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A pro-inflammatory intestinal microbiome is characteristic of Parkinson’s disease (PD). Prebiotic fibers change the microbiome and this study sought to understand the utility of prebiotic fibers for use in PD patients. The first experiments demonstrate that fermentation of PD patient stool with prebiotic fibers increased the production of beneficial metabolites (short chain fatty acids, SCFA) and changed the microbiota demonstrating the capacity of PD microbiota to respond favorably to prebiotics. Subsequently, an open-label, non-randomized study was conducted in newly diagnosed, non-medicated ( n  = 10) and treated PD participants ( n  = 10) wherein the impact of 10 days of prebiotic intervention was evaluated. Outcomes demonstrate that the prebiotic intervention was well tolerated (primary outcome) and safe (secondary outcome) in PD participants and was associated with beneficial biological changes in the microbiota, SCFA, inflammation, and neurofilament light chain. Exploratory analyses indicate effects on clinically relevant outcomes. This proof-of-concept study offers the scientific rationale for placebo-controlled trials using prebiotic fibers in PD patients. ClinicalTrials.gov Identifier: NCT04512599. This study found that a prebiotic intervention was well-tolerated and safe, beneficially changed the microbiome, decreased inflammation and a marker of neurodegeneration, with possible clinical effects in Parkinson’s disease (PD) patients. This study offers the rationale for further investigations using prebiotic fibers in PD.

[...]while there are multiple ways of perceiving tinnitus, it is also associated with multiple causal risk factors—hearing loss, temporomandibular joint disorder, and aging being among the most common ones. Within this topic, current knowledge is reviewed and new theories of tinnitus generation are proposed, animal models are used to understand the neural correlates better, audiological, and psychological aspects are explored, neuroimaging techniques investigate the involved brain networks, new questionnaire instruments are developed and others adapted to new languages, genome-wide associations are pioneered, mobile applications are used to explore tinnitus on new time-scales, and, finally, multiple therapeutic approaches are tested. [...]the fifth chapter refers to advances on tinnitus therapies. Age-related hearing loss and tinnitus can go hand in hand and one of the most well-established theories considers tinnitus as the perceptual consequence of neuronal hyperactivity in the central auditory system; emerging after loss of normal input from the ear.

Tinnitus is the conscious perception of a sound without a corresponding external acoustic stimulus, usually described as a perception. One of the major challenges for tinnitus research is to understand the pathophysiological mechanisms triggering and maintaining the symptoms, especially for subjective chronic tinnitus. Our objective was to synthesize the published literature in order to provide a comprehensive update on theoretical and experimental advances and to identify further research and clinical directions. We performed literature searches in three electronic databases, complemented by scanning reference lists from relevant reviews in our included records, citation searching of the included articles using Web of Science, and manual searching of the last 6 months of principal otology journals. One-hundred and thirty-two records were included in the review and the information related to peripheral and central mechanisms of tinnitus pathophysiology was collected in order to update on theories and models. A narrative synthesis examined the main themes arising from this information. Tinnitus pathophysiology is complex and multifactorial, involving the auditory and non-auditory systems. Recent theories assume the necessary involvement of extra-auditory brain regions for tinnitus to reach consciousness. Tinnitus engages multiple active dynamic and overlapping networks. We conclude that advancing knowledge concerning the origin and maintenance of specific tinnitus subtypes origin and maintenance mechanisms is of paramount importance for identifying adequate treatment.

More than 10% of the population suffers from tinnitus, which is a phantom auditory condition that is coded within the brain. A new neuromodulation approach to treat tinnitus has emerged that combines sound with electrical stimulation of somatosensory pathways, supported by multiple animal studies demonstrating that bimodal stimulation can elicit extensive neural plasticity within the auditory brain. More recently, in a large-scale clinical trial, bimodal neuromodulation combining sound and tongue stimulation drove significant reductions in tinnitus symptom severity during the first 6 weeks of treatment, followed by diminishing improvements during the second 6 weeks of treatment. The primary objective of the large-scale randomized and double-blinded study presented in this paper was to determine if background wideband noise as used in the previous clinical trial was necessary for bimodal treatment efficacy. An additional objective was to determine if adjusting the parameter settings after 6 weeks of treatment could overcome treatment habituation effects observed in the previous study. The primary endpoint at 6-weeks involved within-arm and between-arm comparisons for two treatment arms with different bimodal neuromodulation settings based on two widely used and validated outcome instruments, Tinnitus Handicap Inventory and Tinnitus Functional Index. Both treatment arms exhibited a statistically significant reduction in tinnitus symptoms during the first 6-weeks, which was further reduced significantly during the second 6-weeks by changing the parameter settings (Cohen’s d effect size for full treatment period per arm and outcome measure ranged from − 0.7 to − 1.4). There were no significant differences between arms, in which tongue stimulation combined with only pure tones and without background wideband noise was sufficient to reduce tinnitus symptoms. These therapeutic effects were sustained up to 12 months after the treatment ended. The study included two additional exploratory arms, including one arm that presented only sound stimuli during the first 6 weeks of treatment and bimodal stimulation in the second 6 weeks of treatment. This arm revealed the criticality of combining tongue stimulation with sound for treatment efficacy. Overall, there were no treatment-related serious adverse events and a high compliance rate (83.8%) with 70.3% of participants indicating benefit. The discovery that adjusting stimulation parameters overcomes previously observed treatment habituation can be used to drive greater therapeutic effects and opens up new opportunities for optimizing stimuli and enhancing clinical outcomes for tinnitus patients with bimodal neuromodulation.

Exercise confers short-term benefits for individuals with Parkinson disease (PD). The purpose of the study was to compare short- and long-term responses among 2 supervised exercise programs and a home-based control exercise program. The 16-month randomized controlled exercise intervention investigated 3 exercise approaches: flexibility/balance/function exercise (FBF), supervised aerobic exercise (AE), and home-based exercise (control). This study was conducted in outpatient clinics. The participants were 121 individuals with PD (Hoehn & Yahr stages 1-3). The FBF program (individualized spinal and extremity flexibility exercises followed by group balance/functional training) was supervised by a physical therapist. The AE program (using a treadmill, bike, or elliptical trainer) was supervised by an exercise trainer. Supervision was provided 3 days per week for 4 months, and then monthly (16 months total). The control group participants exercised at home using the National Parkinson Foundation Fitness Counts program, with 1 supervised, clinic-based group session per month. Outcomes, obtained by blinded assessors, were determined at 4, 10, and 16 months. The primary outcome measures were overall physical function (Continuous Scale-Physical Functional Performance [CS-PFP]), balance (Functional Reach Test [FRT]), and walking economy (oxygen uptake [mL/kg/min]). Secondary outcome measures were symptom severity (Unified Parkinson's Disease Rating Scale [UPDRS] activities of daily living [ADL] and motor subscales) and quality of life (39-item Parkinson's Disease Quality of Life Scale [PDQ-39]). Of the 121 participants, 86.8%, 82.6%, and 79.3% completed 4, 10, and 16 months, respectively, of the intervention. At 4 months, improvement in CS-PFP scores was greater in the FBF group than in the control group (mean difference=4.3, 95% confidence interval [CI]=1.2 to 7.3) and the AE group (mean difference=3.1, 95% CI=0.0 to 6.2). Balance was not different among groups at any time point. Walking economy improved in the AE group compared with the FBF group at 4 months (mean difference=-1.2, 95% CI=-1.9 to -0.5), 10 months (mean difference=-1.2, 95% CI=-1.9 to -0.5), and 16 months (mean difference=-1.7, 95% CI=-2.5 to -1.0). The only secondary outcome that showed significant differences was UPDRS ADL subscale scores: the FBF group performed better than the control group at 4 months (mean difference=-1.47, 95% CI=-2.79 to -0.15) and 16 months (mean difference=-1.95, 95% CI=-3.84 to -0.08). Absence of a non-exercise control group was a limitation of the study. Findings demonstrated overall functional benefits at 4 months in the FBF group and improved walking economy (up to 16 months) in the AE group.

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies.

Tinnitus is the awareness of sound in the ear or head in the absence of an external source. It affects around 10%–15% of people, and current treatment options are limited. Experimental treatments include various forms of electrical stimulation of the brain. Currently, there is no consensus on the outcomes that should be measured when investigating the efficacy of this type of intervention for tinnitus.ObjectiveThis study sought to address this issue by establishing a core domain set: a common standard of what specific tinnitus-related complaints are critically important to assess in all clinical trials of electrical stimulation-based interventions for tinnitus.DesignA two-round Delphi survey was conducted, followed by a stakeholder consensus meeting to identify a core domain set. Setting All data collection took place onlineParticipantsParticipants represented one of two stakeholder groups: patients with lived experience of tinnitus and professionals with relevant clinical, commercial or research experience.ResultsStakeholders achieved consensus on the inclusion of ability to ignore, concentration, treatment satisfaction, helplessness (lack of control) and tinnitus intrusiveness in the core domain set, in addition to adverse effects.ConclusionThis study established a core domain set for the evaluation of electrical stimulation-based interventions for tinnitus via an e-Delphi study. This core domain set will act as a minimum standard for reporting in future clinical trials of electrical stimulation interventions for tinnitus. Standardisation will facilitate comparability of research findings.

The ability to reproducibly match tinnitus loudness and pitch is important to research and clinical management. Here we examine agreement and reliability of tinnitus loudness matching and pitch likeness ratings when using a computer-based method to measure the tinnitus spectrum and estimate a dominant tinnitus pitch, using tonal or narrowband sounds. Group level data indicated a significant effect of time between test session 1 and 2 for loudness matching, likely procedural or perceptual learning, which needs to be accounted in study design. Pitch likeness rating across multiple frequencies appeared inherently more variable and with no systematic effect of time. Dominant pitch estimates reached a level of clinical acceptability when sessions were spaced two weeks apart. However when dominant tinnitus pitch assessments were separated by three months, acceptable agreement was achieved only for group mean data, not for individual estimates. This has implications for prescription of some sound-based interventions that rely on accurate measures of individual dominant tinnitus pitch.

Tinnitus is the perception of an internally generated sound that is postulated to emerge as a result of structural and functional changes in the brain. However, the precise pathophysiology of tinnitus remains unknown. Llinas' thalamocortical dysrhythmia model suggests that neural deafferentation due to hearing loss causes a dysregulation of coherent activity between thalamus and auditory cortex. This leads to a pathological coupling of theta and gamma oscillatory activity in the resting state, localised to the auditory cortex where normally alpha oscillations should occur. Numerous studies also suggest that tinnitus perception relies on the interplay between auditory and non-auditory brain areas. According to the Global Brain Model, a network of global fronto-parietal-cingulate areas is important in the generation and maintenance of the conscious perception of tinnitus. Thus, the distress experienced by many individuals with tinnitus is related to the top-down influence of this global network on auditory areas. In this magnetoencephalographic study, we compare resting-state oscillatory activity of tinnitus participants and normal-hearing controls to examine effects on spectral power as well as functional and effective connectivity. The analysis is based on beamformer source projection and an atlas-based region-of-interest approach. We find increased functional connectivity within the auditory cortices in the alpha band. A significant increase is also found for the effective connectivity from a global brain network to the auditory cortices in the alpha and beta bands. We do not find evidence of effects on spectral power. Overall, our results provide only limited support for the thalamocortical dysrhythmia and Global Brain models of tinnitus.

Subjective tinnitus is a chronic heterogeneous condition that is typically managed using intervention approaches based on sound devices, psychologically informed therapies, or pharmaceutical products. For clinical trials, there are currently no common standards for assessing or reporting intervention efficacy. This article reports on the first of two steps to establish a common standard, which identifies what specific tinnitus-related complaints (“outcome domains”) are critical and important to assess in all clinical trials to determine whether an intervention has worked. Using purposive sampling, 719 international health-care users with tinnitus, health-care professionals, clinical researchers, commercial representatives, and funders were recruited. Eligibility was primarily determined by experience of one of the three interventions of interest. Following recommended procedures for gaining consensus, three intervention-specific, three-round, Delphi surveys were delivered online. Each Delphi survey was followed by an in-person consensus meeting. Viewpoints and votes involved all stakeholder groups, with approximately a 1:1 ratio of health-care users to professionals. “Tinnitus intrusiveness” was voted in for all three interventions. For sound-based interventions, the minimum set included “ability to ignore,” “concentration,” “quality of sleep,” and “sense of control.” For psychology-based interventions, the minimum set included “acceptance of tinnitus,” “mood,” “negative thoughts and beliefs,” and “sense of control.” For pharmacology-based interventions, “tinnitus loudness” was the only additional core outcome domain. The second step will next identify how those outcome domains should best be measured. The uptake of these intervention-specific standards in clinical trials will improve research quality, enhance clinical decision-making, and facilitate meta-analysis in systematic reviews.