Publications using TDT

Synchronization has been implicated in neuronal communication, but causal evidence remains indirect. We use optogenetics to generate depolarizing currents in pyramidal neurons of the cat visual cortex, emulating excitatory synaptic inputs under precise temporal control, while measuring spike output. The cortex transforms constant excitation into strong gamma-band synchronization, revealing the well-known cortical resonance. Increasing excitation with ramps increases the strength and frequency of synchronization. Slow, symmetric excitation profiles reveal hysteresis of power and frequency. White-noise input sequences enable causal analysis of network transmission, establishing that the cortical gamma-band resonance preferentially transmits coherent input components. Models composed of recurrently coupled excitatory and inhibitory units uncover a crucial role of feedback inhibition and suggest that hysteresis can arise through spike-frequency adaptation. The presented approach provides a powerful means to investigate the resonance properties of local circuits and probe how these properties transform input and shape transmission.

Active mechanisms that regulate cochlear gain are hypothesized to influence speech-in-noise perception. However, evidence of a relationship between the amount of cochlear gain reduction and speech-in-noise recognition is mixed. Findings may conflict across studies because different signal-to-noise ratios (SNRs) were used to evaluate speech-in-noise recognition. Also, there is evidence that ipsilateral elicitation of cochlear gain reduction may be stronger than contralateral elicitation, yet, most studies have investigated the contralateral descending pathway. The hypothesis that the relationship between ipsilateral cochlear gain reduction and speech-in-noise recognition depends on the SNR was tested. A forward masking technique was used to quantify the ipsilateral cochlear gain reduction in 24 young adult listeners with normal hearing. Speech-in-noise recognition was measured with the PRESTO-R sentence test using speech-shaped noise presented at −3, 0, and +3 dB SNR. Interestingly, greater cochlear gain reduction was associated with lower speech-in-noise recognition, and the strength of this correlation increased as the SNR became more adverse. These findings support the hypothesis that the SNR influences the relationship between ipsilateral cochlear gain reduction and speech-in-noise recognition. Future studies investigating the relationship between cochlear gain reduction and speech-in-noise recognition should consider the SNR and both descending pathways.

Background: Subthalamic deep brain stimulation (DBS) is an effective surgical treatment for Parkinson's disease and continues to advance technologically with an enormous parameter space. As such, in-silico DBS modeling systems have become common tools for research and development, but their underlying methods have yet to be standardized and validated. Objective: Evaluate the accuracy of patient-specific estimates of neural pathway activations in the subthalamic region against intracranial, cortical evoked potential (EP) recordings. Methods: Pathway activations were modeled in eleven patients using the latest advances in connectomic modeling of subthalamic DBS, focusing on the hyperdirect pathway (HDP) and corticospinal/bulbar tract (CSBT) for their relevance in human research studies. Correlations between pathway activations and respective EP amplitudes were quantified. Results: Good model performance required accurate lead localization and image fusions, as well as appropriate selection of fiber diameter in the biophysical model. While optimal model parameters varied across patients, good performance could be achieved using a global set of parameters that explained 60% and 73% of electrophysiologic activations of CSBT and HDP, respectively. Moreover, restricted models fit to only EP amplitudes of eight standard (monopolar and bipolar) electrode configurations were able to extrapolate variation in EP amplitudes across other directional electrode configurations and stimulation parameters, with no significant reduction in model performance across the cohort. Conclusions: Our findings demonstrate that connectomic models of DBS with sufficient anatomical and electrical details can predict recruitment dynamics of white matter. These results will help to define connectomic modeling standards for preoperative surgical targeting and postoperative patient programming applications.

This study investigated the effects of long-term NF-κB inhibition in mitigating retinal vasculopathy in a type 1 diabetic mouse model (Akita, Ins2Akita). Akita and wild-type (C57BL/6J) male mice, 24 to 26 weeks old, were treated with or without a selective inhibitor of NF-κB, 4-methyl-N1-(3-phenyl-propyl) benzene-1,2-diamine (JSH-23), for 4 weeks. Treatment was given when the mice were at least 24 weeks old. Metabolic parameters, key inflammatory mediators, blood-retinal barrier junction molecules, retinal structure, and function were measured. JSH-23 significantly lowered basal glucose levels and intraocular pressure in Akita. It also mitigated vascular remodeling and microaneurysms significantly. Optical coherence tomography of untreated Akita showed thinning of retinal layers; however, treatment with JSH-23 could prevent it. Electroretinogram demonstrated that A- and B-waves in Akita were significantly smaller than in wild type mice, indicating that JSH-23 intervention prevented loss of retinal function. Protein levels and gene expression of key inflammatory mediators, such as NOD-like receptor family pyrin domain-containing 3, intercellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2, were decreased after JSH-23 treatment. At the same time, connexin-43 and occludin were maintained. Vision-guided behavior also improved significantly. The results show that reducing inflammation could protect the diabetic retina and its vasculature. Findings appear to have broader implications in treating not only ocular conditions but also other vasculopathies.

Primate social communication depends on the perceptual integration of visual and auditory cues, reflected in the multimodal mixing of sensory signals in certain cortical areas. The macaque cortical face patch network, identified through visual, face-selective responses measured with fMRI, is assumed to contribute to visual social interactions. However, whether face patch neurons are also influenced by acoustic information, such as the auditory component of a natural vocalization, remains unknown. Here, we recorded single-unit activity in the anterior fundus (AF) face patch, in the superior temporal sulcus, and anterior medial (AM) face patch, on the undersurface of the temporal lobe, in macaques presented with audiovisual, visual-only, and auditory-only renditions of natural movies of macaques vocalizing. The results revealed that 76% of neurons in face patch AF were significantly influenced by the auditory component of the movie, most often through enhancement of visual responses but sometimes in response to the auditory stimulus alone. By contrast, few neurons in face patch AM exhibited significant auditory responses or modulation. Control experiments in AF used an animated macaque avatar to demonstrate, first, that the structural elements of the face were often essential for audiovisual modulation and, second, that the temporal modulation of the acoustic stimulus was more important than its frequency spectrum. Together, these results identify a striking contrast between two face patches and specifically identify AF as playing a potential role in the integration of audiovisual cues during natural modes of social communication.

Control of protein intake is essential for numerous biological processes as several amino acids cannot be synthesized de novo, however, its neurobiological substrates are still poorly understood. In the present study, we combined in vivo fiber photometry with nutrient-conditioned flavor in a rat model of protein appetite to record neuronal activity in the VTA, a central brain region for the control of food-related processes. In adult male rats, protein restriction increased preference for casein (protein) over maltodextrin (carbohydrate). Moreover, protein consumption was associated with a greater VTA response, relative to carbohydrate. After initial nutrient preference, a switch from a normal balanced diet to protein restriction induced rapid development of protein preference but required extensive exposure to macronutrient solutions to induce elevated VTA responses to casein. Furthermore, prior protein restriction induced long-lasting food preference and VTA responses. This study reveals that VTA circuits are involved in protein appetite in times of need, a crucial process for animals to acquire an adequate amount of protein in their diet.SIGNIFICANCE STATEMENT Acquiring insufficient protein in one's diet has severe consequences for health and ultimately will lead to death. In addition, a low level of dietary protein has been proposed as a driver of obesity as it can leverage up intake of fat and carbohydrate. However, much remains unknown about the role of the brain in ensuring adequate intake of protein. Here, we show that in a state of protein restriction a key node in brain reward circuitry, the VTA, is activated more strongly during consumption of protein than carbohydrate. Moreover, although rats' behavior changed to reflect new protein status, patterns of neural activity were more persistent and only loosely linked to protein status.

Objective: This study characterised the relationship between speech intelligibility and quality in listeners with hearing loss for a range of hearing-aid processing settings and acoustic conditions. Design: Binaural speech intelligibility scores and quality ratings were measured for sentences presented in babble noise and processed through a hearing-aid simulation. The intelligibility-quality relationship was investigated by (1) assessing the effects of experimental conditions on each task; (2) directly comparing intelligibility scores and quality ratings for each participant across the range of conditions; and (3) comparing the association between signal envelope fidelity (represented by a cepstral correlation metric) and intelligibility and quality. Study sample: Participants were 15 adults (7 females; age range 59-81 years) with mild to moderately severe sensorineural hearing loss. Results: Intelligibility and quality showed a positive association both with each other and with changes to signal fidelity introduced by the entire acoustic and signal-processing system including the additive noise and the hearing-aid output. As signal fidelity decreased, quality ratings changed at a slower rate than intelligibility scores. Individual psychometric functions were more variable for quality compared to intelligibility. Conclusions: Variability in the intelligibility-quality relationship reinforces the importance of measuring both intelligibility and quality in clinical hearing-aid fittings.

Working memory (WM), the ability to actively hold information in memory over a delay period of seconds, is a fundamental constituent of cognition. Delay-period activity in sensory cortices has been observed in WM tasks, but whether and when the activity plays a functional role for memory maintenance remains unclear. Here, we investigated the causal role of auditory cortex (AC) for memory maintenance in mice performing an auditory WM task. Electrophysiological recordings revealed that AC neurons were active not only during the presentation of the auditory stimulus but also early in the delay period. Furthermore, optogenetic suppression of neural activity in AC during the stimulus epoch and early delay period impaired WM performance, whereas suppression later in the delay period did not. Thus, AC is essential for information encoding and maintenance in auditory WM task, especially during the early delay period.

Objectives: Congenital profound hearing loss with preserved cochlear outer hair cell activity (otoacoustic emissions and cochlear microphonic) is the most common phenotype associated with mutations in the OTOF gene. The aim of this study was to investigate the pathophysiological mechanisms behind the auditory dysfunction in five patients (2 adults and 3 children) carrying biallelic mutations in OTOF , who showed an uncommon phenotype of mild hearing impairment associated with severe difficulties in speech perception and delay of language development. Design: Patients underwent audiometric assessment with pure-tone and speech perception evaluation, and otoacoustic emissions and auditory brainstem response recording. Cochlear potentials were recorded in all subjects through transtympanic electrocochleography in response to clicks delivered in the free field from 120 to 60 dB peak equivalent SPL and were compared to recordings obtained from 20 normally hearing controls and from eight children with profound deafness due to mutations in the OTOF gene. Three patients out of five underwent unilateral cochlear implantation. Speech perception measures and electrically evoked auditory nerve potentials were obtained within 1 year of cochlear implant use. Results: Pathogenic mutations in the two alleles of OTOF were found in all five patients, and five novel mutations were identified. Hearing thresholds indicated mild hearing loss in four patients and moderate hearing loss in one. Distortion product otoacoustic emissions were recorded in all subjects, whereas auditory brainstem responses were absent in all but two patients, who showed a delayed wave V in one ear. In electrocochleography recordings, cochlear microphonics and summating potentials showed normal latency and peak amplitude, consistently with preservation of both outer and inner hair cell activity. In contrast, the neural compound action potential recorded in normally hearing controls was replaced by a prolonged, low-amplitude negative response. No differences in cochlear potentials were found between OTOF subjects showing mild or profound hearing loss. Electrical stimulation through the cochlear implant improved speech perception and restored synchronized auditory nerve responses in all cochlear implant recipients. Conclusions: These findings indicate that disordered synchrony in auditory fiber activity underlies the impairment of speech perception in patients carrying biallelic mutations in OTOF gene who show a stable phenotype of mild hearing loss. Abnormal nerve synchrony with preservation of hearing sensitivity is consistent with selective impairment of vesicle replenishment at the ribbon synapses with relative preservation of synaptic exocytosis. Cochlear implants are effective in restoring speech perception and synchronous activation of the auditory pathway by directly stimulating auditory fibers.

The aging of the population and environmental noise have contributed to high rates of presbycusis, also known as age-related hearing loss (ARHL). Because mice have a relatively short life span, murine models have not been suitable for determining the mechanism of presbycusis development and methods of diagnosis. Although the common marmoset, a non-human primate (NHP), is an ideal animal model for studying age-related diseases, its auditory spectrum has not been systematically studied. Auditory brainstem responses (ABRs) from 38 marmosets of different ages demonstrated that auditory function correlated with age. Hearing loss in geriatric common marmosets started at ultra-high frequency (>16 kHz), then extended to lower frequencies. Despite age-related deterioration of ABR threshold and amplitude in marmosets, outer hair cell (OHC) function remained stable at all ages. Spiral ganglion neurons (SGNs), which are the first auditory neurons in the auditory system, were found to degenerate distinctly in aged common marmosets, indicating that neural degeneration caused presbycusis in these animals. Similarly, age-associated ABR deterioration without loss of OHC function was observed in another NHP, rhesus monkeys. Audiometry results from these two species of NHP suggested that NHPs were ideal for studying ARHL and that neural presbycusis at high frequency may be prevalent in primates.

In the developing auditory system, spontaneous activity generated in the cochleae propagates into the central nervous system to promote circuit formation. The effects of peripheral firing patterns on spontaneous activity in the central auditory system are not well understood. Here, we describe wide-spread bilateral coupling of spontaneous activity that coincides with the period of transient efferent modulation of inner hair cells from the brainstem medial olivocochlear system. Knocking out α9/α10 nicotinic acetylcholine receptors, a requisite part of the efferent pathway, profoundly reduces bilateral correlations. Pharmacological and chemogenetic experiments confirm that the efferent system is necessary for normal bilateral coupling. Moreover, auditory sensitivity at hearing onset is reduced in the absence of pre-hearing efferent modulation. Together, these results demonstrate how afferent and efferent pathways collectively shape spontaneous activity patterns and reveal the important role of efferents in coordinating bilateral spontaneous activity and the emergence of functional responses during the prehearing period.

The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

Cortical and limbic brain areas are regarded as centres for learning. However, how thalamic sensory relays participate in plasticity upon associative learning, yet support stable long-term sensory coding remains unknown. Using a miniature microscope imaging approach, we monitor the activity of populations of auditory thalamus (medial geniculate body) neurons in freely moving mice upon fear conditioning. We find that single cells exhibit mixed selectivity and heterogeneous plasticity patterns to auditory and aversive stimuli upon learning, which is conserved in amygdala-projecting medial geniculate body neurons. Activity in auditory thalamus to amygdala-projecting neurons stabilizes single cell plasticity in the total medial geniculate body population and is necessary for fear memory consolidation. In contrast to individual cells, population level encoding of auditory stimuli remained stable across days. Our data identifies auditory thalamus as a site for complex neuronal plasticity in fear learning upstream of the amygdala that is in an ideal position to drive plasticity in cortical and limbic brain areas. These findings suggest that medial geniculate body’s role goes beyond a sole relay function by balancing experience-dependent, diverse single cell plasticity with consistent ensemble level representations of the sensory environment to support stable auditory perception with minimal affective bias.

The hippocampal local field potential (LFP) exhibits a strong correlation with behavior. During rest, the theta rhythm is not prominent, but during active behavior, there are strong rhythms in the theta, theta harmonics, and gamma ranges. With increasing running velocity, theta, theta harmonics and gamma increase in power and in cross-frequency coupling, suggesting that neural entrainment is a direct consequence of the total excitatory input. While it is common to study the parametric range between the LFP and its complementing power spectra between deep rest and epochs of high running velocity, it is also possible to explore how the spectra degrades as the energy is completely quenched from the system. Specifically, it is unknown whether the 1/f slope is preserved as synaptic activity becomes diminished, as low frequencies are generated by large pools of neurons while higher frequencies comprise the activity of more local neuronal populations. To test this hypothesis, we examined rat LFPs recorded from the hippocampus and entorhinal cortex during barbiturate overdose euthanasia. Within the hippocampus, the initial stage entailed a quasi-stationary LFP state with a power-law feature in the power spectral density. In the second stage, there was a successive erosion of power from high- to low-frequencies in the second stage that continued until the only dominant remaining power was <20 Hz. This stage was followed by a rapid collapse of power spectrum toward the absolute electrothermal noise background. As the collapse of activity occurred later in hippocampus compared with medial entorhinal cortex, it suggests that the ability of a neural network to maintain the 1/f slope with decreasing energy is a function of general connectivity. Broadly, these data support the energy cascade theory where there is a cascade of energy from large cortical populations into smaller loops, such as those that supports the higher frequency gamma rhythm. As energy is pulled from the system, neural entrainment at gamma frequency (and higher) decline first. The larger loops, comprising a larger population, are fault-tolerant to a point capable of maintaining their activity before a final collapse.

Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are the result of impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning.

We derive a theoretical construct that allows for the characterisation of both scalable and scale free systems within the dynamic causal modelling (DCM) framework. We define a dynamical system to be “scalable” if the same equation of motion continues to apply as the system changes in size. As an example of such a system, we simulate planetary orbits varying in size and show that our proposed methodology can be used to recover Kepler’s third law from the timeseries. In contrast, a “scale free” system is one in which there is no characteristic length scale, meaning that images of such a system are statistically unchanged at different levels of magnification. As an example of such a system, we use calcium imaging collected in murine cortex and show that the dynamical critical exponent, as defined in renormalization group theory, can be estimated in an empirical biological setting. We find that a task-relevant region of the cortex is associated with higher dynamical critical exponents in task vs. spontaneous states and vice versa for a task-irrelevant region.

Piccolo is a presynaptic protein with high conservation among different species, and the expression of Piccolo is extensive in vertebrates. Recently, a small fragment of Piccolo (Piccolino), arising due to the incomplete splicing of intron 5/6, was found to be present in the synapses of retinas and cochleae. However, the comprehensive function of Piccolo in the retina and cochlea remains unclear. In this study, we generated Piccolo knockout mice using CRISPR-Cas9 technology to explore the function of Piccolo. Unexpectedly, whereas no abnormalities were found in the cochlear hair cells of the mutant mice, significant differences were found in the retinas, in which two layers (the outer nuclear layer and the outer plexiform layer) were absent. Additionally, the amplitudes of electroretinograms were significantly reduced and pigmentation was observed in the fundoscopy of the mutant mouse retinas. The expression levels of Bassoon, a homolog of Piccolo, as well as synapse-associated proteins CtBP1, CtBP2, Kif3A, and Rim1 were down-regulated. The numbers of ribbon synapses in the retinas of the mutant mice were also reduced. Altogether, the phenotype of Piccolo-/- mice resembled the symptoms of retinitis pigmentosa (RP) in humans, suggesting Piccolo might be a candidate gene of RP and indicates Piccolo knockout mice are a good model for elucidating the molecular mechanisms of RP.

Although moving sound-sources abound in natural auditory scenes, it is not clear how the human brain processes auditory motion. Previous studies have indicated that, although ocular localization responses to stationary sounds are quite accurate, ocular smooth pursuit of moving sounds is very poor. We here demonstrate that human subjects faithfully track a sound’s unpredictable movements in the horizontal plane with smooth-pursuit responses of the head. Our analysis revealed that the stimulus–response relation was well described by an under-damped passive, second-order low-pass filter in series with an idiosyncratic, fixed, pure delay. The model contained only two free parameters: the system’s damping coefficient, and its central (resonance) frequency. We found that the latter remained constant at ∼0.6 Hz throughout the experiment for all subjects. Interestingly, the damping coefficient systematically increased with trial number, suggesting the presence of an adaptive mechanism in the auditory pursuit system (APS). This mechanism functions even for unpredictable sound-motion trajectories endowed with fixed, but covert, frequency characteristics in open-loop tracking conditions. We conjecture that the APS optimizes a trade-off between response speed and effort. Taken together, our data support the existence of a pursuit system for auditory head-tracking, which would suggest the presence of a neural representation of a spatial auditory fovea (AF).

High-frequency peripheral nerve stimulation has emerged as a noninvasive alternative to thalamic deep brain stimulation for some patients with essential tremor. It is not known whether such techniques might be effective for movement disorders in children, nor is the mechanism and transmission of the peripheral stimuli to central brain structures understood. This study was designed to investigate the fidelity of transmission from peripheral nerves to thalamic nuclei in children with dystonia undergoing deep brain stimulation surgery. The ventralis intermediate (VIM) thalamus nuclei showed a robust evoked response to peripheral high-frequency burst stimulation, with a greatest response magnitude to intra-burst frequencies between 50 and 100 Hz, and reliable but smaller responses up to 170 Hz. The earliest response occurred at 12–15 ms following stimulation onset, suggesting rapid high-fidelity transmission between peripheral nerve and thalamic nuclei. A high-bandwidth, low-latency transmission path from peripheral nerve to VIM thalamus is consistent with the importance of rapid and accurate sensory information for the control of coordination and movement via the cerebello-thalamo-cortical pathway. Our results suggest the possibility of non-invasive modulation of thalamic activity in children with dystonia, and therefore the possibility that a subset of children could have beneficial clinical response without the need for invasive deep brain stimulation.

Recovering arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control practically limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts, triggered by intracortical signals produced sustained arm movements enabling monkeys with arm paralysis to perform an unconstrained, three-dimensional reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that artificial recruitment of the sensory afferents was synergistically integrated with spared descending inputs and spinal reflexes to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.