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.

Hippocampal atrophy is associated with hearing loss in cognitively normal adults.

Objectives: A growing body of evidence suggests that age-related hearing loss (HL) is associated with morphological changes of the cerebral cortex, but the results have been drawn from a small amount of data in most studies. The aim of this study is to investigate the correlation between HL and gray matter volume (GMV) in a large number of subjects, strictly controlling for an extensive set of possible biases. Methods: Medical records of 576 subjects who underwent pure tone audiometry, brain magnetic resonance imaging (MRI), and the Korean Mini-Mental State Exam (K-MMSE) were reviewed. Among them, subjects with normal cognitive function and free of central nervous system disorders or coronary artery disease were included. Outliers were excluded after a sample homogeneity check. In the end, 405 subjects were enrolled. Pure tone hearing thresholds were determined at 0.5, 1, 2, and 4 kHz in the better ear. Enrolled subjects were divided into 3 groups according to pure tone average: normal hearing (NH), mild HL (MHL), and moderate-to-severe HL (MSHL) groups. Using voxel-based morphometry, we evaluated GMV changes that may be associated with HL. Sex, age, total intracranial volume, type of MRI scanner, education level, K-MMSE score, smoking status, and presence of hypertension, diabetes mellitus and dyslipidemia were used as covariates. Results: A statistically significant negative correlation between the hearing thresholds and GMV of the hippocampus was elucidated. Additionally, in group comparisons, the left hippocampal GMV of the MSHL group was significantly smaller than that of the NH and MHL groups. Conclusion: Based on the negative correlation between hearing thresholds and hippocampal GMV in cognitively normal old adults, the current study indicates that peripheral deafferentation could be a potential contributing factor to hippocampal atrophy.

Nuances in intensity deviant asymmetric responses as a biomarker for tinnitus.

We attempted to replicate a potential tinnitus biomarker in humans based on the Sensory Precision Integrative Model of Tinnitus called the Intensity Mismatch Asymmetry. A few advances on the design were also included, including tighter matching of participants for gender, and a control stimulus frequency of 1 kHz to investigate whether any differences between control and tinnitus groups are specific to the tinnitus frequency or domain-general. The expectation was that there would be asymmetry in the MMN responses between tinnitus and control groups at the tinnitus frequency, but not at the control frequency, where the tinnitus group would have larger, more negative responses to upward deviants than downward deviants, and the control group would have the opposite pattern or lack of a deviant direction effect. However, no significant group differences were found. There was a striking difference in response amplitude to control frequency stimuli compared to tinnitus frequency stimuli, which could be an intrinsic quality of responses to these frequencies or could reflect high frequency hearing loss in the sample. Additionally, the upward deviants elicited stronger MMN responses in both groups at tinnitus frequency, but not at the control frequency. Factors contributing to these discrepant results at the tinnitus frequency could include hyperacusis, attention, and wider contextual effects of other frequencies used in the experiment (i.e. the control frequency in other blocks).

Predictive coding and stochastic resonance as fundamental principles of auditory phantom perception.

Mechanistic insight is achieved only when experiments are employed to test formal or computational models. Furthermore, in analogy to lesion studies, phantom perception may serve as a vehicle to understand the fundamental processing principles underlying healthy auditory perception. With a special focus on tinnitus-as the prime example of auditory phantom perception-we review recent work at the intersection of artificial intelligence, psychology and neuroscience. In particular, we discuss why everyone with tinnitus suffers from (at least hidden) hearing loss, but not everyone with hearing loss suffers from tinnitus. We argue that intrinsic neural noise is generated and amplified along the auditory pathway as a compensatory mechanism to restore normal hearing based on adaptive stochastic resonance. The neural noise increase can then be misinterpreted as auditory input and perceived as tinnitus. This mechanism can be formalized in the Bayesian brain framework, where the percept (posterior) assimilates a prior prediction (brain's expectations) and likelihood (bottom-up neural signal). A higher mean and lower variance (i.e. enhanced precision) of the likelihood shifts the posterior, evincing a misinterpretation of sensory evidence, which may be further confounded by plastic changes in the brain that underwrite prior predictions. Hence, two fundamental processing principles provide the most explanatory power for the emergence of auditory phantom perceptions: predictive coding as a top-down and adaptive stochastic resonance as a complementary bottom-up mechanism. We conclude that both principles also play a crucial role in healthy auditory perception. Finally, in the context of neuroscience-inspired artificial intelligence, both processing principles may serve to improve contemporary machine learning techniques.

A parahippocampal-sensory Bayesian vicious circle generates pain or tinnitus: a source-localized EEG study.

Pain and tinnitus share common pathophysiological mechanisms, clinical features, and treatment approaches. A source-localized resting-state EEG study was conducted in 150 participants: 50 healthy controls, 50 pain, and 50 tinnitus patients. Resting-state activity as well as functional and effective connectivity was computed in source space. Pain and tinnitus were characterized by increased theta activity in the pregenual anterior cingulate cortex, extending to the lateral prefrontal cortex and medial anterior temporal lobe. Gamma-band activity was increased in both auditory and somatosensory cortex, irrespective of the pathology, and extended to the dorsal anterior cingulate cortex and parahippocampus. Functional and effective connectivity were largely similar in pain and tinnitus, except for a parahippocampal-sensory loop that distinguished pain from tinnitus. In tinnitus, the effective connectivity between parahippocampus and auditory cortex is bidirectional, whereas the effective connectivity between parahippocampus and somatosensory cortex is unidirectional. In pain, the parahippocampal-somatosensory cortex is bidirectional, but parahippocampal auditory cortex unidirectional. These modality-specific loops exhibited theta-gamma nesting. Applying a Bayesian brain model of brain functioning, these findings suggest that the phenomenological difference between auditory and somatosensory phantom percepts result from a vicious circle of belief updating in the context of missing sensory information. This finding may further our understanding of multisensory integration and speaks to a universal treatment for pain and tinnitus-by selectively disrupting parahippocampal-somatosensory and parahippocampal-auditory theta-gamma activity and connectivity.

Temporal lobe perceptual predictions for speech are instantiated in motor cortex and reconciled by inferior frontal cortex.

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phonological information and weighted prediction error. In the presence of intact temporal cortex, frontal neurodegeneration results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predictions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech.

Sensory Loss and Risk of Dementia.

Sensory loss in olfaction, vision, and hearing is a risk factor for dementia, but the reasons for this are unclear. This review presents the neurobiological evidence linking each sensory modality to specific dementias and explores the potential mechanisms underlying this. Olfactory deficits can be linked to direct neuropathologic changes in the olfactory system due to Alzheimer disease and Parkinson disease, and may be a marker of disease severity. Visual deficits potentially increase dementia risk in a vulnerable individual by reducing resilience to dementia. Hearing deficits may indicate a susceptibility to Alzheimer disease through a variety of mechanisms. More generally, sensory impairment could be related to factors associated with resilience against dementia. Further research is needed to tease out the specific and synergistic effects of sensory impairment. Studying sensory loss in relation to neurodegenerative biomarkers is necessary to clarify the mechanisms involved. This could produce new monitoring and management strategies for people at risk of dementia.

The hearing hippocampus.

The hippocampus has a well-established role in spatial and episodic memory but a broader function has been proposed including aspects of perception and relational processing. Neural bases of sound analysis have been described in the pathway to auditory cortex, but wider networks supporting auditory cognition are still being established. We review what is known about the role of the hippocampus in processing auditory information, and how the hippocampus itself is shaped by sound. In examining imaging, recording, and lesion studies in species from rodents to humans, we uncover a hierarchy of hippocampal responses to sound including during passive exposure, active listening, and the learning of associations between sounds and other stimuli. We describe how the hippocampus' connectivity and computational architecture allow it to track and manipulate auditory information - whether in the form of speech, music, or environmental, emotional, or phantom sounds. Functional and structural correlates of auditory experience are also identified. The extent of auditory-hippocampal interactions is consistent with the view that the hippocampus makes broad contributions to perception and cognition, beyond spatial and episodic memory. More deeply understanding these interactions may unlock applications including entraining hippocampal rhythms to support cognition, and intervening in links between hearing loss and dementia.

EEG Responses to auditory figure-ground perception.

Speech-in-noise difficulty is commonly reported among hearing-impaired individuals. Recent work has established generic behavioural measures of sound segregation and grouping that are related to speech-in-noise processing but do not require language. In this study, we assessed potential clinical electroencephalographic (EEG) measures of central auditory grouping (stochastic figure-ground test) and speech-in-noise perception (speech-in-babble test) with and without relevant tasks. Auditory targets were presented within background noise (16 talker-babble or randomly generated pure-tones) in 50% of the trials and composed either a figure (pure-tone frequency chords repeating over time) or speech (English names), while the rest of the trials only had background noise. EEG was recorded while participants were presented with the target stimuli (figure or speech) under different attentional states (relevant task or visual-distractor task). EEG time-domain analysis demonstrated enhanced negative responses during detection of both types of auditory targets within the time window 150-350 ms but only figure detection produced significantly enhanced responses under the distracted condition. Further single-channel analysis showed that simple vertex-to-mastoid acquisition defines a very similar response to more complex arrays based on multiple channels. Evoked-potentials to the generic figure-ground task therefore represent a potential clinical measure of grouping relevant to real-world listening that can be assessed irrespective of language knowledge and expertise even without a relevant task.

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.

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.

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.

Exposing Pathological Sensory Predictions in Tinnitus Using Auditory Intensity Deviant Evoked Responses.

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 STATEMENT In 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.

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.

Prediction and perception: Insights for (and from) tinnitus.

More than 150 years have passed since Helmholtz first described perception as a process of unconscious inference about the causes of sensations. His ideas have since inspired a wealth of literature investigating the mechanisms underlying these inferences. In recent years, much of this work has converged on the notion that the brain is a hierarchical generative model of its environment that predicts sensations and updates itself based on prediction errors. Here, we build a case for modeling tinnitus from this perspective, i.e. predictive coding. We emphasize two key claims: (1) acute tinnitus reflects an increase in sensory precision in related frequency channels and (2) chronic tinnitus reflects a change in the brain's default prediction. We further discuss specific neural biomarkers that would constitute evidence for or against these claims. Finally, we explore the implications of our model for clinical intervention strategies. We conclude that predictive coding offers the basis for a unifying theory of cognitive neuroscience, which we demonstrate with several examples linking tinnitus to other lines of brain research.

Tinnitus: Does Gain Explain?

Many, or most, tinnitus models rely on increased central gain in the auditory pathway as all or part of the explanation, in that central auditory neurones deprived of their usual sensory input maintain homeostasis by increasing the rate at which they fire in response to any given strength of input, including amplifying spontaneous firing which forms the basis of tinnitus. However, dramatic gain changes occur in response to damage to the auditory periphery, irrespective of whether tinnitus occurs. This article considers gain in its broadest sense, summarizes its contributory processes, neural manifestations, behavioral effects, techniques for its measurement, pitfalls in attributing gain changes to tinnitus, a discussion of the minimum evidential requirements to implicate gain as a necessary and/or sufficient basis to explain tinnitus, and the extent of existing evidence in this regard. Overall there is compelling evidence that peripheral auditory insults induce changes in neuronal firing rates, synchrony and neurochemistry and thus increase gain, but specific attribution of these changes to tinnitus is generally hampered by the absence of hearing-matched human control groups or insult-exposed non-tinnitus animals. A few studies show changes specifically attributable to tinnitus at group level, but the limited attempts so far to classify individual subjects based on gain metrics have not proven successful. If gain turns out to be unnecessary or insufficient to cause tinnitus, candidate additional mechanisms include focused attention, resetting of sensory predictions, failure of sensory gating, altered sensory predictions, formation of pervasive memory traces and/or entry into global perceptual networks. This article is part of a Special Issue entitled: Hearing Loss, Tinnitus, Hyperacusis, Central Gain.

Evolutionarily conserved neural signatures involved in sequencing predictions and their relevance for language.

Predicting the occurrence of future events from prior ones is vital for animal perception and cognition. Although how such sequence learning (a form of relational knowledge) relates to particular operations in language remains controversial, recent evidence shows that sequence learning is disrupted in frontal lobe damage associated with aphasia. Also, neural sequencing predictions at different temporal scales resemble those involved in language operations occurring at similar scales. Furthermore, comparative work in humans and monkeys highlights evolutionarily conserved frontal substrates and predictive oscillatory signatures in the temporal lobe processing learned sequences of speech signals. Altogether this evidence supports a relational knowledge hypothesis of language evolution, proposing that language processes in humans are functionally integrated with an ancestral neural system for predictive sequence learning.