Effective Connectivity Network of Aberrant Prediction Error Processing in Auditory Phantom Perception.

Introduction: Prediction error (PE) is key to perception in the predictive coding framework. However, previous studies indicated the varied neural activities evoked by PE in tinnitus patients. Here, we aimed to reconcile the conflict by (1) a more nuanced view of PE, which could be driven by changing stimulus (stimulus-driven PE [sPE]) and violation of current context (context-driven PE [cPE]) and (2) investigating the aberrant connectivity networks that are engaged in the processing of the two types of PEs in tinnitus patients. Methods: Ten tinnitus patients with normal hearing and healthy controls were recruited, and a local-global auditory oddball paradigm was applied to measure the electroencephalographic difference between the two groups during sPE and cPE conditions. Results: Overall, the sPE condition engaged bottom-up and top-down connections, whereas the cPE condition engaged mostly top-down connections. The tinnitus group showed decreased sensitivity to the sPE and increased sensitivity to the cPE condition. Particularly, the auditory cortex and posterior cingulate cortex were the hubs for processing cPE in the control and tinnitus groups, respectively, showing the orientation to an internal state in tinnitus. Furthermore, tinnitus patients showed stronger connectivity to the parahippocampus and pregenual anterior cingulate cortex for the establishment of the prediction during the cPE condition. Conclusion: These results begin to dissect the role of changes in stimulus characteristics versus changes in the context of processing the same stimulus in mechanisms of tinnitus generation.

The Locus Coeruleus in Chronic Pain.

Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates.

Chronic pain - A maladaptive compensation to unbalanced hierarchical predictive processing.

The ability to perceive pain presents an interesting evolutionary advantage to adapt to an ever-changing environment. However, in the case of chronic pain (CP), pain perception hinders the capacity of the system to adapt to changing sensory environments. Similar to other chronic perceptual disorders, CP is also proposed to be a maladaptive compensation to aberrant sensory predictive processing. The local-global oddball paradigm relies on learning hierarchical rules and processing environmental irregularities at a local and global level. Prediction errors (PE) between actual and predicted input typically trigger an update of the forward model to limit the probability of encountering future PEs. It has been hypothesised that CP hinders forward model updating, reflected in increased local deviance and decreased global deviance. In the present study, we used the local-global paradigm to examine how CP influences hierarchical learning relative to healthy controls. As hypothesised, we observed that deviance in the stimulus characteristics evoked heightened local deviance and decreased global deviance of the stimulus-driven PE. This is also accompanied by respective changes in theta phase locking that is correlated with the subjective pain perception. Changes in the global deviant in the stimulus-driven-PE could also be explained by dampened attention-related responses. Changing the context of the auditory stimulus did not however show a difference in the context-driven PE. These findings suggest that CP is accompanied by maladaptive forward model updating where the constant presence of pain perception disrupts local deviance in non-nociceptive domains. Furthermore, we hypothesise that the auditory-processing based biomarker identified here could be a marker of domain-general dysfunction that could be confirmed by future research.

Phantom perception as a Bayesian inference problem: a pilot study.

Tinnitus is the perception of a continuous sound in the absence of an external source. Although the role of the auditory system is well investigated, there is a gap in how multisensory signals are integrated to produce a single percept in tinnitus. Here, we train participants to learn a new sensory environment by associating a cue with a target signal that varies in perceptual threshold. In the test phase, we present only the cue to see whether the person perceives an illusion of the target signal. We perform two separate experiments to observe the behavioral and electrophysiological responses to the learning and test phases in 1) healthy young adults and 2) people with continuous subjective tinnitus and matched control subjects. We observed that in both parts of the study the percentage of false alarms was negatively correlated with the 75% detection threshold. Additionally, the perception of an illusion goes together with increased evoked response potential in frontal regions of the brain. Furthermore, in patients with tinnitus, we observe no significant difference in behavioral or evoked response in the auditory paradigm, whereas patients with tinnitus were more likely to report false alarms along with increased evoked activity during the learning and test phases in the visual paradigm. This emphasizes the importance of integrity of sensory pathways in multisensory integration and how this process may be disrupted in people with tinnitus. Furthermore, the present study also presents preliminary data supporting evidence that tinnitus patients may be building stronger perceptual models, which needs future studies with a larger population to provide concrete evidence on.NEW & NOTEWORTHY Tinnitus is the continuous phantom perception of a ringing in the ears. Recently, it has been suggested that tinnitus may be a maladaptive inference of the brain to auditory anomalies, whether they are detected or undetected by an audiogram. The present study presents empirical evidence for this hypothesis by inducing an illusion in a sensory domain that is damaged (auditory) and one that is intact (visual). It also presents novel information about how people with tinnitus process multisensory stimuli in the audio-visual domain.

Investigating sensitivity to multi-domain prediction errors in chronic auditory phantom perception.

The perception of a continuous phantom in a sensory domain in the absence of an external stimulus is explained as a maladaptive compensation of aberrant predictive coding, a proposed unified theory of brain functioning. If this were true, these changes would occur not only in the domain of the phantom percept but in other sensory domains as well. We confirm this hypothesis by using tinnitus (continuous phantom sound) as a model and probe the predictive coding mechanism using the established local-global oddball paradigm in both the auditory and visual domains. We observe that tinnitus patients are sensitive to changes in predictive coding not only in the auditory but also in the visual domain. We report changes in well-established components of event-related EEG such as the mismatch negativity. Furthermore, deviations in stimulus characteristics were correlated with the subjective tinnitus distress. These results provide an empirical confirmation that aberrant perceptions are a symptom of a higher-order systemic disorder transcending the domain of the percept.

Development, Insults and Predisposing Factors of the Brain's Predictive Coding System to Chronic Perceptual Disorders-A Life-Course Examination.

The predictive coding theory is currently widely accepted as the theoretical basis of perception and chronic perceptual disorders are explained as the maladaptive compensation of the brain to a prediction error. Although this gives us a general framework to work with, it is still not clear who may be more susceptible and/or vulnerable to aberrations in this system. In this paper, we study changes in predictive coding through the lens of tinnitus and pain. We take a step back to understand how the predictive coding system develops from infancy, what are the different neural and bio markers that characterise this system in the acute, transition and chronic phases and what may be the factors that pose a risk to the aberration of this system. Through this paper, we aim to identify people who may be at a higher risk of developing chronic perceptual disorders as a reflection of aberrant predictive coding, thereby giving future studies more facets to incorporate in their investigation of early markers of tinnitus, pain and other disorders of predictive coding. We therefore view this paper to encourage the thinking behind the development of preclinical biomarkers to maladaptive predictive coding.

Tinnitus: A Dimensionally Segregated, yet Perceptually Integrated Heterogeneous Disorder.

OBJECTIVES: Tinnitus subtypes are proposed to lie on a continuum of different symptom dimensions rather than be categorical. However, there is no comprehensive empirical data showing this complex relationship between different tinnitus symptoms. The objective of this study is to provide empirical evidence for the dimensional nature of tinnitus and how different auditory and non-auditory symptoms interact with each other through complex interactions. We do this using graph theory, a mathematical tool that empirically maps this complex interaction. This way, graph theory can be utilised to highlight a new and possibly important outlook on how we can understand the heterogeneous nature of tinnitus. DESIGN: In the current study, we use the screening databases of the Treatment Evaluation of Neuromodulation for Tinnitus-Stage A1 (TENT-A1) and A2 (TENT-A2) randomised trials to delineate the dimensional relationship between different clinical measures of tinnitus as a secondary data analysis. We first calculate the empirical relationship by computing the partial correlation. Following this, we use different measures of centrality to describe the contribution of different clinical measures to the overall network. We also calculate the stability of the network and compare the similarity and differences between TENT-A1 and TENT-A2. RESULTS: Components of the auditory subnetwork (loudness discomfort level, sound sensitivity, average hearing loss and high frequency hearing loss) are highly inter-connected in both networks with sound sensitivity and loudness discomfort level being highly influential with high measures of centrality. Furthermore, the relationship between the densely connected auditory subnetwork with tinnitus-related distress seems to vary at different levels of distress, hearing loss, duration and age of the participants. CONCLUSION: Our findings provide first-time evidence for tinnitus varying in a dimensional fashion illustrating the heterogeneity of this phantom percept and its ability to be perceptually integrated, yet behaviourally segregated on different symptomatic dimensions.

Hope for brain health: impacting the life course and society.

Hope is a cognitive process by which an individual can identify their personal goals and develop actionable steps to achieve results. It has the potential to positively impact people's lives by building resilience, and can be meaningfully experienced at both the individual and group level. Despite this significance, there are sizable gaps in our understanding of the neurobiology of hope. In this perspective paper, the authors discuss why further research is needed on hope and its potency to be harnessed in society as a "tool" to promote brain health across healthy and patient populations. Avenues for future research in hope and the brain are proposed. The authors conclude by identifying strategies for the possible applications of hope in brain health promotion within the areas of technology, arts, media, and education.