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Fulltext Noninvasive Bimodal Neuromodulation for the Treatment of Tinnitus: Protocol for a Second Large-Scale Double-Blind Randomized Clinical Trial to Optimize Stimulation Parameters

Conlon B, Hamilton C, Hughes S, Meade E, Hall DA, Vanneste S, et al.

JMIR Res Protoc, 2019 Sep 27;8(9):e13176.
PMID: 31573942 DOI: 10.2196/13176

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

Conlon B, Hamilton C, Meade E, Leong SL, O Connor C, Langguth B, et al.

Sci Rep, 2022 Jun 30;12(1):10845.
PMID: 35773272 DOI: 10.1038/s41598-022-13875-x

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.
Fulltext Author Correction: Different bimodal neuromodulation settings reduce tinnitus symptoms in a large randomized trial

Conlon B, Hamilton C, Meade E, Leong SL, O Connor C, Langguth B, et al.

Sci Rep, 2023 Jul 10;13(1):11152.
PMID: 37430102 DOI: 10.1038/s41598-023-38312-5
Bimodal neuromodulation combining sound and tongue stimulation reduces tinnitus symptoms in a large randomized clinical study

Conlon B, Langguth B, Hamilton C, Hughes S, Meade E, Connor CO, et al.

Sci Transl Med, 2020 10 07;12(564).
PMID: 33028707 DOI: 10.1126/scitranslmed.abb2830

Tinnitus is a phantom auditory perception coded in the brain that can be bothersome or debilitating, affecting 10 to 15% of the population. Currently, there is no clinically recommended drug or device treatment for this major health condition. Animal research has revealed that sound paired with electrical somatosensory stimulation can drive extensive plasticity within the brain for tinnitus treatment. To investigate this bimodal neuromodulation approach in humans, we evaluated a noninvasive device that delivers sound to the ears and electrical stimulation to the tongue in a randomized, double-blinded, exploratory study that enrolled 326 adults with chronic subjective tinnitus. Participants were randomized into three parallel arms with different stimulation settings. Clinical outcomes were evaluated over a 12-week treatment period and a 12-month posttreatment phase. For the primary endpoints, participants achieved a statistically significant reduction in tinnitus symptom severity at the end of treatment based on two commonly used outcome measures, Tinnitus Handicap Inventory (Cohen's d effect size: -0.87 to -0.92 across arms; P < 0.001) and Tinnitus Functional Index (-0.77 to -0.87; P < 0.001). Therapeutic improvements continued for 12 months after treatment for specific bimodal stimulation settings, which had not previously been demonstrated in a large cohort for a tinnitus intervention. The treatment also achieved high compliance and satisfaction rates with no treatment-related serious adverse events. These positive therapeutic and long-term results motivate further clinical trials toward establishing bimodal neuromodulation as a clinically recommended device treatment for tinnitus.
Fulltext Editorial: Towards an Understanding of Tinnitus Heterogeneity

Cederroth CR, Gallus S, Hall DA, Kleinjung T, Langguth B, Maruotti A, et al.

Front Aging Neurosci, 2019;11:53.
PMID: 30941029 DOI: 10.3389/fnagi.2019.00053
Fulltext Diagnostic Criteria for Somatosensory Tinnitus: A Delphi Process and Face-to-Face Meeting to Establish Consensus

Michiels S, Ganz Sanchez T, Oron Y, Gilles A, Haider HF, Erlandsson S, et al.

Trends Hear, 2018 9 15;22:2331216518796403.
PMID: 30213235 DOI: 10.1177/2331216518796403

Since somatic or somatosensory tinnitus (ST) was first described as a subtype of subjective tinnitus, where altered somatosensory afference from the cervical spine or temporomandibular area causes or changes a patient's tinnitus perception, several studies in humans and animals have provided a neurophysiological explanation for this type of tinnitus. Due to a lack of unambiguous clinical tests, many authors and clinicians use their own criteria for diagnosing ST. This resulted in large differences in prevalence figures in different studies and limits the comparison of clinical trials on ST treatment. This study aimed to reach an international consensus on diagnostic criteria for ST among experts, scientists and clinicians using a Delphi survey and face-to-face consensus meeting strategy. Following recommended procedures to gain expert consensus, a two-round Delphi survey was delivered online, followed by an in-person consensus meeting. Experts agreed upon a set of criteria that strongly suggest ST. These criteria comprise items on somatosensory modulation, specific tinnitus characteristics, and symptoms that can accompany the tinnitus. None of these criteria have to be present in every single patient with ST, but in case they are present, they strongly suggest the presence of ST. Because of the international nature of the survey, we expect these criteria to gain wide acceptance in the research field and to serve as a guideline for clinicians across all disciplines. Criteria developed in this consensus paper should now allow further investigation of the extent of somatosensory influence in individual tinnitus patients and tinnitus populations.
Correction to: Emerging Topics in the Behavioral Neuroscience of Tinnitus

Searchfield GD, Zhang J, Biswas R, De Ridder D, Deutsch B, Hall DA, et al.

Curr Top Behav Neurosci, 2021;51:487.
PMID: 34291436 DOI: 10.1007/7854_2021_230
Emerging Topics in the Behavioral Neuroscience of Tinnitus

Searchfield GD, Zhang J, Biswas R, De Ridder D, Deutsch B, Hall DA, et al.

Curr Top Behav Neurosci, 2021;51:461-483.
PMID: 33665781 DOI: 10.1007/7854_2020_217

This volume has highlighted the many recent advances in tinnitus theory, models, diagnostics, therapies, and therapeutics. But tinnitus knowledge is far from complete. In this chapter, contributors to the Behavioral Neuroscience of Tinnitus consider emerging topics and areas of research needed in light of recent findings. New research avenues and methods to explore are discussed. Issues pertaining to current assessment, treatment, and research methods are outlined, along with recommendations on new avenues to explore with research.
Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal)

De Ridder D, Schlee W, Vanneste S, Londero A, Weisz N, Kleinjung T, et al.

Prog Brain Res, 2021;260:1-25.
PMID: 33637213 DOI: 10.1016/bs.pbr.2020.12.002

As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO's ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association's DSM-V doesn't mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: "Tinnitus" for the former and "Tinnitus Disorder" for the latter. The proposed definition then becomes "Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder "when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.". In other words "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder.