What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a "limbic system," a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain-that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept.

Migraine as an allostatic reset triggered by unresolved interoceptive prediction errors.

Until now, a satisfying account of the cause and purpose of migraine has remained elusive. We explain migraine within the frameworks of allostasis (the situationally-flexible, forward-looking equivalent of homeostasis) and active inference (interacting with the environment via internally-generated predictions). Due to its multimodality, and long timescales between cause and effect, allostasis is inherently prone to catastrophic error, which might be impossible to correct once fully manifest, an early indicator which is elevated prediction error (discrepancy between prediction and sensory input) associated with internal sensations (interoception). Errors can usually be resolved in a targeted manner by action (correcting the physiological state) or perception (updating predictions in light of sensory input); persistent errors are amplified broadly and multimodally, to prioritise their resolution (the migraine premonitory phase); finally, if still unresolved, progressive amplification renders further changes to internal or external sensory inputs intolerably intense, enforcing physiological stability, and facilitating accurate allostatic prediction updating. As such, migraine is an effective 'failsafe' for allostasis, however it has potential to become excessively triggered, therefore maladaptive.

Mimicry in misophonia: A large-scale survey of prevalence and relationship with trigger sounds.

BACKGROUND: Misophonia is often referred to as a disorder that is characterized by excessive negative emotional responses, including anger and anxiety, to "trigger sounds" which are typically day-to-day sounds, such as those generated from people eating, chewing, and breathing. Misophonia (literally "hatred of sounds") has commonly been understood within an auditory processing framework where sounds cause distress due to aberrant processing in the auditory and emotional systems of the brain. However, a recent proposal suggests that it is the perceived action (e.g., mouth movement in eating/chewing sounds as triggers) of the trigger person, and not the sounds per se, that drives the distress in misophonia. Since observation or listening to sounds of actions of others are known to prompt mimicry in perceivers, we hypothesized that mimicking the action of the trigger person may be prevalent in misophonia. Apart from a few case studies and anecdotal information, a relation between mimicking and misophonia has not been systematically evaluated. METHOD: In this work, we addressed this limitation by collecting data on misophonia symptoms and mimicry behavior using online questionnaires from 676 participants. RESULTS: Analysis of these data shows that (i) more than 45% of individuals with misophonia reported mimicry, indicating its wide prevalence, (ii) the tendency to mimic varies in direct proportion to misophonia severity, (iii) compared to other human and environmental sounds, trigger sounds of eating and chewing are more likely to trigger mimicking, and (iv) the act of mimicking provides some degree of relief from distress to people with misophonia. CONCLUSION: This study shows prevalence of mimicry and its relation to misophonia severity and trigger types. The theoretical framework of misophonia needs to incorporate the phenomenon of mimicry and its effect on management of misophonia distress.

Failure to breathe persists without air hunger or alarm following amygdala seizures.

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level-dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.

Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

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.

Consensus Definition of Misophonia: A Delphi Study.

Misophonia is a disorder of decreased tolerance to specific sounds or their associated stimuli that has been characterized using different language and methodologies. The absence of a common understanding or foundational definition of misophonia hinders progress in research to understand the disorder and develop effective treatments for individuals suffering from misophonia. From June 2020 through January 2021, the authors conducted a study to determine whether a committee of experts with diverse expertise related to misophonia could develop a consensus definition of misophonia. An expert committee used a modified Delphi method to evaluate candidate definitional statements that were identified through a systematic review of the published literature. Over four rounds of iterative voting, revision, and exclusion, the committee made decisions to include, exclude, or revise these statements in the definition based on the currently available scientific and clinical evidence. A definitional statement was included in the final definition only after reaching consensus at 80% or more of the committee agreeing with its premise and phrasing. The results of this rigorous consensus-building process were compiled into a final definition of misophonia that is presented here. This definition will serve as an important step to bring cohesion to the growing field of researchers and clinicians who seek to better understand and support individuals experiencing misophonia.

A specific relationship between musical sophistication and auditory working memory.

Previous studies have found conflicting results between individual measures related to music and fundamental aspects of auditory perception and cognition. The results have been difficult to compare because of different musical measures being used and lack of uniformity in the auditory perceptual and cognitive measures. In this study we used a general construct of musicianship, musical sophistication, that can be applied to populations with widely different backgrounds. We investigated the relationship between musical sophistication and measures of perception and working memory for sound by using a task suitable to measure both. We related scores from the Goldsmiths Musical Sophistication Index to performance on tests of perception and working memory for two acoustic features-frequency and amplitude modulation. The data show that musical sophistication scores are best related to working memory for frequency in an analysis that accounts for age and non-verbal intelligence. Musical sophistication was not significantly associated with working memory for amplitude modulation rate or with the perception of either acoustic feature. The work supports a specific association between musical sophistication and working memory for sound frequency.

MEG correlates of temporal regularity relevant to pitch perception in human auditory cortex.

We recorded neural responses in human participants to three types of pitch-evoking regular stimuli at rates below and above the lower limit of pitch using magnetoencephalography (MEG). These bandpass filtered (1-4 kHz) stimuli were harmonic complex tones (HC), click trains (CT), and regular interval noise (RIN). Trials consisted of noise-regular-noise (NRN) or regular-noise-regular (RNR) segments in which the repetition rate (or fundamental frequency F0) was either above (250 Hz) or below (20 Hz) the lower limit of pitch. Neural activation was estimated and compared at the senor and source levels. The pitch-relevant regular stimuli (F0 = 250 Hz) were all associated with marked evoked responses at around 140 ms after noise-to-regular transitions at both sensor and source levels. In particular, greater evoked responses to pitch-relevant stimuli than pitch-irrelevant stimuli (F0 = 20 Hz) were localized along the Heschl's sulcus around 140 ms. The regularity-onset responses for RIN were much weaker than for the other types of regular stimuli (HC, CT). This effect was localized over planum temporale, planum polare, and lateral Heschl's gyrus. Importantly, the effect of pitch did not interact with the stimulus type. That is, we did not find evidence to support different responses for different types of regular stimuli from the spatiotemporal cluster of the pitch effect (∼140 ms). The current data demonstrate cortical sensitivity to temporal regularity relevant to pitch that is consistently present across different pitch-relevant stimuli in the Heschl's sulcus between Heschl's gyrus and planum temporale, both of which have been identified as a "pitch center" based on different modalities.

Dynamics underlying auditory-object-boundary detection in primary auditory cortex.

Auditory object analysis requires the fundamental perceptual process of detecting boundaries between auditory objects. However, the dynamics underlying the identification of discontinuities at object boundaries are not well understood. Here, we employed a synthetic stimulus composed of frequency-modulated ramps known as 'acoustic textures', where boundaries were created by changing the underlying spectrotemporal statistics. We collected magnetoencephalographic (MEG) data from human volunteers and observed a slow (<1 Hz) post-boundary drift in the neuromagnetic signal. The response evoking this drift signal was source localised close to Heschl's gyrus (HG) bilaterally, which is in agreement with a previous functional magnetic resonance imaging (fMRI) study that found HG to be involved in the detection of similar auditory object boundaries. Time-frequency analysis demonstrated suppression in alpha and beta bands that occurred after the drift signal.

The Motor Basis for Misophonia.

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.

Oscillatory correlates of auditory working memory examined with human electrocorticography.

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.

How Can Hearing Loss Cause Dementia?

Epidemiological studies identify midlife hearing loss as an independent risk factor for dementia, estimated to account for 9% of cases. We evaluate candidate brain bases for this relationship. These bases include a common pathology affecting the ascending auditory pathway and multimodal cortex, depletion of cognitive reserve due to an impoverished listening environment, and the occupation of cognitive resources when listening in difficult conditions. We also put forward an alternate mechanism, drawing on new insights into the role of the medial temporal lobe in auditory cognition. In particular, we consider how aberrant activity in the service of auditory pattern analysis, working memory, and object processing may interact with dementia pathology in people with hearing loss. We highlight how the effect of hearing interventions on dementia depends on the specific mechanism and suggest avenues for work at the molecular, neuronal, and systems levels to pin this down.

Multivoxel codes for representing and integrating acoustic features in human cortex.

Using fMRI and multivariate pattern analysis, we determined whether spectral and temporal acoustic features are represented by independent or integrated multivoxel codes in human cortex. Listeners heard band-pass noise varying in frequency (spectral) and amplitude-modulation (AM) rate (temporal) features. In the superior temporal plane, changes in multivoxel activity due to frequency were largely invariant with respect to AM rate (and vice versa), consistent with an independent representation. In contrast, in posterior parietal cortex, multivoxel representation was exclusively integrated and tuned to specific conjunctions of frequency and AM features (albeit weakly). Direct between-region comparisons show that whereas independent coding of frequency weakened with increasing levels of the hierarchy, such a progression for AM and integrated coding was less fine-grained and only evident in the higher hierarchical levels from non-core to parietal cortex (with AM coding weakening and integrated coding strengthening). Our findings support the notion that primary auditory cortex can represent spectral and temporal acoustic features in an independent fashion and suggest a role for parietal cortex in feature integration and the structuring of sensory input.

Direct electrophysiological mapping of human pitch-related processing in auditory cortex.

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 distribution and nature of responses to broadband sounds associated with pitch in the macaque auditory cortex.

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.

Interactions between Conscious and Subconscious Signals: Selective Attention under Feature-Based Competition Increases Neural Selectivity during Brain Adaptation.

Efficient perception in natural environments depends on neural interactions between voluntary processes within cognitive control, such as attention, and those that are automatic and subconscious, such as brain adaptation to predictable input (also called repetition suppression). Although both attention and adaptation have been studied separately and there is considerable knowledge of the neurobiology involved in each of these processes, how attention interacts with adaptation remains equivocal. We examined how attention interacts with visual and auditory adaptation by measuring neuroimaging effects consistent with changes in either neural gain or selectivity. Male and female human participants were scanned with functional magnetic resonance imaging (fMRI) first while they discriminated repetition of morphed faces or voices and either directed their attention to stimulus identity or spatial location. Attention to face or voice identity, while ignoring stimulus location, solely increased the gain of respectively face- or voice-sensitive cortex. The results were strikingly different in an experiment when participants attended to voice identity versus stimulus loudness. In this case, attention to voice while ignoring sound loudness increased neural selectivity. The combined results show that how attention affects adaptation depends on the level of feature-based competition, reconciling prior conflicting observations. The findings are theoretically important and are discussed in relation to neurobiological interactions between attention and different types of predictive signals.SIGNIFICANCE STATEMENT Adaptation to repeated environmental events is ubiquitous in the animal brain, an automatic typically subconscious, predictive signal. Cognitive influences, such as by attention, powerfully affect sensory processing and can overcome brain adaptation. However, how neural interactions occur between adaptation and attention remains controversial. We conducted fMRI experiments regulating the focus of attention during adaptation to repeated stimuli with perceptually balanced stimulus expectancy. We observed an interaction between attention and adaptation consistent with increased neural selectivity, but only under conditions of feature-based competition, challenging the notion that attention interacts with brain adaptation by only affecting response gain. This demonstrates that attention retains its full complement of mechanistic influences on sensory cortex even as it interacts with more automatic or subconscious predictive processes.

Musical hallucinations, musical imagery, and earworms: A new phenomenological survey.

Musical hallucinations (MH) account for a significant proportion of auditory hallucinations, but there is a relative lack of research into their phenomenology. In contrast, much research has focused on other forms of internally generated musical experience, such as earworms (involuntary and repetitive inner music), showing that they can vary in perceived control, repetitiveness, and in their effect on mood. We conducted a large online survey (N = 270), including 44 participants with MH, asking participants to rate imagery, earworms, or MH on several variables. MH were reported as occurring less frequently, with less controllability, less lyrical content, and lower familiarity, than other forms of inner music. MH were also less likely to be reported by participants with higher levels of musical expertise. The findings are outlined in relation to other forms of hallucinatory experience and inner music, and their implications for psychological models of hallucinations discussed.

Investigating Misophonia: A Review of the Empirical Literature, Clinical Implications, and a Research Agenda.

Misophonia is a neurobehavioral syndrome phenotypically characterized by heightened autonomic nervous system arousal and negative emotional reactivity (e. g., irritation, anger, anxiety) in response to a decreased tolerance for specific sounds. The aims of this review are to (a) characterize the current state of the field of research on misophonia, (b) highlight what can be inferred from the small research literature to inform treatment of individuals with misophonia, and (c) outline an agenda for research on this topic. We extend previous reviews on this topic by critically reviewing the research investigating mechanisms of misophonia and differences between misophonia and other conditions. In addition, we integrate this small but growing literature with basic and applied research from other literatures in a cross-disciplinary manner.