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The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl’s gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli.

Physical exercise acutely improves hippocampal-based learning and memory in rodents and humans. While animal studies have mainly offered cellular- and synaptic-level accounts of these effects, human neuroimaging studies show that exercise improves hippocampal-cortical connectivity at the macroscale level. However, the neurophysiological basis for exercise-induced effects on human hippocampal-cortical circuits remains unknown. A growing body of evidence supports the critical role of hippocampal sharp wave-ripples (SWRs) in learning and memory. Moreover, recent studies suggest that the coupling between ripples in the hippocampus and neocortex reflect acute modulations in inter-regional connectivity required by mnemonic processes. Here, we examine the hypothesis that exercise modulates hippocampal SWR events and their coupling with ripples in other cortical areas. We performed intracranial recordings in neurosurgery patients during awake resting state, before and after one session of aerobic exercise. Exercise elicited an increase in ripple rate and duration in mesio-temporal areas (hippocampus, amygdala and parahippocampal gyrus). These changes in ripple features were also observed in the limbic and the default mode (DMN) networks. Furthermore, after exercise, we observed an increase in coupling and phase synchrony between ripples in these two networks and hippocampal SWRs. Our results elucidate the potential mechanisms by which aerobic exercise elicits its reported short-term effects in cognition. Further investigations are needed to explore how these exercise-induced acute modulations contribute to long-term changes in neural plasticity.Significance StatementPhysical activity is a modifiable lifestyle factor that improves cognitive function and prevents age-related cognitive decline. Even one session of exercise can enhance hippocampal-based memory and learning. However, the neurophysiological mechanisms by which exercise acutely affects human cognition remain unknown. Using intracranial recordings in neurosurgical patients we show that the hippocampus and neocortex often synchronize their activities via high-frequency neural synchrony events known as ripples. After exercise, hippocampal and neocortical ripples were prolonged and emerged more frequently. Moreover, hippocampal and neocortical ripples exhibited increased coupling and phase synchrony. These effects were neocortical region-specific, favoring structures of the limbic and default mode networks. Ultimately, our results shed light on the mechanisms behind the preventive and therapeutic potential of exercise interventions.

The value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time. We present evidence of locally distributed representations of reward and risk variables that are temporally organized across multiple regions of interest. Reward outcome representations across wide-spread regions follow a temporally cascading order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We highlight the role of the anterior insula in generalizing between reward prediction error (RePE) and risk prediction error (RiPE), within which the encoding of RePE in the distributed iEEG signal predicts RiPE. Together our results emphasize the utility of uncovering temporal dynamics in the human brain for understanding how computational processes critical for value-based decisions under uncertainty unfold.

Misophonia is a common disorder characterized by the experience of strong negative emotions of anger and anxiety in response to certain everyday sounds, such as those generated by other people eating, drinking, and breathing. The commonplace nature of these “trigger” sounds makes misophonia a devastating disorder for sufferers and their families. How such innocuous sounds trigger this response is unknown. Since most trigger sounds are generated by orofacial movements (e.g., chewing) in others, we hypothesized that the mirror neuron system related to orofacial movements could underlie misophonia. We analyzed resting state fMRI (rs-fMRI) connectivity (N = 33, 16 females) and sound-evoked fMRI responses (N = 42, 29 females) in misophonia sufferers and controls. We demonstrate that, compared with controls, the misophonia group show no difference in auditory cortex responses to trigger sounds, but do show: (1) stronger rs-fMRI connectivity between both auditory and visual cortex and the ventral premotor cortex responsible for orofacial movements; (2) stronger functional connectivity between the auditory cortex and orofacial motor area during sound perception in general; and (3) stronger activation of the orofacial motor area, specifically, in response to trigger sounds. Our results support a model of misophonia based on “hyper-mirroring” of the orofacial actions of others with sounds being the “medium” via which action of others is excessively mirrored. Misophonia is therefore not an abreaction to sounds, per se, but a manifestation of activity in parts of the motor system involved in producing those sounds. This new framework to understand misophonia can explain behavioral and emotional responses and has important consequences for devising effective therapies. SIGNIFICANCE STATEMENT Conventionally, misophonia, literally “hatred of sounds” has been considered as a disorder of sound emotion processing, in which “simple” eating and chewing sounds produced by others cause negative emotional responses. Our data provide an alternative but complementary perspective on misophonia that emphasizes the action of the trigger-person rather than the sounds which are a byproduct of that action. Sounds, in this new perspective, are only a “medium” via which action of the triggering-person is mirrored onto the listener. This change in perspective has important consequences for devising therapies and treatment methods for misophonia. It suggests that, instead of focusing on sounds, which many existing therapies do, effective therapies should target the brain representation of movement.

ObjectivesCochlear implant (CI) users exhibit a large variance in understanding speech in noise (SiN). Past works in CI users found that spectral and temporal resolutions correlate with the SiN ability, but a large portion of variance has been remaining unexplained. Our group’s recent work on normal-hearing listeners showed that the ability of grouping temporally coherent tones in a complex auditory scene predicts SiN ability, highlighting a central mechanism of auditory scene analysis that contributes to SiN. The current study examined whether the auditory grouping ability contributes to SiN understanding in CI users as well.Design47 post-lingually deafened CI users performed multiple tasks including sentence-in-noise understanding, spectral ripple discrimination, temporal modulation detection, and stochastic figure-ground task in which listeners detect temporally coherent tone pips in the cloud of many tone pips that rise at random times at random frequencies. Accuracies from the latter three tasks were used as predictor variables while the sentence-in-noise performance was used as the dependent variable in a multiple linear regression analysis.ResultsNo co-linearity was found between any predictor variables. All the three predictors exhibited significant contribution in the multiple linear regression model, indicating that the ability to detect temporal coherence in a complex auditory scene explains a further amount of variance in CI users’ SiN performance that was not explained by spectral and temporal resolution.ConclusionsThis result indicates that the across-frequency comparison builds an important auditory cognitive mechanism in CI users’ SiN understanding. Clinically, this result proposes a novel paradigm to reveal a source of SiN difficulty in CI users and a potential rehabilitative strategy.

Transcranial magnetic stimulation (TMS) is increasingly used as a noninvasive technique for neuromodulation in research and clinical applications, yet its mechanisms are not well understood. Here, we present the first in-human study evaluating the effects of TMS using intracranial electrocorticography (iEEG) in neurosurgical patients. We first evaluated safety in a gel-based phantom. We then performed TMS-iEEG in 20 neurosurgical participants with no adverse events. Next, we evaluated brain-wide intracranial responses to single pulses of TMS to the dorsolateral prefrontal cortex (dlPFC) (N=10, 1414 electrodes). We demonstrate that TMS preferentially induces neuronal responses locally within the dlPFC at sites with higher electric field strength. Evoked responses were also noted downstream in the anterior cingulate and anterior insular cortex, regions functionally connected to the dlPFC. These findings support the safety and promise of TMS-iEEG in humans to examine local and network-level effects of TMS with higher spatiotemporal resolution than currently available methods.

The perception of pitch requires the abstraction of stimulus properties related to the spectrotemporal structure of sound. Previous studies utilizing both animal electrophysiology and human imaging have indicated the presence of a center for pitch representation in the auditory cortex. Recent data from our own group - examining local field potentials (LFPs) in humans - indicate more widely distributed pitch-associated responses within the auditory cortex (Gander et al., 2019). To probe this with greater spatial resolution, we examined multi-unit activity related to three different auditory stimuli, in seven epilepsy patients who were implanted with high-impedance electrodes in auditory cortex for the clinical purpose of localizing seizures. The stimuli were regular-interval noise (RIN) with a pitch strength that is related to the temporal regularity, and pitch value determined by repetition rate, and harmonic complexes with missing fundamentals. We demonstrated increases in spiking activity in 69 of 104 (66%) responsive multiunit activity in auditory cortex due to pitch-associated stimuli. Importantly, these responses were distributed across the entire extent of Heschl’s gyrus (HG), in both primary and non-primary areas, rather than isolated to a specific region, and this finding was evident regardless of the stimulus presented. These findings are the first multi-unit pitch responses recorded from humans, and align with a recent study in macaques (Kikuchi et al., 2019) demonstrating that both local field potential and unit responses to pitch-inducing stimuli are distributed throughout auditory cortex.Significance StatementThe perception of pitch is a fundamental acoustic attribute that is mediated by the auditory system. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to differences in the recording measures and choices of stimuli used in previous studies. Here, we present the first study to measure multi-unit pitch responses in the auditory cortices of intracranially-implanted humans. Importantly, we demonstrate reliable responses to three different pitch-inducing paradigms that are distributed throughout Heschl’s gyrus, rather than being localized to a particular region. These data provide a bridge across animal and human studies, and aid in our understanding of the processing of a critical attribute of acoustic stimuli.

Speech perception (especially in background noise) is a critical problem for hearing-impaired listeners and an important issue for cognitive hearing science. Despite a plethora of standardized measures, few single-word closed-set tests uniformly sample the most frequently used phonemes and use response choices that equally sample phonetic features like place and voicing. The Iowa Test of Consonant Perception (ITCP) attempts to solve this. It is a proportionally balanced phonemic word recognition task designed to assess perception of the initial consonant of monosyllabic consonant-vowel-consonant (CVC) words. The ITCP consists of 120 sampled CVC words. Words were recorded from four different talkers (two female) and uniformly sampled from all four quadrants of the vowel space to control for coarticulation. Response choices on each trial are balanced to equate difficulty and sample a single phonetic feature. This study evaluated the psychometric properties of ITCP by examining reliability (test-retest) and validity in a sample of online normal-hearing participants. Ninety-eight participants completed two sessions of the ITCP along with standardized tests of words and sentence in noise (CNC words and AzBio sentences). The ITCP showed good test-retest reliability and convergent validity with two popular tests presented in noise. All the materials to use the ITCP or to construct your own version of the ITCP are freely available [Geller, McMurray, Holmes, and Choi (2020). https://osf.io/hycdu/].

We tested the popular, unproven theory that tinnitus is caused by resetting of auditory predictions toward a persistent low-intensity sound. Electroencephalographic mismatch negativity responses, which quantify the violation of sensory predictions, to unattended tinnitus-like sounds were greater in response to upward than downward intensity deviants in 26 unselected chronic tinnitus subjects with normal to severely impaired hearing, and in 15 acute tinnitus subjects, but not in 26 hearing and age-matched controls (p< 0.001, receiver operator characteristic, area under the curve, 0.77), or in 20 healthy and hearing-impaired controls presented with simulated tinnitus. The findings support a prediction resetting model of tinnitus generation, and may form the basis of a convenient tinnitus biomarker, which we name Intensity Mismatch Asymmetry, which is usable across species, is quick and tolerable, and requires no training.SIGNIFICANCE STATEMENTIn current models, perception is based around the generation of internal predictions of the environment, which are tested and updated using evidence from the senses. Here, we test the theory that auditory phantom perception (tinnitus) occurs when a default auditory prediction is formed to explain spontaneous activity in the subcortical pathway, rather than ignoring it as noise. We find that chronic tinnitus patients show an abnormal pattern of evoked responses to unexpectedly loud and quiet sounds that both supports this hypothesis and provides fairly accurate classification of tinnitus status at the individual subject level. This approach to objectively demonstrating the predictions underlying pathological perceptual states may also have a much wider utility, for instance, in chronic pain.

ObjectivesUnderstanding speech in noise (SiN) is a complex task that recruits multiple cortical subsystems. Individuals vary in their ability to understand SiN. This cannot be explained by simple peripheral hearing profiles, but recent work by our group (Kim et al., 2021, Neuroimage) highlighted central neural factors underlying the variance in SiN ability in normal hearing (NH) subjects. The current study examined neural predictors of speech-in-noise ability in a large cohort of cochlear-implant (CI) users, with the long-term goal of developing a simple electrophysiological correlate that could be implemented in clinics.DesignWe recorded electroencephalography (EEG) in 114 post-lingually deafened CI users while they completed the California Consonant Test (CCT): a word-in-noise task. In many subjects, data were also collected on two other commonly used clinical measures of speech perception: a word-in-quiet task (Consonant-Nucleus-Consonant [CNC]) word and a sentence-in-noise task (AzBio sentences). Neural activity was assessed at a single vertex electrode (Cz), to maximize generalizability to clinical situations. The N1-P2 complex of event-related potentials (ERPs) at this location were included in multiple linear regression analyses, along with several other demographic and hearing factors as predictors of speech in noise performance.ResultsIn general, there was a good agreement between the scores on the three speech perception tasks. ERP amplitudes did not predict AzBio performance which was predicted by the duration of device use, low-frequency hearing thresholds, and age. However, ERP amplitudes were strong predictors for performance for both word recognition tasks: the CCT (which was conducted simultaneously with EEG recording), and the CNC (conducted offline). These correlations held even after accounting for known predictors of performance including residual low-frequency hearing thresholds. In CI-users, better performance was predicted by an increased cortical response to the target word, in contrast to previous reports in normal-hearing subjects in whom speech perception ability was accounted for by the ability to suppress noise.ConclusionsThese data indicate a neurophysiological correlate of speech-in-noise performance that can be relatively easily captured within the clinic, thereby revealing a richer profile of an individual’s hearing performance than shown by psychoacoustic measures alone. These results also highlight important differences between sentence and word recognition measures of performance and suggest that individual differences in these measures may be underwritten by different mechanisms. Finally, the contrast with prior reports of NH listeners in the same task suggests CI-users performance may be explained by a different weighting of neural processes than NH listeners.

SUMMARYNon-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease.

Non-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease.

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., Highlights • Local field potentials recorded in humans while they keep sound in working memory. • Sustained increase in delta power observed in primary auditory cortex. • Pattern of change in power in non-primary cortex depends on the hierarchical level. • Hippocampus and parahippocampus showed increase in low frequency power.

Speech motor control requires integration of sensory and motor information. Bidirectional communication between frontal and auditory cortices is crucial for speech production, self-monitoring and motor control. We used cortical direct electrical stimulation (DES) to functionally dissect audio-motor interactions underlying speech production and motor control. Eleven neurosurgical patients performed a visually cued vocal task in which a short auditory feedback perturbation was introduced during vocalization. We evaluated the effect of DES on vocal initiation, voice fundamental frequency (F0) and feedback-dependent motor control. DES of frontal sites modulated vocal onset latencies. Stimulation of different inferior frontal gyrus sites elicited either shortening or prolongation of vocal latencies. DES distinctly modulated voice F0 at different vocalization stages. Frontal and temporal areas played an important role in setting voice F0 in the first 250 ms of an utterance, while Heschls gyrus was involved later when auditory input is available for self-monitoring. Vocal responses to pitch-shifted auditory feedback were mostly reduced by DES of non-core auditory cortices. Overall, we demonstrate that vocal planning and initiation are driven by frontal cortices, while feedback-dependent control relies predominantly on non-core auditory cortices. Our findings represent direct evidence of the role played by different auditory and frontal regions in vocal motor control.

Musicogenic epilepsy (ME) is an extremely rare form of the disorder that is provoked by listening to or playing music, and it has been localized to the temporal lobe. The number of reported cases of ME in which intracranial electroencephalography (iEEG) has been used for seizure focus localization is extremely small, especially with coverage of the superior temporal plane (STP) and specifically, Heschl’s gyrus (HG). The authors describe the case of a 17-year-old boy with a history of medically intractable ME who underwent iEEG monitoring that involved significant frontotemporal coverage as well as coverage of the STP with an HG depth electrode anteriorly and a planum temporale depth electrode posteriorly. Five seizures occurred during the monitoring period, and a seizure onset zone was localized to HG and the STP. The patient subsequently underwent right temporal neocortical resection, involving the STP and including HG, with preservation of the mesial temporal structures. The patient remains seizure free 1 year postoperatively. To the authors’ knowledge, this is the first reported case of ME in which the seizure focus has been localized to HG and the STP with iEEG monitoring. The authors review the literature on iEEG findings in ME, explain their approach to HG depth electrode placement, and discuss the utility of STP depth electrodes in temporal lobe epilepsy.

Natural environments elicit both phase-locked and non-phase-locked neural responses to the stimulus in the brain. The interpretation of the BOLD signal to date has been based on an association of the non-phase-locked power of high-frequency local field potentials (LFPs), or the related spiking activity in single neurons or groups of neurons. Previous studies have not examined the prediction of the BOLD signal by phase-locked responses. We examined the relationship between the BOLD response and LFPs in the same nine human subjects from multiple corresponding points in the auditory cortex, using amplitude modulated pure tone stimuli of a duration to allow an analysis of phase locking of the sustained time period without contamination from the onset response. The results demonstrate that both phase locking at the modulation frequency and its harmonics, and the oscillatory power in gamma/high-gamma bands are required to predict the BOLD response. Biophysical models of BOLD signal generation in auditory cortex therefore require revision and the incorporation of both phase locking to rhythmic sensory stimuli and power changes in the ensemble neural activity.

Roughly 10–15% of the general population is affected by tinnitus and this percentage is estimated to rise in future. Because there is currently no cure for tinnitus, treatment is limited and is primarily achieved through management of symptoms and counseling.This study compared audiologists’ and patients’ responses to related survey questions about their expectations regarding tinnitus treatment. Two separate surveys were created, one for patients with tinnitus, and one for practicing audiologists who may treat such patients. The surveys included several related questions, such that comparison of the two could reveal where patients’ and audiologists’ expectations for tinnitus care were in agreement and areas in which they differed.The surveys for audiologists and adults with tinnitus were 31- and 38-item questionnaires, respectively. Both surveys comprised demographic questions followed by several tinnitus-related questions in either multiple-choice or Likert-scale format.We received 230 completed Patient Surveys and 68 completed Audiologist Surveys.All survey recruitment was completed online. Responses were collected via the Survey Monkey web tool (http://www.surveymonkey.com/). Responses were analyzed within and between surveys and grouped into topical categories (assessment, counseling, current available tinnitus information, satisfaction and expectations, improving tinnitus management). For data within each survey, descriptive statistics and correlation analyses were used. For selected comparisons between surveys, cross-tabulations were used. Hierarchical regression modeling was conducted to further explore (1) the perceived effectiveness of treatment received, and (2) how each group defined treatment success.Differences were noted between the two groups’ responses to the question on the definition of treatment success; audiologists reported decreased awareness (77%), stress/anxiety relief (63%), and increased knowledge of tinnitus (63%) most commonly, whereas patients reported reduction of tinnitus loudness (63%) and complete elimination of tinnitus (57%) most often. The topic of greatest agreement was the desire for more information on tinnitus; 62% of patients felt more information from their healthcare provider would be the most important factor for improved tinnitus management, and 67% of audiologists reported currently having “some access” or less to appropriate resources for tinnitus treatment. Modeling results for effective tinnitus management and definitions of treatment success highlighted the importance of resource access and information sharing for both audiologists and patients.Patients and audiologists differed in terms of their expectations for successful treatment, with the patients focusing on perceptual factors and the audiologists on the reaction to the sound. Patient satisfaction with tinnitus treatment may be improved through access to more information, specifically, more information about current tinnitus treatment options and how these focus on the patient’s reaction to the tinnitus rather than the percept itself. Providing credible tinnitus information resources to audiologists, and focusing resources on training a small number of tinnitus specialist audiologists could greatly improve patient satisfaction with the current state of tinnitus palliative care.

Understanding speech in noise (SiN) is a complex task that recruits multiple cortical subsystems. There is a variance in individuals’ ability to understand SiN that cannot be explained by simple hearing profiles, which suggests that central factors may underlie the variance in SiN ability. Here, we elucidated a few cortical functions involved during a SiN task and their contributions to individual variance using both within- and across-subject approaches. Through our within-subject analysis of source-localized electroencephalography, we investigated how acoustic signal-to-noise ratio (SNR) alters cortical evoked responses to a target word across the speech recognition areas, finding stronger responses in left supramarginal gyrus (SMG, BA40 the dorsal lexicon area) with quieter noise. Through an individual differences approach, we found that listeners show different neural sensitivity to the background noise and target speech, reflected in the amplitude ratio of earlier auditory-cortical responses to speech and noise, named as an internal SNR. Listeners with better internal SNR showed better SiN performance. Further, we found that the post-speech time SMG activity explains a further amount of variance in SiN performance that is not accounted for by internal SNR. This result demonstrates that at least two cortical processes contribute to SiN performance independently: pre-target time processing to attenuate neural representation of background noise and post-target time processing to extract information from speech sounds.

This work sought correlates of pitch perception, defined by neural activity above the lower limit of pitch (LLP), in auditory cortical neural ensembles, and examined their topographical distribution. Local field potentials (LFPs) were recorded in eight patients undergoing invasive recordings for pharmaco-resistant epilepsy. Stimuli consisted of bursts of broadband noise followed by regular interval noise (RIN). RIN was presented at rates below and above the LLP to distinguish responses related to the regularity of the stimulus and the presence of pitch itself. LFPs were recorded from human cortical homologues of auditory core, belt, and parabelt regions using multicontact depth electrodes implanted in Heschl’s gyrus (HG) and Planum Temporale (PT), and subdural grid electrodes implanted over lateral superior temporal gyrus (STG). Evoked responses corresponding to the temporal regularity of the stimulus were assessed using autocorrelation of the evoked responses, and occurred for stimuli below and above the LLP. Induced responses throughout the high gamma range (60–200 Hz) were present for pitch values above the LLP, with onset latencies of approximately 70 ms. Mapping of the induced responses onto a common brain space demonstrated variability in the topographical distribution of high gamma responses across subjects. Induced responses were present throughout the length of HG and on PT, which is consistent with previous functional neuroimaging studies. Moreover, in each subject, a region within lateral STG showed robust induced responses at pitch-evoking stimulus rates. This work suggests a distributed representation of pitch processing in neural ensembles in human homologues of core and non-core auditory cortex.

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 (four 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 StatementTo 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.

Background: Windowed Fourier decompositions (WFD) are widely used in measuring stationary and non-stationary spectral phenomena and in describing pairwise relationships among multiple signals. Although a variety of WFDs see frequent application in electrophysiological research, including the short-time Fourier transform, continuous wavelets, band-pass filtering and multitaper-based approaches, each carries certain drawbacks related to computational efficiency and spectral leakage. This work surveys the advantages of a WFD not previously applied in electrophysiological settings. New Methods: A computationally efficient form of complex demodulation, the demodulated band transform (DBT), is described. Results: DBT is shown to provide an efficient approach to spectral estimation with minimal susceptibility to spectral leakage. In addition, it lends itself well to adaptive filtering of non-stationary narrowband noise. Comparison with existing methods: A detailed comparison with alternative WFDs is offered, with an emphasis on the relationship between DBT and Thomson's multitaper. DBT is shown to perform favorably in combining computational efficiency with minimal introduction of spectral leakage. Conclusion: DBT is ideally suited to efficient estimation of both stationary and non-stationary spectral and cross-spectral statistics with minimal susceptibility to spectral leakage. These qualities are broadly desirable in many settings., Comment: This version fixes a number of minor errors and typos

The organisation of pitch-perception mechanisms in the primate cortex is controversial, in that divergent results have been obtained, ranging from a single circumscribed ‘pitch centre’ to systems widely distributed across auditory cortex. Possible reasons for such discrepancies include different species, recording techniques, pitch stimuli, sampling of auditory fields, and the neural metrics recorded. In the present study, we sought to bridge some of these divisions by examining activity related to pitch in both neurons and neuronal ensembles within the auditory cortex of the rhesus macaque, a primate species with similar pitch perception and auditory cortical organisation to humans. We demonstrate similar responses, in primary and non-primary auditory cortex, to two different types of broadband pitch above the macaque lower limit in both neurons and local field potential (LFP) gamma oscillations. The majority of broadband pitch responses in neurons and LFP sites did not show equivalent tuning for sine tones.

It has been proposed that tinnitus is generated by aberrant neural activity that develops among neurons in tonotopic of regions of primary auditory cortex (A1) affected by hearing loss, which is also the frequency region where tinnitus percepts localize ( Eggermont and Roberts, 2004 , Roberts et al., 2010 , Roberts et al., 2013 ). These models suggest (1) that differences between tinnitus and control groups of similar age and audiometric function should depend on whether A1 is probed in tinnitus frequency region (TFR) or below it, and (2) that brain responses evoked from A1 should track changes in the tinnitus percept when residual inhibition (RI) is induced by forward masking. We tested these predictions by measuring (128-channel EEG) the sound-evoked 40-Hz auditory steady-state response (ASSR) known to localize tonotopically to neural sources in A1. For comparison the N1 transient response localizing to distributed neural sources in nonprimary cortex (A2) was also studied. When tested under baseline conditions where tinnitus subjects would have heard their tinnitus, ASSR responses were larger in a tinnitus group than in controls when evoked by 500 Hz probes while the reverse was true for tinnitus and control groups tested with 5 kHz probes, confirming frequency-dependent group differences in this measure. On subsequent trials where RI was induced by masking (narrow band noise centered at 5 kHz), ASSR amplitude increased in the tinnitus group probed at 5 kHz but not in the tinnitus group probed at 500 Hz. When collapsed into a single sample tinnitus subjects reporting comparatively greater RI depth and duration showed comparatively larger ASSR increases after masking regardless of probe frequency. Effects of masking on ASSR amplitude in the control groups were completely reversed from those in the tinnitus groups, with no change seen to 5 kHz probes but ASSR increases to 500 Hz probes even though the masking sound contained no energy at 500 Hz (an “off-frequency” masking effect). In contrast to these findings for the ASSR, N1 amplitude was larger in tinnitus than control groups at both probe frequencies under baseline conditions, decreased after masking in all conditions, and did not relate to RI. These results suggest that aberrant neural activity occurring in the TFR of A1 underlies tinnitus and its modulation during RI. They indicate further that while neural changes occur in A2 in tinnitus, these changes do not reflect the tinnitus percept. Models for tinnitus and forward masking are described that integrate these findings within a common framework.

PurposeThe use of acoustic stimuli to reduce the prominence of tinnitus has been used for decades. Counseling and tinnitus sound therapy options are not currently widespread for cochlear implant (CI) users. The goal of this study was to determine whether tinnitus therapy sounds created for individuals with acoustic hearing may also benefit CI users.MethodSixteen sounds from the ReSound Relief app (Version 3.0) were selected for the study. Sixteen participants were asked to rate the overall acceptability of each sound and to write the description of the sound they perceived. Sounds were streamed from an Apple™ iPod (6th generation) to the CI using a Cochlear™ Wireless Mini Microphone 2+. Thirteen participants then completed a 5-min trial where they rated their pretrial and posttrial tinnitus and the acceptability of a subset of preferred sounds. Ten out of these 13 participants completed a 2-week home trial with a preferred sound after which they answered an online tinnitus questionnaire and rated the effectiveness of the sound therapy.ResultsIndividual differences were large. Results from the 5-min trial showed that sounds perceived as rain, music, and waves were rated the most acceptable. For all of the participants, the posttrial tinnitus loudness rating was lower than the pretrial rating, with some participants experiencing greater difference in their tinnitus loudness than others. At the end of the 2-week home trial, 3 of 10 participants rated the effectiveness of sound therapy 70% or higher.ConclusionThe results suggest that the use of tinnitus therapy sounds delivered through a CI can be acceptable and provides relief for some tinnitus sufferers.

OBJECTIVEThe epileptogenic zones in some patients with temporal lobe epilepsy (TLE) involve regions outside the typical extent of anterior temporal lobectomy (i.e., “temporal plus epilepsy”), including portions of the supratemporal plane (STP). Failure to identify this subset of patients and adjust the surgical plan accordingly results in suboptimum surgical outcomes. There are unique technical challenges associated with obtaining recordings from the STP. The authors sought to examine the clinical utility and safety of placing depth electrodes within the STP in patients with TLE.METHODSThis study is a retrospective review and analysis of all cases in which patients underwent intracranial electroencephalography (iEEG) with use of at least one STP depth electrode over the 10 years from January 2006 through December 2015 at University of Iowa Hospitals and Clinics. Basic clinical information was collected, including the presence of ictal auditory symptoms, electrode coverage, monitoring results, resection extent, outcomes, and complications. Additionally, cases in which the temporal lobe was primarily or secondarily involved in seizure onset and propagation were categorized based upon how rapidly epileptic activity was observed within the STP following seizure onsets: within 1 second, between 1 and 15 seconds, after 15 seconds, and not involved.RESULTSFifty-two patients underwent iEEG with STP coverage, with 1 STP electrode used in 45 (86.5%) cases and 2 STP electrodes in the other cases. There were no complications related to STP electrode placement. Of 42 cases in which the temporal lobe was primarily or secondarily involved, seizure activity was recorded from the STP in 36 cases (85.7%): in 5 cases (11.9%) within 1 second, in 5 (11.9%) between 1 and 15 seconds, and in 26 (61.9%) more than 15 seconds following seizure onset. Seizure outcomes inversely correlated with rapid ictal involvement of the STP (Engel class I achieved in 25%, 67%, and 82% of patients in the above categories, respectively). All patients without ictal STP involvement achieved seizure freedom. Only 4 (11.1%) patients with STP ictal involvement reported auditory symptoms.CONCLUSIONSIctal involvement of the STP is common even in the absence of auditory symptoms and can be effectively detected by the STP electrodes. These electrodes are safe to implant and provide useful prognostic information.

Open access article Tinnitus is often associated with strong negative thoughts and emotions which can contribute to a distressing and chronic long-term condition. The amygdala, the “feeling and reacting” part of the brain, may play a key role in this process. Although implicated in several theoretical models of tinnitus, quantification of activity in the human amygdala has only been made possible more recently through neuroimaging methods such as functional magnetic resonance imaging (fMRI) but benefits from modified scanning parameters using a double-echo acquisition for improved BOLD sensitivity. This study thus examined the role of the amygdala in emotional sound processing in people with tinnitus using a novel double-echo imaging sequence for optimal detectability of subcortical activity. Our hypotheses were: (1) emotionally evocative sound clips rated as pleasant or unpleasant would elicit stronger amygdalar activation than sound clips rated as neutral, (2) people with tinnitus have greater amygdalar activation in response to emotionally evocative sounds (relative to neutral sounds) compared to controls. Methods: Twelve participants all with chronic, constant tinnitus took part. We also recruited 11 age and hearing-matched controls. Participants listened to a range of emotionally evocative sound clips; rated as pleasant, unpleasant or neutral. A region-of-interest analysis was chosen to test our a priori hypotheses. Results: Both groups displayed a robust and similar overall response to sounds vs. silence in the following ascending auditory pathways; inferior colliculus, medial geniculate body and the primary auditory cortex. In support of our first hypothesis, the amygdala's response to pleasant and unpleasant sound clips was significantly greater than neutral sounds. Opposing our second hypothesis, we found that the amygdala's overall response to pleasant and unpleasant sounds (compared to neutral sounds) was actually lower in the tinnitus group as compared to the controls. Conclusions: The “muted” amygdala activation observed in the tinnitus group could reflect an internal modification of emotional response perhaps as a result of successful habituation to emotionally negative sound. This interpretation would predict a heightened amygdala emotional response in individuals with a more clinically bothersome tinnitus

Generative models, such as predictive coding, posit that perception results from a combination of sensory input and prior prediction, each weighted by its precision (inverse variance), with incongruence between these termed prediction error (deviation from prediction) or surprise (negative log probability of the sensory input). However, direct evidence for such a system, and the physiological basis of its computations, is lacking. Using an auditory stimulus whose pitch value changed according to specific rules, we controlled and separated the three key computational variables underlying perception, and discovered, using direct recordings from human auditory cortex, that surprise due to prediction violations is encoded by local field potential oscillations in the gamma band (>30 Hz), changes to predictions in the beta band (12-30 Hz), and that the precision of predictions appears to quantitatively relate to alpha band oscillations (8-12 Hz). These results confirm oscillatory codes for critical aspects of generative models of perception. DOI: http://dx.doi.org/10.7554/eLife.11476.001, eLife digest Our perception of the world is not only based on input from our senses. Instead, what we perceive is also heavily altered by the context of what is being sensed and our expectations about it. Some researchers have suggested that perception results from combining information from our senses and our predictions. This school of thought, referred to as “predictive coding”, essentially proposed that the brain stores a model of the world and weighs it up against information from our senses in order to determine what we perceive. Nevertheless, direct evidence for the brain working in this way was still missing. While neuroscientists had seen the brain respond when there was a mismatch between an expectation and incoming sensory information, no one has observed the predictions themselves within the brain. Sedley et al. now provide such direct evidence for predictions about upcoming sensory information, by directly recording the electrical activity in the brains of human volunteers who were undergoing surgery for epilepsy. The experiment made use of a new method in which the volunteers listened to a sequence of sounds that was semi-predictable. That is to say that, at first, the volunteers heard a selection of similarly pitched sounds. After random intervals, the average pitch of these sounds changed and they became more or less variable for a while before randomly changing again. This approach meant that the volunteers had to continually update their predictions throughout the experiment In keeping with previous studies, the unexpected sounds, which caused a mismatch between the sensory information and the brain’s prediction, were linked to high-frequency brainwaves. However, Sedley et al. discovered that updating the predictions themselves was linked to middle-frequency brainwaves; this confirms what the predictive coding model had suggested. Finally, this approach also unexpectedly revealed that how confident the volunteer was about the prediction was linked to low-frequency brainwaves. In the future, this new method will provide an easy way of directly studying elements of perception in humans and, since the experiments do not require complex learning, in other animals too. DOI: http://dx.doi.org/10.7554/eLife.11476.002

The brain basis for auditory working memory, the process of actively maintaining sounds in memory over short periods of time, is controversial. Using functional magnetic resonance imaging in human participants, we demonstrate that the maintenance of single tones in memory is associated with activation in auditory cortex. In addition, sustained activation was observed in hippocampus and inferior frontal gyrus. Multivoxel pattern analysis showed that patterns of activity in auditory cortex and left inferior frontal gyrus distinguished the tone that was maintained in memory. Functional connectivity during maintenance was demonstrated between auditory cortex and both the hippocampus and inferior frontal cortex. The data support a system for auditory working memory based on the maintenance of sound-specific representations in auditory cortex by projections from higher-order areas, including the hippocampus and frontal cortex.In this work, we demonstrate a system for maintaining sound in working memory based on activity in auditory cortex, hippocampus, and frontal cortex, and functional connectivity among them. Specifically, our work makes three advances from the previous work. First, we robustly demonstrate hippocampal involvement in all phases of auditory working memory (encoding, maintenance, and retrieval): the role of hippocampus in working memory is controversial. Second, using a pattern classification technique, we show that activity in the auditory cortex and inferior frontal gyrus is specific to the maintained tones in working memory. Third, we show long-range connectivity of auditory cortex to hippocampus and frontal cortex, which may be responsible for keeping such representations active during working memory maintenance.

Rationale, aim and objective Effective tinnitus management starts with appropriate general practitioner (GP) triage, which in England can be guided by the Department of Health's Good Practice Guide (GPG). Despite the prevalence of the condition, there has never been a systematic survey of its management in primary care in England. We aimed to evaluate how people with tinnitus are assessed and managed in general practice, noting variation in practice across GPs and health authorities, and evaluating how closely typical practice aligns to the GPG for tinnitus.

Rationale, aim and objective In 2009, the UK Department of Health formalized recommended National Health Service practices for the management of tinnitus from primary care onwards. It is timely therefore to evaluate the perceived practicality, utility and impact of those guidelines in the context of current practice. Methods We surveyed current practice by posting a 36-item questionnaire to all audiology and hearing therapy staff that we were able to identify as being involved in tinnitus patient care in England. Results In total, 138 out of 351 clinicians responded (39% response rate). The findings indicate a consensus opinion that management should be tailored to individual symptom profiles but that there is little standardization of assessment procedures or tools in use. Conclusions While the lack of standardized practice might provide flexibility to meet local demand, it has drawbacks. It makes it difficult to ascertain key standards of best practice, it complicates the process of clinical audit, it implies unequal patient access to care, and it limits the implementation of translational research outcomes. We recommend that core elements of practice should be standardized, including use of a validated tinnitus questionnaires and an agreed pathway for decision making to better understand the rationale for management strategies offered.

Several components of evoked auditory potentials and magnetic fields have been reported to be enhanced by musical training and by laboratory discrimination training. The P2 component, believed to originate in secondary auditory cortex (A2), is highly plastic, and enhanced both in trained musicians and by a variety of acoustic discrimination tasks. The 40-Hz auditory steady-state response (SSR) is believed to be generated in primary auditory cortex (A1). This response has been reported to be larger for trained musicians; however, in previous research SSR amplitude was not enhanced by laboratory training at pitch discrimination in non-musician adults. To explore whether competitive interactions among frequency representations in A1 may constrain remodeling, we designed a training procedure that provided subjects with experience of a single carrier frequency for 10 training sessions, alternating training and passive control blocks. P2 amplitude increased across sessions (p

We investigated whether attention modulates the 40-Hz auditory steady-state response (SSR) which localizes to cortical sources in the region of primary auditory cortex (A1). Subjects in Group E performed a tone discrimination task requiring sustained attention. This task was preceded and followed by a passive stage in which identical stimuli were presented while subjects viewed a silent video. Control groups received three successive passive stages only (with or without the video). SSR amplitude increased from the passive baseline in Group E and with respect to both control groups when the discrimination task was performed, and reverted to baseline afterwards. The SSR source waveform was enhanced in the right hemisphere, implying modulation of A1 by attention in this hemisphere. SSR phase and 3d source parameters did not shift when the discrimination task was introduced, implying similar SSR A1 generators in the passive and task conditions. Enhancement of N1, P2, and N2 during the discrimination task pointed to concurrent modulation of secondary auditory cortex by attention.

Objective: Resting-state functional magnetic resonance imaging (fMRI) uncovers correlated activity between spatially distinct functionally related brain regions and offers clues about the integrity of functional brain circuits in people with chronic subjective tinnitus. We chose to investigate auditory network connectivity, adopting and extending previously used analyses methods to provide an independent evaluation of replicability. Design: Independent components analysis (ICA) was used to identify coherent patterns arising from spontaneous brain signals within the resting-state data. The auditory network component was extracted and evaluated. Bivariate and partial correlation analyses were performed on pre-defined regions of bilateral auditory cortex to assess functional connectivity. Study sample: Our design carefully matched participant groups for possible confounds, such as hearing status. Twelve patients (seven male, five female; mean age 66 years) all with chronic constant tinnitus and eleven controls (eight male, three female; mean age 68 years) took part. Results: No significant differences were found in auditory network connectivity between groups after correcting for multiple statistical comparisons in the analysis. This contradicts previous findings reporting reduced auditory network connectivity; albeit at a less stringent statistical threshold. Conclusions: Auditory network connectivity does not appear to be reliably altered by the experience of chronic subjective tinnitus.

The ability to reproducibly match tinnitus loudness and pitch is important to research and clinical management. Here we examine agreement and reliability of tinnitus loudness matching and pitch likeness ratings when using a computer-based method to measure the tinnitus spectrum and estimate a dominant tinnitus pitch, using tonal or narrowband sounds. Group level data indicated a significant effect of time between test session 1 and 2 for loudness matching, likely procedural or perceptual learning, which needs to be accounted in study design. Pitch likeness rating across multiple frequencies appeared inherently more variable and with no systematic effect of time. Dominant pitch estimates reached a level of clinical acceptability when sessions were spaced two weeks apart. However when dominant tinnitus pitch assessments were separated by three months, acceptable agreement was achieved only for group mean data, not for individual estimates. This has implications for prescription of some sound-based interventions that rely on accurate measures of individual dominant tinnitus pitch.