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.

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.

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.

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.

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.

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.

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.

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.

A Brain System for Auditory Working Memory.

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. SIGNIFICANCE STATEMENT: 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.

Representations of specific acoustic patterns in the auditory cortex and hippocampus.

Previous behavioural studies have shown that repeated presentation of a randomly chosen acoustic pattern leads to the unsupervised learning of some of its specific acoustic features. The objective of our study was to determine the neural substrate for the representation of freshly learnt acoustic patterns. Subjects first performed a behavioural task that resulted in the incidental learning of three different noise-like acoustic patterns. During subsequent high-resolution functional magnetic resonance imaging scanning, subjects were then exposed again to these three learnt patterns and to others that had not been learned. Multi-voxel pattern analysis was used to test if the learnt acoustic patterns could be 'decoded' from the patterns of activity in the auditory cortex and medial temporal lobe. We found that activity in planum temporale and the hippocampus reliably distinguished between the learnt acoustic patterns. Our results demonstrate that these structures are involved in the neural representation of specific acoustic patterns after they have been learnt.

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.

Neuromodulation with Ultrasound: Hypotheses on the Directionality of Effects and a Community Resource.

Low-intensity Transcranial Ultrasound Stimulation (TUS) is a promising non-invasive technique for deep-brain stimulation and focal neuromodulation. Research with animal models and computational modelling has raised the possibility that TUS can be biased towards enhancing or suppressing neural function. Here, we first conduct a systematic review of human TUS studies for perturbing neural function and alleviating brain disorders. We then collate a set of hypotheses on the directionality of TUS effects and conduct an initial meta-analysis on the human TUS study reported outcomes to date ( n = 32 studies, 37 experiments). We find that parameters such as the duty cycle show some predictability regarding whether the targeted area's function is likely to be enhanced or suppressed. Given that human TUS sample sizes are exponentially increasing, we recognize that results can stabilize or change as further studies are reported. Therefore, we conclude by establishing an Iowa-Newcastle (inTUS) resource for the systematic reporting of TUS parameters and outcomes to support further hypothesis testing for greater precision in brain stimulation and neuromodulation with TUS. Highlights: Systematic review of human TUS studies for enhancing or suppressing neural functionCollated set of hypotheses on using TUS to bias towards enhancement or suppressionMeta-analysis results identify parameters that may bias the directionality of effectsTUS resource established for systematic reporting of TUS parameters and outcomes.

Mapping human pitch representation in a distributed system using depth-electrode recordings and modeling.

Depth-electrode recordings from the auditory cortex of humans undergoing presurgical evaluation for epilepsy allow the recording of ensemble responses to pitch in the form of local field potentials. These recordings allow another test of the hypothesis that there is a specialized neural ensemble for pitch within auditory cortex. Moreover, the technique allows recordings from multiple sites with millisecond temporal resolution to allow modeling of the effective connectivity between these sites. Here we argue that this takes the form of a hierarchical network of pitch-sensitive regions. Activity can be understood as reflecting predictive coding, in which perceptual predictions and error messages are continuously exchanged between a higher pitch center and lower-level auditory cortex.

Features versus feelings: dissociable representations of the acoustic features and valence of aversive sounds.

This study addresses the neuronal representation of aversive sounds that are perceived as unpleasant. Functional magnetic resonance imaging in humans demonstrated responses in the amygdala and auditory cortex to aversive sounds. We show that the amygdala encodes both the acoustic features of a stimulus and its valence (perceived unpleasantness). Dynamic causal modeling of this system revealed that evoked responses to sounds are relayed to the amygdala via auditory cortex. While acoustic features modulate effective connectivity from auditory cortex to the amygdala, the valence modulates the effective connectivity from amygdala to the auditory cortex. These results support a complex (recurrent) interaction between the auditory cortex and amygdala based on object-level analysis in the auditory cortex that portends the assignment of emotional valence in amygdala that in turn influences the representation of salient information in auditory cortex.

Navigating the auditory scene: an expert role for the hippocampus.

Over a typical career piano tuners spend tens of thousands of hours exploring a specialized acoustic environment. Tuning requires accurate perception and adjustment of beats in two-note chords that serve as a navigational device to move between points in previously learned acoustic scenes. It is a two-stage process that depends on the following: first, selective listening to beats within frequency windows, and, second, the subsequent use of those beats to navigate through a complex soundscape. The neuroanatomical substrates underlying brain specialization for such fundamental organization of sound scenes are unknown. Here, we demonstrate that professional piano tuners are significantly better than controls matched for age and musical ability on a psychophysical task simulating active listening to beats within frequency windows that is based on amplitude modulation rate discrimination. Tuners show a categorical increase in gray matter volume in the right frontal operculum and right superior temporal lobe. Tuners also show a striking enhancement of gray matter volume in the anterior hippocampus, parahippocampal gyrus, and superior temporal gyrus, and an increase in white matter volume in the posterior hippocampus as a function of years of tuning experience. The relationship with gray matter volume is sensitive to years of tuning experience and starting age but not actual age or level of musicality. Our findings support a role for a core set of regions in the hippocampus and superior temporal cortex in skilled exploration of complex sound scenes in which precise sound "templates" are encoded and consolidated into memory over time in an experience-dependent manner.

Single-subject oscillatory γ responses in tinnitus.

This study used magnetoencephalography to record oscillatory activity in a group of 17 patients with chronic tinnitus. Two methods, residual inhibition and residual excitation, were used to bring about transient changes in spontaneous tinnitus intensity in order to measure dynamic tinnitus correlates in individual patients. In residual inhibition, a positive correlation was seen between tinnitus intensity and both delta/theta (6/14 patients) and gamma band (8/14 patients) oscillations in auditory cortex, suggesting an increased thalamocortical input and cortical gamma response, respectively, associated with higher tinnitus states. Conversely, 4/4 patients exhibiting residual excitation demonstrated an inverse correlation between perceived tinnitus intensity and auditory cortex gamma oscillations (with no delta/theta changes) that cannot be explained by existing models. Significant oscillatory power changes were also identified in a variety of cortical regions, most commonly midline lobar regions in the default mode network, cerebellum, insula and anterior temporal lobe. These were highly variable across patients in terms of areas and frequency bands involved, and in direction of power change. We suggest a model based on a local circuit function of cortical gamma-band oscillations as a process of mutual inhibition that might suppress abnormal cortical activity in tinnitus. The work implicates auditory cortex gamma-band oscillations as a fundamental intrinsic mechanism for attenuating phantom auditory perception.

A dynamic system for the analysis of acoustic features and valence of aversive sounds in the human brain.

Certain sounds, for example, the squeal of chalk on a blackboard, are perceived as highly unpleasant. Functional magnetic resonance imaging (fMRI) in humans shows responses in the amygdala and auditory cortex to aversive sounds. Dynamic causal modelling (DCM) of the interaction between auditory cortex and the amygdala revealed that evoked responses to aversive sounds are relayed to the amygdala via the auditory cortex. There is a complex interaction between the -auditory cortex and amygdala involving effective connectivity in both directions. While acoustic features modulate forward connections from auditory cortex to the amygdala, the valence modulates effective connectivity from the amygdala to the auditory cortex. The results support interaction between the auditory cortex and amygdala where stimuli are first processed to a higher (object) level in the auditory cortex before assignment of valence in the amygdala.

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.