Future studies using this mouse otocystic injection model in vivo will provide further clues for developing treatment modalities for congenital hearing loss in humans.

The prolonged masking of auditory inputs with white noise has been shown to reopen the critical period for spectral tuning in the adult rat auditory cortex. Here, we argue that the masking of salient temporal inputs in particular is responsible for changes in neuronal activity that lead to this experience-dependent plasticity. We tested this hypothesis by passively exposing adult rats to 2 weeks of amplitude-modulated (AM) white noise with different modulation depths from 0% (no modulation) to 100% (strong modulation). All exposed rats displayed evidence of cortical plasticity as measured by receptive field bandwidths, tonotopic gradients, and synchronization during spontaneous activity. However, this plasticity was fundamentally different in nature for rats exposed to unmodulated noise, as a second passive exposure to pure tones elicited tonotopic reorganization in rats exposed to 0% AM noise only. Detection of c-FOS expression in excitatory and inhibitory cells through post-mortem immunohistochemistry also revealed different patterns of cellular activation depending on modulation depth. Together, these results indicate that the absence of temporal modulation promotes noise-induced plasticity in the adult auditory cortex and suggest an important and continuous role for temporally salient inputs in the maintenance of mature auditory circuits.

Capabilities for recording neural activity in behaving mammals have greatly expanded our understanding of brain function. Some of the most sophisticated approaches use light delivered by an implanted fiber-optic cable to optically excite genetically encoded calcium indicators and to record the resulting changes in fluorescence. Physical constraints induced by the cables and the bulk, size, and weight of the associated fixtures complicate studies on natural behaviors, including social interactions and movements in environments that include obstacles, housings, and other complex features. Here, we introduce a wireless, injectable fluorescence photometer that integrates a miniaturized light source and a photodetector on a flexible, needle-shaped polymer support, suitable for injection into the deep brain at sites of interest. The ultrathin geometry and compliant mechanics of these probes allow minimally invasive implantation and stable chronic operation. In vivo studies in freely moving animals demonstrate that this technology allows high-fidelity recording of calcium fluorescence in the deep brain, with measurement characteristics that match or exceed those associated with fiber photometry systems. The resulting capabilities in optical recordings of neuronal dynamics in untethered, freely moving animals have potential for widespread applications in neuroscience research.

The interhemispheric circuit connecting the left and the right mammalian brain plays a key role in integration of signals from the left and the right side of the body. The information transfer is carried out by modulation of simultaneous excitation and inhibition. Hemodynamic studies of this circuit are inconsistent since little is known about neurovascular coupling of mixed excitatory and inhibitory signals. We investigated the variability in hemodynamic responses driven by the interhemispheric circuit during optogenetic and somatosensory activation. We observed differences in the neurovascular response based on the stimulation site – cell bodies versus distal projections. In half of the experiments, optogenetic stimulation of the cell bodies evoked a predominant post-synaptic inhibition in the other hemisphere, accompanied by metabolic oxygen consumption without coupled functional hyperemia. When the same transcallosal stimulation resulted in predominant post-synaptic excitation, the hemodynamic response was biphasic, consisting of metabolic dip followed by functional hyperemia. Optogenetic suppression of the postsynaptic excitation abolished the coupled functional hyperemia. In contrast, light stimulation at distal projections evoked consistently a metabolic response. Our findings suggest that functional hyperemia requires signals originating from the cell body and the hemodynamic response variability appears to reflect the balance between the post-synaptic excitation and inhibition.

Objective . Controlling neural activity enables the possibility of manipulating sensory perception, cognitive processes, and body movement, in addition to providing a powerful framework for functionally disentangling the neural circuits that underlie these complex phenomena. Over the last decade, optogenetic stimulation has become an increasingly important and powerful tool for understanding neural circuit function, owing to the ability to target specific cell types and bidirectionally modulate neural activity. To date, most stimulation has been provided in open-loop or in an on/off closed-loop fashion, where previously-determined stimulation is triggered by an event. Here, we describe and demonstrate a design approach for precise optogenetic control of neuronal firing rate modulation using feedback to guide stimulation continuously. Approach . Using the rodent somatosensory thalamus as an experimental testbed for realizing desired time-varying patterns of firing rate modulation, we utilized a moving average exponential filter to estimate firing rate online from single-unit spiking measured extracellularly. This estimate of instantaneous rate served as feedback for a proportional integral (PI) controller, which was designed during the experiment based on a linear-nonlinear Poisson (LNP) model of the neuronal response to light. Main results . The LNP model fit during the experiment enabled robust closed-loop control, resulting in good tracking of sinusoidal and non-sinusoidal targets, and rejection of unmeasured disturbances. Closed-loop control also enabled manipulation of trial-to-trial variability. Significance . Because neuroscientists are faced with the challenge of dissecting the functions of circuit components, the ability to maintain control of a region of interest in spite of changes in ongoing neural activity will be important for disambiguating function within networks. Closed-loop stimulation strategies are ideal for control that is robust to such changes, and the employment of continuous feedback to adjust stimulation in real-time can improve the quality of data collected using optogenetic manipulation.

Objective . The aim of this work is to improve the state of the art for motor-control with a brain–machine interface (BMI). BMIs use neurological recording devices and decoding algorithms to transform brain activity directly into real-time control of a machine, archetypically a robotic arm or a cursor. The standard procedure treats neural activity—vectors of spike counts in small temporal windows—as noisy observations of the kinematic state (position, velocity, acceleration) of the fingertip. Inferring the state from the observations then takes the form of a dynamical filter , typically some variant on Kalman’s (KF). The KF, however, although fairly robust in practice, is optimal only when the relationships between variables are linear and the noise is Gaussian, conditions usually violated in practice. Approach . To overcome these limitations we introduce a new filter, the ‘recurrent exponential-family harmonium’ (rEFH), that models the spike counts explicitly as Poisson-distributed, and allows for arbitrary nonlinear dynamics and observation models. Furthermore, the model underlying the filter is acquired through unsupervised learning, which allows temporal correlations in spike counts to be explained by latent dynamics that do not necessarily correspond to the kinematic state of the fingertip. Main results . We test the rEFH on offline reconstruction of the kinematics of reaches in the plane. The rEFH outperforms the standard, as well as three other state-of-the-art, decoders, across three monkeys, two different tasks, most kinematic variables, and a range of bin widths, amounts of training data, and numbers of neurons. Significance . Our algorithm establishes a new state of the art for offline decoding of reaches—in particular, for fingertip velocities, the variable used for control in most online decoders.

Extracellular recording studies have revealed diverse and selective neural responses in the primary auditory cortex (A1) of awake animals. However, we have limited knowledge on subthreshold events that give rise to these responses, especially in non-human primates, as intracellular recordings in awake animals pose substantial technical challenges. We developed a novel intracellular recording technique in awake marmosets to systematically study subthreshold activity of A1 neurons that underlies their diverse and selective spiking responses. Our findings showed that in contrast to predominantly transient depolarization observed in A1 of anesthetized animals, both transient and sustained depolarization (during or beyond the stimulus period) were observed. Comparing with spiking responses, subthreshold responses were often longer lasting in duration and more broadly tuned in frequency, and showed narrower intensity tuning in non-monotonic neurons and lower response threshold in monotonic neurons. These observations demonstrated the enhancement of stimulus selectivity from subthreshold to spiking responses in individual A1 neurons. Furthermore, A1 neurons classified as regular- or fast-spiking subpopulation based on their spike shapes exhibited distinct response properties in frequency and intensity domains. These findings provide valuable insights into cortical integration and transformation of auditory information at the cellular level in auditory cortex of awake non-human primates.

Excitatory and inhibitory neurons in the mammalian sensory cortex form interconnected circuits that control cortical stimulus selectivity and sensory acuity. Theoretical studies have predicted that suppression of inhibition in such excitatory–inhibitory networks can lead to either an increase or, paradoxically, a decrease in excitatory neuronal firing, with consequent effects on stimulus selectivity. We tested whether modulation of inhibition or excitation in the auditory cortex of male mice could evoke such a variety of effects in tone-evoked responses and in behavioral frequency discrimination acuity. We found that, indeed, the effects of optogenetic manipulation on stimulus selectivity and behavior varied in both magnitude and sign across subjects, possibly reflecting differences in circuitry or expression of optogenetic factors. Changes in neural population responses consistently predicted behavioral changes for individuals separately, including improvement and impairment in acuity. This correlation between cortical and behavioral change demonstrates that, despite the complex and varied effects that these manipulations can have on neuronal dynamics, the resulting changes in cortical activity account for accompanying changes in behavioral acuity. SIGNIFICANCE STATEMENT Excitatory and inhibitory interactions determine stimulus specificity and tuning in sensory cortex, thereby controlling perceptual discrimination acuity. Modeling has predicted that suppressing the activity of inhibitory neurons can lead to increased or, paradoxically, decreased excitatory activity depending on the architecture of the network. Here, we capitalized on differences between subjects to test whether suppressing/activating inhibition and excitation can in fact exhibit such paradoxical effects for both stimulus sensitivity and behavioral discriminability. Indeed, the same optogenetic manipulation in the auditory cortex of different mice could improve or impair frequency discrimination acuity, predictable from the effects on cortical responses to tones. The same manipulations sometimes produced opposite changes in the behavior of different individuals, supporting theoretical predictions for inhibition-stabilized networks.

Mammalian sleep consists of distinct rapid eye movement (REM) and non-REM (NREM) states. The midbrain region ventrolateral periaqueductal gray (vlPAG) is known to be important for gating REM sleep, but the underlying neuronal mechanism is not well understood. Here, we show that activating vlPAG GABAergic neurons in mice suppresses the initiation and maintenance of REM sleep while consolidating NREM sleep, partly through their projection to the dorsolateral pons. Cell-type-specific recording and calcium imaging reveal that most vlPAG GABAergic neurons are strongly suppressed at REM sleep onset and activated at its termination. In addition to the rapid changes at brain state transitions, their activity decreases gradually between REM sleep and is reset by each REM episode in a duration-dependent manner, mirroring the accumulation and dissipation of REM sleep pressure. Thus, vlPAG GABAergic neurons powerfully gate REM sleep, and their firing rate modulation may contribute to the ultradian rhythm of REM/NREM alternation.