Ignite Creation Date:
2024-05-06 @ 4:04 PM
Last Modification Date:
2024-10-26 @ 2:03 PM
Study NCT ID:
NCT04862572
Status:
COMPLETED
Last Update Posted:
2023-12-18
First Post:
2021-03-22
Brief Title:
Investigating Disinhibitory Brain Mechanism in Tinnitus and Hearing Loss
Sponsor:
University of Nottingham
Organization:
University of Nottingham
Study Overview
Official Title:
Investigating Disinhibitory Brain Mechanism in Tinnitus and Hearing Loss Is There a Maladaptive Signature of Auditory Cortex GABA Loss and Dysconnectivity
Status:
COMPLETED
Status Verified Date:
2023-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
IGNITE
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 0125-8 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 eg 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
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 0125-8 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 eg 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
Detailed Description:
SELECTION AND WITHDRAWAL OF PARTICIPANTS
Recruitment
1 Clinical routes Suitable candidates may be identified by the sites at Ropewalk House Nottingham Audiology Services and ear nose and throat ENT services at Nottingham University Hospitals National Health Service NHS trust via searches of their clinical databases or opportunistically during routine clinical appointments Candidates will only be approached by a member of staff at the site or NIHR Clinical Research Network CRN staff to whom recruitment activities have been delegated by the local PI All patient contact information will be kept confidential and undisclosed to the research team The initial approach will be providing the participant with the information packs that will contain i an invitation letter ii a participant information sheet explaining all aspects pertaining to participation in the study and iii a reply slip Potential participants who wish to find out more about the study will then be able to opt to be contacted by the researcher by completing a reply slip attached to the invitation letter and returning it in a pre-paid and addressed envelope Alternatively potential participants can contact the researcher directly via email and phone number that is written on the participant information sheet
It will be explained to the potential participant that entry into the trial is entirely voluntary and that their treatment and care will not be affected by their decision It will also be explained that they can withdraw at any time but attempts will be made to avoid this occurrence In the event of their withdrawal it will be explained that their data collected so far cannot be erased and the investigators will seek consent to use the data in the final analyses where appropriate
Posters about the study will be on display in the relevant clinical areas
2 Non-clinical routes
Non-clinical routes will include advertising the study via
Invitation emails to NIHR Nottingham Hearing participant database This database includes everyone that previously stating interest to takes part in tinnitus and hearing loss study including healthy participants and hearing-related patients
Newsletter articles and announcements published by the relevant patient and professional organisations
Posts on social media channels Twitter hearingnhir TIN_ACT UoNPIBeacon and Facebook
In all cases fully informed consent will be sought by explaining the studys procedures and requirements following the standard script to interested potential participants The potential participants will have ideally a minimum of 24 hours in which to decide whether or not to take part in this study If the participant agrees to take part in the study the consent form will be signed during COVID-19 time this will be done electronically In all cases informed consent will be obtained and the consent form will have to be signed prior to any assessment or intervention
Expected duration of participant participation
The study is expected to run between August 2021 until April 2022 The expected total duration of participation in the study from the time of informed consent is likely to range from one week to eight weeks This prolonged time estimate is due to possible organisational difficulties in arranging the audiology assessment and the MRI scans especially during the COVID-19 pandemic There will be two visits for each participant where each visit will last for around 15 hours
Removal of participants from therapy or assessmentsParticipant Withdrawal
Participants may choose to withdraw from the study at any time without giving a reason They will be withdrawn from the study if they are unable to be scanned due to uncontrollable movement or if they are unable for any reason to complete the audiology assessment Participants will also be removed in the event of pregnancy taking GABA enhancing or anti-depressants medication having a cochlear or any metal implant that is not compatible with MRI scan or having metal implants during the time that they first agree to participate and the booked date for scanning or withdrawal of consent
In the unique case relating to COVID-19 if participants report symptoms of the virus before the study appointment it will be discussed if they still want to continue participating in the study and while waiting for their 14 days quarantine the investigators will reschedule their appointment However in the case where participants are confirmed to have coronavirus before the study appointment participants will be removed from the study
Participants will be made aware via the information sheet and consent form that should they withdraw the data collected to date cannot be erased and may still be used in the final analysis If a participant withdraws from the study the investigators will record the reason for and date of discontinuation They will be replaced such that at the end of the study the number of completed scans not the number of enrolled participants defines the end Abrupt termination of enrolment in the study will not affect participant safety The participants will be made aware that this will not affect their future care
STATISTICS
Methods
The investigators will use three tests to analyse the data primary secondary and exploratory test
Primary test
Univariate group comparison between-group differences in imaging outcomes this includes a comparison between
Auditory cortex GABA GABAGlx and Cho level Auditory cortex cerebral blood flow CBF Local functional connectivity density Interhemispheric auditory cortices functional connectivity Cross-modal functional connectivity between auditory and visual cortex and Auditory cortex blood oxygen level-dependent BOLD response to visual attention task
Between-group test for differences in correlation between
GABA and hearing loss and Auditory cortex functional connectivity and hearing loss
Secondary test Within-group correlation analysis of imaging markers of inhibition such as GABA functional connectivity CBF and BOLD response to attention with audiometric results indexing sensory deafferentation The investigators will also do regression analysis of imaging metrics with tinnitus severity
Exploratory Multivariate prediction model of tinnitus severity and regression of brain network metrics with affective tinnitus phenotypes
The findings will be evaluated by the investigator team Due to the complex statistic question and strategy the investigators will seek advice throughout the analysis from both experienced statistician and senior researcher The analysis will take place on the University of Nottingham UoN computers using R statistical software package and Matlab and backed up to the UoN servers
Sample size and justification
Approximately 60 subjects in total 30 per group For details please see below All tests were done using the R statistical software package and STATA SE16
GABA
Previous studies investigating GABA alteration in tinnitus and hearing loss patients are very limited with the discrepancy between them In Gaos study with a total sample of 36 subjects reported around 50 r-057 of total GABA variance is explained by hearing loss in the elderly cohort with the assumption that half of their subjects have tinnitus tin and the rest of the half did not have tinnitus tin- while in Sedleys study with a total sample of 28 subjects reported significant GABA concentration reduced median 112 vs 128 mML in right auditory cortex for tin tin- respectively
Using these values the investigators can estimate their effect size using
Cohens d M_1-M_2SD pooled Also Cohens d 2r1-r2
Where effect size for Gao and Sedleys study respectively are r-057 correlation between hearing loss and GABA and d-37 GABA effect size between patient and control One might think of this as a promising effect but the investigators are aware of the low power of these studies considering their small sample size compared to the population and thus these effect sizes might be inflated and not represent the true effect size
The investigators then propose to recruit a bigger sample size and with the time constraint and the limitation due to the COVID-19 pandemic the realistic number of subjects that the investigators are pursuing is 30 per group N total60 With this sample size and based on knowledge from previous studies the investigators estimated effect size of d07 two-sided test and r04 using 005 alpha value and 80 power
The investigators will also use a relative measurement to quantify GABA such as GABACr ratio that presumably has a lower variance and thus will power the effect size compared to the absolute measure ie mML
Previous pilot measurement has shown that GABA measurement was good enough in terms of repeatability and showing the right trend but failed to reach significance in within-subject measurement Therefore the other strategy is to involve and inter-relate the GABA measurement with other functional measures resting- visual task tonotopy scan The analysis will not be limited to only between-subject analysis but the investigators will also do within-subject analysis that has shown to have more robust results
Functional connectivity
In fMRI the combination of a large number of dependent variables ie huge number of voxel comparison and a relatively small number of observations subjects resulted in underpowered studies with grossly inflated effect size and thus poorly represent the actual effects in the full samplepopulation However using meta-analysis one can study whether reported findings from selected pooled studies with a small sample are really significant or not
Similar to the GABA approach the investigators then estimate the effect size from a meta-analysis study of functional changes between tin and tin - and compared it with the estimated effect size
r zN Cohens d 2r1-r2
The investigators estimate to be able to detect medium effect size d06 N total 30 whole brain 005 alpha value and 80 power
As the investigators are fully aware that the results might not represent the full picture of the true effect the proposed study will still benefit tinnitus field research and add more power to validate previous findings It is also noted that the meta-analysis study was using a whole-brain measurement ie ReHo where high variance is expected due to the big number of voxel comparison
Instead the study proposes to focus on region-of-interest ROIs analysis to lower the variance thus increasing the effect size Defining the ROIs will be guided by an independent condition such as visual task and tonotopy scan using Independent Component Analysis ICA analysis andor using anatomical maps such as Brodmann area Some functional measures that will be applied are regional connectivity density interregional correlations and fractional amplitude of low-frequency fluctuations fALFF Cross-validation with GABA measurement both between-subject and within-subject is expected to enrich the current knowledge between inhibition and neural activation changes in tinnitus patients
Procedures for missing unused and spurious data
In the case of missing or spurious data the participants whose data is in question will be excluded from that particular analysis
Recruitment
1 Clinical routes Suitable candidates may be identified by the sites at Ropewalk House Nottingham Audiology Services and ear nose and throat ENT services at Nottingham University Hospitals National Health Service NHS trust via searches of their clinical databases or opportunistically during routine clinical appointments Candidates will only be approached by a member of staff at the site or NIHR Clinical Research Network CRN staff to whom recruitment activities have been delegated by the local PI All patient contact information will be kept confidential and undisclosed to the research team The initial approach will be providing the participant with the information packs that will contain i an invitation letter ii a participant information sheet explaining all aspects pertaining to participation in the study and iii a reply slip Potential participants who wish to find out more about the study will then be able to opt to be contacted by the researcher by completing a reply slip attached to the invitation letter and returning it in a pre-paid and addressed envelope Alternatively potential participants can contact the researcher directly via email and phone number that is written on the participant information sheet
It will be explained to the potential participant that entry into the trial is entirely voluntary and that their treatment and care will not be affected by their decision It will also be explained that they can withdraw at any time but attempts will be made to avoid this occurrence In the event of their withdrawal it will be explained that their data collected so far cannot be erased and the investigators will seek consent to use the data in the final analyses where appropriate
Posters about the study will be on display in the relevant clinical areas
2 Non-clinical routes
Non-clinical routes will include advertising the study via
Invitation emails to NIHR Nottingham Hearing participant database This database includes everyone that previously stating interest to takes part in tinnitus and hearing loss study including healthy participants and hearing-related patients
Newsletter articles and announcements published by the relevant patient and professional organisations
Posts on social media channels Twitter hearingnhir TIN_ACT UoNPIBeacon and Facebook
In all cases fully informed consent will be sought by explaining the studys procedures and requirements following the standard script to interested potential participants The potential participants will have ideally a minimum of 24 hours in which to decide whether or not to take part in this study If the participant agrees to take part in the study the consent form will be signed during COVID-19 time this will be done electronically In all cases informed consent will be obtained and the consent form will have to be signed prior to any assessment or intervention
Expected duration of participant participation
The study is expected to run between August 2021 until April 2022 The expected total duration of participation in the study from the time of informed consent is likely to range from one week to eight weeks This prolonged time estimate is due to possible organisational difficulties in arranging the audiology assessment and the MRI scans especially during the COVID-19 pandemic There will be two visits for each participant where each visit will last for around 15 hours
Removal of participants from therapy or assessmentsParticipant Withdrawal
Participants may choose to withdraw from the study at any time without giving a reason They will be withdrawn from the study if they are unable to be scanned due to uncontrollable movement or if they are unable for any reason to complete the audiology assessment Participants will also be removed in the event of pregnancy taking GABA enhancing or anti-depressants medication having a cochlear or any metal implant that is not compatible with MRI scan or having metal implants during the time that they first agree to participate and the booked date for scanning or withdrawal of consent
In the unique case relating to COVID-19 if participants report symptoms of the virus before the study appointment it will be discussed if they still want to continue participating in the study and while waiting for their 14 days quarantine the investigators will reschedule their appointment However in the case where participants are confirmed to have coronavirus before the study appointment participants will be removed from the study
Participants will be made aware via the information sheet and consent form that should they withdraw the data collected to date cannot be erased and may still be used in the final analysis If a participant withdraws from the study the investigators will record the reason for and date of discontinuation They will be replaced such that at the end of the study the number of completed scans not the number of enrolled participants defines the end Abrupt termination of enrolment in the study will not affect participant safety The participants will be made aware that this will not affect their future care
STATISTICS
Methods
The investigators will use three tests to analyse the data primary secondary and exploratory test
Primary test
Univariate group comparison between-group differences in imaging outcomes this includes a comparison between
Auditory cortex GABA GABAGlx and Cho level Auditory cortex cerebral blood flow CBF Local functional connectivity density Interhemispheric auditory cortices functional connectivity Cross-modal functional connectivity between auditory and visual cortex and Auditory cortex blood oxygen level-dependent BOLD response to visual attention task
Between-group test for differences in correlation between
GABA and hearing loss and Auditory cortex functional connectivity and hearing loss
Secondary test Within-group correlation analysis of imaging markers of inhibition such as GABA functional connectivity CBF and BOLD response to attention with audiometric results indexing sensory deafferentation The investigators will also do regression analysis of imaging metrics with tinnitus severity
Exploratory Multivariate prediction model of tinnitus severity and regression of brain network metrics with affective tinnitus phenotypes
The findings will be evaluated by the investigator team Due to the complex statistic question and strategy the investigators will seek advice throughout the analysis from both experienced statistician and senior researcher The analysis will take place on the University of Nottingham UoN computers using R statistical software package and Matlab and backed up to the UoN servers
Sample size and justification
Approximately 60 subjects in total 30 per group For details please see below All tests were done using the R statistical software package and STATA SE16
GABA
Previous studies investigating GABA alteration in tinnitus and hearing loss patients are very limited with the discrepancy between them In Gaos study with a total sample of 36 subjects reported around 50 r-057 of total GABA variance is explained by hearing loss in the elderly cohort with the assumption that half of their subjects have tinnitus tin and the rest of the half did not have tinnitus tin- while in Sedleys study with a total sample of 28 subjects reported significant GABA concentration reduced median 112 vs 128 mML in right auditory cortex for tin tin- respectively
Using these values the investigators can estimate their effect size using
Cohens d M_1-M_2SD pooled Also Cohens d 2r1-r2
Where effect size for Gao and Sedleys study respectively are r-057 correlation between hearing loss and GABA and d-37 GABA effect size between patient and control One might think of this as a promising effect but the investigators are aware of the low power of these studies considering their small sample size compared to the population and thus these effect sizes might be inflated and not represent the true effect size
The investigators then propose to recruit a bigger sample size and with the time constraint and the limitation due to the COVID-19 pandemic the realistic number of subjects that the investigators are pursuing is 30 per group N total60 With this sample size and based on knowledge from previous studies the investigators estimated effect size of d07 two-sided test and r04 using 005 alpha value and 80 power
The investigators will also use a relative measurement to quantify GABA such as GABACr ratio that presumably has a lower variance and thus will power the effect size compared to the absolute measure ie mML
Previous pilot measurement has shown that GABA measurement was good enough in terms of repeatability and showing the right trend but failed to reach significance in within-subject measurement Therefore the other strategy is to involve and inter-relate the GABA measurement with other functional measures resting- visual task tonotopy scan The analysis will not be limited to only between-subject analysis but the investigators will also do within-subject analysis that has shown to have more robust results
Functional connectivity
In fMRI the combination of a large number of dependent variables ie huge number of voxel comparison and a relatively small number of observations subjects resulted in underpowered studies with grossly inflated effect size and thus poorly represent the actual effects in the full samplepopulation However using meta-analysis one can study whether reported findings from selected pooled studies with a small sample are really significant or not
Similar to the GABA approach the investigators then estimate the effect size from a meta-analysis study of functional changes between tin and tin - and compared it with the estimated effect size
r zN Cohens d 2r1-r2
The investigators estimate to be able to detect medium effect size d06 N total 30 whole brain 005 alpha value and 80 power
As the investigators are fully aware that the results might not represent the full picture of the true effect the proposed study will still benefit tinnitus field research and add more power to validate previous findings It is also noted that the meta-analysis study was using a whole-brain measurement ie ReHo where high variance is expected due to the big number of voxel comparison
Instead the study proposes to focus on region-of-interest ROIs analysis to lower the variance thus increasing the effect size Defining the ROIs will be guided by an independent condition such as visual task and tonotopy scan using Independent Component Analysis ICA analysis andor using anatomical maps such as Brodmann area Some functional measures that will be applied are regional connectivity density interregional correlations and fractional amplitude of low-frequency fluctuations fALFF Cross-validation with GABA measurement both between-subject and within-subject is expected to enrich the current knowledge between inhibition and neural activation changes in tinnitus patients
Procedures for missing unused and spurious data
In the case of missing or spurious data the participants whose data is in question will be excluded from that particular analysis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None