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Different bimodal neuromodulation settings reduce tinnitus symptoms in a large randomized trial.

ABSTRACT: 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.

SUBMITTER: Conlon B

PROVIDER: S-EPMC9246951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:There is increasing evidence from animal and human studies that bimodal neuromodulation combining sound and electrical somatosensory stimulation of the tongue can induce extensive brain changes and treat tinnitus. OBJECTIVE:The main objectives of the proposed clinical study are to confirm the efficacy, safety, and tolerability of treatment demonstrated in a previous large-scale study of bimodal auditory and trigeminal nerve (tongue) stimulation (Treatment Evaluation of Neuromodulation for Tinnitus - Stage A1); evaluate the therapeutic effects of adjusting stimulation parameters over time; and determine the contribution of different features of bimodal stimulation in improving tinnitus outcomes. METHODS:This study will be a prospective, randomized, double-blind, parallel-arm, comparative clinical trial of a 12-week treatment for tinnitus using a Conformité Européenne (CE)-marked device with a pre-post and 12-month follow-up design. Four treatment arms will be investigated, in which each arm consists of two different stimulation settings, with the first setting presented during the first 6 weeks and the second setting presented during the next 6 weeks of treatment. The study will enroll 192 participants, split in a ratio of 80:80:16:16 across the four arms. Participants will be randomized to one of four arms and stratified to minimize baseline variability in four categories: two separate strata for sound level tolerance (using loudness discomfort level as indicators for hyperacusis severity), high tinnitus symptom severity based on the Tinnitus Handicap Inventory (THI), and tinnitus laterality. The primary efficacy endpoints are within-arm changes in THI and Tinnitus Functional Index as well as between-arm changes in THI after 6 weeks of treatment for the full cohort and two subgroups of tinnitus participants (ie, one hyperacusis subgroup and a high tinnitus symptom severity subgroup). Additional efficacy endpoints include within-arm or between-arm changes in THI after 6 or 12 weeks of treatment and in different subgroups of tinnitus participants as well as at posttreatment assessments at 6 weeks, 6 months, and 12 months. Treatment safety, attrition rates, and compliance rates will also be assessed and reported. RESULTS:This study protocol was approved by the Tallaght University Hospital/St. James's Hospital Joint Research Ethics Committee in Dublin, Ireland. The first participant was enrolled on March 20, 2018. The data collection and database lock are expected to be completed by February 2020, and the data analysis and manuscript submission are expected to be conducted in autumn of 2020. CONCLUSIONS:The findings of this study will be disseminated to relevant research, clinical, and health services and patient communities through publications in peer-reviewed journals and presentations at scientific and clinical conferences. TRIAL REGISTRATION:ClinicalTrials.gov NCT03530306; https://clinicaltrials.gov/ct2/show/NCT03530306. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/13176.

Project description:IntroductionTo date, guidelines recommend the use of a stepped care approach to treat tinnitus. The current clinical management of tinnitus frequently consists of audiologic interventions and tinnitus retraining therapy (TRT) or cognitive behavioral therapy (CBT). Due to the high heterogeneity of the tinnitus population and comorbidity of tinnitus with insomnia, anxiety, and depression, these interventions may not be sufficient for every patient. The current study aims to determine whether a bimodal therapy for chronic, subjective tinnitus consisting of the combination of TRT and eye movement desensitization reprocessing (EMDR) results in a clinically significant different efficacy in comparison with the prevailing bimodal TRT and CBT therapy.MethodsPatients were randomized in two treatment groups. The experimental group received the bimodal therapy TRT/EMDR and the active control group received the bimodal therapy TRT/CBT. Evaluations took place at baseline (T0), at the end of the treatment (T1), and 3 months after therapy (T2). The tinnitus functional index (TFI) was used as primary outcome measurement. Secondary outcome measurements were the visual analog scale of tinnitus loudness (VASLoudness), tinnitus questionnaire (TQ), hospital anxiety and depression scale (HADS), hyperacusis questionnaire (HQ), global perceived effect (GPE), and psychoacoustic measurements.FindingsThe TFI showed clinically significant improvement in both bimodal therapies (mean decrease 15.1 in TRT/CBT; p < 0.001 vs. 16.2 in TRT/EMDR; p < 0.001). The total score on the TQ, HADS, HQ, and VASLoudness all demonstrated significant decrease after treatment and follow-up (p < 0.001) in the experimental and the active control group. GPE-measurements revealed that more than 80% (i.e., 84% in TRT/CBT vs. 80% in TRT/EMDR) of the patients experienced substantial improvement of tinnitus at follow up. Treatment outcome remained stable after 3 month follow-up and no adverse events were observed.ConclusionBoth psychotherapeutic protocols result in a clinically significant improvement for patients with chronic subjective tinnitus. No significant different efficacy was found for the TRT/EMDR treatment compared to the combination of TRT and CBT.Clinical trial registrationClinicalTrials.gov, ID: NCT03114878. April 14, 2017.

Project description:BackgroundCurrent theories of tinnitus assume that the phantom sound is generated either through increased spontaneous activity of neurons in the auditory brain, or through pathological temporal firing patterns of the spontaneous neuronal discharge, or a combination of both factors. With this in mind, Tass and colleagues recently tested a number of temporally patterned acoustic stimulation strategies in a proof of concept study. Potential therapeutic sound regimes were derived according to a paradigm assumed to disrupt hypersynchronous neuronal activity, and promote plasticity mechanisms that stabilize a state of asynchronous spontaneous activity. This would correspond to a permanent reduction of tinnitus. The proof of concept study, conducted in Germany, confirmed the safety of the acoustic stimuli for use in tinnitus, and exploratory results indicated modulation of tinnitus-related pathological synchronous activity with potential therapeutic benefit. The most effective stimulation paradigm is now in clinical use as a sound therapy device, the acoustic coordinated reset (CR®) neuromodulation (Adaptive Neuromodulation GmbH (ANM), Köln, Germany).Methods/designTo measure the efficacy of CR® neuromodulation, we devised a powered, two-center, randomized controlled trial (RCT) compliant with the reporting standards defined in the Consolidated Standards of Reporting Trials (CONSORT) Statement. The RCT design also addresses the recent call for international standards within the tinnitus community for high-quality clinical trials. The design uses a between-subjects comparison with minimized allocation of participants to treatment and placebo groups. A minimization approach was selected to ensure that the two groups are balanced with respect to age, gender, hearing, and baseline tinnitus severity. The protocol ensures double blinding, with crossover of the placebo group to receive the proprietary intervention after 12 weeks. The primary endpoints are the pre- and post-treatment measures that provide the primary measures of efficacy, namely a validated and sensitive questionnaire measure of the functional impact of tinnitus. The trial is also designed to capture secondary changes in tinnitus handicap, quality (pitch, loudness, bandwidth), and changes in tinnitus-related pathological synchronous brain activity using electroencephalography (EEG).DiscussionThis RCT was designed to provide a confident high-level estimate of the efficacy of sound therapy using CR® neuromodulation compared to a well-matched placebo intervention, and uniquely in terms of sound therapy, examine the physiological effects of the intervention against its putative mechanism of action.Trial registrationClinicalTrials.gov, NCT01541969.

Project description:ObjectiveTo estimate the impact of the PediBIRN (Pediatric Brain Injury Research Network) 4-variable clinical decision rule (CDR) on abuse evaluations and missed abusive head trauma in pediatric intensive care settings.Study designThis was a cluster randomized trial. Participants included 8 pediatric intensive care units (PICUs) in US academic medical centers; PICU and child abuse physicians; and consecutive patients with acute head injures <3 years (n = 183 and n = 237, intervention vs control). PICUs were stratified by patient volumes, pair-matched, and randomized equally to intervention or control conditions. Randomization was concealed from the biostatistician. Physician-directed, cluster-level interventions included initial and booster training, access to an abusive head trauma probability calculator, and information sessions. Outcomes included "higher risk" patients evaluated thoroughly for abuse (with skeletal survey and retinal examination), potential cases of missed abusive head trauma (patients lacking either evaluation), and estimates of missed abusive head trauma (among potential cases). Group comparisons were performed using generalized linear mixed-effects models.ResultsIntervention physicians evaluated a greater proportion of higher risk patients thoroughly (81% vs 73%, P = .11) and had fewer potential cases of missed abusive head trauma (21% vs 32%, P = .05), although estimated cases of missed abusive head trauma did not differ (7% vs 13%, P = .22). From baseline (in previous studies) to trial, the change in higher risk patients evaluated thoroughly (67%→81% vs 78%→73%, P = .01), and potential cases of missed abusive head trauma (40%→21% vs 29%→32%, P = .003), diverged significantly. We did not identify a significant divergence in the number of estimated cases of missed abusive head trauma (15%→7% vs 11%→13%, P = .22).ConclusionsPediBIRN-4 CDR application facilitated changes in abuse evaluations that reduced potential cases of missed abusive head trauma in PICU settings.Trial registrationClinicalTrials.gov: NCT03162354.

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Different bimodal neuromodulation settings reduce tinnitus symptoms in a large randomized trial.

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