Clinical Otolaryngology - 2023 - Nikookam - The effect of photobiomodulation on hearing loss A systematic review

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S Y S T EMA T I C R E V I EW
The effect of photobiomodulation on hearing loss:
A systematic review
Yasmin Nikookam1 | Nawal Zia1 | Andrew Lotfallah1 |
Jameel Muzaffar1,2 | Jennifer Davis-Manders1 | Peter Kullar2 |
Matthew Smith2 | Gemma Bale3,4 | Patrick Boyle5 | Richard Irving1 |
Dan Jiang6,7 | Manohar Bance2
1University Hospitals Birmingham NHS
Foundation Trust, Queen Elizabeth Hospital
Birmingham, Birmingham, UK
2University of Cambridge, Department of
Clinical Neurosciences, Addenbrooke's Health
Campus, Cambridge, UK
3Department of Physics, Cavendish
Laboratory, Cambridge, UK
4Electrical Engineering, Cambridge, UK
5Advanced Bionics, Cambridge, UK
6Guy's and St Thomas' NHS Foundation Trust,
Hearing Implant Centre, St. Thomas' Hospital,
London, UK
7King's College London, Centre for
Craniofacial and Regenerative Biology,
London, UK
Correspondence
Manohar Bance, Addenbrookes Hospital,
Box 48, ENT Clinic, Hills Road, Cambridge,
CB2 0QQ, UK.
Email: mlb59@cam.ac.uk
Abstract
Objectives: To assess outcomes associated with photobiomodulation therapy
(PBMT) for hearing loss in human and animal studies.
Design: Systematic review and narrative synthesis in accordance with PRISMA
guidelines.
Setting: Data bases searched: MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov and
Web of Science. No limits were placed on language or year of publication. Review
conducted in accordance with the PRISMA 2020 statement.
Participants: All human and animal subjects treated with PBMT for hearing loss.
Main outcome measures: Pre‐ and post‐PBMT audio metric outcomes.
Results: Searches identified 122 abstracts and 49 full text articles. Of these, 17 stud-
ies met the inclusion criteria, reporting outcomes in 327 animals (11 studies), 30
humans (1 study), and 40 animal specimens (5 studies). PBMT parameters included 6
different wavelengths: 908 nm (1 study), 810 nm (1 study), 532 & 635 nm (1 study),
830 nm (3 studies), 808 nm (11 studies). The duration ranged from 4 to 60 minutes in
a session, and the follow‐up ranged from 5–28 days. Outcomes improved signifi-
cantly when wavelengths within the range of 800–830 nm were used, and with
greater duration of PBMT exposure. Included studies predominantly consisted of
non‐randomized controlled trials (10 studies).
Conclusions: Hearing outcomes following PBMT appear to be superior to no PBMT
for subjects with hearing loss, although higher level evidence is required to verify
this. PBMT enables concentrated, focused delivery of light therapy to the inner ear
through a non‐invasive manner with minimal side effects. As a result of heterogene-
ity in reporting PBMT parameters and outcomes across the included studies, direct
comparison is challenging.
K E YWORD S
hearing loss, low level light therapy, near infrared light, otoprotection, photobiomodulation
Received: 31 May 2023 Accepted: 7 October 2023
DOI: 10.1111/coa.14113
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.
Clinical Otolaryngology. 2024;49:41–61. wileyonlinelibrary.com/journal/coa 41
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1 | INTRODUCTION
1.1 | Background and epidemiology
Hearing impairment is one of the most common medical conditions,1
affecting approximately 466 million people worldwide.2 Impact can
adversely affect employment, communication and social interaction.
This can lead to manifold psychosocial burdens,3 as well as significant
detrimental economic impacts to the individual and wider society.4
Common rehabilitation options include hearing aids, and surgery
such as cochlear implantation, although operative trauma can poten-
tially exacerbate existing hearing loss. Current research suggests there
may be scope for photobiomodulation therapy (PBMT) to mitigate
ototoxic trauma associated with surgery, traumatic noise exposure or
from chemical trauma by ototoxic medications such as platinum-based
chemotherapy.
Photobiomodulation therapy (PBMT), also referred to as ‘low-
level laser light (LLLT)’ and ‘near-infrared light’, is a non-invasive ther-
apy that uses light energy to enhance or modulate the activities of
specific cells to improve or change the function of body tissues. It is
increasingly used to treat medical conditions, including skin lesions
and neurodegenerative disorders, to reduce pain, and to stimulate the
regeneration of body tissues.5–8
1.2 | PBMT mechanism of action
Cell damage within the inner ear is a complex combination of inflamma-
tory and oxidative stress. The mechanism of PBMT on neural-cell recov-
ery and regeneration is yet to be clarified. The prevailing theory focuses
on mitochondrial cytochrome c oxidase, a key protein in cellular metab-
olism and repair, and one of three major proteins in the human body
responding to near infrared wavelength.9 These proteins absorb near-
infrared wavelength energy and then modulate biochemical reactions
within cells. Cytochrome c oxidase is a large transmembrane protein
complex in the mitochondrial electron transport chain that consists of
five protein complexes that together produce adenosine 5-triphosphate
(ATP).10 This theory is supported by research showing that PBMT
enhances ATP production.11 Increased ATP production may lead to
enhanced cell metabolism, promoting the damage-repair process.
Several studies have shown that PBMT can reduce inflammation
within inner ear cells in vitro.12,13 Clinical studies on the use of PBMT
to protect against hearing loss, tinnitus, and vestibular dysfunction
have been published. To the best of the author's knowledge, there are
presently no systematic reviews synthesising the effect of PBMT on
hearing loss.
1.3 | Objectives
This review is to assess the application of PBMT in the treatment of
hearing loss, examining evidence from both animal and human
studies.
Population: Humans or animals
Intervention: Photobiomodulation therapy
Comparator: There is no formal comparator or control.
Comparators were expected to vary according
to the study type. Comparators may include
other methods of hearing preservation, for
example, administration of drugs via systemic
or local routes.
Outcomes: Pre- and post-PBMT audiometric outcomes,
evidence of inflammation e.g., fibrosis (imped-
ance values, histology), measures of neural
responses (evoked compound action poten-
tials, auditory brainstem evoked potentials),
spiral ganglion neuron density and/or number,
neo-osteogenesis, and hair cell count.
Adverse events associated with PBMT.
2 | METHODS
The study protocol was registered in the PROSPERO prospective data-
base of systematic reviews (CRD42020210574 and CRD42020212259)
and was created according to the PRISMA (Preferred Reporting Items
for Systematic Reviews and Meta Analyses) guidelines.14
2.1 | Study inclusion criteria
All human experimental study designs were eligible, including case–
control, case series, cohort, randomised controlled trials. Animal stud-
ies (live, in vitro) were eligible if they included at least one quantitative
outcome measure. There were no restrictions placed on the follow-up
length or the study duration. Only studies with full texts available
were included. Studies with insufficient*
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onditions (https://onlinelibrary.w
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/term
s-and-conditions) on W
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common.13,19–25,27,28,30,31 All studies, except two, outlined where
PBMT was anatomically focussed.12,25
3.5 | Photobiomodulation therapy outcomes
Twelve studies summarised all three of wavelength used, duration of
PBMT, and follow-up period. Wavelength size of 808 nm was used
most frequently (n = 11). PBMT was effective in hearing enhancing
recovery, reducing loss of hair cells and reducing the immune inflamma-
tory response in the included animal studies. One study found pre-
emptive PBMT therapy before noise-induced hearing loss (NIHL) was
effective at hearing preservation.18 One study found that pre-
treatment using PBMT prior to cochlear implantation resulted in better
hearing outcomes.29 Another study found a PBMT power of 165 versus
110 mW/cm2 resulted in a greater preservation of hearing.30
A range of otological insults were used to induce hearing losses in
each animal study: noise induced hearing loss (NIHL) (n = 9),
gentamicin-induced ototoxicity (n = 4), surgical trauma (n = 1),
oubain-induced auditory neuropathy (n = 1) and pre-treatment for CI
surgery induced hearing loss (n = 1).12,13,18–31 Direct comparison of
differing ototoxic agents was not conducted in any of the studies
included.
One study assessed the effect of PBMT in combination with anti-
oxidants N acetyl-L-cysteine (NAC) or acetyl-L-carnitine (ALCAR).20
This study showed conflicting results on the effectiveness of PBMT,
in that the laser in combination with an antioxidant was not superior
to the antioxidant alone when comparing ABRs. However, the hair cell
count illustrated that PBMT in addition to an antioxidant was superior
to the antioxidant alone.
Overall, there was a trend toward benefit from PBMT in animal
studies, irrespective of delivery method, wavelength and power used
or the animal species treated. Audiological outcomes improved in all
16 animal studies following PBMT compared to no PBMT, with statis-
tically significant improvement stated in 11 studies.12,13,19,20,22–27,29
In the single human study included, no statistically significant effect of
PBMT on hearing was detected.7 Notably, the PBMT wavelength was
shorter, and the power used lower compared to all animal studies. No
study reported any intra- or post-PBMT adverse events or deaths.
4 | DISCUSSION
This systematic review is the first to report outcomes of PBMT on
hearing loss. Generally, animal subjects showed improvements in
hearing preservation outcomes whereas no statistically significant
improvement was detected in the single human study.
4.1 | PBMT versus placebo
The only human results from Goodman et al.'s study found none of
the three measures of hearing (audiometric thresholds, speech recog-
nition test, or otoacoustic emissions) showed statistically significant
difference between the treatment, placebo, or control groups.7 There-
fore, this study concluded that PBMT was not effective in recovering
hearing loss. However, the sample size was small (n = 30) and com-
parison with animal studies is difficult as the delivery characteristics
differed. In the human study, PBMT was delivered in seven cycles
across different anatomical locations, including the temporomandibu-
lar joint, spine, ear and top of the head. The duration of therapy ran-
ged from 15 to 60 s. Overall duration of therapy was relatively very
short, lasting approximately 4 min in total with low power (7.5 mW).
In contrast, animal studies that produced positive results from PBMT,
typically irradiated through the tympanic membrane for 60 min. More-
over, the wavelength used by Goodman et al. was 532 nm constantly,
with 635 nmin a pulsed manner.7 Prior evidence suggests that the
wavelength with the highest potency of biomodulation is 800–
830 nm.27 This is likely due to the absorption spectrum of cytochrome
c oxidase which has a peak of 830 nm, and the penetration of light
through tissue is superior at 830 nm than 532 nm.32 Hence, there
were duration, power, anatomical site and wavelength differences
between the human and animal studies.
Goodman et al.'s findings contrast with the 16 animal studies that
assessed the effect of PBMT for a range of ototoxic insults. Ten stud-
ies assessed ABRs and showed an improvement in hearing, and inner
ear elements on histology when compared to the placebo or
non-treatment group.18,20,22–25,27,29,30,31 Hearing was better pre-
served or maintained in the PBMT group versus non-PBMT group in
most studies.12,13,18,20,22,23,25,26,28–31 The effect of PBMT in reducing
TABLE 4 Cochrane risk of bias 2 tool.
Author(s), year, country 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
S. Goodman et al., 2013, USA
Note: Green = low risk of bias; red = high risk of bias; yellow = unclear risk of bias. 1. Was the allocation sequence random? Yes. 2. Was the allocation
sequence concealed until participants were enrolled and assigned to interventions? Yes. 3. Did baseline differences between intervention groups suggest a
problem with the randomisation processs? No. 4. Were participants aware of their assigned intervention during the trial? No. 5. Were carers and trial
personnel aware of participants' assigned intervention during the trial? Yes and No. 6. Deviations that arose because of the trial context? No. 7. Was an
appropriate analysis used to estimate the effect of assignment to intervention? Yes. 8. Participants aware of intervention? No. 9. Personnel Aware of
intervention? Yes and No. 10. Balanced non-protocol interventions? Yes. 11. Failures in implementation affecting outcome? No. 12. Non-adherence
affecting outcome? No. 13. Outcome data for all participants? Yes. 14. Method of measuring the outcome inappropriate? No. 15. Measurement or
ascertainment of outcome differ between groups? No. 16. Outcome assessors aware of intervention received? Unsure. 17. Could assessment have been
influenced by knowledge of intervention? No. 18. Results selected from multiple outcome measurements and multiple analyses of the data? No. 19. Trial
analysed in accordance with a pre-specified plan? Yes.
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s and C
onditions (https://onlinelibrary.w
iley.com
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inflammation was also supported through histology and immunohisto-
chemistry findings, such as increased SGNs, hair cells, and
ATP.18,23,25,28
4.2 | PBMT versus systemic therapy
One animal study evaluated the added effect of PBMT in addition to
systemic antioxidant therapy (NAC and ALCAR).20 This study found
combination therapy of NAC and PBMT to significantly improve NIHL
when compared to a previous study that assessed the effect of PBMT
alone. It appears that NAC may have a role in accelerating hearing
improvement with PBMT (improved on the 6th day of irradiation),
when compared to PBMT alone (improved on the 10th day of irradia-
tion).20,26 Additionally, authors found the antioxidant NAC to be supe-
rior to ALCAR, but NAC and ALCAR alone was not superior to
combination therapy with PBMT.20
4.3 | PBMT positioning and characteristics
In contrast to most animal studies which irradiated in close proximity
to the tympanic membrane, Goodman et al.'s human study utilised
external irradiation (temporomandibular joint, cervical spine, top of
head and external auditory meatus). They state that a transmeatal
approach would have resulted in greater penetration but suggest that
it would be less practical.7
The positioning of PBMT for optimal delivery varied across stud-
ies. Beyer et al. found that irradiation of the mastoid leads to thera-
peutically insufficient light doses when compared to irradiation
through the tympanic membrane.33 Beyer et al. used a PBMT power
and dose similar to Goodman et al. (1 mW, 593 and 633 nm
vs. 7.5 mW, 532 and 635 nm in Goodman et al).7 Therefore, for opti-
mum dosimetry, evaluation of light transmission factors for chosen
irradiation modalities is necessary. The externally applied light dose
needs to be calculated according to the tonotopy of the cochlea, as
different anatomical landmarks and mediums will transduce different
frequencies; this is relevant when considering the anatomical location
of the PBMT probe.
An excess amount of laser irradiation may lead to destruction
rather than promotion.34 Subsequently, determining optimal PBMT
parameters is vital and must be balanced against safe PBMT delivery.
There are peaks in the typical responsive wavelengths for cytochrome
c oxidase (670 and 830 nm).9 Cytochrome c oxidase mediates photo-
biomodulation in the far-red and near-infrared range. Although cyto-
chrome c oxidase also absorbs strongly at wavelengths less than
630 nm, this is within the visible light range andhas a lower rate of
tissue penetrance than wavelengths in the near-infrared range.9 Pene-
trance of lasers through the tympanic membrane and other tissue
structures of the inner otic capsule is superior in the near infrared
range (780–1100 nm).25 Therefore, wavelengths must be carefully
selected according to PBMT delivery method and structures the light
must pass through to reach the cochlea. Additionally, it is important to
ascertain whether shorter, concentrated delivery of PBMT induces a
more significant effect on hearing loss when compared to a more pro-
longed delivery at lower concentration.
4.4 | PBMT as a pre-treatment therapy
Basta et al. assessed the effect of PBMT prior to noise exposure. They
found a single pre-treatment dose of PBMT induced statistically sig-
nificant protection of cochlear structures based on ABR recording and
histological analysis.18 Pre-exposure of 10 min was the optimal dos-
ing.18 These findings suggest the scope for the implementation of
PBMT as a pre-treatment therapy prior to procedures known to cause
inner ear damage and hearing loss, such as cochlear implantation.
More research is required to ascertain the true benefits of PBMT as a
pre-treatment in hearing preservation.
4.5 | Future of PBMT
Overall, results suggest that PBMT could be an effective method for
hearing preservation. However, almost all studies to date have been
conducted on animal models with only one conducted on human sub-
jects. Most studies assessed outcomes over a short duration of time,
with the longest period of follow up being 28 days. This precludes
comment on the long-term effects PBMT may have on hearing loss,
or whether further courses are needed to maintain benefit. Including
a longer follow-up period would enable researchers to assess the
longer-term effects and complications of PBMT. Thus, enabling
researchers to determine the suitability of using PBMT in further
human trials.
5 | CONCLUSION
Though the evidence base is far from comprehensive, hearing out-
comes following PBMT appear to be superior to non-PBMT in animal
studies. PBMT theoretically enables a non-invasive mode of delivering
therapy which may enable audiological function to be preserved and
maintained following injury to inner ear structures. The low-risk pro-
file and promising data from animal models suggest PBMT warrants
further investigation as an intervention to prevent or treat hearing
loss. Further research should focus on optimising PBMT light delivery
and dosing for the inner ear to inform future human trials.
AUTHOR CONTRIBUTIONS
Manohar Bance, Jameel Muzaffar and Peter Kullar conceived the
paper and supervised the work undertaken. Searches and data extrac-
tion were performed by Yasmin Nikookam, Nawal Zia, Andrew Lotfal-
lah and Jennifer Davis-Manders. All authors reviewed the study
protocol and were involved in drafting and providing critical edits to
the manuscript. All authors agree to be accountable for all aspects of
the work presented.
NIKOOKAM ET AL. 59
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ibrary on [29/10/2025]. See the T
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/term
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icense
ACKNOWLEDGEMENT
None.
FUNDING INFORMATION
None.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
PEER REVIEW
The peer review history for this article is available at https://www.
webofscience.com/api/gateway/wos/peer-review/10.1111/coa.14113.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
ORCID
Yasmin Nikookam https://orcid.org/0000-0003-0796-7233
Nawal Zia https://orcid.org/0000-0001-5012-3648
Andrew Lotfallah https://orcid.org/0000-0001-5161-1192
Jameel Muzaffar https://orcid.org/0000-0003-3065-0269
Peter Kullar https://orcid.org/0000-0001-7124-6356
Matthew Smith https://orcid.org/0000-0001-8147-1549
Gemma Bale https://orcid.org/0000-0002-2709-2035
Patrick Boyle https://orcid.org/0000-0001-7712-5977
Richard Irving https://orcid.org/0000-0003-0013-719X
Dan Jiang https://orcid.org/0000-0003-1490-6658
Manohar Bance https://orcid.org/0000-0001-8050-3617
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104454701750066910
SUPPORTING INFORMATION
Additional supporting information can be found online in the Support-
ing Information section at the end of this article.
How to cite this article: Nikookam Y, Zia N, Lotfallah A,
Muzaffar J, Davis-Manders J, Kullar P, et al. The effect of
photobiomodulation on hearing loss: A systematic review.
Clinical Otolaryngology. 2024;49(1):41–61. https://doi.org/
10.1111/coa.14113
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https://doi.org/10.1007/s10103-011-1028-5https://doi.org/10.1117/1.JBO.17.6.068002
https://doi.org/10.1117/1.JBO.17.6.068002
https://doi.org/10.1117/1.JBO.18.12.128003
https://doi.org/10.1117/1.JBO.18.12.128003
https://doi.org/10.1007/s10103-021-03304-2
https://doi.org/10.1159/000508619
https://doi.org/10.1159/000508619
https://doi.org/10.1016/j.neulet.2015.03.031
https://doi.org/10.1016/j.neulet.2015.03.031
https://doi.org/10.1016/j.brainres.2016.06.031
https://doi.org/10.1117/1.JBO.21.9.091307
https://doi.org/10.1117/12.334384
https://doi.org/10.1089/104454701750066910
https://doi.org/10.1089/104454701750066910
https://doi.org/10.1111/coa.14113
https://doi.org/10.1111/coa.14113
	The effect of photobiomodulation on hearing loss: A systematic review
	1 INTRODUCTION
	1.1 Background and epidemiology
	1.2 PBMT mechanism of action
	1.3 Objectives
	2 METHODS
	2.1 Study inclusion criteria
	2.2 Search strategy
	2.3 Selection of studies
	2.4 Data extraction
	2.5 Risk of bias quality assessment
	3 RESULTS
	3.1 Description of studies
	3.2 Quality of studies
	3.3 Audiological outcomes
	3.4 PBMT delivery method
	3.5 Photobiomodulation therapy outcomes
	4 DISCUSSION
	4.1 PBMT versus placebo
	4.2 PBMT versus systemic therapy
	4.3 PBMT positioning and characteristics
	4.4 PBMT as a pre-treatment therapy
	4.5 Future of PBMT
	5 CONCLUSION
	AUTHOR CONTRIBUTIONS
	ACKNOWLEDGEMENT
	FUNDING INFORMATION
	CONFLICT OF INTEREST STATEMENT
	PEER REVIEW
	DATA AVAILABILITY STATEMENT
	REFERENCESreporting data on pre-and
post-intervention audiometric outcomes and those that did not assess
the effect of PBMT on hearing outcomes were excluded.
Key points
• Photobiomodulation therapy (PBMT) is a potential non-
invasive treatment option for hearing loss with minimal
adverse effects.
• To date, only one human trial has assessed the use of
PBMT in the treatment of hearing loss.
• This study showed no statistically significant improve-
ment in hearing outcomes.
• Animal studies utilising longer wavelength PBMT for lon-
ger duration of therapy demonstrated improvements in
audiological outcomes.
• Further human trials are required to determine the effi-
cacy and safety of PBMT to treat hearing loss.
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onditions (https://onlinelibrary.w
iley.com
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ibrary for rules of use; O
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reative C
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icense
2.2 | Search strategy
The initial search was conducted in September 2020 and repeated in
July 2022 to include relevant papers published since the original
search. The following electronic databases were searched: MEDLINE,
EMBASE, CENTRAL, ClinicalTrials.gov and Web of Science including
Web of Science Core collection. No limit was placed on language or
publication year. Search strategy terms used are summarised in the
Appendix S2. Hand-searching reference lists of the included relevant
systematic reviews and citation searches were conducted to identify
additional studies missed from the electronic database searches.
2.3 | Selection of studies
Initial searches were performed by Yasmin Nikookam and verified by
Nawal Zia. The two reviewers independently screened titles and
abstracts of the studies from the database search inclusion and to
identify duplicates. Full texts were reviewed independently against
the inclusion and exclusion criteria. Disagreements at the abstract and
full-text screening stages were discussed within the author team
(Yasmin Nikookam/Nawal Zia) and where applicable, with a third
reviewer (Jameel Muzaffar), and consensus was reached in determin-
ing eligible studies. The second search was conducted in the same
manner by two authors (Jennifer Davis-Manders/Andrew Lotfallah)
and corroborated by a third (Jameel Muzaffar).
2.4 | Data extraction
A standardised Microsoft Excel sheet was used for data
extraction from the included studies. This was designed and piloted
prior to the data extraction phase. The data of interest comprised of
study characteristics (study design, location, duration), primary and
secondary outcome data and operative adverse events. Missing data
were sought, where possible, by email contact with study authors.
Any discrepancies were identified and resolved through discussion
within the author team.
2.5 | Risk of bias quality assessment
Two reviewers (Yasmin Nikookam/Nawal Zia) independently assessed
the methodological quality of the included studies. Animal studies
were assessed using the SYRCLE tool.15 Human studies were
assessed using the Oxford Centre for Evidence Based Medicine
(OCEBM) grading system, and the Cochrane Risk of Bias 2 (RoB2) tool
for randomised control trials.16,17 Any disagreements were resolved
through discussion between the two authors (Yasmin Nikookam/
Nawal Zia), and where necessary, consultation with the third review
author (Jameel Muzaffar). The above process was followed for the
second search conducted by two authors (Andrew Lotfallah/Jameel
Muzaffar).
3 | RESULTS
A flowchart detailing study selection according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines is included in Figure 1 (See Supplementary Materials).
3.1 | Description of studies
Seventeen studies met the inclusion criteria with a total of 397 sub-
jects (30 humans in a single study, 327 animals in 11 studies, and
40 animal specimens in 5 laboratory studies).7,12,13,18–31
Only one study, a randomised controlled trial, assessed the effect
of PBMT on humans. Subjects were selected for inclusion using an
unspecified screening questionnaire and randomly allocated to a con-
trol, treatment and placebo group.7 This study used 532/635 nm com-
bination laser, a shorter wavelength than all animal studies. Clinical
follow-up period was not stated.
Sixteen studies were conducted on animal models, published
between 2012 and 2021. From these, 10 were non-randomised con-
trolled trials, 4 were in vitro studies, one ex vivo study, and one
randomised-controlled trial. Three studies used mouse models, ten
used rat models, two used a guinea pig model, and one used a gerbil
model. The wavelength used was classified in all studies: 11 used
808 nm, 3 used 830 nm, 1 used 908 nm, 1 used 810 nm. The duration
of PBMT ranged from 4 to 60 min in a session. The follow-up
duration of PBMT in animals ranged from 5 to 28 days. Table 1 sum-
marises study characteristics for both human and animal studies.
3.2 | Quality of studies
The methodological quality of included studies was modest, mainly
consisting of non-randomised controlled studies (n = 10). All animal
studies (n = 16) were prospective, and all studies had a minimum of
five animals, or two cell lines which underwent PBMT.
The single human study7 comprised a randomised, double-blind con-
trolled prospective study that had 30 subjects. This study was OCEBM
grade I. Participants were randomly allocated to treatment, placebo and
control groups with adjustment to ensure similar baseline characteristics,
although the method of randomisation was not described. Double blind-
ing of subjects and researchers administering placebo and treatment
laser therapy was also implemented to limit potential bias.
Heterogeneity of audiological, PBMT duration, power, and wave-
length outcomes within and between human (n = 1) and animal
(n = 16) studies precluded a meta-analysis. Within the human study,
the limitations were the reporting of complications following PBMT
and the follow-up duration of patients who had PBMT. Quality
assessment of the human studies is summarised in Table 4. Within the
animal studies there were limitations in post-treatment observation
duration of animals receiving PBMT, audiological data prior to PBMT
delivery, age of subjects, housing of animals and PBMT technique.
Quality assessment of animal studies is summarised in Table 5.
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http://clinicaltrials.gov
3.3 | Audiological outcomes
Audiological outcomes in humans are summarised in Table 2. Audio-
logical outcome measures were assessed using pure-tone audiome-
try, speech perception, and transient evoked otoacoustic emissions.
Pre-PBMT hearing status was reported, and all patients recruited
had moderate to severe, non-fluctuating hearing loss, with an
average pure-tone audiometric score of 39.6 dB HL (SD 15.3 dB).7
The causes of hearing loss were not stated. The PBMT treatment
protocol was based on a pilot study conducted by HearingMed
(unpublished) showing an improvement of word recognition scores
following PBMT.7
Audiological outcomes in animals are summarised in Table 3. A
total of 12 different audiological outcomes measures were used with
inconsistency of pre- and post-PBMT reporting across all included
studies. Twelve studies reported pre-PBMT audiological assessments.
Auditory brainstem responses (ABR) were recorded in 12 studies
post-PBMT and 11 pre-PBMT, compoundaction potential (CAP)
scores were measured in 1 study pre- and post-PBMT, distortion
product otoacoustic emissions (DPOAE) were recorded in 1 study
post-PBMT, and tympanic membrane assessment in 1 study post-
PBMT. Histological analysis and immunohistochemistry were also
used to assess several outcome parameters post-PBMT including hair
cell count (10 studies), inducible nitric oxide synthase (iNOS) (2 stud-
ies), cleaved caspase 3 (2 studies), spiral ganglion cell number (SGN)
(1 study), cell viability (1 study), reactive oxygen species (ROS) inten-
sity (1 study), morphology of nerve fibres (1 study) and ATP (1 study).
3.4 | PBMT delivery method
All 17 studies outlined the PBMT technique. Twelve studies
outlined the distance of the optical fibre tip from the PBMT target
site, ranging from 1 mm to 8 cm, with a distance of 1 mm most
Records identified from: 
(n = 239) 
� WEB OF SCIENCE* (n = 139) 
� EMBASE (n = 54) 
� MEDLINE (n = 32) 
� COCHRANE (n = 13) 
� CLINICALTRIALS.GOV (n = 1) 
Records removed before 
screening:
Duplicate records removed (n 
= 117) 
Records screened 
(n = 122) 
Records excluded 
(n = 73) 
Reports assessed for eligibility 
(n = 49) 
Reports excluded (n = 32) 
� Study unsuitable e.g. editorial, 
conference abstract (n = 5) 
� Could not access full text (n = 9) 
� Wrong population (n = 5) 
� No relevant primary or secondary 
outcomes (n = 12) 
� Foreign language (n = 1) 
Studies included in review 
(n = 17) 
Identification of studies via databases and registers 
Id
en
tif
ic
at
io
n 
Sc
re
en
in
g 
In
cl
ud
ed
 
*WEB OF SCIENCE includes the databases: Web of Science Core collection, BIOSIS, Data Citation Index, Derwent Innovations 
Index, KCI-Korean Journal Database, MEDLINE, Russian Citation Index, SciELO Citation Index and Zoological Records 
F IGURE 1 PRISMA flow diagram.16
44 NIKOOKAM ET AL.
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3
0
m
in
/d
ay
fo
r
5
d
ay
s
5
1
7
A
.T
am
ur
a
et
al
.,
2
0
1
6
3
1
Ja
pa
n
A
ni
m
al
s
(r
at
s)
N
o
n-
R
C
T
P
ro
sp
ec
ti
ve
6
9
3
5
1
0
1
6
5
8
0
8
3
0
m
in
/d
ay
fo
r
5
d
ay
s
5
N
ot
e:
-
C
o
rr
el
at
es
to
no
t
st
at
ed
.
a
C
o
rr
el
at
es
to
nu
m
be
r
o
f
ce
ll
w
el
ls
us
ed
.
NIKOOKAM ET AL. 45
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
2
P
ri
m
ar
y
o
ut
co
m
es
in
hu
m
an
st
ud
ie
s.
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
S.
G
o
o
dm
an
et
al
.,
2
0
1
3
,
U
SA
G
ro
up
s:
3
G
ro
up
1
:l
as
er
tr
ea
tm
en
t
(n
=
9
)
G
ro
up
2
:p
la
ce
bo
(n
=
1
0
)
G
ro
up
3
:c
o
nt
ro
l(
n
=
1
1
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
E
rc
ho
ni
aE
H
Ll
as
er
T
w
o
la
se
r
di
o
de
s:
5
3
2
nm
w
av
el
en
gt
h,
an
d
6
3
5
nm
w
av
el
en
gt
h
P
B
M
T
po
w
er
:7
.5
m
W
P
B
M
T
du
ra
ti
o
n:
4
m
in
M
ea
n
ag
e
o
f
su
bj
ec
ts
:
5
2
.8
H
ea
ri
ng
lo
ss
:
N
o
t
st
at
ed
?
Se
ve
re
?
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
F
o
llo
w
ed
a
pr
o
to
co
lt
ha
t
in
cl
ud
ed
7
st
ep
s.
T
he
la
se
r
w
as
pl
ac
ed
in
4
di
ff
er
en
t
po
si
ti
o
ns
:
1
).
T
em
po
ro
m
an
di
b
ul
ar
jo
in
t,
an
te
ri
o
r
to
th
e
ex
te
rn
al
au
d
it
o
ry
m
ea
tu
s
o
f
th
e
ea
r,
2
in
ch
es
fr
o
m
th
e
su
rf
ac
e
o
f
th
e
sk
in
.
2
).
M
id
lin
e
o
f
th
e
ce
rv
ic
al
sp
in
e,
3
in
ch
es
fr
o
m
th
e
sk
in
su
rf
ac
e.
3
)T
o
p
o
f
th
e
he
ad
,2
in
ch
es
fr
o
m
th
e
sk
in
su
rf
ac
e.
4
)E
xt
er
na
la
ud
it
o
ry
m
ea
tu
s.
A
ud
io
lo
gi
ca
ld
at
a:
P
ur
e-
to
ne
au
d
io
m
et
ry
,
T
E
O
A
E
an
d
H
IN
T
co
nd
uc
te
d
pr
et
es
t.
B
ef
o
re
en
ro
lm
en
t
a
lis
t
o
f
sc
re
en
in
g
qu
es
ti
o
ns
de
te
rm
in
ed
el
ig
ib
ili
ty
.
T
hi
s
w
as
us
ed
to
ex
cl
ud
e
su
bj
ec
ts
w
ho
se
he
ar
in
g
m
ay
fl
uc
tu
at
e
P
ur
e-
T
o
ne
A
ud
io
m
et
ry
:*
C
al
cu
la
te
d
as
ch
an
ge
in
PT
A
(p
os
tt
es
t
m
in
us
pr
et
es
t)
,n
eg
at
iv
e
va
lu
es
in
di
ca
te
im
pr
ov
em
en
t
in
th
re
sh
ol
ds
.F
ol
lo
w
in
g
ex
pr
es
se
d
as
a
ra
ng
e:
G
ro
up
1
:�
1
.8
to
+
1
.8
G
ro
up
2
:�
1
.8
to
+
1
.8
G
ro
up
3
:0
to
�1
.8
C
ha
ng
e
in
th
e
au
di
om
et
ri
c
H
FA
.C
ha
ng
e
ca
lc
ul
at
ed
aspo
st
te
st
m
in
us
pr
et
es
t;
ne
ga
ti
ve
va
lu
es
in
di
ca
te
im
pr
ov
em
en
t
in
th
re
sh
ol
ds
.F
ol
lo
w
in
g
ex
pr
es
se
d
as
a
ra
ng
e:
G
ro
up
1
:�
1
.8
to
+
1
.8
G
ro
up
2
:�
1
.8
to
+
2
.5
G
ro
up
3
:�
1
.8
to
+
3
.2
Sp
ee
ch
un
de
rs
ta
nd
in
g:
*
C
ha
ng
e
in
C
ST
sc
or
es
ex
pr
es
se
d
as
ra
ti
on
al
is
ed
ar
cs
in
e
un
it
s
(r
au
).
Fo
llo
w
in
g
re
po
rt
ed
as
a
ra
ng
e:
G
ro
up
1
:�
1
3
.0
to
+
8
.0
G
ro
up
2
:�
9
.0
to
+
8
.0
G
ro
up
3
:+
2
.0
to
+
1
0
.0
T
ra
ns
ie
nt
E
vo
ke
d
O
to
ac
o
us
ti
c
E
m
is
si
o
ns
:*
C
ha
ng
e
in
TE
O
A
E
PT
A
am
pl
it
ud
es
(1
–2
kH
z)
.F
ol
lo
w
in
g
re
po
rt
ed
as
am
pl
it
ud
e
di
ff
er
en
ce
(d
B
SP
L)
ra
ng
e:
G
ro
up
1
:�
2
.0
to
+
1
.5
G
ro
up
2
:�
3
.0
to
+
1
.5
G
ro
up
3
:�
2
.2
to
+
1
.5
C
ha
ng
e
in
TE
O
A
E
H
FA
(2
–8
kH
z)
am
pl
it
ud
es
.F
ol
lo
w
in
g
re
po
rt
ed
as
am
pl
it
ud
e
di
ff
er
en
ce
(d
B
SP
L)
ra
ng
e:
G
ro
up
1
:�
1
.6
to
+
1
.8
G
ro
up
2
:�
1
.8
to
+
0
.8
G
ro
up
3
:�
1
.6
to
+
0
.2
5
su
bj
ec
ts
no
t
in
cl
ud
ed
in
th
e
an
al
ys
is
.
N
o
st
at
is
ti
ca
lly
si
gn
if
ic
an
t
ef
fe
ct
o
f
LL
LT
o
n
au
d
it
o
ry
fu
n
ct
io
n
w
as
fo
u
n
d
,a
s
as
se
ss
ed
b
y
p
u
re
-t
o
n
e
au
d
io
m
et
ry
,s
p
ee
ch
u
n
d
er
st
an
d
in
g,
an
d
T
E
O
A
E
s.
A
d
d
it
io
n
al
ly
,
n
o
in
d
iv
id
u
al
su
b
je
ct
s
sh
o
w
ed
an
y
cl
in
ic
al
ly
si
gn
if
ic
an
t
ch
an
ge
.
O
C
E
B
M
gr
ad
e:
1
B
ra
zz
el
li
ri
sk
o
f
b
ia
s
ch
ec
kl
is
t:
lo
w
=
1
2
,
h
ig
h
=
0
,u
n
cl
ea
r
=
6
46 NIKOOKAM ET AL.
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
P
ri
m
ar
y
o
ut
co
m
es
in
an
im
al
st
ud
ie
s.
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
D
.B
as
ta
et
al
.,
2
0
2
0
,
G
er
m
an
y
G
ro
up
s:
G
ro
up
1
:c
o
nt
ro
l,
no
no
is
e
ex
po
su
re
o
r
N
IR
pr
e-
tr
ea
tm
en
t
(n
=
7
)
G
ro
up
2
:n
o
is
e
o
nl
y,
no
is
e-
ex
po
su
re
bu
t
w
it
ho
ut
N
IR
-t
re
at
m
en
t
(n
=
1
6
)
G
ro
up
3
:5
m
in
N
IR
-t
re
at
m
en
t
(n
=
1
6
)
G
ro
up
4
:1
0
m
in
N
IR
-t
re
at
m
en
t
(n
=
1
6
)
G
ro
up
5
:2
0
m
in
N
IR
-t
re
at
m
en
t
(n
=
7
)
G
ro
up
6
:3
0
m
in
N
IR
-t
re
at
m
en
t
(n
=
8
)
G
ro
up
7
:4
0
m
in
N
IR
-t
re
at
m
en
t
(n
=
8
).
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
nm
(D
B
8
0
8
-1
2
0
-3
(2
2
�
6
5
),
P
ic
o
tr
o
ni
c,
G
er
m
an
y)
P
o
w
er
de
ns
it
y:
3
1
2
m
W
/c
m
2
.
P
B
M
T
po
w
er
:1
2
0
m
W
P
B
M
T
du
ra
ti
o
n:
5
–4
0
m
in
M
ea
n
ag
e
o
f
su
bj
ec
ts
:1
0
–1
1
w
ee
ks
H
ea
ri
ng
lo
ss
:
N
o
is
e-
in
du
ce
d
he
ar
in
g
lo
ss
.
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
T
he
la
se
r
m
o
du
le
w
as
pl
ac
ed
at
th
e
o
ut
er
ea
r
ca
na
la
t
ex
ac
tl
y
th
e
an
gl
e
th
at
al
lo
w
ed
a
to
ta
l
co
ve
ra
ge
o
f
th
e
co
ch
le
a
w
it
h
th
e
la
se
r
be
am
o
f
ap
pr
o
xi
m
at
el
y
7
m
m
di
am
et
er
.
N
O
T
E
:P
B
M
w
as
ad
m
in
is
te
re
d
be
fo
re
N
IH
L
w
as
in
du
ce
d.
A
ud
io
lo
gi
ca
ld
at
a:
A
B
R
re
co
rd
in
gs
2
da
ys
be
fo
re
an
d
2
w
ee
ks
af
te
r
no
is
e
ex
po
su
re
.
A
B
R
-t
hr
es
ho
ld
sh
if
t
G
ro
up
s
3
–7
sh
o
w
ed
a
lo
w
er
gr
o
up
m
ea
n
he
ar
in
g
lo
ss
fo
llo
w
in
g
th
e
no
is
e
ex
po
su
re
co
m
pa
re
d
to
gr
o
up
2
.
C
o
ch
le
ar
ha
ir
ce
lls
N
o
lo
ss
o
f
in
ne
r
ha
ir
ce
lls
co
ul
d
be
de
te
ct
ed
bi
la
te
ra
lly
fo
r
an
y
o
f
th
e
gr
o
up
s.
G
ro
up
2
:a
si
gn
if
ic
an
t
de
cr
ea
se
in
o
ut
er
ha
ir
ce
ll
co
u
n
ts
w
as
fo
un
d
fo
r
bo
th
ea
rs
co
m
pa
re
d
to
gr
o
up
1
.
G
o
o
d
o
u
tc
o
m
es
.
A
si
n
gl
e
N
IR
p
re
-t
re
at
m
en
t
in
d
u
ce
s
a
ve
ry
ef
fe
ct
iv
e
p
ro
te
ct
io
n
o
f
co
ch
le
ar
st
ru
ct
u
re
s
fr
o
m
n
o
is
e
ex
p
o
su
re
.P
re
-e
xp
o
su
re
o
f
1
0
m
in
se
em
s
to
em
er
ge
as
th
e
o
p
ti
m
al
d
o
sa
ge
fo
r
o
u
r
ex
p
er
im
en
ta
ls
et
u
p
.A
sa
tu
ra
te
d
ef
fe
ct
o
cc
u
rr
ed
w
it
h
h
ig
h
er
d
o
sa
ge
-
tr
ea
tm
en
ts
.T
h
es
e
re
su
lt
s
ar
e
re
le
va
n
t
fo
r
p
ro
te
ct
io
n
o
f
re
si
d
u
al
h
ea
ri
n
g
in
o
to
n
eu
ro
su
rg
er
y
su
ch
as
co
ch
le
ar
im
p
la
n
ta
ti
o
n
.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
7
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
3
S.
C
ha
ng
et
al
.,
2
0
1
2
,K
o
re
a
G
ro
up
s:
2
G
ro
up
1
:L
LL
T
3
da
ys
po
st
no
is
e
ex
po
su
re
G
ro
up
2
:L
LL
T
7
da
ys
po
st
no
is
e
ex
po
su
re
G
ro
up
3
:c
o
nt
ro
le
ar
s
(r
ig
ht
ea
rs
fr
o
m
gr
o
up
1
)
G
ro
up
4
:c
o
nt
ro
le
ar
s
(r
ig
ht
ea
rs
fr
o
m
gr
o
up
2
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
3
0
nm
di
o
de
la
se
r
P
B
M
T
po
w
er
:1
6
5
m
W
/c
m
2
(5
9
4
J/
cm
2
)
P
B
M
T
du
ra
ti
o
n:
6
0
m
in
fo
r
1
2
da
ys
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
H
ea
ri
ng
lo
ss
:
N
o
is
e-
in
du
ce
d
—
su
bj
ec
ts
ex
po
se
d
to
na
rr
o
w
ba
nd
no
is
e,
1
2
0
dB
,1
6
kH
z,
6
h
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
Le
ft
ea
rs
w
er
e
ir
ra
di
at
ed
fr
o
m
gr
o
up
s
1
an
d
2
.
La
se
r
fi
br
e
w
as
de
liv
er
ed
th
ro
ug
h
a
ho
llo
w
tu
be
in
to
th
e
ex
te
rn
al
au
di
to
ry
ca
na
ls
o
th
at
th
e
di
st
an
ce
fr
o
m
th
e
ti
p
o
f
th
e
fi
br
e
to
th
e
su
rf
ac
e
o
f
th
e
ty
m
pa
ni
c
m
em
br
an
e
w
as
ap
pr
o
xi
m
at
el
y
Im
m
.
A
ud
io
lo
gi
ca
ld
at
a:
N
o
t
st
at
ed
.
A
B
R
T
hr
es
ho
ld
Sh
if
ts
kH
z
ar
e
in
o
rd
er
o
f
4
,8
,1
2
,1
6
,3
2
.
A
ft
er
th
e
1
2
th
ir
ra
di
at
io
n:
G
ro
up
1
:2
2
±
4
.2
,3
0
±
3
.5
,6
5
±
1
1
.9
,
3
0
±
1
2
.9
an
d
2
5
±
2
.2
dB
SP
L
G
ro
up
2
:3
2
.5
,4
1
.3
,6
0
.0
,5
7
.5
,a
nd
4
5
.0
dB
SP
L
G
ro
up
3
:7
0
±
2
2
.9
,8
5
±
1
5
.8
,9
0
.3
±
2
2
.9
,
8
0
±
1
6
.8
an
d
7
5
.8
±
2
1
.4
dB
SP
L
G
ro
up
4
:2
5
.0
,3
7
.5
,5
2
.5
,3
8
.8
,a
nd
2
6
.3
dB
SP
L.
G
o
o
d
o
u
tc
o
m
es
.
T
re
at
in
g
ea
rs
w
it
h
LL
LT
so
o
n
er
(g
ro
u
p
1
)v
er
su
s
la
te
r
(g
ro
u
p
2
)l
ea
d
s
to
b
et
te
r
o
u
tc
o
m
es
an
d
b
et
te
r
h
ea
ri
n
g
re
co
ve
ry
.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
2
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
1
0
S.
C
ha
ng
et
al
.,
2
0
1
6
,K
o
re
a
N
um
be
r
o
f
pa
rt
ic
ip
an
ts
:1
7
G
ro
up
s:
5
G
ro
up
1
:C
o
nt
ro
l(
no
is
e
o
nl
y)
(n
=
6
ea
rs
).
G
ro
up
2
:N
A
C
(N
=
6
ea
rs
).
G
ro
up
3
:A
LC
A
R
(N
=
4
ea
rs
).
G
ro
up
4
:N
A
C
pl
us
La
se
r
(N
=
7
ea
rs
).
G
ro
up
5
:A
LC
A
R
pl
us
La
se
r
(N
=
7
ea
rs
).
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
-n
m
di
o
de
la
se
r
(W
O
N
-T
E
C
H
,K
o
re
a)
.
[in
se
rt
th
e
de
ta
ils
o
f
th
e
P
B
M
T
de
vi
ce
e.
g.
th
e
w
av
el
en
gt
h
us
ed
]
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
P
B
M
T
de
liv
er
ed
1
da
y
af
te
r
no
is
e
in
su
lt
.
D
el
iv
er
ed
vi
a
o
pt
ic
fi
br
e
(c
o
re
fi
br
e
6
2
.5
μm
/
cl
ad
di
ng
1
2
5
μm
)
in
se
rt
ed
in
to
th
e
ex
te
rn
al
ac
o
us
ti
c
ca
na
l
th
ro
ug
h
a
ho
llo
w
tu
be
.
T
ip
o
f
fi
br
e
po
si
ti
o
ne
d
A
ud
it
o
ry
br
ai
ns
te
m
re
sp
o
ns
e
(A
B
R
)
Th
re
sh
ol
d
of
6t
h
la
se
r
ir
ra
di
at
io
n:
G
ro
up
1
:8
kH
z
=
6
9
.2
±
8
.9
;1
6
kH
z
=
6
0
.8
±
7
.1
;
3
2
kH
z
=
5
3
.3
±
8
.0
G
ro
up
2
:8
kH
z
=
6
1
.7
±
1
1
.9
;1
6
kH
z
=
5
0
.8
±
5
.0
;
3
2
kH
z
=
4
7
.5
±
3
.8
.
G
ro
up
3
:8
kH
z
=
5
9
.0
±
1
5
.1
;1
6
kH
z
=
4
3
.0
±
8
.7
;
3
2
kH
z
=
4
1
.0
±
7
.1
G
ro
up
4
:8
kH
z
=
5
9
.2
±
1
4
.6
;1
6
kH
z
=
5
0
.0
±
8
.0
;
3
2
kH
z
=
4
5
.0
±
7
.8
G
o
o
d
o
u
tco
m
es
.
N
A
C
in
co
m
b
in
at
io
n
w
it
h
LL
LT
w
as
m
o
re
ef
fe
ct
iv
e
at
im
p
ro
vi
n
g
N
IH
L
ea
rl
ie
r
th
an
LL
LT
al
o
n
e.
H
o
w
ev
er
,t
h
is
ad
d
it
iv
e
o
r
sy
n
er
gi
st
ic
ef
fe
ct
w
as
n
't
as
ef
fe
ct
iv
e
at
im
p
ro
vi
n
g
N
IH
L
w
h
en
co
m
p
ar
ed
to
LL
LT
al
o
n
e
af
te
r
1
2
d
ai
ly
th
er
ap
y.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
7
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
3
(C
o
n
ti
n
u
es
)
NIKOOKAM ET AL. 47
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
(C
o
nt
in
ue
d)
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
P
B
M
T
po
w
er
:1
6
5
m
W
(5
9
.4
J)
.
P
B
M
T
du
ra
ti
o
n:
6
0
m
in
a
da
y
o
ve
r
1
2
da
ys
.
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
.
H
ea
ri
ng
lo
ss
:
N
o
is
e-
in
du
ce
d
he
ar
in
g
lo
ss
.
R
at
s
ex
po
se
d
to
o
ne
-t
im
e
ex
po
su
re
to
a
na
rr
o
w
ba
nd
no
is
e
o
f
1
1
6
dB
SP
L
ce
nt
er
ed
at
a
fr
eq
ue
nc
y
o
f
1
6
kH
z
(b
an
dw
id
th
1
kH
z)
fo
r
5
h.
1
–2
m
m
aw
ay
fr
o
m
th
e
ty
m
pa
ni
c
m
em
br
an
e.
A
ud
io
lo
gi
ca
ld
at
a:
A
B
R
s
w
er
e
m
ea
su
re
d
be
fo
re
no
is
e
ex
po
su
re
fo
r
gr
o
up
1
o
nl
y.
P
ri
o
r
to
P
B
M
T
al
l
pa
rt
ic
ip
an
ts
w
er
e
de
em
ed
to
ha
ve
N
IH
L.
A
B
R
re
ad
in
gs
fr
o
m
gr
o
up
s
2
–5
fo
llo
w
in
g
P
B
M
T
w
er
e
co
m
pa
re
d
to
gr
o
up
1
.
G
ro
up
5
:8
kH
z
=
5
7
.0
±
1
2
.1
;1
6
kH
z
=
4
9
.0
±
8
.2
;
3
2
kH
z
=
4
3
.8
±
6
.6
Th
re
sh
ol
d
of
1
2
th
la
se
r
ir
ra
di
at
io
n:
G
ro
up
1
:8
kH
z
=
7
5
.0
±
3
.8
;1
6
kH
z
=
6
0
.0
±
1
0
.0
;
3
2
kH
z
=
5
5
.0
±
7
.7
G
ro
up
2
:8
kH
z
=
7
5
.0
±
1
1
.9
;1
6
kH
z
=
5
0
.0
±
1
1
.5
;
3
2
kH
z
=
4
2
.5
±
8
.7
G
ro
up
3
:8
kH
z
=
5
2
.5
±
2
.9
;1
6
kH
z
=
3
5
.0
±
4
.5
;
3
2
kH
z
=
3
0
.0
±
5
.3
G
ro
up
4
:8
kH
z
=
6
5
.0
±
8
.8
;1
6
kH
z
=
5
0
.0
±
7
.7
;
3
2
kH
z
=
4
6
.7
±
6
.8
G
ro
up
5
:8
kH
z
=
6
1
.7
±
2
.6
;1
6
kH
z
=
4
5
.0
±
4
.5
;
3
2
kH
z
=
4
0
.0
±
3
.8
H
ai
r
ce
ll
co
un
t
A
pi
ca
l:
G
ro
up
1
:8
2
.4
±
5
.8
G
ro
up
2
:8
1
.8
±
4
.1
G
ro
up
3
:8
8
.9
±
2
.3
G
ro
up
4
:8
4
.8
±
1
.4
G
ro
up
5
:8
4
.3
±
2
.9
M
id
dl
e:
G
ro
up
1
:7
2
.0
±
6
.9
G
ro
up
2
:8
0
.6
±
2
.2
G
ro
up
3
:8
5
.1
±
1
.5
G
ro
up
4
:8
0
.8
±
2
.5
G
ro
up
5
:8
0
.6
±
3
.2
B
as
al
:
G
ro
up
1
:6
1
.2
±
9
.7
G
ro
up
2
:8
1
.0
±
1
.2
G
ro
up
3
:8
2
.4
±
3
.6
G
ro
up
4
:7
1
.6
±
8
.6
G
ro
up
5
:7
5
.8
±
2
.5
S.
C
ha
ng
et
al
.,
2
0
1
9
,K
o
re
a
G
ro
up
s:
4
G
ro
up
1
:c
o
nt
ro
l(
no
G
M
an
d
no
P
B
M
)
G
ro
up
2
:P
B
M
o
nl
y
G
ro
up
3
:G
M
o
nl
y
G
ro
up
4
:G
M
an
d
P
B
M
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
nm
ne
ar
-i
nf
ra
re
d
di
o
de
la
se
r
(W
o
nT
ec
h,
D
ae
je
o
n,
R
ep
ub
lic
o
f
K
o
re
a)
P
B
M
T
po
w
er
:1
5
m
W
fo
r
1
5
m
in
(t
o
ta
le
ne
rg
y
de
ns
it
y:
1
3
.5
J/
cm
2
)
P
B
M
T
du
ra
ti
o
n:
1
5
m
in
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
St
ar
te
d
0
.5
–9
h
af
te
r
G
M
tr
ea
tm
en
t.
A
ud
io
lo
gi
ca
ld
at
a:
N
o
t
st
at
ed
.
A
T
P
le
ve
ls
:*
R
el
at
iv
e
A
TP
le
ve
li
n
1
0
6
ce
lls
fo
llo
w
in
g
PB
M
:
G
ro
up
1
:i
m
m
ed
ia
te
ly
=
1
.0
0
;+
1
h
=
0
.9
8
;+
2
h
=
1
.0
0
G
ro
up
2
:i
m
m
ed
ia
te
ly
=
1
.1
9
;+
1
h
=
1
.1
2
;+
2
h
=
1
.0
0
G
ro
up
3
:i
m
m
ed
ia
te
ly
=
0
.5
5
;+
1
h
=
0
.6
8
;+
2
h
=
0
.8
2
G
ro
up
4
:i
m
m
ed
ia
te
ly
=
0
.9
2
;+
1
h
=
0
.8
2
;+
2
h
=
0
.8
4
C
el
lv
ia
bi
lit
y:
In
cr
ea
se
d
ce
ll
vi
ab
ili
ty
o
f
au
di
to
ry
ce
lls
by
P
B
M
af
te
r
G
M
-
in
du
ce
d
o
to
to
xi
ci
ty
,w
hi
ch
ca
n
ca
us
e
pe
rm
an
en
t
h
ai
r
ce
ll
da
m
ag
e
an
d
se
ns
o
ri
ne
ur
al
he
ar
in
g
lo
ss
,b
y
in
cr
ea
si
n
g
A
T
P
le
ve
ls
an
d
M
M
P
G
o
o
d
o
u
tc
o
m
es
.
LL
LT
im
p
ro
ve
d
ce
ll
vi
ab
ili
ty
o
f
au
d
it
o
ry
ce
lls
an
d
in
cr
ea
se
s
A
T
P
im
m
ed
ia
te
ly
af
te
r
ex
p
o
su
re
.H
o
w
ev
er
,i
t
re
ac
h
es
co
n
tr
o
l(
gr
o
u
p
1
le
ve
ls
)a
ft
er
2
h
o
f
ex
p
o
su
re
to
P
B
M
.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
6
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
4
48 NIKOOKAM ET AL.
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
(C
o
nt
in
ue
d)
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
H
ea
ri
ng
lo
ss
:
G
en
ta
m
ic
in
-i
nd
uc
ed
o
to
to
xi
ct
y
T
.G
ua
n
et
al
.,
2
0
1
5
,C
hi
na
G
ro
up
s:
un
cl
ea
r
In
ve
st
ig
at
io
na
ld
ev
ic
e:
9
8
0
-n
m
di
o
de
la
se
r
P
B
M
T
po
w
er
:0
to
2
.2
W
P
B
M
T
du
ra
ti
o
n:
un
cl
ea
r
O
th
er
:c
al
cu
la
te
d
ra
di
an
t
ex
po
su
re
s
ra
ng
ed
fr
o
m
0
to
5
3
.2
m
J/
cm
2
at
a
pu
ls
e
du
ra
ti
o
n
o
f
5
0
μs
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
H
ea
ri
ng
lo
ss
:
Su
rg
er
y
to
de
af
en
th
e
an
im
al
.
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
T
he
en
d
o
f
th
e
o
pt
ic
al
fi
br
e
w
as
pl
ac
ed
in
pr
o
x-
im
it
y
to
th
e
ro
un
d
w
in
do
w
m
em
br
an
e
an
d
w
as
vi
su
al
ly
o
ri
en
te
d
to
w
ar
d
th
e
sp
ir
al
ga
ng
lio
n
ce
lls
in
R
o
se
nt
ha
l's
ca
na
li
n
th
e
ba
sa
lt
ur
n.
T
he
di
st
an
ce
be
tw
ee
n
th
e
en
d
o
f
th
e
fi
br
e
an
d
th
e
sp
ir
al
ga
ng
lio
n
ce
lls
in
th
e
R
o
se
nt
ha
l's
ca
na
li
s
ap
pr
o
xi
-
m
at
el
y
1
.0
3
m
m
an
d
th
e
sp
o
t
si
ze
is
ab
o
ut
0
.2
1
m
m
2
in
si
de
th
e
co
ch
le
ar
.
A
ud
io
lo
gi
ca
ld
at
a
aC
A
P
:
T
he
am
pl
it
ud
e
o
f
th
e
aC
A
P
be
tw
ee
n
N
1
–P
1
is
m
o
re
th
an
4
0
0
μV
be
fo
re
de
af
en
in
g,
w
hi
le
af
te
r
su
rg
er
y
no
o
bv
io
us
aC
A
P
s
w
er
e
ev
o
ke
d
by
ac
o
us
ti
c
st
im
ul
i.
o
C
A
P
s:
W
it
h
di
ff
er
en
t
ra
di
an
t
ex
po
su
re
s:
P
o
w
er
at
th
e
en
d
o
f
th
e
o
pt
ic
al
fi
br
e
w
as
gr
ad
ua
lly
in
cr
ea
se
d
fr
o
m
1
.5
2
to
2
1
9
0
m
W
,w
it
h
th
e
co
rr
es
po
nd
in
g
ra
di
at
io
n
ex
po
su
re
ra
ng
in
g
fr
o
m
0
.0
3
7
to
5
3
.2
m
J/
cm
2
at
a
pu
ls
e
du
ra
ti
o
n
o
f
5
0
μs
.
T
he
am
pl
it
ud
e
o
f
o
C
A
P
s
di
d
no
t
o
bv
i-
2
ho
ur
ly
in
cr
ea
se
w
he
n
th
e
ra
di
an
t
ex
po
su
re
w
as
ab
o
ve
3
0
m
J/
cm
W
it
h
di
ff
er
en
t
st
im
ul
us
ra
te
:
St
im
ul
at
io
n
ra
te
s
fr
o
m
1
8
2
to
1
0
0
0
H
z
w
it
h
a
co
ns
ta
n
t
pu
ls
e
w
id
th
o
f
5
0
μs
.
N
2
in
th
e
o
C
A
P
s
w
as
ev
id
en
t
at
st
im
ul
at
io
n
ra
te
s
o
f
le
ss
th
an
4
0
0
H
z,
ho
w
ev
er
,a
t
st
im
ul
at
io
n
ra
te
s
ab
o
ve
6
6
7
H
z,
o
nl
y
N
1
an
d
P
1
ca
n
be
se
en
.
aC
A
P
s:
G
o
o
d
o
u
tc
o
m
es
.
St
im
u
la
ti
o
n
w
it
h
a
la
se
r
o
f
9
8
0
n
m
w
av
el
en
gt
h
ca
n
su
cc
es
sf
u
lly
in
d
u
ce
C
A
P
s
o
u
ts
id
e
th
e
co
ch
le
a.
T
h
is
sh
o
w
ed
th
at
sh
o
rt
er
-
w
av
el
en
gt
h
n
ea
r-
in
fr
ar
ed
p
u
ls
ed
la
se
r
(9
8
0
n
m
)c
an
el
ic
it
C
A
P
fr
o
m
a
d
ea
fe
n
ed
gu
in
ea
p
ig
co
ch
le
a,
su
gg
es
ti
n
g
th
e
u
se
o
f
a
sh
o
rt
-w
av
el
en
gt
h
n
ea
r-
in
fr
ar
ed
la
se
r
as
an
al
te
rn
at
iv
e
st
im
u
lu
s
fo
r
co
ch
lea
im
p
la
n
ts
.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
0
;
h
ig
h
=
3
;
u
n
cl
ea
r
=
7
M
.L
ee
et
al
.,
2
0
1
6
,K
o
re
a
G
ro
up
s:
3
G
ro
up
1
:c
o
nt
ro
l(
n
=
1
1
)
G
ro
up
2
:o
ua
ba
in
o
nl
y
gr
o
up
(n
=
1
8
)G
ro
up
3
:
o
ua
ba
in
pl
us
la
se
r
gr
o
up
(n
=
1
8
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
-n
m
di
o
de
la
se
r
(W
O
N
T
E
C
H
C
o
.,
Lt
d,
K
o
re
a)
P
B
M
T
po
w
er
:2
0
0
m
W
P
B
M
T
du
ra
ti
o
n:
1
h/
da
y
fo
r
7
da
ys
M
ea
n
ag
e
o
f
su
bj
ec
ts
:4
–6
m
o
nt
hs
H
ea
ri
ng
lo
ss
:
A
ud
it
o
ry
ne
ur
o
pa
th
y
in
du
ce
d
by
o
ub
ai
n
ad
m
in
is
tr
at
io
n
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
O
pt
ic
fi
br
e
(c
o
re
si
ze
:
6
2
.5
m
m
)w
as
de
liv
er
ed
th
ro
ug
h
a
ho
llo
w
tu
be
in
to
th
e
ex
te
rn
al
ac
o
us
ti
c
ca
na
l.
La
se
r
w
as
ir
ra
di
at
ed
to
th
e
ty
m
pa
ni
c
m
em
br
an
e.
La
se
r
en
er
gy
w
as
ex
pe
ct
ed
to
be
de
liv
er
ed
to
th
e
co
ch
le
a,
sp
ec
if
ic
al
ly
sp
ir
al
ga
ng
lio
n
(R
o
se
nt
ha
l
A
B
R
B
as
el
in
e:
G
ro
up
1
:4
kH
z
=
2
3
.0
±
1
2
.3
;8
kH
z
=
2
2
.3
±
1
2
.3
;
1
2
kH
z
=
2
5
.7
±
1
4
.0
;1
6
kH
z
=
2
3
.0
±
1
4
.1
;
3
2
kH
z
=
2
5
.9
±
1
2
.7
dB
SP
L
G
ro
up
2
:4
kH
z
=
3
0
.6
±
1
7
.4
;8
kH
z
=
2
2
.2
±
1
1
.3
;
1
2
kH
z
=
2
5
.3
±
1
3
.2
;1
6
kH
z
=
2
3
.1
±
1
1
.9
;
3
2
kH
z
=
2
5
.0
±
1
3
.2
dB
SP
L
G
ro
up
3
:4
kH
z
=
3
2
.6
±
1
2
.3
;8
kH
z
=
2
7
.1
±
1
0
.0
;1
2
kH
z
=
2
6
.5
±
1
0
.7
;
1
6
kH
z
=
2
6
.2
±
1
0
.5
;3
2
kH
z
=
2
9
.4
±
9
.8
dB
SP
L
1
da
y
af
te
r
ou
ba
in
ap
pl
ic
at
io
n:
G
ro
up
2
:4
kH
z
=
8
0
.0
±
0
.0
;8
kH
z
=
7
8
.9
±
2
.2
;
1
2
kH
z
=
7
8
.9
±
2
.2
;1
6
kH
z
=
7
7
.2
±
3
.6
;
3
2
kH
z
=
7
7
.2
±
3
.6
dB
SP
L
G
o
o
d
o
u
tc
o
m
es
.
P
h
o
to
b
io
m
o
d
u
la
ti
o
n
al
le
vi
at
ed
th
e
h
ea
ri
n
g
lo
ss
ca
u
se
d
b
y
o
u
ab
ai
n
in
d
u
ce
d
au
d
it
o
ry
n
eu
ro
p
at
h
y.
P
h
o
to
b
io
m
o
d
u
la
ti
o
n
ef
fe
ct
o
n
h
ea
r-
in
g
re
sc
u
e
w
as
re
la
te
d
w
it
h
p
re
se
rv
ed
n
u
m
b
er
s
o
f
sp
ir
al
ga
n
gl
io
n
ce
lls
th
ro
u
gh
o
u
t
th
e
co
ch
le
ar
tu
rn
,s
yn
ap
ti
c
p
u
n
ct
a,
an
d
n
er
ve
fi
b
re
s.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
6
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
4
(C
o
n
ti
n
u
es
)
NIKOOKAM ET AL. 49
 17494486, 2024, 1, D
ow
nloaded from
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iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
(C
o
nt
in
ue
d)
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
ca
na
l)
w
hi
ch
is
lo
ca
te
d
w
it
hi
n
th
e
co
ch
le
a.
A
ud
io
lo
gi
ca
ld
at
a:
A
B
R
s
m
ea
su
re
d
be
fo
re
,o
n
da
y
1
an
d
da
y
7
af
te
r
o
ua
ba
in
ad
m
in
is
tr
at
io
n
.
G
ro
up
3
:4
kH
z
=
7
8
.8
±
3
.5
;8
kH
z
=
7
6
.9
±
4
.6
;
1
2
kH
z
=
8
0
.0
±
0
.0
;1
6
kH
z
=
7
8
.8
±
2
.3
;
3
2
kH
z
=
7
7
.5
±
3
.8
dB
SP
L
7
da
ys
af
te
r
ou
ba
in
ap
pl
ic
at
io
n:
G
ro
up
2
:4
kH
z
=
7
8
.1
±
4
.2
;8
kH
z
=
7
7
.5
±
4
.6
;
1
2
kH
z
=
7
6
.4
±
4
.8
;1
6
kH
z
=
7
5
.0
±
6
.2
;
3
2
kH
z
=
7
0
.0
±
8
.4
dB
SP
L
G
ro
up
3
:4
kH
z
=
6
9
.7
±
7
.2
;8
kH
z
=
6
4
.4
±
6
.8
;1
2
kH
z
=
6
5
.3
±
8
.6
;
1
6
kH
z
=
6
1
.5
±
7
.5
;3
2
kH
z
=
5
7
.9
±
8
.1
dB
SP
L
D
P
O
A
E
B
as
el
in
e:
G
ro
up
1
:4
kH
z
=
6
5
.9
±
4
.8
;8
kH
z
=
3
7
.7
±
5
.5
;
1
2
kH
z
=
3
9
.1
±
5
.0
;1
6
kH
z
=
3
5
.7
±
5
.0
dB
SP
L
G
ro
up
2
:4
kH
z
=
6
4
.2
±
9
.3
;8
kH
z
=
3
8
.9
±
7
.0
;
1
2
kH
z
=
3
6
.7
±
5
.7
;1
6
kH
z
=
3
9
.4
±
8
.2
dB
SP
L
G
ro
up
3
:4
kH
z
=
6
5
.0
±
7
.7
;8
kH
z
=
3
9
.7
±
4
.8
;
1
2
kH
z
=
3
7
.1
±
5
.0
;1
6
kH
z
=
3
5
.0
±
4
.7
dB
SP
L
A
t
7
da
ys
:
G
ro
up
1
:4
kH
z
=
6
8
.9
±
6
.9
;8
kH
z
=
3
7
.3
±
4
.0
;
1
2
kH
z
=
3
7
.5
±
4
.6
;1
6
kH
z
=
3
7
.3
±
5
.5
dB
SP
L
G
ro
up
2
:4
kH
z
=
6
7
.5
±
5
.8
;8
kH
z
=
3
9
.2
±
6
.0
;
1
2
kH
z
=
3
9
.4
±
4
.5
;1
6
kH
z
=
3
9
.7
±
5
.0
dB
SP
L
G
ro
up
3
:4
kH
z
=
6
7
.6
±
5
.0
;8
kH
z
=
4
1
.5
±
4
.6
;
1
2
kH
z
=
4
1
.5
±
5
.5
;1
6
kH
z
=
3
9
.7
±
6
.5
dB
SP
L
N
o
si
gn
ifi
ca
nt
di
ff
er
en
ce
M
o
rp
ho
lo
gi
es
o
f
ne
rv
e
fi
br
es
an
d
sy
na
pt
ic
pu
n
ct
a
G
ro
up
1
:p
er
ip
he
ra
ln
er
ve
fi
br
es
w
er
e
vi
si
bl
e
as
a
de
n
se
m
es
hw
o
rk
o
f
ne
ur
o
na
lp
ro
ce
ss
es
m
ed
ia
lt
o
IH
C
(IH
C
s
w
er
e
co
nt
ac
te
d
by
ro
ug
hl
y
1
0
af
fe
re
nt
ne
rv
e
fi
br
es
).
G
lu
R
2
pu
nc
ta
co
un
t
=
1
7
2
±
1
2
.7
.
G
ro
up
2
:t
hi
n
an
d
lo
o
se
m
es
h-
w
o
rk
o
f
ne
ur
o
na
lp
ro
ce
ss
w
as
ev
id
en
t
(IH
C
s
w
er
e
co
nt
ac
te
d
by
ab
o
ut
th
re
e
af
fe
re
nt
ne
rv
e
fi
br
es
)a
nd
m
ar
ke
dl
y
fe
w
er
po
st
sy
n
ap
-
ti
c
pu
nc
ta
w
er
e
o
bs
er
ve
d
co
m
pa
re
d
to
th
e
co
nt
ro
l
gr
o
up
.G
lu
R
2
pu
nc
ta
co
un
t
=
4
0
±
6
.1
.
G
ro
up
3
:p
un
ct
a
w
er
e
re
du
ce
d
in
nu
m
be
r
co
m
pa
re
d
to
th
e
co
nt
ro
lg
ro
up
bu
t
w
er
e
m
o
re
nu
m
er
o
us
th
an
in
th
e
o
ua
ba
in
o
nl
y
gr
o
up
.G
lu
R
2
pu
nc
ta
co
un
t
=
1
0
4
±
1
3
.1
.
M
o
rp
ho
lo
gy
an
d
de
ns
it
y
o
f
SG
N
s
G
ro
up
2
:s
ig
ni
fi
ca
nt
de
cl
in
e
o
f
SG
N
de
ns
it
y,
bu
t
th
er
e
w
as
no
ch
an
ge
in
IH
C
s
an
d
O
H
C
s
in
th
e
lo
w
ba
sa
l,
hi
gh
ba
sa
l,
lo
w
m
id
-
dl
e,
an
d
hi
gh
m
id
dl
e
re
gi
o
n.
G
ro
up
3
:S
G
N
co
un
ts
si
gn
if
ic
an
tl
y
hi
gh
er
in
lo
w
ba
sa
l,
h
ig
h
ba
sa
l,
lo
w
m
id
dl
e,
an
d
hi
gh
m
id
dl
e
re
gi
o
ns
co
m
pa
re
d
to
th
e
o
ua
ba
in
gr
o
up
,b
ut
le
ss
th
an
gr
o
up
1
(w
it
ho
ut
st
at
is
ti
ca
ls
ig
ni
fi
ca
nc
e)
.
50 NIKOOKAM ET AL.
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
(C
o
nt
in
ue
d)
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
J.
Le
e
et
al
.,
2
0
1
6
,
K
o
re
a
G
ro
up
s:
3
G
ro
up
1
:c
o
nt
ro
l,
no
is
e
o
nl
y
(n
=
6
)
G
ro
up
2
:u
ni
la
te
ra
ll
as
er
(n
=
6
)
G
ro
up
3
:b
ila
te
ra
ll
as
er
(n
=
6
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
nm
di
o
de
la
se
r
(W
o
nt
ec
,S
eo
ul
,S
o
ut
h
K
o
re
a)
P
B
M
T
po
w
er
:1
6
5
m
W
/c
m
2
(5
9
4
J)
P
B
M
T
du
ra
ti
o
n:
6
0
m
in
s
fo
r
1
5
da
ys
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
H
ea
ri
ng
lo
ss
:
N
o
is
e-
in
du
ce
d
(a
cu
te
ac
o
us
ti
c
tr
au
m
a)
.
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
O
pt
ic
al
fi
br
e
w
as
at
ta
ch
ed
to
a
ho
llo
w
tu
be
an
d
pl
ac
ed
in
to
th
e
ex
te
rn
al
ea
r
ca
na
lw
hi
le
le
av
in
g
a
di
st
an
ce
o
f
1
m
m
be
tw
ee
n
th
e
fi
br
e
ti
p
an
d
ty
m
pa
ni
c
m
em
br
an
e.
A
ud
io
lo
gi
ca
ld
at
a:
A
B
R
pe
rf
o
rm
ed
.
A
B
R
A
re
in
o
rd
er
o
f
4
,8
,1
2
,1
6
,3
2
kH
z.
B
as
el
in
e:
G
ro
up
1
:1
8
.3
3
,1
5
.8
3
,1
5
,1
4
.1
7
,1
5
.8
3
G
ro
up
2
:2
0
,1
5
,2
0
,1
5
.8
3
,1
7
.5
G
ro
up
3
:1
7
.5
,1
7
.5
,1
5
.8
3
,1
8
.3
3
,1
5
.8
3
A
ft
er
no
is
e
ex
po
su
re
:
G
ro
up
1
:4
8
.3
3
,5
6
.6
7
,5
7
.5
,6
3
.3
3
,6
1
.6
7
G
ro
up
2
:5
3
.3
3
,6
3
.3
3
,6
0
,6
2
.5
,6
0
G
ro
up
3
:5
1
.6
7
,5
3
.3
3
,6
3
.3
3
,63
.3
3
,6
0
A
ft
er
6t
h
la
se
r
ir
ra
di
at
io
n:
G
ro
up
1
:4
3
.3
3
,5
2
.5
,6
0
.8
3
,6
3
.3
3
,6
1
.6
7
G
ro
up
2
:4
2
.5
,4
9
.1
7
,5
5
.8
3
,6
2
.5
,5
6
.6
7
G
ro
up
3
:3
6
.6
7
,4
0
,5
1
.5
7
,5
1
.6
7
,4
6
.6
7
A
ft
er
1
5
th
la
se
r
ir
ra
di
at
io
n:
G
ro
up
1
:3
8
.3
3
,4
2
.5
,5
0
,4
8
.3
3
,4
7
.5
G
ro
up
2
:2
5
.8
3
,3
5
,3
1
.6
7
,3
0
,3
2
.5
G
ro
up
3
:2
2
.5
,2
5
,2
4
.1
7
,2
5
.8
3
,2
1
.6
7
H
ai
r
ce
ll
co
un
t
A
ve
ra
ge
O
H
C
s
at
th
e:
A
pe
x:
G
ro
up
1
:7
0
.3
3
G
ro
up
2
:7
2
G
ro
up
3
:7
3
.6
7
M
id
dl
e:
G
ro
up
1
:7
3
G
ro
up
2
:7
2
.6
7
G
ro
up
3
:7
1
B
as
al
tu
rn
:
G
ro
up
1
:5
9
G
ro
up
2
:6
7
.5
G
ro
up
3
:7
2
.6
7
G
o
o
d
o
u
tc
o
m
es
.
G
re
at
er
p
o
si
ti
ve
ef
fe
ct
s
o
f
b
ila
te
ra
ll
as
er
th
er
ap
y
af
te
r
n
o
is
e-
in
d
u
ce
d
h
ea
ri
n
g
lo
ss
.
B
ila
te
ra
ll
as
er
th
er
ap
y
re
su
lt
ed
in
fa
st
er
h
ea
ri
n
g
th
re
sh
o
ld
re
co
ve
ry
th
an
d
id
u
n
ila
te
ra
l
la
se
r
th
er
ap
y.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
4
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
6
J.
Le
e
et
al
.,
2
0
1
9
,K
o
re
a
G
ro
up
s:
2
G
ro
up
1
:n
o
is
e
o
nl
y
(n
=
8
)
G
ro
up
2
:P
B
M
(n
=
7
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
nm
di
o
de
la
se
r
(W
o
nt
ec
,D
ae
je
o
n,
So
ut
h
K
o
re
a)
P
B
M
T
po
w
er
:1
6
5
m
W
/c
m
2
(5
9
4
J)
P
B
M
T
du
ra
ti
o
n:
6
0
m
in
fo
r
7
da
ys
M
ea
n
ag
e
o
f
su
bj
ec
ts
:5
–6
w
ee
ks
H
ea
ri
ng
lo
ss
:
N
o
is
e-
in
du
ce
d
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
T
he
o
pt
ic
al
fi
br
e
w
as
at
ta
ch
ed
to
a
ho
llo
w
tu
be
an
d
pl
ac
ed
in
to
th
e
ex
te
rn
al
ea
r
ca
na
l1
m
m
fr
o
m
th
e
ty
m
pa
ni
c
m
em
br
an
e.
A
ud
io
lo
gi
ca
ld
at
a:
T
he
A
B
R
s
w
er
e
m
ea
su
re
d
w
it
h
ea
ch
to
ne
st
im
ul
ia
t
th
e
le
ft
ea
r
to
id
en
ti
fy
ch
an
ge
s
in
th
e
he
ar
in
g
A
B
R
*
C
ha
ng
es
in
th
re
sh
ol
d
(d
B
)a
ft
er
no
is
e
ex
po
su
re
(d
ay
[d
B
])
*:
1
2
kH
z:
G
ro
up
1
:1
[2
0
],
3
[1
0
],
7
[1
2
],
1
4
[7
]
G
ro
up
2
:1
[2
0
],
3
[4
],
7
[5
],
1
4
[2
]
1
6
kH
z:
G
ro
up
1
:1
[3
8
],
3
[2
5
],
7
[2
2
],
1
4
[8
]
G
ro
up
2
:1
[3
5
],
3
[1
3
],
7
[1
1
],
1
4
[4
]
3
2
kH
z:
G
ro
up
1
:1
[3
3
],
3
[2
3
].
7
[1
6
],
1
4
[1
0
]
G
ro
up
2
:1
[3
8
],
3
[1
7
],
7
[1
6
],
1
4
[7
]
A
B
R
re
co
ve
ry
th
re
sh
ol
d
(m
s)
*
G
ro
up
1
:5
.5
G
o
o
d
o
u
tc
o
m
es
.
P
B
M
h
ad
a
p
ro
te
ct
iv
e
ef
fe
ct
o
n
sy
n
ap
ti
c
ri
b
b
o
n
s
an
d
th
e
A
B
R
re
co
ve
ry
th
re
sh
o
ld
,
su
gg
es
ti
n
g
th
at
th
e
P
B
M
ca
n
ta
rg
et
n
o
t
o
n
ly
th
e
H
C
le
ve
l
b
u
t
al
so
th
e
su
b
ce
llu
la
r
le
ve
l,
su
ch
as
sy
n
ap
ti
c
ri
b
b
o
n
s.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
5
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
5
(C
o
n
ti
n
u
es
)
NIKOOKAM ET AL. 51
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
(C
o
nt
in
ue
d)
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
th
re
sh
o
ld
be
fo
re
an
d
af
te
r
no
is
e
ex
po
su
re
.
G
ro
up
2
:2
.7
5
C
o
nt
ro
l:
3
.5
Im
m
un
o
fl
uo
re
sc
en
ce
an
al
ys
is
N
um
be
r
o
f
ri
bb
o
ns
/I
H
C
s*
A
pe
x:
G
ro
up
1
:1
2
.5
G
ro
up
2
:1
4
M
id
dl
e:
G
ro
up
1
:1
1
G
ro
up
2
:1
6
B
as
e:
G
ro
up
1
:7
G
ro
up
2
:1
7
C
.R
he
e
et
al
.,
2
0
1
2
,K
o
re
a
G
ro
up
s:
G
ro
up
1
:C
o
nt
ro
le
ar
s
(C
,n
=
6
)
G
ro
up
2
:N
o
is
e
o
nl
y
ea
rs
(N
,n
=
1
6
)
G
ro
up
3
:N
o
is
e
an
d
la
se
r
ea
rs
(N
L,
n
=
1
6
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
A
n
8
3
0
-n
m
di
o
de
la
se
r
(H
i-
T
ec
h
O
pt
o
el
ec
tr
o
n
ic
s,
B
ei
jin
g,
C
hi
na
)
P
o
w
er
de
ns
it
y:
1
0
0
–1
6
5
m
W
/c
m
2
P
B
M
T
du
ra
ti
o
n:
6
0
m
in
fo
r
1
2
co
ns
ec
ut
iv
e
da
ys
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
H
ea
ri
ng
lo
ss
:
T
he
ra
ts
w
er
e
pl
ac
ed
in
sm
al
l,
se
pa
ra
te
ca
ge
s
to
pr
ev
en
t
de
fe
ns
iv
e
be
ha
vi
o
ur
s
su
ch
as
bl
o
ck
ag
e
o
f
th
e
ea
rs
an
d
w
er
e
se
t
in
si
de
th
e
no
is
e
bo
x.
T
he
ra
ts
w
er
e
gi
ve
n
a
o
ne
-t
im
e
ex
po
su
re
to
a
na
rr
o
w
ba
nd
no
is
e
o
f
1
1
6
dB
SP
L
ce
nt
re
d
at
a
fr
eq
ue
nc
y
o
f
1
6
kH
z
(b
an
dw
id
th
1
kH
z)
fo
r
6
h
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
T
he
fo
llo
w
in
g
da
y
af
te
r
th
e
no
is
e
ex
po
su
re
,t
he
ra
ts
w
er
e
ir
ra
di
at
ed
at
th
ei
r
le
ft
ea
rs
fo
r
6
0
m
in
at
an
en
er
gy
de
ns
it
y
o
f
1
0
0
to
1
6
5
m
W
/c
m
2
fo
r
1
2
da
ys
in
a
ro
w
.T
he
o
pt
ic
fi
br
e
(c
o
re
fi
br
e
6
2
.5
μm
/c
la
dd
in
g
1
2
5
μm
)w
as
de
liv
er
ed
th
ro
ug
h
a
ho
llo
w
tu
be
in
to
th
e
ex
te
rn
al
ac
o
us
ti
c
ca
na
ls
o
th
at
th
e
di
st
an
ce
fr
o
m
th
e
ti
p
o
f
th
e
fi
br
e
to
th
e
su
rf
ac
e
o
f
th
e
ty
m
pa
ni
c
m
em
br
an
e
w
as
ar
o
un
d
1
m
m
.L
as
er
ir
ra
di
at
io
n
w
as
do
ne
o
nl
y
in
th
e
le
ft
ea
r
(N
L
ea
r)
an
d
th
e
ri
gh
t
ea
r
(N
ea
r)
se
rv
ed
as
th
e
co
nt
ro
l.
A
ud
io
lo
gi
ca
ld
at
a:
A
B
R
s
w
er
e
re
co
rd
ed
us
in
g
to
ne
-b
ur
st
au
di
to
ry
st
im
ul
i,
de
liv
er
ed
th
ro
ug
h
a
tu
be
in
to
th
e
ra
t's
ea
r
ca
na
lw
it
h
m
ea
su
re
m
en
ts
ta
ke
n
at
4
,8
,1
2
,1
6
an
d
3
2
kH
z.
A
B
R
th
re
sh
o
ld
sh
if
t:
A
t
2
4
h
Po
st
N
oi
se
G
ro
up
2
(N
ea
rs
)—
5
8
.3
±
8
.7
,5
5
.0
±
1
4
.9
,7
1
.3
±
1
6
.3
,
6
0
.6
±
6
.8
an
d
5
5
.3
±
1
1
.2
dB
at
4
,8
,1
2
,1
6
an
d
3
2
kH
z
re
sp
ec
ti
ve
ly
G
ro
up
3
(N
L
ea
rs
)—
5
4
.4
±
8
.8
,5
2
.2
±
1
1
.5
,7
0
.9
±
6
.4
,
6
0
.6
±
6
.3
an
d
5
2
.5
±
8
.0
dB
at
4
,8
,1
2
,1
6
an
d
3
2
kH
z
re
sp
ec
ti
ve
ly
A
ft
er
1
2
th
ir
ra
di
at
io
n
G
ro
up
2
(N
ea
rs
)—
4
6
.7
±
1
6
.2
,4
5
.3
±
1
7
.3
,5
9
.1
±
1
8
.5
,
5
0
.6
±
1
2
.6
an
d
4
5
.6
±
1
2
.0
dB
at
4
,8
,1
2
,1
6
an
d
3
2
kH
z
re
sp
ec
ti
ve
ly
G
ro
up
3
(N
L
ea
rs
)—
2
7
.2
±
4
.4
,2
6
.9
±
7
.3
,3
8
.1
±
1
4
.6
,
3
0
.0
±
9
.3
an
d
2
9
.7
±
6
.2
dB
at
4
,8
,1
2
,1
6
an
d
3
2
kH
z
re
sp
ec
ti
ve
ly
C
o
ch
le
ar
ha
ir
ce
lls
:
G
ro
up
1
(C
ea
rs
)—
1
7
6
.5
±
1
6
.3
,1
4
6
.0
±
5
.6
an
d
1
5
4
.8
±
6
.7
at
ap
ic
al
,m
id
,a
nd
ba
sa
lt
ur
ns
re
sp
ec
ti
ve
ly
G
ro
up
2
(N
ea
rs
)—
1
1
0
.3
±
2
1
.1
,9
5
.2
±
2
1
.7
an
d
1
0
1
.1
±
3
2
.4
at
ap
ic
al
,m
id
,a
nd
ba
sa
lt
ur
ns
re
sp
ec
ti
ve
ly
G
ro
up
3
(N
L
ea
rs
)—
1
4
7
.2
±
4
1
.1
,1
3
6
.2
±
3
3
.5
an
d
1
1
4
.7
±
3
8
.7
at
ap
ic
al
,m
id
,a
nd
ba
sa
lt
ur
ns
re
sp
ec
ti
ve
ly
G
o
o
d
o
u
tc
o
m
e:
LL
LT
m
ay
h
av
e
a
p
o
si
ti
ve
ef
fe
ct
o
n
h
ai
r-
ce
ll
re
co
ve
ry
af
te
r
ac
u
te
ac
o
u
st
ic
tr
au
m
a.
T
h
e
h
ea
ri
n
g
th
re
sh
o
ld
b
ec
am
e
lo
w
er
af
te
r
re
p
ea
te
d
la
se
r
ir
ra
d
ia
ti
o
n
,a
n
d
th
e
fi
n
al
h
ea
ri
n
g
re
su
lt
w
as
si
gn
if
ic
an
tl
y
b
et
te
r
th
an
th
at
o
f
th
e
u
n
tr
ea
te
d
ea
rs
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
H
ig
h
=
1
,
Lo
w
=
4
,
U
n
cl
ea
r
=
5
52 NIKOOKAM ET AL.
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
(C
o
nt
in
ue
d)
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
data
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
C
.R
he
e
et
al
.,
2
0
1
2
,K
o
re
a
G
ro
up
s:
G
ro
up
1
:c
o
nt
ro
l(
n
=
8
)
G
ro
up
2
:l
as
er
-o
nl
y
(n
=
8
)
G
ro
up
3
:g
en
ta
m
ic
in
o
nl
y
(n
=
8
)
G
ro
up
4
:g
en
ta
m
ic
in
+
la
se
r
(n
=
7
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
1
0
-n
m
di
o
de
la
se
r
(L
A
S-
3
0
A
,T
N
L,
In
ch
eo
n,
K
o
re
a)
P
B
M
T
po
w
er
:8
m
W
/c
m
2
(0
.4
8
J/
cm
2
)
P
B
M
T
du
ra
ti
o
n:
6
da
ys
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
.
H
ea
ri
ng
lo
ss
:
G
en
ta
m
ic
in
-i
nd
uc
ed
he
ar
in
g
lo
ss
/
o
to
to
xi
ci
ty
-
in
du
ce
d.
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
St
ar
te
d
o
n
da
y
5
.
A
ud
io
lo
gi
ca
ld
at
a:
N
o
t
co
m
pl
et
ed
.
H
ai
r
ce
ll
co
un
t:
G
ro
up
1
:D
ay
5
=
6
7
.5
±
1
8
.6
;d
ay
8
=
5
9
.9
±
3
1
.6
;d
ay
1
1
=
5
4
.0
±
2
5
.9
(p
er
2
0
0
μm
)
G
ro
up
2
:d
ay
5
=
7
0
.9
±
2
8
.4
;d
ay
8
=
7
7
.1
±
3
2
.0
;d
ay
1
1
=
8
0
.0
±
2
9
.2
(p
er
2
0
0
μm
)
G
ro
up
3
:d
ay
5
=
2
7
.3
±
1
3
.2
;d
ay
8
=
2
3
.8
±
5
.6
;d
ay
1
1
=
2
5
.0
±
9
.1
(p
er
2
0
0
μm
)
G
ro
up
4
:d
ay
5
=
3
7
.3
±
1
2
.9
;d
ay
8
=
3
6
.0
±
2
3
.7
;d
ay
1
1
=
5
8
.6
±
2
7
.8
(p
er
2
0
0
μm
)
G
o
o
d
o
u
tc
o
m
es
.
Si
gn
if
ic
an
t
ef
fe
ct
o
f
LL
LT
in
gr
o
u
p
4
co
m
p
ar
ed
to
gr
o
u
p
3
.L
LL
T
w
as
ef
fe
ct
iv
e
fo
r
ge
n
ta
m
ic
in
-i
n
d
u
ce
d
o
to
to
xi
ci
ty
.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
7
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
3
C
.R
he
e
et
al
.,
2
0
1
3
,K
o
re
a
G
ro
up
s:
G
ro
up
1
:u
nt
re
at
ed
G
ro
up
2
:G
M
G
ro
up
3
:G
M
+
la
se
r
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
3
0
-n
m
di
o
de
la
se
r
(H
i-
te
ch
O
pt
o
el
ec
tr
o
ni
cs
,
B
ei
jin
g,
C
hi
na
)
P
B
M
T
po
w
er
:2
0
0
m
W
T
o
ta
lr
ad
ia
nt
en
er
gy
:3
5
6
–4
2
8
J
P
o
sw
er
de
ns
it
y:
9
0
0
m
W
/c
m
2
(1
6
2
–1
9
4
J)
P
B
M
T
du
ra
ti
o
n:
M
ea
n
ag
e
o
f
su
bj
ec
ts
:8
w
ee
ks
H
ea
ri
ng
lo
ss
:
O
to
to
xi
c
he
ar
in
g
lo
ss
—
ge
nt
am
ic
in
/f
ur
o
se
m
id
e
in
du
ce
d
he
ar
in
g
lo
ss
.
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
La
se
r
w
as
o
nl
y
pe
rf
o
rm
ed
in
th
e
ri
gh
t
ea
r.
D
is
ta
nc
e
fr
o
m
th
e
ti
p
o
f
th
e
fi
br
e
to
th
e
su
rf
ac
e
o
f
ty
m
pa
ni
c
m
em
br
an
e
=
1
m
m
.
La
se
r
w
as
pe
rf
o
rm
ed
af
te
r
da
y
2
.
A
ud
io
lo
gi
ca
ld
at
a:
A
ni
m
al
s
w
er
e
tr
ea
te
d
da
ily
by
ge
nt
am
ic
in
1
0
0
m
g/
kg
in
tr
av
en
o
us
ly
(i.
v.
)f
o
llo
w
ed
1
0
m
in
la
te
r
by
fu
ro
se
m
id
e
9
0
m
g/
kg
i.v
.f
o
r
2
da
ys
.
4
8
h
af
te
r
ge
nt
aa
m
ic
in
+
fu
ro
se
m
id
e
tr
ea
tm
en
t,
he
ar
in
g
lo
ss
w
as
co
nf
ir
m
ed
w
it
h
cl
ic
ke
d
A
B
R
.
H
ea
ri
ng
th
re
sh
o
ld
w
as
no
rm
al
in
al
la
ni
m
al
s
be
fo
re
:re
le
ve
l(
SP
L)
o
f
1
1
6
dB
.
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
1
da
y
af
te
r
no
is
e
ex
po
su
re
th
e
le
ft
ea
r
o
f
ra
ts
in
th
e
P
B
M
gr
o
up
s
(G
ro
up
s
3
&
5
)w
er
e
ir
ra
di
at
ed
fo
r
1
h
at
an
en
er
gy
de
ns
it
y
o
f
1
6
5
m
W
cm
2
da
ily
fo
r
1
2
da
ys
.A
n
o
pt
ic
fi
br
e
w
as
pl
ac
ed
th
ro
ug
h
a
ho
llo
w
tu
be
in
to
th
e
ex
te
rn
al
ea
r
ca
na
lw
it
h
th
e
ti
p
ap
pr
o
xi
m
at
el
y
1
m
m
fr
o
m
th
e
ty
m
pa
ni
c
m
em
br
an
e.
A
ud
io
lo
gi
ca
ld
at
a:
A
B
R
s
w
er
e
m
ea
su
re
d
us
in
g
to
ne
-b
ur
st
fr
eq
ue
nc
y-
sp
ec
if
ic
st
im
ul
i.
T
o
ne
bu
rs
t
st
im
ul
io
f
8
,1
6
an
d
3
2
kH
z
w
er
e
de
liv
er
ed
vi
a
a
tu
be
in
se
rt
ed
in
to
th
e
le
ft
ea
r
ca
na
l.
A
B
R
m
ea
su
re
m
en
ts
ta
ke
n
be
fo
re
an
d
af
te
r
no
is
e
ex
po
su
re
bu
t
pr
ec
is
e
ti
m
in
g
no
t
st
at
ed
.
A
B
R
th
re
sh
o
ld
sh
if
t:
Pr
e-
no
is
e
G
ro
up
1
:8
kH
z–
1
0
.0
±
0
.0
,1
6
kH
z–
1
0
.6
±
1
.7
,3
2
kH
z–
1
1
.3
±
2
.2
G
ro
up
2
:8
kH
z–
1
0
.8
±
2
.0
,1
6
kH
z–
1
2
.5
±
4
.0
,3
2
kH
z–
1
1
.7
±
2
.5
G
ro
up
3
:8
kH
z–
1
2
.5
±
4
.0
,1
6
kH
z–
1
2
.5
±
4
.0
,3
2
kH
z–
1
0
.0
.3
±
0
.0
G
ro
up
4
:8
kH
z–
1
0
.8
±
2
.0
,1
6
kH
z–
1
2
.0
±
2
.5
,3
2
kH
z–
1
0
.8
±
2
.0
G
ro
up
5
:8
kH
z–
1
0
.8
±
2
.0
,1
6
kH
z–
1
0
.8
±
2
.0
,3
2
kH
z–
1
2
.0
±
2
.5
Po
st
no
is
e
G
ro
up
1
:8
kH
z–
7
3
.1
±
9
.6
,1
6
kH
z–
6
9
.4
±
4
.8
,3
2
kH
z-
6
1
.2
±
4
.3
G
ro
up
2
:8
kH
z–
7
1
.7
±
1
2
.7
,1
6
kH
z–
6
5
.0
±
8
.0
,3
2
kH
z–
5
7
.5
±
4
.0
G
ro
up
3
:8
kH
z
–
6
5
.8
±
1
7
.4
,1
6
kH
z
–
6
1
.7
±
5
.8
,
3
2
kH
z-
5
7
.5
.3
±
4
.0
G
ro
up
4
:8
kH
z–
7
3
.1
±
9
.6
,1
6
kH
z–
6
5
.6
±
5
.4
,3
2
kH
z-
6
0
.0
±
5
.2
G
ro
up
5
:8
kH
z–
7
0
.0
±
1
5
.1
,1
6
kH
z–
6
4
.2
±
6
.3
,3
2
kH
z-
5
9
.2
±
4
.7
C
o
ch
le
ar
ha
ir
ce
lls
:
T
he
m
o
rp
ho
lo
gy
in
th
e
P
B
M
/N
A
C
gr
o
up
sh
o
w
ed
le
ss
h
ai
r
ce
ll
lo
ss
th
an
th
e
o
th
er
gr
o
up
s.
G
o
o
d
o
u
tc
o
m
e:
P
B
M
/N
A
C
co
m
b
in
at
io
n
th
er
ap
y
m
ay
p
re
ve
n
t
h
ea
ri
n
g
lo
ss
m
o
re
ef
fe
ct
iv
el
y
th
an
P
B
M
al
o
n
e.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
H
ig
h
=
1
,
Lo
w
=
1
,
U
n
cl
ea
r
=
8
54 NIKOOKAM ET AL.
 17494486, 2024, 1, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1111/coa.14113 by C
apes, W
iley O
nline L
ibrary on [29/10/2025]. See the T
erm
s and C
onditions (https://onlinelibrary.w
iley.com
/term
s-and-conditions) on W
iley O
nline L
ibrary for rules of use; O
A
 articles are governed by the applicable C
reative C
om
m
ons L
icense
T
A
B
L
E
3
(C
o
nt
in
ue
d)
St
ud
y
re
fe
re
nc
e
St
ud
y
da
ta
P
re
-P
B
M
T
da
ta
P
o
st
-P
B
M
T
da
ta
O
ve
ra
ll
b
en
ef
it
(s
u
b
je
ct
iv
e
as
se
ss
m
en
t)
Q
u
al
it
y
as
se
ss
m
en
t
I.
St
rü
bi
ng
et
al
.,
2
0
2
0
,
G
er
m
an
y
G
ro
up
s:
2
G
ro
up
1
:P
B
M
T
(n
=
8
ea
rs
)
G
ro
up
2
:C
o
nt
ro
l(
n
=
8
ea
rs
)
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
-n
m
di
o
de
la
se
r
P
B
M
T
po
w
er
:1
2
0
m
W
P
B
M
T
du
ra
ti
o
n:
1
5
m
in
M
ea
n
ag
e
o
f
su
bj
ec
ts
:2
8
–3
2
w
ee
ks
H
ea
ri
ng
lo
ss
:
N
o
t
ap
pl
ic
ab
le
/n
o
t
st
at
ed
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
B
ef
o
re
co
ch
le
a
im
pl
an
ta
ti
o
n,
vi
a
th
e
o
pe
n
bu
lla
a
ra
nd
o
m
ly
se
le
ct
ed
co
ch
le
a
w
as
pr
et
re
at
ed
w
it
h
P
B
M
T
.
A
ud
io
lo
gi
ca
ld
at
a:
2
w
ee
ks
be
fo
re
su
rg
er
y
A
B
R
pe
rf
o
rm
ed
.
A
B
R
—
av
er
ag
e
he
ar
in
g
lo
ss
G
ro
up
1
:1
8
.4
±
5
.8
dB
G
ro
up
2
:3
3
.5
±
5
.1
dB
P
ro
te
ct
iv
e
ef
fe
ct
o
f
P
B
M
T
:1
0
.7
–2
1
.4
dB
H
ai
r
C
el
lC
o
un
t
IH
C
:n
o
lo
ss
bi
la
te
ra
lly
O
H
C
:s
ta
ti
st
ic
al
ly
si
gn
if
ic
an
t
di
ff
er
en
ce
be
tw
ee
n
gr
o
u
p
1
an
d
2
.A
ve
ra
ge
lo
ss
:
G
ro
up
1
:8
8
.7
±
7
.3
ce
lls
G
ro
up
2
:1
2
9
.3
±
7
.8
ce
lls
G
o
o
d
o
u
tc
o
m
es
.
Si
n
gl
e
P
B
M
T
p
re
tr
ea
tm
en
t
b
ef
o
re
C
Is
u
rg
er
y
ap
p
ea
rs
to
b
e
n
eu
ro
p
ro
te
ct
iv
e.
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
3
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
7
A
.T
am
ur
a
et
al
.,
2
0
1
5
,J
ap
an
G
ro
up
s:
3
G
ro
up
1
:n
o
n-
tr
ea
tm
en
t
(n
o
is
e
ex
po
su
re
o
nl
y)
(n
=
5
)
G
ro
up
2
:L
LL
T
1
1
0
m
W
/c
m
2
(n
=
6
)
G
ro
up
3
:L
LL
T
1
6
5
m
W
/c
m
2
(n
=
5
).
N
o
te
:
A
ni
m
al
s
w
er
e
al
so
di
vi
de
d
in
to
th
re
e
gr
o
up
s
fo
r
im
m
un
o
hi
st
o
ch
em
is
tr
y
o
f
iN
O
S:
na
iv
e
(n
=
3
),
no
n-
tr
ea
tm
en
t
(n
o
is
e
ex
po
su
re
o
nl
y)
(n
=
3
)a
nd
LL
LT
(1
6
5
m
W
/c
m
2
,n
=
3
)a
nd
fo
r
im
m
un
o
hi
st
o
ch
em
is
tr
y
o
f
cl
ea
ve
d
ca
sp
as
e-
3
:n
aï
ve
(n
o
no
is
e
ex
po
su
re
)(
n
=
3
),
no
n-
tr
ea
tm
en
t
(n
o
is
e
ex
po
su
re
o
nl
y)
(n
=
3
)
an
d
LL
LT
(1
6
5
m
W
/c
m
2
,n
=
3
).
In
ve
st
ig
at
io
na
ld
ev
ic
e:
8
0
8
nm
C
W
di
o
de
la
se
r
be
am
(B
&
W
T
ek
-I
nc
.,
N
ew
ar
k,
D
E
,U
SA
)
P
B
M
T
po
w
er
:1
1
0
m
W
/c
m
2
(n
=
6
0
o
r
1
6
5
m
W
/c
m
2
(n
=
5
)
P
B
M
T
du
ra
ti
o
n:
3
0
m
in
M
ea
n
ag
e
o
f
su
bj
ec
ts
:n
o
t
st
at
ed
H
ea
ri
ng
lo
ss
:
N
o
is
e-
in
du
ce
d
he
ar
in
g
lo
ss
.
In
du
ce
d
he
ar
in
g
lo
ss
—
ex
po
se
d
to
1
o
ct
av
e
ba
nd
no
is
e
ce
nt
er
ed
at
4
kH
z
fo
r
5
h
(1
2
1
dB
so
un
d
pr
es
su
re
le
ve
l)
in
a
ve
nt
ila
te
d
so
un
d
ex
po
su
re
ch
am
be
r.
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
T
ra
ns
m
it
te
d
th
ro
ug
h
an
o
pt
ic
al
fi
br
e
w
as
ap
pl
ie
d
to
th
e
ri
gh
t
ty
m
pa
ni
c
m
em
br
an
e
th
ro
ug
h
th
e
ex
te
rn
al
au
di
to
ry
ca
na
l.
O
pt
ic
al
fi
br
e
ti
p
w
as
po
si
ti
o
ne
d
6
m
m
aw
ay
fr
o
m
th
e
ri
gh
t
ty
m
pa
ni
c
m
em
br
an
e.
A
ud
io
lo
gi
ca
ld
at
a:
A
B
R
ta
ke
n
be
fo
re
,
im
m
ed
ia
te
ly
af
te
r,
an
d
at
2
,4
,7
,1
4
an
d
2
8
da
ys
af
te
r
no
is
e
ex
po
su
re
.
T
hr
es
ho
ld
s
o
bt
ai
ne
d
im
m
ed
ia
te
ly
be
fo
re
no
is
e
ex
po
su
re
w
er
e
us
ed
as
th
e
ba
se
lin
e
fo
r
es
ti
m
at
in
g
no
is
e-
in
du
ce
d
th
re
sh
o
ld
sh
if
ts
.
A
B
R
Lo
w
er
in
gr
o
up
s
2
–3
.
Im
m
un
o
hi
st
o
ch
em
is
tr
y
iN
O
S
1
h
af
te
r
no
is
e
ex
po
su
re
,s
tr
o
ng
im
m
un
o
re
ac
ti
vi
ty
fo
r
iN
O
S
w
as
o
bs
er
ve
d
in
gr
o
up
1
in
th
e
o
rg
an
o
f
C
o
rt
ia
n
d
in
th
e
fi
br
o
cy
te
s
o
f
th
e
la
te
ra
lw
al
l.
Le
ss
im
m
un
o
re
ac
ti
vi
ty
w
as
o
bs
er
ve
d
in
gr
o
up
s
2
–3
.
C
le
av
ed
ca
sp
as
e-
3
8
h
af
te
r
no
is
e
ex
po
su
re
,s
tr
o
ng
im
m
un
o
re
ac
ti
vi
ti
es
fo
r
cl
ea
ve
d
ca
sp
as
e-
3
w
er
e
o
bs
er
ve
d
in
th
e
o
rg
an
o
f
C
o
rt
i
an
d
in
th
e
fi
br
o
cy
te
s
o
f
th
e
la
te
ra
lw
al
l.
Le
ss
im
m
un
o
re
ac
ti
vi
ty
w
as
o
bs
er
ve
d
in
gr
o
up
s
2
–3
.
O
H
C
s
IH
C
s
in
gr
o
up
s
1
–3
w
er
e
w
el
lp
re
se
rv
ed
af
te
r
so
un
d
ex
po
su
re
.
2
8
da
ys
af
te
r
no
is
e
ex
po
su
re
,a
ve
ra
ge
O
H
C
lo
ss
es
in
:
B
as
al
tu
rn
G
ro
up
1
=
2
0
.0
%
G
ro
up
2
=
2
.0
%
G
ro
up
3
=
2
.2
%
M
id
dl
e
tu
rn
G
ro
up
1
=
3
0
.2
%
G
ro
up
2
=
2
.8
%
G
ro
up
3
=
2
.2
%
A
pi
ca
l
G
ro
up
1
=
3
2
.7
%
G
ro
up
2
=
4
.6
%
G
ro
up
3
=
8
.3
%
T
h
is
st
u
d
y
h
as
sh
o
w
n
th
at
LL
LT
p
re
ve
n
ts
co
ch
le
a
d
am
ag
e
if
st
ar
te
d
w
it
h
in
1
h
o
f
n
o
is
e
ex
p
o
su
re
SY
R
C
LE
's
ri
sk
o
f
b
ia
s
to
o
l:
Lo
w
=
7
;
h
ig
h
=
0
;
u
n
cl
ea
r
=
3
A
.T
am
ur
a
et
al
.,
2
0
1
6
,J
ap
an
G
ro
up
s:
3
A
ss
es
se
m
en
t
of
au
di
to
ry
fu
nc
ti
on
:
G
ro
up
1
:c
o
nt
ro
l,
no
no
is
e
ex
po
su
re
(n
=
5
)
G
ro
up
2
:n
o
n-
tr
ea
tm
en
t,
no
is
e
ex
po
su
re
o
nl
y
(n
=
5
)
P
B
M
T
ad
m
in
is
tr
at
io
n
de
ta
ils
:
In
it
ia
te
d
w
it
hi
n
1
h
af
te
r
no
is
e
ex
po
su
re
.A
pp
lie
d
to
th
e
ri
gh
t
ty
m
pa
ni
c
m
em
br
an
e
th
ro
ug
h
th
e
A
B
R