Hyperacusis in Autism Spectrum Disorders
Round 1
Reviewer 1 Report
This is a well-written review paper.
Just one minor comment. Key word: decreased sound tolerance disorder.
It is already in the title of the paper.
Author Response
Dear Reviewer,
Thank you for your kind words. We have modified by changing the title.
Best Regards
Reviewer 2 Report
Danesh et al. review the literature on sound level tolerance in ASD. It is an interesting and timely subject, but their treatment is a bit superficial and sometimes misleading. The review would benefit from a deeper reading of the literature and more editorial focusing.
Specific Comments:
1) Ln 34 - Reference 7 is not the most appropriate citation for this statement as this summary of conference proceedings makes essentially no mention of the ideas stated here. Instead, I would suggest citing:
Gu JW, Halpin CF, Nam E-CE-CE-C et al (2010) Tinnitus, diminished sound-level tolerance, and elevated auditory activity in humans with clinically normal hearing sensitivity. J Neurophysiol 104:3361–3370. https://doi.org/10.1152/jn.00226.2010
Koops, E.A. and van Dijk, P., 2021. Hyperacusis in tinnitus patients relates to enlarged subcortical and cortical responses to sound except at the tinnitus frequency. Hear Res, 401, p.108158.
Auerbach, B.D., Rodrigues, P.V. and Salvi, R.J., 2014. Central gain control in tinnitus and hyperacusis. Frontiers in neurology, 5, p.206.
2) The last sentence in section 3 (beginning with "This is not surprising") is duplicative and should be removed (or at least needs a comma after "surprising").
3) Ln 103, it seems like the authors buried the lede. Previous work on abnormal encoding of sound level with autism is the main focus of the piece, so it would seem that the sentence beginning with "Across a variety..." should be highlighted as the leading sentence of the paragraph ending on 123.
4) "encode" might be a better word than "detect" in line 103, as detect implies a behavioral/perceptual report.
5) Ln 124 - "Etiology" is not the right word here, as there is no strong evidence that the observations below are mechanistically/causally related to the hyperacusis phenotype in ASD. "Correlates" or "Biomarkers" would be more appropriate.
6) Ln 149 - Sorry, what do DPOAE measures have to do with the temporal lobe, limbic system, or autonomic nervous system? It's a measure of outer hair cell function. Kaf and Danesh did not find substantive differences in the DPOAE or contra suppression of the DPOAE in children on the ASD spectrum and therefore speculated that their phenotype is likely related to abnormalities further downstream. This study is not cited correctly and the cause seems to be a literature review that consisted of quickly reading the abstracts and then repeating key phrases. This issue comes up in a few places.
7) The paragraph on lns 151-167 is kind of a mystery to me. It leads with a description of efferent acoustic reflexes in humans (which would may fit better with the preceding paragraph on OAEs) but finishes with an odd set of citations on changes in the central auditory pathway in a thalidomide model of ASD in rats. There are so many papers on abnormal sound processing in animal models of autism, many more directly related to hyperacusis then these studies. The logic of why the authors chose to focus on this tiny sliver of the literature and ignore the far larger corpus of work does not compute for me (e.g., the valproic acid model, the FMRP mouse model [which has dozens if not hundreds of papers on startle hyperreactivity], or many more recent papers that introduce mutations into genes linked to familial autism [ptchd1, shank3, etc. etc. etc.]). It seems to me, that the authors should either commit to reviewing the literature on animal models for auditory phenotypes of ASD or else make a statement that it is beyond the scope. In its present form, their treatment is neither here nor there.
8) Ln 160 - It does not make sense to write "decreased immunoreactivity". I see that they copied this from the abstract of the corresponding paper, but it was taken out of context. Instead, they could either write: 1) "decreased calbindin expression, a calcium-binding protein enriched in inhibitory neurons" or 2) "decreased expression of protein markers for inhibitory neurons".
9) The paragraph from lines 168-184 is problematic as well. It begins with a few descriptions of case studies with contradictory results. It's unclear what value is contributed by describing case studies as it will come as a surprise to no one that two autistic individuals would respond differently to the same medication. Then, they shift to describing the effects of noise exposure in animals. Why? What do the effects of acoustic trauma have to do with case studies of risperidone? Why are these in the same paragraph? To be honest, the review would not suffer if this paragraph were removed. If they want to mention the effects of acoustic trauma having opposing effects on central responses in subcortical vs cortical centers of processing, there is a vast literature on that very topic, although again they have not made it clear why the short-term acquired effects of acoustic trauma in mature animals are important for understanding a neurodevelopmental disorder.
10) Ln 197 - I would suggest that the authors define what they mean by "increased perceptual capacity". In the earlier mention of the Remington and Fairnie work they say something about processing an "increased amount of cognitive information". Neither description is very precise but nor are they equivalent as enhancements in the cognitive domain might refer to (for example) auditory spatial attention, whereas enhancements in the perceptual domain could refer to (again, just an example) frequency discrimination thresholds. In both cases, it would be better for future readers if the authors could be explicit about what was done/observed instead of using these more general/vague descriptions.
11) A general point inspired by the paragraph beginning on Ln 226 - I would suggest that the authors add a statement or paragraph under the CBT to address how CBT would only be useful in high-functioning autistic persons who have sufficient communication and language abilities. The same goes even for relatively simple measures of ULLs earlier in the paper. Many autistic individuals would not be able to understand/communicate the concept of level-dependent discomfort (at least not in the way that a non-specialist clinician would recognize). These communication failures could be confused with hypo-reactivity, for example. Overall, a broader point is to discuss how measurements and therapies could be calibrated to the level of function.
Author Response
Dear Reviewer,
Thank you for your extensive comments and suggestions. They are very much appreciated.
You may find our responses below or in the attached file.
Best Regards,
Thank you for this comprehensive review. Your time and excellent comments and suggestions are very much appreciated. Please see our modifications and responses below based on your comments.
Specific Comments:
1) Ln 34 - Reference 7 is not the most appropriate citation for this statement as this summary of conference proceedings makes essentially no mention of the ideas stated here. Instead, I would suggest citing:
Gu JW, Halpin CF, Nam E-CE-CE-C et al (2010) Tinnitus, diminished sound-level tolerance, and elevated auditory activity in humans with clinically normal hearing sensitivity. J Neurophysiol 104:3361–3370. https://doi.org/10.1152/jn.00226.2010
Koops, E.A. and van Dijk, P., 2021. Hyperacusis in tinnitus patients relates to enlarged subcortical and cortical responses to sound except at the tinnitus frequency. Hear Res, 401, p.108158.
Auerbach, B.D., Rodrigues, P.V. and Salvi, R.J., 2014. Central gain control in tinnitus and hyperacusis. Frontiers in neurology, 5, p.206.
Your comment is very much appreciated. We agree with your suggested list and have added them to the reference list. However, the statement in our manuscript was partially adopted from the statement below from reference #7:
“The mechanisms underlying hyperacusis are unknown. One possibility is that neurons that normally respond at higher sound levels begin to respond to sounds with lower levels, leading to the perception of increased loudness”. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122267/
2) The last sentence in section 3 (beginning with "This is not surprising") is duplicative and should be removed (or at least needs a comma after "surprising").
Thank you for this comment. A comma has been added after “surprising”.
3) Ln 103, it seems like the authors buried the lede. Previous work on abnormal encoding of sound level with autism is the main focus of the piece, so it would seem that the sentence beginning with "Across a variety..." should be highlighted as the leading sentence of the paragraph ending on 123.
Agreed. That sentence is now the leading sentence and reference order has been reformatted.
4) "encode" might be a better word than "detect" in line 103, as detect implies a behavioral/perceptual report.
Excellent suggestion. The word “encode” is used here based on your comment.
5) Ln 124 - "Etiology" is not the right word here, as there is no strong evidence that the observations below are mechanistically/causally related to the hyperacusis phenotype in ASD. "Correlates" or "Biomarkers" would be more appropriate.
Your point makes sense. The word “correlates” was used in two places replacing Etiology. The new manuscript is modified accordingly to show this change:
“ 5. Correlates of Hyperacusis in the ASD Population
A number of proposed causes of hyperacusis have been introduced, but it is important to consider that correlates of hyperacusis may differ across individual cases of ASD.”
6) Ln 149 - Sorry, what do DPOAE measures have to do with the temporal lobe, limbic system, or autonomic nervous system? It's a measure of outer hair cell function. Kaf and Danesh did not find substantive differences in the DPOAE or contra suppression of the DPOAE in children on the ASD spectrum and therefore speculated that their phenotype is likely related to abnormalities further downstream. This study is not cited correctly and the cause seems to be a literature review that consisted of quickly reading the abstracts and then repeating key phrases. This issue comes up in a few places.
Thank you. That sentence has been modified per your comment and additional references have been added to support the notion of the brain structural differences in this population.
7) The paragraph on lns 151-167 is kind of a mystery to me. It leads with a description of efferent acoustic reflexes in humans (which would may fit better with the preceding paragraph on OAEs) but finishes with an odd set of citations on changes in the central auditory pathway in a thalidomide model of ASD in rats. There are so many papers on abnormal sound processing in animal models of autism, many more directly related to hyperacusis then these studies. The logic of why the authors chose to focus on this tiny sliver of the literature and ignore the far larger corpus of work does not compute for me (e.g., the valproic acid model, the FMRP mouse model [which has dozens if not hundreds of papers on startle hyperreactivity], or many more recent papers that introduce mutations into genes linked to familial autism [ptchd1, shank3, etc. etc. etc.]). It seems to me, that the authors should either commit to reviewing the literature on animal models for auditory phenotypes of ASD or else make a statement that it is beyond the scope. In its present form, their treatment is neither here nor there.
Good point. Our intention was not to expand deeply into the animal models as it was not the major concentration area of our manuscript. We value all of the contributions from the animal studies related to autism; however, we could not fit all in this review. The idea of animal models, ASD and altered processing of auditory stimuli, including hyperacusis, was addressed in that paragraph. The role of MOC has been depicted here and it has been emphasized to be very contributary in hyperacusis in ASD. The statement about Thalidomine and brainstem studies has been removed.
8) Ln 160 - It does not make sense to write "decreased immunoreactivity". I see that they copied this from the abstract of the corresponding paper, but it was taken out of context. Instead, they could either write: 1) "decreased calbindin expression, a calcium-binding protein enriched in inhibitory neurons" or 2) "decreased expression of protein markers for inhibitory neurons".
Outstanding comment. Thank you! The statement changed to: “This study found decreased expression of protein markers for inhibitory neurons (i.e., immunoreactivity) of the superior olivary complex…”
9) The paragraph from lines 168-184 is problematic as well. It begins with a few descriptions of case studies with contradictory results. It's unclear what value is contributed by describing case studies as it will come as a surprise to no one that two autistic individuals would respond differently to the same medication. Then, they shift to describing the effects of noise exposure in animals. Why? What do the effects of acoustic trauma have to do with case studies of risperidone? Why are these in the same paragraph? To be honest, the review would not suffer if this paragraph were removed. If they want to mention the effects of acoustic trauma having opposing effects on central responses in subcortical vs cortical centers of processing, there is a vast literature on that very topic, although again they have not made it clear why the short-term acquired effects of acoustic trauma in mature animals are important for understanding a neurodevelopmental disorder.
We agree with this yet another useful comment. The section about noise exposure is a very wide range topic and this may not be the right place to discuss this as it has not been thoroughly studied in the ASD population. The corresponding reference was removed. The statement regarding the use of risperidone remained unchanged as it is followed by a sentence about future research on medications.
10) Ln 197 - I would suggest that the authors define what they mean by "increased perceptual capacity". In the earlier mention of the Remington and Fairnie work they say something about processing an "increased amount of cognitive information". Neither description is very precise but nor are they equivalent as enhancements in the cognitive domain might refer to (for example) auditory spatial attention, whereas enhancements in the perceptual domain could refer to (again, just an example) frequency discrimination thresholds. In both cases, it would be better for future readers if the authors could be explicit about what was done/observed instead of using these more general/vague descriptions.
Very interesting point. The ambiguity about autistic brain and mind is incomprehensible. We have observed autistic children who have limited communication skills but ability to sing national anthem in a stadium! With your permission, we would like to keep this paragraph as is, in order to inspire the future readers to appreciate the potential “increased perceptual capacity” and “increased amount of cognitive information” in the ASD population.
11) A general point inspired by the paragraph beginning on Ln 226 - I would suggest that the authors add a statement or paragraph under the CBT to address how CBT would only be useful in high-functioning autistic persons who have sufficient communication and language abilities. The same goes even for relatively simple measures of ULLs earlier in the paper. Many autistic individuals would not be able to understand/communicate the concept of level-dependent discomfort (at least not in the way that a non-specialist clinician would recognize). These communication failures could be confused with hypo-reactivity, for example. Overall, a broader point is to discuss how measurements and therapies could be calibrated to the level of function.
Thank you for this comment. We have now added more information about ULLs (section 2) and CBT (section 6) in ASD population. We have highlighted that some ASD individuals with learning difficulties may not be able to comprehend the instructions for ULLs or access CBT.
Author Response File: 
Author Response.pdf
Round 2
Reviewer 2 Report
revision is improved. no further comments.
