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.

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.

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.

Treatment of Periodontitis Affecting Human Primary Teeth-A Systematic Review.

The aim of this systematic review is to report the treatment options (Intervention) and outcomes (O) for primary teeth affected by periodontitis (Population) and if the treatment of primary teeth can prevent the spread of periodontitis to permanent teeth (Outcomes). The following databases were searched for papers published before December 2022: PubMed, Embase, Web of Science, and Ebscohost. Studies on children affected by periodontitis involving the primary teeth were included and those on children who presented with periodontitis as a manifestation of systemic disease were excluded. Narrative synthesis and methodological quality assessments were performed for the included studies. Three interventional studies (without a control group) that evaluated treatments involving scaling and root planing (SRP with antibiotics) and extraction were included (total n = 60 patients). Additionally, twelve case reports/case series articles (n = 19 patients) were identified. The diagnoses ranged from aggressive periodontitis to juvenile periodontitis and pre-pubertal periodontitis. Based on a limited number of published studies, it was found that the early treatment of periodontitis affecting the primary teeth using SRP and systemic antibiotics resulted in favorable improvements in PD and CAL. Limited evidence suggests that SRP and the extraction of the primary teeth involved have the potential to prevent periodontitis affecting permanent teeth. Future trials are required to standardize the treatment protocols and to confirm these findings.

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.

Making memories last using the peripheral effect of direct current stimulation.

Most memories that are formed are forgotten, while others are retained longer and are subject to memory stabilization. We show that non-invasive transcutaneous electrical stimulation of the greater occipital nerve (NITESGON) using direct current during learning elicited a long-term memory effect. However, it did not trigger an immediate effect on learning. A neurobiological model of long-term memory proposes a mechanism by which memories that are initially unstable can be strengthened through subsequent novel experiences. In a series of studies, we demonstrate NITESGON's capability to boost the retention of memories when applied shortly before, during, or shortly after the time of learning by enhancing memory consolidation via activation and communication in and between the locus coeruleus pathway and hippocampus by plausibly modulating dopaminergic input. These findings may have a significant impact for neurocognitive disorders that inhibit memory consolidation such as Alzheimer's disease.

Online administration of the ADOS for research with adolescents and adults in response to the pandemic.

This study evaluates an online ADOS-2 Module 4 administration. Adolescents and adults with (n = 24; 7 females) and without (n = 13; 5 females) a history of autism spectrum disorder (ASD) completed the ADOS-2 Module 4 via videoconference. Parents or caregivers completed the Parent/Caregiver Form of the Vineland Adaptive Behavior Scales and the Achenbach Adult Behavior Checklist. The ADOS-2 was reviewed and scored by five trained clinicians and supervised by a senior clinician with established research reliability. The autistic group's scores differed on ADOS total (Calibrated Severity Score, WPS instrument) and domain scores, KSADS domain scores, and Achenbach T-scores. Inter-rater reliability was "moderate" (κ = 0.732), and percentage item-wise agreement was r = 0.69. The online ADOS-2 showed significant convergence with parent-reported assessments of ASD-relevant symptoms and characteristics, suggesting it was a valid assessment. While any online assessments must be used with caution, results suggest that the approach described here could have sufficient validity and reliability to fill the urgent need to assess and evaluate ASD symptomatology, as one component of a thorough clinical evaluation of ASD-related behaviors. LAY SUMMARY: In this exploratory study, we asked whether it was possible to give the ADOS-2 to adolescents and adults in a completely online way. Results showed that expert clinicians agreed on 69% of ADOS-2 items; also, participants with autism had higher scores on all parts of the ADOS-2. The online ADOS-2 scores had strong and significant relationships with parents' reports of friendship and social skills. While we need more research that tests this method, this way of doing the ADOS-2 online may be useful for clinicians and researchers who have an urgent need to evaluate autism during the pandemic.

Potential role for peripheral nerve stimulation on learning and long-term memory: A comparison of alternating and direct current stimulations.

BACKGROUND: In the past decade, a rising interest in transcranial electrical stimulation has emerged owing to its advantageous capacity to facilitate the extraction of casual links between neuromodulation and the obtained behavioral effects in cognitive performance. However, an insufficient number of direct comparative studies between transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) effects on associative memory have caused optimal parameters and procedural application to remain undefined. OBJECTIVE: The current study aimed to comparatively investigate the effects of tDCS and tACS applied to the occipital nerve (ON), targeting the locus coeruleus, on associative memory performance. METHODS: We employed a randomized, double-blind, two-visit, active-controlled study design. 85 cognitively normal adults were assigned to receive either active ON-tDCS, 40 Hz ON-tACS, sham ON-tDCS, or 1 Hz ON-tACS during encoding of a 50-word Swahili-English associative memory recall task. To evaluate the effects of electrical stimulation, we measured the cumulative rate of learning on Day 1 and to assess possible long-term effects, we measured the number of words recalled on Day 7. RESULTS: Results presented two notable findings: (1) participants who received 40 Hz ON-tACS learned significantly more words on Day 1 (F3,81 = 4.37, p = .007, η2 = 0.14), and (2) participants who received 40 Hz ON-tACS or active ON-tDCS recalled significantly more words on Day 7 (F3,81 = 11.08, p < .001, η2 = 0.29). CONCLUSIONS: The evidence from this study alludes to 40 Hz ON-tACS and active ON-tDCS inducing distinct behavioral effects, whereby 40 Hz ON-tACS generated an effect during memory encoding via enhanced attention, however, active ON-tDCS elicited an offline effect transpiring during consolidation. Further neuroimaging studies are needed to validate these findings and proposed mechanisms of action.

Symptom dimensions to address heterogeneity in tinnitus.

Tinnitus, the auditory phantom percept, is a well-known heterogenous disorder with multiple subtypes. Researchers and clinicians have tried to classify these subtypes according to clinical profiles, aetiologies, and response to treatment with little success. The occurrence of overlapping tinnitus subtypes suggests that the disorder exists along a continuum of severity, with no clear distinct boundaries. In this perspective, we propose a neuro-mechanical framework, viewing tinnitus as a dimensional disorder which is a complex interplay of its behavioural, biological and neurophysiological phenotypes. Moreover, we explore the potential of these dimensions as interacting networks without a common existing cause, giving rise to tinnitus. Considering tinnitus as partially overlapping, dynamically changing, interacting networks, each representing a different aspect of the unified tinnitus percept, suggests that the interaction of these networks determines the phenomenology of the tinnitus, ultimately leading to a dimensional spectrum, rather than a categorical subtyping. A combination of a robust theoretical framework and strong empirical evidence can advance our understanding of the functional mechanisms underlying tinnitus and ultimately, improve treatment strategies.

Predisposition to domain-wide maladaptive changes in predictive coding in auditory phantom perception.

Tinnitus is hypothesised to be a predictive coding problem. Previous research indicates lower sensitivity to prediction errors (PEs) in tinnitus patients while processing auditory deviants corresponding to tinnitus-specific stimuli. However, based on research with patients with hallucinations and no psychosis we hypothesise tinnitus patients may be more sensitive to PEs produced by auditory stimuli that are not related to tinnitus characteristics. Specifically in patients with minimal to no hearing loss, we hypothesise a more top-down subtype of tinnitus that may be driven by maladaptive changes in an auditory predictive coding network. To test this, we use an auditory oddball paradigm with omission of global deviants, a measure that is previously shown to empirically characterise hierarchical prediction errors (PEs). We observe: (1) increased predictions characterised by increased pre-stimulus response and increased alpha connectivity between the parahippocampus, dorsal anterior cingulate cortex and parahippocampus, pregenual anterior cingulate cortex and posterior cingulate cortex; (2) increased PEs characterised by increased P300 amplitude and gamma activity and increased theta connectivity between auditory cortices, parahippocampus and dorsal anterior cingulate cortex in the tinnitus group; (3) increased overall feed-forward connectivity in theta from the auditory cortex and parahippocampus to the dorsal anterior cingulate cortex; (4) correlations of pre-stimulus theta activity to tinnitus loudness and alpha activity to tinnitus distress. These results provide empirical evidence of maladaptive changes in a hierarchical predictive coding network in a subgroup of tinnitus patients with minimal to no hearing loss. The changes in pre-stimulus activity and connectivity to non-tinnitus specific stimuli suggest that tinnitus patients not only produce strong predictions about upcoming stimuli but also may be predisposed to stimulus a-specific PEs in the auditory domain. Correlations with tinnitus-related characteristics may be a biomarker for maladaptive changes in auditory predictive coding.

Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer's Disease in Females.

This article aims to reevaluate our approach to female vulnerability to Alzheimer's disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ4 polymorphism (APOEɛ4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach.

Impact of Pediatric Dentistry Residents Posted in Pediatrics Department: A Retrospective Assessment of 6 Years.

AIM: To measure the influence of rotatory pediatrics postings for dental residents on the outpatient census of the pediatric dentistry department. The secondary aims were to assess the change in trend toward the number of preschool children visiting the department before and after the initiation of pediatrics posting and also to find the percentage of children affected with caries among children visiting the pediatricians. MATERIALS AND METHODS: Retrospectively, the census of the pediatric dentistry department was calculated from 2010 to 2016. The number of preschool children who visited the pediatric dentistry department during this period was determined. From the pediatrics posting records, the dental status of the children, the number screened, the number referred, and the number reported to dentistry following referral were tabulated. Descriptive statistics and Chi-square tests were performed. RESULTS: After the initiation of pediatrics postings for residents, the outpatient census has increased by 26%. There was a significant increase in the number of preschool children visiting the pediatric dentist. About 57.09% of children screened in the pediatrics department had dental disease. CONCLUSION: There is an increase in the patient flow of the pediatric dentistry department with a greater number of preschool children visiting the pediatric dentist after initiation of the pediatrics postings for residents. More than half the children visiting pediatricians had dental disease requiring professional care. CLINICAL SIGNIFICANCE: Pediatrics postings for residents can be used in teaching centers as an opportunity to spread awareness and increase the number of preschool children visiting pediatric dentists, thereby increasing prevention and early intervention of early childhood caries. HOW TO CITE THIS ARTICLE: Mohan A, Muthu MS, Ramachandran P, et al. Impact of Pediatric Dentistry Residents Posted in Pediatrics Department: A Retrospective Assessment of 6 Years. Int J Clin Pediatr Dent 2021;14(1):84-87.

Effect of Sustained Interventions from Infancy to Toddlerhood in Children with Cleft Lip and Palate for Preventing Early Childhood Caries.

The study aimed to evaluate the effectiveness of sustained interventions in children with cleft lip and palate (CLP) for preventing early childhood caries (ECC). This prospective, nonrandomized interventional cohort study was conducted in infants aged 0-12 months with congenital CLP. Interventions were given to parents/primary caregivers in the form of combined oral health-care measures (sterile wet gauze piece, finger brush, toothbrush, and toothpaste) by a motivational interviewing approach. Education of primary caregivers on oral hygiene was provided by audiovisual aids and demonstration. Reinforcement of the prescribed regimen was done through daily short message services in caregivers' preferred language and bimonthly telephone calls. Participants were followed up for 9-32 months from the time of recruitment, with a mean period of 18.3 ± 5.1 months. Rates of dental caries were represented as prevalence rates, incidence density, and transitional probability. The distribution of the International Caries Detection and Assessment System (ICDAS) scores on different tooth surfaces affected in the intervention group was compared descriptively with that of the age- and sex-matched historical control groups. On analysis of surface-wise distribution of the ICDAS scores in the intervention group (n = 1,919), 1.2% (n = 24) had noncavitated lesions (ICDAS codes 1 and 2), 0.88% (n = 17) had cavitated lesions (ICDAS codes 3-6), and 0.26% (n = 5) had both cavitated and noncavitated lesions (ICDAS codes 1-6). The incidence density of caries-affected children observed at the first and last follow-ups was 1.2 persons/100 person-months and 1.3 persons/100 person-months of observation, respectively. The incidence density of new caries-affected tooth surfaces at the first and last follow-ups was 0.163 surfaces/100 surface-months and 0.062 surfaces/100 surface-months, respectively. Maxillary first molars had the maximum transition from sound to the cavitated lesion (11.5%), followed by maxillary incisors from sound to noncavitated (7.5%) at the last follow-up. Based on the newly developed assessment criteria in our study, sustained interventions proved to be significantly effective in preventing ECC in children with CLP.

Polarity-specific high-definition transcranial direct current stimulation of the anterior and posterior default mode network improves remote memory retrieval.

BACKGROUND: Previous studies show that activity in the posterior default mode network (pDMN), including the posterior cingulate cortex and the precuneus, is correlated with the success of long-term episodic memory retrieval. However, the role of the anterior DMN (aDMN) including the medial prefrontal cortex is still unclear. Some studies show that activating the medial prefrontal cortex improves memory retrieval while other studies show deactivation of the medial prefrontal cortex in successful retrieval of episodic memories, suggesting a possible functional dissociation between the aDMN and pDMN. OBJECTIVE: In the current study, we aim to causally explore this probable dissociation using high-definition transcranial direct current stimulation (HD-tDCS). METHODS: We perform a randomised double-blinded two-visit placebo-controlled study with 84 healthy young adults. During Visit 1 they learn 75 Swahili-English word-associations. Seven days later, they randomly receive either anodal, cathodal or sham HD-tDCS targeting the pDMN or aDMN while they recall what they have previously learned. RESULTS: We demonstrate that anodal stimulation of the pDMN and cathodal stimulation of the aDMN, equally improve the percentage of Swahili-English word-associations recalled 7 days after learning. CONCLUSIONS: Modulating the activity in the aDMN and pDMN causally affect memory retrieval performance. HD-tDCS of the aDMN and pDMN shows that anodal stimulation of the pDMN and cathodal stimulation of the aDMN increases memory retrieval performance one week after the learning phase. Given consistent evidence, it is highly likely that we are increasing the activity in the pDMN with anodal pDMN stimulation. However, it is not clear if cathodal HD-tDCS targetting aDMN works via decoupling from the pDMN or via indirectly disinhibit pDMN.

Structural correlates of the audiological and emotional components of chronic tinnitus.

The objective is to investigate white matter tracts, more specifically the arcuate fasciculus and acoustic radiation, in tinnitus and assess their relationship with distress, loudness and hearing loss. DTI images were acquired for 58 tinnitus patients and 65 control subjects. Deterministic tractography was first performed to visualize the arcuate fasciculus and acoustic radiation tracts bilaterally and to calculate tract density, fractional anisotropy, radial diffusivity, and axial diffusivity for tinnitus and control subjects. Tinnitus patients had a significantly reduced tract density compared to controls in both tracts of interest. They also exhibited increased axial diffusivity in the left acoustic radiation, as well as increased radial diffusivity in the left arcuate fasciculus, and both the left and right acoustic radiation. Furthermore, they exhibited decreased fractional anisotropy in the left arcuate fasciculus, as well as the left and right acoustic radiation tracts. Partial correlation analysis showed: (1) a negative correlation between arcuate fasciculus tract density and tinnitus distress, (2) a negative correlation between acoustic radiation tract density and hearing loss, (3) a negative correlation between acoustic radiation tract density and loudness, (4) a positive correlation between left arcuate fasciculus and tinnitus distress for radial diffusivity, (5) a negative correlation between left arcuate fasciculus and tinnitus distress for fractional anisotropy, (6) a positive correlation between left and right acoustic radiation and hearing loss for radial diffusivity, (7) No correlation between any of the white matter characteristics and tinnitus loudness. Structural alterations in the acoustic radiation and arcuate fasciculus correlate with hearing loss and distress in tinnitus but not tinnitus loudness showing that loudness is a more functional correlate of the disorder which does not manifest structurally.

The BDNF Val66Met polymorphism regulates vulnerability to chronic stress and phantom perception.

Auditory phantom percepts, such as tinnitus, are a heterogeneous condition with great interindividual variations regarding both the percept itself and its concomitants. Tinnitus causes a considerable amount of distress, with as many as 25% of affected people reporting that it interferes with their daily lives. Although previous research gives an idea about the neural correlates of tinnitus-related distress, it cannot explain why some tinnitus patients develop distress and while others are not bothered by their tinnitus. BDNF Val66Met polymorphism (rs6265) is a known risk factor for affective disorders due to its common frequency and established functionality. To elucidate, we explore the neural activation pattern of tinnitus associated with the BDNF Val66Met polymorphism using electrophysiological data to assess activity and connectivity changes. A total of 110 participants (55 tinnitus and 55 matched control subjects) were included. In this study, we validate that the BDNF Val66Met polymorphism plays an important role in the susceptibility to the clinical manifestation of tinnitus-related distress. We demonstrate that Val/Met carriers have increased alpha power in the subgenual anterior cingulate cortex that correlates with distress levels. Furthermore, distress mediates the relationship between BDNF Val66Met polymorphism and tinnitus loudness. In other words, for Val/Met carriers, the subgenual anterior cingulate cortex sends distress-related information to the parahippocampus, which likely integrates the loudness and distress of the tinnitus percept.

Paradoxical relationship between distress and functional network topology in phantom sound perception.

Distress is a domain-general symptom that accompanies several disorders, including tinnitus. Based on previous studies, we know that distress is encoded by changes in functional connectivity between cortical and subcortical regions. However, how distress relates to large-scale brain networks is not yet clear. In the current study, we investigate the relationship between distress and the efficiency of a network by examining its topological properties using resting state fMRI collected from 90 chronic tinnitus patients. The present results indicate that distress negatively correlates with path length and positively correlates with clustering coefficient, small-worldness, and efficiency of information transfer. Specifically, path analysis showed that the relationship between distress and efficiency is significantly mediated by the resilience of the feeder connections and the centrality of the rich-club connections. In other words, the higher the network efficiency, the lower the resilience of the feeder connections and the centrality of the rich-club connections, which in turn reflects in higher distress in tinnitus patients. This indicates a reorganization of the network towards a paradoxically more efficient topology in patients with high distress, potentially explaining their increased rumination on the tinnitus percept itself.