Electrophysiology publications

Detecting rapid, coincident changes across sensory modalities is essential for recognition of sudden threats or events. Using two-photon calcium imaging in identified cell types in awake, head-fixed mice, we show that, among the basic features of a sound envelope, loud sound onsets are a dominant feature coded by the auditory cortex neurons projecting to primary visual cortex (V1). In V1, a small number of layer 1 interneurons gates this cross-modal information flow in a context-dependent manner. In dark conditions, auditory cortex inputs lead to suppression of the V1 population. However, when sound input coincides with a visual stimulus, visual responses are boosted in V1, most strongly after loud sound onsets. Thus, a dynamic, asymmetric circuit connecting AC and V1 contributes to the encoding of visual events that are coincident with sounds.

Kinase signaling plays an important role in acquired epilepsy, but only a small percentage of the total kinome has been investigated in this context. A major roadblock that prevents the systematic investigation of the contributions of kinase signaling networks is the slow speed of experiments designed to test the chronic effects of target inhibition in epilepsy models. We developed a novel in vitro screening platform based on microwire recordings from an organotypic hippocampal culture model of acquired epilepsy. This platform enables the direct, parallel determination of the effects of compounds on spontaneous epileptiform activity. The platform also enables repeated recordings from the same culture over two-week long experiments. We screened 45 kinase inhibitors and quantified their effects on seizure duration, the frequency of paroxysmal activity, and electrographic load. We identified several inhibitors with previously unknown antiepileptic properties. We also used kinase inhibition profile cross-referencing to identify kinases that are inhibited by seizure-suppressing compounds, but not by compounds that had no effect on seizures.

Throughout the past decade, silicon-based neural probes have become a driving force in neural engineering. Such probes comprise sophisticated, integrated CMOS electronics which provide a large number of recording sites along slender probe shanks. Using such neural probes in a chronic setting often requires them to be mechanically anchored with respect to the skull. However, any relative motion between brain and implant causes recording instabilities and tissue responses such as glial scarring, thereby shielding recordable neurons from the recording sites integrated on the probe and thus decreasing the signal quality. In the current work, we present a comparison of results obtained using mechanically fixed and floating silicon neural probes chronically implanted into the cortex of a non-human primate. We demonstrate that the neural signal quality estimated by the quality of the spiking and local field potential (LFP) recordings over time is initially superior for the floating probe compared to the fixed device. Nonetheless, the skull-fixed probe also allowed long-term recording of multi-unit activity (MUA) and low frequency signals over several months, especially once pulsations of the brain were properly controlled.

Partial hearing loss can cause neurons in the auditory and audiovisual cortices to increase their responsiveness to visual stimuli; however, behavioral studies in hearing-impaired humans and rats have found that the perceptual ability to accurately judge the relative timing of auditory and visual stimuli is largely unaffected. To investigate the neurophysiological basis of how audiovisual temporal acuity may be preserved in the presence of hearing loss-induced crossmodal plasticity, we exposed adult rats to loud noise and two weeks later performed in vivo electrophysiological recordings in two neighboring regions within the lateral extrastriate visual (V2L) cortex—a multisensory zone known to be responsive to audiovisual stimuli (V2L-Mz) and a predominantly auditory zone (V2L-Az). To examine the cortical layer-specific effects at the level of postsynaptic potentials, a current source density (CSD) analysis was applied to the local field potential (LFP) data recorded in response to auditory and visual stimuli presented at various stimulus onset asynchronies (SOAs). As predicted, differential effects were observed in the neighboring cortical regions’ postnoise exposure. Most notably, an analysis of the strength of multisensory response interactions revealed that V2L-Mz lost its sensitivity to the relative timing of the auditory and visual stimuli, due to an increased responsiveness to visual stimulation that produced a prominent audiovisual response irrespective of the SOA. In contrast, not only did the V2L-Az in noise-exposed rats become more responsive to visual stimuli but neurons in this region also inherited the capacity to process audiovisual stimuli with the temporal precision and specificity that was previously restricted to the V2L-Mz. Thus, the present study provides the first demonstration that audiovisual temporal processing can be preserved following moderate hearing loss via compensatory plasticity in the higher-order sensory cortices that is ultimately characterized by a functional transition in the cortical region capable of temporal sensitivity.

Accurate sound localization requires normal binaural input and precise auditory neuronal representation of sound spatial locations. Previous studies showed that unilateral hearing loss profoundly impaired the sound localization abilities. However, the underlying neural mechanism is not fully understood. Here, we investigated how chronic unilateral conductive hearing loss (UCHL) affected the neural tuning to sound source azimuth in the primary auditory cortex (AI). The UCHL was manipulated by the removal of tympanic membrane and malleus in the right ear of young (P14) rats and adult (P57) rats. We recorded the azimuth tuning of neurons in the left AI contralateral to the operated ear in the two groups of rats that experienced 2 months of UCHL, and in the left AI of age-matched control rats. We found that AI neurons in control rats showed predominant preference to sound from contralateral azimuths. However, UCHL weakened the cortical neuronal representation of contralateral azimuths on the operated ear side and strengthened the cortical neuronal representation of ipsilateral azimuths on the intact ear side. This effect was stronger in rats with UCHL at young age than in rats with UCHL in adulthood. Moreover, UCHL degraded the azimuth selectivity and azimuth sensitivity of AI neurons, and this effect was stronger in rats with UCHL in adulthood than in rats with UCHL at young age. These findings highlight a remarkable age-related experience-dependent plasticity of neural tuning to sound source azimuth in AI, and imply a neural mechanism for the impacts of chronic UCHL on sound localization abilities.

Appetite is driven by nutritional state, environmental cues, mood, and reward pathways. Environmental cues strongly influence feeding behavior, as they can dramatically induce or diminish the drive to consume food despite homeostatic state. Here, we have uncovered an excitatory neuronal population in the basal forebrain that is activated by food-odor related stimuli, and potently drives hypophagia. Notably, we found that the basal forebrain directly integrates environmental sensory cues to govern feeding behavior, and that basal forebrain signaling, mediated through projections to the lateral hypothalamus, promotes selective avoidance of food and food-related stimuli. Together, these findings reveal a novel role for the excitatory basal forebrain in regulating appetite suppression through food avoidance mechanisms, highlighting a key function for this structure as a potent integrator of sensory information towards governing consummatory behaviors.

To effectively interact with their environment, humans must often select actions from multiple incompatible options. Existing theories propose that during motoric response-conflict, inappropriate motor activity is actively (and perhaps non-selectively) suppressed by an inhibitory fronto-basal ganglia mechanism. We here tested this theory across three experiments. First, using scalp-EEG, we found that both outright action-stopping and response-conflict during action-selection invoke low-frequency activity of a common fronto-central source, whose activity relates to trial-by-trial behavioral indices of inhibition in both tasks. Second, using simultaneous intracranial recordings from the basal ganglia and motor cortex, we found that response-conflict increases the influence of the subthalamic nucleus on M1-representations of incorrect response-tendencies. Finally, using transcranial magnetic stimulation, we found that during the same time period when conflict-related STN-to-M1 communication is increased, cortico-spinal excitability is broadly suppressed. Together, these findings demonstrate that fronto-basal ganglia networks buttress action-selection under response-conflict by rapidly and non-selectively net-inhibiting inappropriate motor tendencies.

Objective: The purpose of this study was to investigate perceptual and electrophysiological encoding of complex periodic signals as a function of age. Design: Two groups of adults completed three listening tasks: a behavioural task of detection of a mistuned harmonic component in a complex tone, an electrophysiological measure of speech-evoked auditory brainstem response (sABR), and a speech-in-noise measure. Between group comparisons were undertaken for each task as well as pairwise correlation analyses for all tasks. Study sample: One group of younger adults (n = 20) and one group of older adults (n = 20) participated. All listeners had relatively normal audiometric thresholds (≤20 dB HL) from 250-4000 Hz. Results: Younger adults had better results than the older adults on all three tasks: sensitivity for detecting a mistuned harmonic, spectral encoding for sABR, and release from masking for the speech-in-noise test. There were no significant correlations between measures when evaluating the older adults in isolation. Conclusions: The results are consistent with the body of literature that demonstrates reduced temporal processing abilities for older adults. The combined method approach undertaken in this investigation did not result in correlations between the perceptual and electrophysiological measures of temporal processing.

Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage in coherent subthreshold oscillations and are extensively coupled via gap junctions. Studies in reduced preparations suggest that these properties promote rhythmic, synchronized output. However, the interaction of these properties with torrential synaptic inputs in awake behaving animals is not well understood. Here we combine electrophysiological recordings in awake mice with a realistic tissue-scale computational model of the inferior olive to study the relative impact of intrinsic and extrinsic mechanisms governing its activity. Our data and model suggest that if subthreshold oscillations are present in the awake state, the period of these oscillations will be transient and variable. Accordingly, by using different temporal patterns of sensory stimulation, we found that complex spike rhythmicity was readily evoked but limited to short intervals of no more than a few hundred milliseconds and that the periodicity of this rhythmic activity was not fixed but dynamically related to the synaptic input to the inferior olive as well as to motor output. In contrast, in the long-term, the average olivary spiking activity was not affected by the strength and duration of the sensory stimulation, while the level of gap junctional coupling determined the stiffness of the rhythmic activity in the olivary network during its dynamic response to sensory modulation. Thus, interactions between intrinsic properties and extrinsic inputs can explain the variations of spiking activity of olivary neurons, providing a temporal framework for the creation of both the short-term and long-term changes in cerebellar output.

Our system separates simultaneous voices and compares them with brain waves of a listener to amplify attended speech.

Reward modulation (M1) could be exploited in developing an autonomously updating brain-computer interface (BCI) based on a reinforcement learning (RL) architecture. For an autonomously updating RL-based BCI system, we would need a reward prediction error, or a state-value representation from the user’s neural activity, which the RL-BCI agent could use to update its BCI decoder. In order to understand the multifaceted effects of reward on M1 activity, we investigated how neural spiking, oscillatory activities and their functional interactions are modulated by conditioned stimuli related reward expectation. To do so, local field potentials (LFPs) and single/multi-unit activities were recorded simultaneously and bilaterally from M1 cortices while four non-human primates (NHPs) performed cued center-out reaching or grip force tasks either manually using their right arm/hand or observed passively. We found that reward expectation influenced the strength of α (8–14 Hz) power, α-γ comodulation, α spike-field coherence (SFC), and firing rates (FRs) in general in M1. Furthermore, we found that an increase in α-band power was correlated with a decrease in neural spiking activity, that FRs were highest at the trough of the α-band cycle and lowest at the peak of its cycle. These findings imply that α oscillations modulated by reward expectation have an influence on spike FR and spike timing during both reaching and grasping tasks in M1. These LFP, spike, and spike-field interactions could be used to follow the M1 neural state in order to enhance BCI decoding (An et al., 2018; Zhao et al., 2018).

In neural circuits, action potentials (spikes) are conventionally caused by excitatory inputs whereas inhibitory inputs reduce or modulate neuronal excitability. We previously showed that neurons in the superior paraolivary nucleus (SPN) require solely synaptic inhibition to generate their hallmark offset response, a burst of spikes at the end of a sound stimulus, via a post-inhibitory rebound mechanism. In addition SPN neurons receive excitatory inputs, but their functional significance is not yet known. Here we used mice of both sexes to demonstrate that in SPN neurons, the classical roles for excitation and inhibition are switched, with inhibitory inputs driving spike firing and excitatory inputs modulating this response. Hodgkin–Huxley modeling suggests that a slow, NMDA receptor (NMDAR)-mediated excitation would accelerate the offset response. We find corroborating evidence from in vitro and in vivo recordings that lack of excitation prolonged offset-response latencies and rendered them more variable to changing sound intensity levels. Our results reveal an unsuspected function for slow excitation in improving the timing of post-inhibitory rebound firing even when the firing itself does not depend on excitation. This shows the auditory system employs highly specialized mechanisms to encode timing-sensitive features of sound offsets which are crucial for sound-duration encoding and have profound biological importance for encoding the temporal structure of speech.

Objectives: The aims of this study were to systematically explore the effects of stimulus duration, background (quiet versus noise), and three consonant–vowels on speech-auditory brainstem responses (ABRs). Additionally, the minimum number of epochs required to record speech-ABRs with clearly identifiable waveform components was assessed. The purpose was to evaluate whether shorter duration stimuli could be reliably used to record speech-ABRs both in quiet and in background noise to the three consonant–vowels, as opposed to longer duration stimuli that are commonly used in the literature. Shorter duration stimuli and a smaller number of epochs would require shorter test sessions and thus encourage the transition of the speech-ABR from research to clinical practice. Design: Speech-ABRs in response to 40 msec [da], 50 msec [ba] [da] [ga], and 170 msec [ba] [da] [ga] stimuli were collected from 12 normal-hearing adults with confirmed normal click-ABRs. Monaural (right-ear) speech-ABRs were recorded to all stimuli in quiet and to 40 msec [da], 50 msec [ba] [da] [ga], and 170 msec [da] in a background of two-talker babble at +10 dB signal to noise ratio using a 2-channel electrode montage (Cz-Active, A1 and A2-reference, Fz-ground). Twelve thousand epochs (6000 per polarity) were collected for each stimulus and background from all participants. Latencies and amplitudes of speech-ABR peaks (V, A, D, E, F, O) were compared across backgrounds (quiet and noise) for all stimulus durations, across stimulus durations (50 and 170 msec) and across consonant–vowels ([ba], [da], and [ga]). Additionally, degree of phase locking to the stimulus fundamental frequency (in quiet versus noise) was evaluated for the frequency following response in speech-ABRs to the 170 msec [da]. Finally, the number of epochs required for a robust response was evaluated using F sp statistic and bootstrap analysis at different epoch iterations. Results: Background effect: the addition of background noise resulted in speech-ABRs with longer peak latencies and smaller peak amplitudes compared with speech-ABRs in quiet, irrespective of stimulus duration. However, there was no effect of background noise on the degree of phase locking of the frequency following response to the stimulus fundamental frequency in speech-ABRs to the 170 msec [da]. Duration effect: speech-ABR peak latencies and amplitudes did not differ in response to the 50 and 170 msec stimuli. Consonant–vowel effect: different consonant–vowels did not have an effect on speech-ABR peak latencies regardless of stimulus duration. Number of epochs: a larger number of epochs was required to record speech-ABRs in noise compared with in quiet, and a smaller number of epochs was required to record speech-ABRs to the 40 msec [da] compared with the 170 msec [da]. Conclusions: This is the first study that systematically investigated the clinical feasibility of speech-ABRs in terms of stimulus duration, background noise, and number of epochs. Speech-ABRs can be reliably recorded to the 40 msec [da] without compromising response quality even when presented in background noise. Because fewer epochs were needed for the 40 msec [da], this would be the optimal stimulus for clinical use. Finally, given that there was no effect of consonant–vowel on speech-ABR peak latencies, there is no evidence that speech-ABRs are suitable for assessing auditory discrimination of the stimuli used.

Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an auditory stimulus drives reorganization of primary auditory cortex (A1), and the magnitude of this VNS-dependent plasticity is dependent on the stimulation parameters, including intensity and pulse rate. However, there is currently little data to guide the selection of VNS train durations, an easily adjusted parameter that could influence the effect of VNS-based therapies. Here, we tested the effect of varying the duration of the VNS train on the extent of VNS-dependent cortical plasticity. Rats were exposed to a 9 kHz tone 300 times per day for 20 days. Coincident with tone presentation, groups received trains of 4, 16, or 64 pulses of VNS delivered at 30 Hz, corresponding to train durations of 0.125 s, 0.5 s, and 2.0 s, respectively. High-density microelectrode mapping of A1 revealed that 0.5 s duration VNS trains significantly increased the number of neurons in A1 that responded to tones near the paired tone frequency. Trains lasting 0.125 or 2.0 s failed to alter A1 responses, indicating that both shorter and longer stimulation durations are less effective at enhancing plasticity. A second set of experiments evaluating the effect of delivering 4 or 64 pulses in a fixed 0.5 s VNS train duration paired with tone presentation reveal that both slower and faster stimulation rates are less effective at enhancing plasticity. We incorporated these results with previous findings describing the effect of stimulation parameters on VNS-dependent plasticity and activation of neuromodulatory networks to generate a model of synaptic activation by VNS.

The central gain model of hyperacusis proposes that loss of auditory input can result in maladaptive neuronal gain increases in the central auditory system, leading to the over-amplification of sound-evoked activity and excessive loudness perception. Despite the attractiveness of this model, and supporting evidence for it, a critical test of the central gain theory requires that changes in sound-evoked activity be explicitly linked to perceptual alterations of loudness. Here we combined an operant conditioning task that uses a subject's reaction time to auditory stimuli to produce reliable measures of loudness growth with chronic electrophysiological recordings from the auditory cortex and inferior colliculus of awake, behaviorally-phenotyped animals. In this manner, we could directly correlate daily assessments of loudness perception with neurophysiological measures of sound encoding within the same animal. We validated this novel psychophysical-electrophysiological paradigm with a salicylate-induced model of hearing loss and hyperacusis, as high doses of sodium salicylate reliably induce temporary hearing loss, neural hyperactivity, and auditory perceptual disruptions like tinnitus and hyperacusis. Salicylate induced parallel changes to loudness growth and evoked response-intensity functions consistent with temporary hearing loss and hyperacusis. Most importantly, we found that salicylate-mediated changes in loudness growth and sound-evoked activity were correlated within individual animals. These results provide strong support for the central gain model of hyperacusis and demonstrate the utility of using an experimental design that allows for within-subject comparison of behavioral and electrophysiological measures, thereby making inter-subject variability a strength rather than a limitation.

Purpose As pulse rate increases beyond a few hundred Hertz, younger normal-hearing (NH) participants' ability to encode temporal information in band-limited acoustic pulse trains decreases, demonstrating a rate limitation in processing rapid temporal information. Rate discrimination abilities, however, have yet to be investigated in older NH participants—a population that experiences age-related temporal processing deficits. It was hypothesized that age-related temporal processing deficits lead to decreased temporal rate discrimination abilities in older compared with younger NH participants, which could be observed in both perceptual and electrophysiological measurements. Method Fifteen younger and 15 older NH participants were presented acoustic pulse trains with a 4-kHz center frequency and 1-kHz bandwidth at 75 dB SPL monaurally. The pulse rate was 80, 200, or 400 Hz. Just noticeable differences were obtained using an adaptive procedure that instructed the participants to identify the pulse train with the highest pitch. Auditory steady-state responses (ASSRs) were recorded to the same pulse trains with 2 additional rates—20 and 40 Hz. The Digit Symbol Coding and Digit Symbol Search subtests of the Wechsler Adult Intelligence Scale ( Wechsler, 1997 ) were measured as correlates to domain-general cognitive processing speed. Results As rate increased from 80 to 400 Hz, performance on the perceptual rate discrimination task worsened in both groups. ASSR spectral energy also decreased, but only in the older group. Perceptual performance was equivalent between groups across rates. The older group had lower ASSR spectral energy (lower signal-to-noise ratios) at the 400-Hz rate than the younger group, but there were no group differences for the other rates. The overall strength of neural rate representation, along with speed of processing performance, predicted perceptual performance for the 400-Hz rate. Conclusion These results suggest that neural representation at early levels of the auditory system and processing speed are factors in perceptual auditory temporal processing performance, especially in older adults.

Prominent 7-12 Hz oscillations in frontal cortical networks in rats have been reported. However, the mechanism of generation and the physiological function of this brain rhythm have not yet been clarified. Multichannel extracellular field potentials of the ACC were recorded and analyzed using the current source density method in halothane-anesthetized rats. Spontaneous high-current spikes (HCSs) were localized in the deep part of layer II/III and upper part of layer V of the ACC. The frequency of HCSs in the ACC was 7-12 Hz, with an amplitude of 6.5 ± 0.76 mV/mm2 and duration of 55.24 ± 2.43 ms. The power density significantly decreased (84.56 ± 6.93%, p < 0.05, t test) after pinching the hindpaw and significantly increased (149.28 ± 15.96%) after treatment with morphine. The suppressive effect of pinching was reversed by naloxone (0.7 mg/kg, i.p.). HCSs coincided with initiation of the depolarization of cingulate neurons and remained in a depolarized upstate. The occurrence of cingulate HCSs was persistently preceded by a hyperpolarization phase and a burst of multiunit spike activity in the medial dorsal thalamic nucleus. Spontaneous field-potential oscillations changed from 10 Hz to a lower band (i.e., ∼7.5 Hz) when a central poststroke pain condition was induced. The central poststroke pain group had a higher average coherence coefficient compared with the control group. Our results indicate that spontaneous cingulate cortical HCSs could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms in physiological and pathological pain states.SIGNIFICANCE STATEMENT This study elucidated the mechanism of generation and physiological function of prominent 7-12 Hz frequency oscillations in frontal cortical networks in rats. Spontaneous cingulate cortical high-current spikes in anesthetized rats could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms. Suppression of the anterior cingulate cortex-filtered EEG during noxious stimulation may have resulted from the desynchronization of high-current spikes in the ACC. The enhancement of fast Fourier transform power after a systemic morphine injection suggested that the opioid system may play an important role in synchronizing cingulate cortical neuronal networks. Spontaneous cingulate high-current spikes may also play an important role in thalamocortical dysrhythmia in central poststroke pain.

Technology that translates neural activity into speech would be transformative for people who are unable to communicate as a result of neurological impairments. Decoding speech from neural activity is challenging because speaking requires very precise and rapid multi-dimensional control of vocal tract articulators. Here we designed a neural decoder that explicitly leverages kinematic and sound representations encoded in human cortical activity to synthesize audible speech. Recurrent neural networks first decoded directly recorded cortical activity into representations of articulatory movement, and then transformed these representations into speech acoustics. In closed vocabulary tests, listeners could readily identify and transcribe speech synthesized from cortical activity. Intermediate articulatory dynamics enhanced performance even with limited data. Decoded articulatory representations were highly conserved across speakers, enabling a component of the decoder to be transferrable across participants. Furthermore, the decoder could synthesize speech when a participant silently mimed sentences. These findings advance the clinical viability of using speech neuroprosthetic technology to restore spoken communication.

Despite extensive research on primate cognitive function, understanding how anatomical connectivity at a neural circuit level relates to information transformation across different cortical areas remains primitive. New technology is needed to visualize inter-areal anatomical connectivity in living monkeys and to tie this directly to neurophysiological function. Here, we developed a novel method to investigate this structure-function relationship, by combining optical intrinsic signal imaging (OISI) with optogenetic stimulation in living monkeys (opto-OISI). The method involves expressing channelrhodophsin-2 in one area (source) followed by optical imaging of optogenetic activations in the other area (target). We successfully demonstrated the potential of the method with interhemispheric columnar projection patterns between V1/V2 border regions. Unlike the combination of optogenetics and functional magnetic resonance imaging (opto-fMRI), opto-OISI has the advantage of enabling us to detect responses of small clusters of neurons, even if the clusters are sparsely distributed. We suggest that opto-OISI can be a powerful approach to understanding cognitive function at the neural circuit level, directly linking inter-areal circuitry to fine-scale structure and function.

Neuron–glia communication contributes to the fine-tuning of synaptic functions. Oligodendrocytes near synapses detect and respond to neuronal activity, but their role in synapse development and plasticity remains largely unexplored. We show that oligodendrocytes modulate neurotransmitter release at presynaptic terminals through secretion of brain-derived neurotrophic factor (BDNF). Oligodendrocyte-derived BDNF functions via presynaptic tropomyosin receptor kinase B (TrkB) to ensure fast, reliable neurotransmitter release and auditory transmission in the developing brain. In auditory brainstem slices from Bdnf+/– mice, reduction in endogenous BDNF significantly decreased vesicular glutamate release by reducing the readily releasable pool of glutamate vesicles, without altering presynaptic Ca2+ channel activation or release probability. Using conditional knockout mice, cell-specific ablation of BDNF in oligodendrocytes largely recapitulated this effect, which was recovered by BDNF or TrkB agonist application. This study highlights a novel function for oligodendrocytes in synaptic transmission and their potential role in the activity-dependent refinement of presynaptic properties.