Investigating Disinhibitory Brain Mechanism in Tinnitus and Hearing Loss

NCT04862572 | Completed

• 1 other identifier: 21020
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 3

Brief Summary

Tinnitus, the perception of sound in the absence of an external acoustic stimulus. Tinnitus is often perceived inside the head rather than the ear and is a common condition with a prevalence estimated between 10 and 15% in adults. Between 1 and 3% of this population are having a significant impact on their quality of life. Despite its high prevalence, the underlying mechanisms of tinnitus still remain unclear. The majority of tinnitus cases associated with some degree of hearing loss, making hearing loss the biggest risk factor for tinnitus. Recently, it has been suggested that hearing deficits, such as speech-in-noise difficulty, can exist in the absence of any overt hearing loss within the audiometric range (0.125-8 kHz). This is referred to as "hidden hearing loss" and has been suggested to be associated with hearing loss at above-audiometric (\> 8 kHz) frequencies. This project is aimed at studying the underlying mechanisms of tinnitus and the possible relation with overt or hidden hearing loss. Specifically, the investigators want to test the hypothesis that tinnitus is caused by maladaptive plasticity arising as a result of auditory input deprivation. This idea is supported by the finding that tinnitus may disappear when the hearing, and thus auditory input, recover. Disruptions at lower levels of the auditory pathway could lead to alterations in synaptic transmission and neurotransmitter release in more central regions of the auditory system (e.g., in the auditory cortex). This may create an imbalance between neuronal excitation and inhibition, and re-routing of auditory pathways, leading to abnormal neural excitability and connectivity. In this study, the investigators question whether auditory cortex disinhibition is specifically related to tinnitus, or is a consequence of hearing loss. To answer this question, the investigators propose to conduct a study that aims to investigate the inhibition mechanism by quantifying GABA concentration level, neural activity and functional connectivity strength of auditory cortex using non-invasive imaging techniques, namely Magnetic Resonance Spectroscopy (MRS) and functional Magnetic Resonance Imaging (fMRI). The investigators expected to possibly provide a tinnitus biomarker, and this may help to direct future treatments.

Conditions

Tinnitus; Hearing Loss

Keywords

Tinnitus; Hearing loss; Inhibition; Functional connectivity; Structural connectivity

Outcome Measures

Primary Outcomes (1)

• GABA neurotransmitter level measured using MRS and neural activity and connectivity strength in auditory resting-state networks using functional MRI scan.

  Primary test: * Univariate group comparison between-group differences in imaging outcomes: auditory cortex GABA, local functional connectivity density (REHO), interhemispheric auditory cortices functional connectivity, cross-modal functional connectivity between auditory and visual cortex, auditory cortex neural activity (using BOLD response) to visual attention task. * Between-group test for differences in correlation: GABA and hearing loss, auditory cortex functional connectivity and hearing loss.

  During 3-6 months after the data has been collected

Secondary Outcomes (2)

• Measures of GABA level in the auditory cortex and correlation with tinnitus severity scores and tinnitus negative affect scores.

  During 3-6 months after the data has been collected

• Measures of neural activity, and connectivity changes in brain-wide and correlation of these measures with tinnitus severity scores and tinnitus negative affect scores.

  During 3-6 months after the data has been collected

Study Arms (2)

People with tinnitus

EXPERIMENTAL

People with tinnitus will undergo all interventions (audiology test, MRI scans, tinnitus-related questionnaires).

Other: MRI scanning

People without tinnitus

EXPERIMENTAL

People with tinnitus will undergo most of all interventions (audiology test, MRI scans) except filling up the tinnitus-related questionnaires.

Other: MRI scanning

Interventions

MRI scanning OTHER

In the audiological assessment, participants will undergo various audiometric test, such as pure tone audiometry with extended high-frequency range, speech audiometry, tympanometry, and auditory reflex threshold. These tests are all noninvasive and aim to assess participants hearing threshold, speech-in-noise difficulty, whether or not they have conductive hearing loss, and test efferent auditory function. The appointment will take around 60-90 minutes. An experienced audiologist on-site will be in charge of this procedure. In the MRI appointment, participant will undergo MRI scanning. Before the MRI scan, a researcher with experienced radiographer will re-check that the participant is safe to be scanned, with the standard University of Nottingham safety questionnaire. This rechecking step is necessary to make sure that participants are still eligible for the scanning. An experience radiographer will be in charge of this procedure.

Also known as: Audiological assessment

People with tinnitus; People without tinnitus

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Are age 18-80 years.
• Are eligible to be scanned using MRI and to undergo audiometry and psychometry.
• Are able to give informed consent.
• Must have a good comprehension of English in order to complete the hearing-related questionnaires

You may not qualify if:

• Pregnant women will be excluded based on MRI safety recommendations.
• Past medical history of acoustic neuroma and Ménière's disease.
• Significant past medical history that may affect brain GABA and functional metrics such as stroke, multiple sclerosis, epilepsy, diabetes, cardiovascular, major neurodegenerative or psychiatric conditions, cancer requiring systemic chemotherapy or brain radiotherapy.
• Individuals who had in last 3 months and/or currently taking a sedating or GABA enhancing or psychoactive drugs (opioids, anti-depressants).

Sponsors & Collaborators

• University of Nottingham: lead
• Nottingham University Hospitals NHS Trust: collaborator

Study Sites (3)

Greater Nottingham and Midlands areas

Nottingham, United Kingdom

Location

NIHR Hearing Research

Nottingham, United Kingdom

Location

Nottingham Audiology clinics

Nottingham, United Kingdom

Location

Related Publications (34)

• Alain C, Roye A, Salloum C. Effects of age-related hearing loss and background noise on neuromagnetic activity from auditory cortex. Front Syst Neurosci. 2014 Jan 31;8:8. doi: 10.3389/fnsys.2014.00008. eCollection 2014.

  PMID: 24550790 BACKGROUND

• Auerbach BD, Rodrigues PV, Salvi RJ. Central gain control in tinnitus and hyperacusis. Front Neurol. 2014 Oct 24;5:206. doi: 10.3389/fneur.2014.00206. eCollection 2014.

  PMID: 25386157 BACKGROUND

• Baguley D, McFerran D, Hall D. Tinnitus. Lancet. 2013 Nov 9;382(9904):1600-7. doi: 10.1016/S0140-6736(13)60142-7. Epub 2013 Jul 2.

  PMID: 23827090 BACKGROUND

• Bauer CA. Tinnitus. N Engl J Med. 2018 Mar 29;378(13):1224-1231. doi: 10.1056/NEJMcp1506631. No abstract available.

  PMID: 29601255 BACKGROUND

• Bauer CA, Turner JG, Caspary DM, Myers KS, Brozoski TJ. Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. J Neurosci Res. 2008 Aug 15;86(11):2564-78. doi: 10.1002/jnr.21699.

  PMID: 18438941 BACKGROUND

• Deco G, Ponce-Alvarez A, Hagmann P, Romani GL, Mantini D, Corbetta M. How local excitation-inhibition ratio impacts the whole brain dynamics. J Neurosci. 2014 Jun 4;34(23):7886-98. doi: 10.1523/JNEUROSCI.5068-13.2014.

  PMID: 24899711 BACKGROUND

• Demeester K, van Wieringen A, Hendrickx JJ, Topsakal V, Fransen E, Van Laer L, De Ridder D, Van Camp G, Van de Heyning P. Prevalence of tinnitus and audiometric shape. B-ENT. 2007;3 Suppl 7:37-49.

  PMID: 18225607 BACKGROUND

• Dempsey MF, Condon B, Hadley DM. MRI safety review. Semin Ultrasound CT MR. 2002 Oct;23(5):392-401. doi: 10.1016/s0887-2171(02)90010-7.

  PMID: 12509109 BACKGROUND

• Eggermont JJ, Roberts LE. Tinnitus: animal models and findings in humans. Cell Tissue Res. 2015 Jul;361(1):311-36. doi: 10.1007/s00441-014-1992-8. Epub 2014 Sep 30.

  PMID: 25266340 BACKGROUND

• Eggermont JJ, Tass PA. Maladaptive neural synchrony in tinnitus: origin and restoration. Front Neurol. 2015 Feb 17;6:29. doi: 10.3389/fneur.2015.00029. eCollection 2015.

  PMID: 25741316 BACKGROUND

• Gao F, Wang G, Ma W, Ren F, Li M, Dong Y, Liu C, Liu B, Bai X, Zhao B, Edden RA. Decreased auditory GABA+ concentrations in presbycusis demonstrated by edited magnetic resonance spectroscopy. Neuroimage. 2015 Feb 1;106:311-6. doi: 10.1016/j.neuroimage.2014.11.023. Epub 2014 Nov 15.

  PMID: 25463460 BACKGROUND

• Gao Y, Manzoor N, Kaltenbach JA. Evidence of activity-dependent plasticity in the dorsal cochlear nucleus, in vivo, induced by brief sound exposure. Hear Res. 2016 Nov;341:31-42. doi: 10.1016/j.heares.2016.07.011. Epub 2016 Aug 1.

  PMID: 27490001 BACKGROUND

• Hoffman, H. J., & Reed, G. W. (2004). Epidemiology of tinnitus. Tinnitus: Theory and management, 16, 16-41.

  BACKGROUND

• Ito T, Brincat SL, Siegel M, Mill RD, He BJ, Miller EK, Rotstein HG, Cole MW. Task-evoked activity quenches neural correlations and variability across cortical areas. PLoS Comput Biol. 2020 Aug 3;16(8):e1007983. doi: 10.1371/journal.pcbi.1007983. eCollection 2020 Aug.

  PMID: 32745096 BACKGROUND

• Kalappa BI, Brozoski TJ, Turner JG, Caspary DM. Single unit hyperactivity and bursting in the auditory thalamus of awake rats directly correlates with behavioural evidence of tinnitus. J Physiol. 2014 Nov 15;592(22):5065-78. doi: 10.1113/jphysiol.2014.278572. Epub 2014 Sep 12.

  PMID: 25217380 BACKGROUND

• Kaltenbach JA, Afman CE. Hyperactivity in the dorsal cochlear nucleus after intense sound exposure and its resemblance to tone-evoked activity: a physiological model for tinnitus. Hear Res. 2000 Feb;140(1-2):165-72. doi: 10.1016/s0378-5955(99)00197-5.

  PMID: 10675644 BACKGROUND

• Kim JY, Kim YH, Lee S, Seo JH, Song HJ, Cho JH, Chang Y. Alteration of functional connectivity in tinnitus brain revealed by resting-state fMRI? A pilot study. Int J Audiol. 2012 May;51(5):413-7. doi: 10.3109/14992027.2011.652677. Epub 2012 Jan 30.

  PMID: 22283490 BACKGROUND

• C Kohrman D, Wan G, Cassinotti L, Corfas G. Hidden Hearing Loss: A Disorder with Multiple Etiologies and Mechanisms. Cold Spring Harb Perspect Med. 2020 Jan 2;10(1):a035493. doi: 10.1101/cshperspect.a035493.

  PMID: 30617057 BACKGROUND

• Kotak VC, Fujisawa S, Lee FA, Karthikeyan O, Aoki C, Sanes DH. Hearing loss raises excitability in the auditory cortex. J Neurosci. 2005 Apr 13;25(15):3908-18. doi: 10.1523/JNEUROSCI.5169-04.2005.

  PMID: 15829643 BACKGROUND

• Koush Y, de Graaf RA, Kupers R, Dricot L, Ptito M, Behar KL, Rothman DL, Hyder F. Metabolic underpinnings of activated and deactivated cortical areas in human brain. J Cereb Blood Flow Metab. 2021 May;41(5):986-1000. doi: 10.1177/0271678X21989186. Epub 2021 Jan 20.

  PMID: 33472521 BACKGROUND

• Lefeuvre J, Chedeau J, Boulet M, Fain G, Papon JF, Nguyen Y, Nevoux J. Hidden hearing loss and tinnitus: Utility of the high-definition audiograms in diagnosis. Clin Otolaryngol. 2019 Nov;44(6):1170-1175. doi: 10.1111/coa.13435. Epub 2019 Oct 4. No abstract available.

  PMID: 31535428 BACKGROUND

• Lockwood AH, Salvi RJ, Burkard RF. Tinnitus. N Engl J Med. 2002 Sep 19;347(12):904-10. doi: 10.1056/NEJMra013395. No abstract available.

  PMID: 12239260 BACKGROUND

• Middleton JW, Kiritani T, Pedersen C, Turner JG, Shepherd GM, Tzounopoulos T. Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7601-6. doi: 10.1073/pnas.1100223108. Epub 2011 Apr 18.

  PMID: 21502491 BACKGROUND

• Moller AR. The role of neural plasticity in tinnitus. Prog Brain Res. 2007;166:37-45. doi: 10.1016/S0079-6123(07)66003-8.

  PMID: 17956769 BACKGROUND

• Nondahl DM, Cruickshanks KJ, Wiley TL, Klein R, Klein BE, Tweed TS. Prevalence and 5-year incidence of tinnitus among older adults: the epidemiology of hearing loss study. J Am Acad Audiol. 2002 Jun;13(6):323-31.

  PMID: 12141389 BACKGROUND

• Norena AJ, Farley BJ. Tinnitus-related neural activity: theories of generation, propagation, and centralization. Hear Res. 2013 Jan;295:161-71. doi: 10.1016/j.heares.2012.09.010. Epub 2012 Oct 23.

  PMID: 23088832 BACKGROUND

• Roberts LE, Eggermont JJ, Caspary DM, Shore SE, Melcher JR, Kaltenbach JA. Ringing ears: the neuroscience of tinnitus. J Neurosci. 2010 Nov 10;30(45):14972-9. doi: 10.1523/JNEUROSCI.4028-10.2010.

  PMID: 21068300 BACKGROUND

• Schaette R, Kempter R. Development of tinnitus-related neuronal hyperactivity through homeostatic plasticity after hearing loss: a computational model. Eur J Neurosci. 2006 Jun;23(11):3124-38. doi: 10.1111/j.1460-9568.2006.04774.x.

  PMID: 16820003 BACKGROUND

• Schreiber BE, Agrup C, Haskard DO, Luxon LM. Sudden sensorineural hearing loss. Lancet. 2010 Apr 3;375(9721):1203-11. doi: 10.1016/S0140-6736(09)62071-7.

  PMID: 20362815 BACKGROUND

• Sedley W, Parikh J, Edden RA, Tait V, Blamire A, Griffiths TD. Human Auditory Cortex Neurochemistry Reflects the Presence and Severity of Tinnitus. J Neurosci. 2015 Nov 4;35(44):14822-8. doi: 10.1523/JNEUROSCI.2695-15.2015.

  PMID: 26538652 BACKGROUND

• Shore SE, Roberts LE, Langguth B. Maladaptive plasticity in tinnitus--triggers, mechanisms and treatment. Nat Rev Neurol. 2016 Mar;12(3):150-60. doi: 10.1038/nrneurol.2016.12. Epub 2016 Feb 12.

  PMID: 26868680 BACKGROUND

• Vielsmeier V, Lehner A, Strutz J, Steffens T, Kreuzer PM, Schecklmann M, Landgrebe M, Langguth B, Kleinjung T. The Relevance of the High Frequency Audiometry in Tinnitus Patients with Normal Hearing in Conventional Pure-Tone Audiometry. Biomed Res Int. 2015;2015:302515. doi: 10.1155/2015/302515. Epub 2015 Oct 25.

  PMID: 26583098 BACKGROUND

• Xiong B, Liu Z, Liu Q, Peng Y, Wu H, Lin Y, Zhao X, Sun W. Missed hearing loss in tinnitus patients with normal audiograms. Hear Res. 2019 Dec;384:107826. doi: 10.1016/j.heares.2019.107826. Epub 2019 Oct 17.

  PMID: 31683074 BACKGROUND

• Yang S, Weiner BD, Zhang LS, Cho SJ, Bao S. Homeostatic plasticity drives tinnitus perception in an animal model. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14974-9. doi: 10.1073/pnas.1107998108. Epub 2011 Sep 6.

  PMID: 21896771 BACKGROUND

Related Links

• Project website

MeSH Terms

Conditions

Tinnitus; Hearing Loss; Inhibition, Psychological

Condition Hierarchy (Ancestors)

Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Behavior

Study Officials

• Dorothee Auer, Prof.

  University of Nottingham

  STUDY DIRECTOR

• Anissa Ramadhani

  University of Nottingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Cross sectional case-control multimodal MRI, audio- and psychometric study

Study Record Dates

• First Submitted: March 22, 2021
• First Posted: April 28, 2021
• Study Start: August 9, 2021
• Primary Completion: October 31, 2022
• Study Completion: October 31, 2022
• Last Updated: December 18, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: ANALYTIC CODE
• Time Frame: Data will become available 3 months after the last data acquisition. They will be available up to 3 years.

Locations

GB (3)