Misophonia is an affective sound-processing disorder characterized by the experience of strong negative emotions (anger and anxiety) in response to everyday sounds, such as those generated by other people eating, drinking, chewing, and breathing [1-8]. The commonplace nature of these sounds (often referred to as "trigger sounds") makes misophonia a devastating disorder for sufferers and their families, and yet nothing is known about the underlying mechanism. Using functional and structural MRI coupled with physiological measurements, we demonstrate that misophonic subjects show specific trigger-sound-related responses in brain and body. Specifically, fMRI showed that in misophonic subjects, trigger sounds elicit greatly exaggerated blood-oxygen-level-dependent (BOLD) responses in the anterior insular cortex (AIC), a core hub of the "salience network" that is critical for perception of interoceptive signals and emotion processing. Trigger sounds in misophonics were associated with abnormal functional connectivity between AIC and a network of regions responsible for the processing and regulation of emotions, including ventromedial prefrontal cortex (vmPFC), posteromedial cortex (PMC), hippocampus, and amygdala. Trigger sounds elicited heightened heart rate (HR) and galvanic skin response (GSR) in misophonic subjects, which were mediated by AIC activity. Questionnaire analysis showed that misophonic subjects perceived their bodies differently: they scored higher on interoceptive sensibility than controls, consistent with abnormal functioning of AIC. Finally, brain structural measurements implied greater myelination within vmPFC in misophonic individuals. Overall, our results show that misophonia is a disorder in which abnormal salience is attributed to particular sounds based on the abnormal activation and functional connectivity of AIC.

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.

Tinnitus is a common disorder that often complicates hearing loss. Its mechanisms are incompletely understood. Current theories proposing pathophysiology from the ear to the cortex cannot individually - or collectively - explain the range of experimental evidence available. We propose a new framework, based on predictive coding, in which spontaneous activity in the subcortical auditory pathway constitutes a 'tinnitus precursor' which is normally ignored as imprecise evidence against the prevailing percept of 'silence'. Extant models feature as contributory mechanisms acting to increase either the intensity of the precursor or its precision. If precision (i.e., postsynaptic gain) rises sufficiently then tinnitus is perceived. Perpetuation arises through focused attention, which further increases the precision of the precursor, and resetting of the default prediction to expect tinnitus.

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 STATEMENTIn 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.

Tinnitus can occur when damage to the peripheral auditory system leads to spontaneous brain activity that is interpreted as sound [1, 2]. Many abnormalities of brain activity are associated with tinnitus, but it is unclear how these relate to the phantom sound itself, as opposed to predisposing factors or secondary consequences [3]. Demonstrating "core" tinnitus correlates (processes that are both necessary and sufficient for tinnitus perception) requires high-precision recordings of neural activity combined with a behavioral paradigm in which the perception of tinnitus is manipulated and accurately reported by the subject. This has been previously impossible in animal and human research. Here we present extensive intracranial recordings from an awake, behaving tinnitus patient during short-term modifications in perceived tinnitus loudness after acoustic stimulation (residual inhibition) [4], permitting robust characterization of core tinnitus processes. As anticipated, we observed tinnitus-linked low-frequency (delta) oscillations [5-9], thought to be triggered by low-frequency bursting in the thalamus [10, 11]. Contrary to expectation, these delta changes extended far beyond circumscribed auditory cortical regions to encompass almost all of auditory cortex, plus large parts of temporal, parietal, sensorimotor, and limbic cortex. In discrete auditory, parahippocampal, and inferior parietal "hub" regions [12], these delta oscillations interacted with middle-frequency (alpha) and high-frequency (beta and gamma) activity, resulting in a coherent system of tightly coupled oscillations associated with high-level functions including memory and perception.