Auditory Neurophysiology publications

This work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/gamma) were demonstrated in primary auditory cortex in medial Heschl's gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. This work demonstrates sustained activity patterns during AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions.

Continuous acoustic streams, such as speech signals, can be chunked into segments containing reoccurring patterns (e.g., words). Noninvasive recordings of neural activity in humans suggest that chunking is underpinned by low-frequency cortical entrainment to the segment presentation rate, and modulated by prior segment experience (e.g., words belonging to a familiar language). Interestingly, previous studies suggest that also primates and rodents may be able to chunk acoustic streams. Here, we test whether neural activity in the rat auditory cortex is modulated by previous segment experience. We recorded subdural responses using electrocorticography (ECoG) from the auditory cortex of 11 anesthetized rats. Prior to recording, four rats were trained to detect familiar triplets of acoustic stimuli (artificial syllables), three were passively exposed to the triplets, while another four rats had no training experience. While low-frequency neural activity peaks were observed at the syllable level, no triplet-rate peaks were observed. Notably, in trained rats (but not in passively exposed and naïve rats), familiar triplets could be decoded more accurately than unfamiliar triplets based on neural activity in the auditory cortex. These results suggest that rats process acoustic sequences, and that their cortical activity is modulated by the training experience even under subsequent anesthesia.

There is considerable interest in understanding cortical processing and the function of top-down and bottom-up human neural circuits that control speech production. Research efforts to investigate these circuits are aided by analysis of spectro-temporal response characteristics of neural activity recorded by electrocorticography (ECoG). Further, cortical processing may be altered in the case of hearing-impaired cochlear implant (CI) users, as electric excitation of the auditory nerve creates a markedly different neural code for speech compared with that of the functionally intact hearing system. Studies of cortical activity in CI users typically record scalp potentials and are hampered by stimulus artifact contamination and by spatiotemporal filtering imposed by the skull. We present a unique case of a CI user who required direct recordings from the cortical surface using subdural electrodes implanted for epilepsy assessment. Using experimental conditions where the subject vocalized in the presence (CIs ON) or absence (CIs OFF) of auditory feedback, or listened to playback of self-vocalizations without production, we observed ECoG activity primarily in γ (32-70 Hz) and high γ (70-150 Hz) bands at focal regions on the lateral surface of the superior temporal gyrus (STG). High γ band responses differed in their amplitudes across conditions and cortical sites, possibly reflecting different rates of stimulus presentation and differing levels of neural adaptation. STG γ responses to playback and vocalization with auditory feedback were not different from responses to vocalization without feedback, indicating this activity reflects not only auditory, but also attentional, efference-copy, and sensorimotor processing during speech production.

Cortical synchrony is theorized to contribute to communication between connected networks during executive functioning. To understand the functional role of neural synchrony in cognitive flexibility, we recorded from auditory cortex (AC) and medial prefrontal cortex (mPFC), while mice performed an auditory extinction learning task. We found that while animals gradually showed reduced responding to the unrewarded tone over hundreds of trials, the power of local field potential (LFP) oscillations (8-18 Hz, centered at alpha/beta frequencies) in AC and mPFC exhibited immediate and robust increases, prior to behavioral changes. The strength of LFP alpha/beta power in the mPFC, but not AC, was strongly correlated with the behavioral performance that mice would achieve later in the training session. Further, we found that coherence between AC and mPFC at 8-18Hz was selectively enhanced only after mice learned to suppress licking, and this LFP coherence increase coincided with a reduction in spiking rate for the unrewarded tone in AC. These results reveal that enhanced interactions between PFC and AC is an inherent property of auditory discrimination learning, and that coordinated alpha/beta oscillations contribute to cognitive flexibility.

Despite extensive knowledge of its molecular and cellular effects, how anesthesia affects sensory processing remains poorly understood. In particular, it remains unclear whether anesthesia modestly or robustly degrades activity in primary sensory regions, and whether such changes are linked to anesthesia drug concentration vs. behavioral unresponsiveness, since these are typically confounded. Here, we employed slow gradual intravenous propofol anesthesia induction together with auditory stimulation and intermittent assessment of behavioral responsiveness while recording epidural EEG, and neuronal spiking activity in the primary auditory cortex (PAC) of eight rats. We found that all main components of neuronal activity including spontaneous firing rates, onset response magnitudes, onset response latencies, post-onset neuronal silence duration, and late-locking to 40Hz click-trains, gradually deteriorated in a dose- dependent manner with increasing anesthesia levels without showing abrupt changes around loss of righting reflex or other time-points. Thus, the dominant factor affecting PAC responses is the anesthesia drug concentration rather than any sudden, dichotomous behavioral state changes. Our findings explain a wide array of seemingly conflicting results in the literature that, depending on the precise definition of wakefulness (vigilant vs. drowsy) and anesthesia (light vs. deep/surgical), report a spectrum of effects in primary regions ranging from minimal to dramatic differences.

Neural implants that deliver multi-site electrical stimulation to the nervous systems are no longer the last resort but routine treatment options for various neurological disorders. Multi-site electrical stimulation is also widely used to study nervous system function and neural circuit transformations. These technologies increasingly demand dynamic electrical stimulation and closed-loop feedback control for real-time assessment of neural function, which is technically challenging since stimulus-evoked artifacts overwhelm the small neural signals of interest. We report a novel and versatile artifact removal method that can be applied in a variety of settings, from single- to multi-site stimulation and recording and for current waveforms of arbitrary shape and size. The method capitalizes on linear electrical coupling between stimulating currents and recording artifacts, which allows us to estimate a multi-channel linear Wiener filter to predict and subsequently remove artifacts via subtraction. We confirm and verify the linearity assumption and demonstrate feasibility in a variety of recording modalities, including in vitro sciatic nerve stimulation, bilateral cochlear implant stimulation, and multi-channel stimulation and recording between the auditory midbrain and cortex. We demonstrate a vast enhancement in the recording quality with a typical artifact reduction of 25-40 dB. The method is efficient and can be scaled to arbitrary number of stimulus and recording sites, making it ideal for applications in large-scale arrays, closed-loop implants, and high-resolution multi-channel brain-machine interfaces.

Do noises wake you up at night? Blame your locus coeruleus.

We investigated whether contrast gain control is mediated by shunting inhibition from parvalbumin-positive interneurons in auditory cortex. We performed extracellular and intracellular recordings in mouse auditory cortex while presenting sensory stimuli with varying contrasts and manipulated parvalbumin-positive interneuron activity using optogenetics. We show that while parvalbumin-positive interneuron activity modulates the gain of cortical responses, this activity is not the primary mechanism for contrast gain control in auditory cortex.

Neural adaptation enables sensory information to be represented optimally in the brain despite large fluctuations over time in the statistics of the environment. Auditory contrast gain control represents an important example, which is thought to arise primarily from cortical processing. Here we show that neurons in the auditory thalamus and midbrain of mice show robust contrast gain control, and that this is implemented independently of cortical activity. Although neurons at each level exhibit contrast gain control to similar degrees, adaptation time constants become longer at later stages of the processing hierarchy, resulting in progressively more stable representations. We also show that auditory discrimination thresholds in human listeners compensate for changes in contrast, and that the strength of this perceptual adaptation can be predicted from physiological measurements. Contrast adaptation is therefore a robust property of both the subcortical and cortical auditory system and accounts for the short-term adaptability of perceptual judgments.

Animal behavioral paradigms, such as classical conditioning and operant conditioning, are an important tool to study the neural basis of cognition and behavior. These paradigms involve manipulating sensory stimuli in a way that learning processes are induced under controlled experimental conditions. However, the majority of the commercially available equipment did not offer flexibility to manipulate stimuli. Therefore, the development of most versatile devices would allow the study of more complex cognitive functions. The purpose of this work is to present a low-cost, customized and wireless-operated chamber for animal behavior conditioning, based on the joint operation of two microcontroller modules: Arduino Due and ESP8266-12E. Our results showed that the auditory stimulation system allows setting the carrier frequency in the range of 1 Hz up to more than 100 kHz and the sound stimulus can be modulated in amplitude, also over a wide range of frequencies. Likewise, foot-shock could be precisely manipulated regarding its amplitude (from ∼200 μA to ∼1500 μA) and frequency (up to 20 pulses per second). Finally, adult rats exposed to a protocol of cued fear conditioning in our device showed consistent behavioral response and electrophysiological evoked responses in the midbrain auditory pathway. Furthermore, the device developed in the current study represents an open source alternative to develop customized protocols to study fear memory under conditions of varied sensory stimuli.

The ability to recognize sounds in noise is a key part of hearing, and the mechanisms by which the brain identifies sounds in noise are of considerable interest to scientists, clinicians and engineers. Yet we know little about the necessity of regions such as auditory cortex for hearing in noise, or how cortical processing of sounds is adversely affected by noise. Here we used reversible cortical inactivation and extracellular electrophysiology in ferrets performing a vowel discrimination task to identify and understand the causal contribution of auditory cortex to hearing in noise. Cortical inactivation by cooling impaired task performance in noisy but not clean conditions, while responses of auditory cortical neurons were less informative about vowel identity in noise. Simulations mimicking cortical inactivation indicated that effects of inactivation were related to the loss of information about sounds represented across neural populations. The addition of noise to target sounds drove spiking activity in auditory cortex and recruitment of additional neural populations that were linked to degraded behavioral performance. To suppress noise-related activity, we used continuous exposure to background noise to adapt the auditory system and recover behavioral performance in both ferrets and humans. Inactivation by cooling revealed that the benefits of continuous exposure were not cortically dependent. Together our results highlight the importance of auditory cortex in sound discrimination in noise and the underlying mechanisms through which noise-related activity and adaptation shape hearing.

Scientists find how syllable timing and stress are represented in human speech cortex.

Manipulations that enhance neuroplasticity may inadvertently create opportunities for maladaptation. We have previously used passive exposures to non-traumatic white noise to open windows of plasticity in the adult rat auditory cortex and induce frequency-specific functional reorganizations of the tonotopic map. However, similar reorganizations in the central auditory pathway are thought to contribute to the generation of hearing disorders such as tinnitus and hyperacusis. Here, we investigate whether noise-induced reorganizations are accompanied by electrophysiological or behavioral evidence of tinnitus or hyperacusis in adult Long-Evans rats. We used a 2-week passive exposure to moderate-intensity (70 dB SPL) broadband white noise to reopen a critical period for spectral tuning such that a second 1-week exposure to 7 kHz tone pips produced an expansion of the 7 kHz frequency region in the primary auditory cortex (A1). We demonstrate for the first time that this expansion also takes place in the ventral auditory field (VAF). Sound exposure also led to spontaneous and sound-evoked hyperactivity in the anterior auditory field (AAF). Rats were assessed for behavioral evidence of tinnitus or hyperacusis using gap and tone prepulse inhibition of the acoustic startle response. We found that sound exposure did not affect gap-prepulse inhibition. However, sound exposure led to an improvement in prepulse inhibition when the prepulse was a 7 kHz tone, showing that exposed rats had enhanced sensorimotor gating for the exposure frequency. Together, our electrophysiological and behavioral results provide evidence of hyperacusis but not tinnitus in sound-exposed animals. Our findings demonstrate that periods of prolonged noise exposure may open windows of plasticity that can also be understood as windows of vulnerability, potentially increasing the likelihood for maladaptive plasticity to take place.

The gaseous free radical, nitric oxide ( NO ) acts as a ubiquitous neuromodulator, contributing to synaptic plasticity in a complex way that can involve either long term potentiation or depression. It is produced by neuronal nitric oxide synthase ( nNOS ) which is presynaptically expressed and also located postsynaptically in the membrane and cytoplasm of a subpopulation of each major neuronal type in the ventral cochlear nucleus ( VCN ). We have used iontophoresis in vivo to study the effect of the NOS inhibitor L‐ NAME (L‐ NG ‐Nitroarginine methyl ester) and the NO donors SIN ‐1 (3‐Morpholinosydnonimine hydrochloride) and SNOG (S‐Nitrosoglutathione) on VCN units under urethane anaesthesia. Collectively, both donors produced increases and decreases in driven and spontaneous firing rates of some neurones. Inhibition of endogenous NO production with L‐ NAME evoked a consistent increase in driven firing rates in 18% of units without much effect on spontaneous rate. This reduction of gain produced by endogenous NO was mirrored when studying the effect of L‐ NAME on NMDA ( N ‐Methyl‐D‐aspartic acid)‐evoked excitation, with 30% of units showing enhanced NMDA ‐evoked excitation during L‐ NAME application (reduced NO levels). Approximately 25% of neurones contain nNOS and the NO produced can modulate the firing rate of the main principal cells: medium stellates (choppers), large stellates (onset responses) and bushy cells (primary‐like responses). The main endogenous role of NO seems to be to partly suppress driven firing rates associated with NMDA channel activity but there is scope for it to increase neural gain if there were a pathological increase in its production following hearing loss.

Humans and other animals effortlessly identify natural sounds and categorize them into behaviorally relevant categories. Yet, the acoustic features and neural transformations that enable sound recognition and the formation of perceptual categories are largely unknown. Here, using multichannel neural recordings in the auditory midbrain of unanesthetized female rabbits, we first demonstrate that neural ensemble activity in the auditory midbrain displays highly structured correlations that vary with distinct natural sound stimuli. These stimulus-driven correlations can be used to accurately identify individual sounds using single-response trials, even when the sounds do not differ in their spectral content. Combining neural recordings and an auditory model, we then show how correlations between frequency-organized auditory channels can contribute to discrimination of not just individual sounds but sound categories. For both the model and neural data, spectral and temporal correlations achieved similar categorization performance and appear to contribute equally. Moreover, both the neural and model classifiers achieve their best task performance when they accumulate evidence over a time frame of approximately 1-2 seconds, mirroring human perceptual trends. These results together suggest that time-frequency correlations in sounds may be reflected in the correlations between auditory midbrain ensembles and that these correlations may play an important role in the identification and categorization of natural sounds.

The functional organization of human auditory cortex can be probed by characterizing responses to various classes of sound at different anatomical locations. Along with histological studies this approach has revealed a primary field in posteromedial Heschl's gyrus (HG) with pronounced induced high-frequency (70–150 Hz) activity and short-latency responses that phase-lock to rapid transient sounds. Low-frequency neural oscillations are also relevant to stimulus processing and information flow, however, their distribution within auditory cortex has not been established. Alpha activity (7–14 Hz) in particular has been associated with processes that may differentially engage earlier versus later levels of the cortical hierarchy, including functional inhibition and the communication of sensory predictions. These theories derive largely from the study of occipitoparietal sources readily detectable in scalp electroencephalography. To characterize the anatomical basis and functional significance of less accessible temporal-lobe alpha activity we analyzed responses to sentences in seven human adults (4 female) with epilepsy who had been implanted with electrodes in superior temporal cortex. In contrast to primary cortex in posteromedial HG, a non-primary field in anterolateral HG was characterized by high spontaneous alpha activity that was strongly suppressed during auditory stimulation. Alpha-power suppression decreased with distance from anterolateral HG throughout superior temporal cortex, and was more pronounced for clear compared to degraded speech. This suppression could not be accounted for solely by a change in the slope of the power spectrum. The differential manifestation and stimulus-sensitivity of alpha oscillations across auditory fields should be accounted for in theories of their generation and function. SIGNIFICANCE STATEMENT To understand how auditory cortex is organized in support of perception, we recorded from patients implanted with electrodes for clinical reasons. This allowed measurement of activity in brain regions at different levels of sensory processing. Oscillations in the alpha range (7–14 Hz) have been associated with functions including sensory prediction and inhibition of regions handling irrelevant information, but their distribution within auditory cortex is not known. A key finding was that these oscillations dominated in one particular non-primary field, anterolateral Heschl's gyrus, and were suppressed when subjects listened to sentences. These results build on our knowledge of the functional organization of auditory cortex and provide anatomical constraints on theories of the generation and function of alpha oscillations.

Neural adaptation enables sensory information to be represented optimally in the brain despite large fluctuations over time in the statistics of the environment. Auditory contrast gain control represents an important example, which is thought to arise primarily from cortical processing. We find, however, that neurons in both the auditory thalamus and midbrain of mice show robust contrast gain control, and that this is implemented independently of cortical activity. Although neurons at each level exhibit contrast gain control to similar degrees, adaptation time constants become longer at later stages of the processing hierarchy, resulting in progressively more stable representations. We also show that auditory discrimination thresholds in human listeners compensate for changes in contrast, and that the strength of this perceptual adaptation can be predicted from physiological measurements. Contrast adaptation is therefore a robust property of both the subcortical and cortical auditory system and accounts for the short-term adaptability of perceptual judgments.

Auditory cortex is required for sound localisation, but how neural firing in auditory cortex underlies our perception of sound sources in space remains unclear. Specifically, whether neurons in auditory cortex represent spatial cues or an integrated representation of auditory space across cues is not known. Here, we measured the spatial receptive fields of neurons in primary auditory cortex (A1) while ferrets performed a relative localisation task. Manipulating the availability of binaural and spectral localisation cues had little impact on ferrets’ performance, or on neural spatial tuning. A subpopulation of neurons encoded spatial position consistently across localisation cue type. Furthermore, neural firing pattern decoders outperformed two-channel model decoders using population activity. Together, these observations suggest that A1 encodes the location of sound sources, as opposed to spatial cue values.

The accuracy of the neural code depends on the relative embedding of signal and noise in the activity of neural populations. Despite a wealth of theoretical work on population codes, there are few empirical characterizations of the high-dimensional signal and noise subspaces. We studied the geometry of population codes in the rat auditory cortex across brain states along the activation-inactivation continuum, using sounds varying in difference and mean level across the ears. As the cortex becomes more activated, single-hemisphere populations go from preferring contralateral loud sounds to a symmetric preference across lateralizations and intensities, gain-modulation effectively disappears, and the signal and noise subspaces become approximately orthogonal to each other and to the direction corresponding to global activity modulations. Level-invariant decoding of sound lateralization also becomes possible in the active state. Our results provide an empirical foundation for the geometry and state-dependence of cortical population codes.