Characterizing Behavior, Sex and Subtype in Childhood ADHD via the Related Spectrum of Functional Network Connectivity at Rest

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1) The study includes a relatively small sample size, particularly for the hyperactive and inattentive ADHD subtypes. This limits the statistical power and generalizability of the findings. The authors acknowledge this limitation, but it remains a significant drawback, as it may affect the robustness of the results, especially when examining subtype-specific differences. The sample is predominantly composed of English-speaking, white, non-Hispanic/Latino children from high socioeconomic backgrounds. This lack of diversity limits the generalizability of the findings to more diverse populations, including children from different racial, ethnic, and socioeconomic backgrounds. Future studies should aim to include a more representative sample.

2) While functional near-infrared spectroscopy (fNIRS) is a valuable tool for studying functional connectivity in young children, it has limited spatial resolution compared to other neuroimaging techniques like fMRI. This limitation may affect the precision of the connectivity patterns observed. The authors should discuss how this limitation might impact the interpretation of their findings and suggest future studies using higher-resolution imaging techniques to validate the results. The study excluded participants with significant motion artifacts, which is common in neuroimaging studies with children. However, this exclusion may introduce bias, as children with ADHD are more likely to exhibit movement during scanning. The authors should discuss how this might have affected the results and consider alternative methods for motion correction in future studies.

3) The study is cross-sectional, which limits the ability to draw conclusions about the developmental trajectories of functional connectivity in children with ADHD. Longitudinal data would provide more insight into how these neural profiles evolve over time and how they relate to symptom severity and treatment outcomes. The authors should acknowledge this limitation and suggest future longitudinal studies to address this gap.

4) The study does not extensively explore the impact of comorbidities (e.g., anxiety, depression, learning disabilities) on functional connectivity patterns. Given that ADHD often co-occurs with other psychiatric and developmental disorders, the presence of comorbidities could influence the observed neural profiles. The authors should consider controlling for or examining the effects of comorbidities in future research.

5) The study involves multiple comparisons, particularly in the analysis of functional connectivity across different brain regions. While the authors use a false-discovery rate (FDR) correction, they should explicitly discuss the potential for Type I errors and how they addressed this issue in their analysis. Also, the manuscript does not consistently report effect sizes, which are important for understanding the magnitude of the observed differences. Including effect sizes would strengthen the interpretation of the results and provide a clearer picture of the clinical significance of the findings.

6) While the study highlights sex and subtype differences in functional connectivity, the clinical implications of these findings are not fully explored. The authors should discuss how these neural differences might inform diagnostic practices, treatment strategies, and interventions for children with ADHD, particularly in terms of tailoring approaches based on sex and subtype.

7) The study does not thoroughly discuss potential confounding factors, such as medication status, that could influence functional connectivity. Many children with ADHD are on stimulant medications, which have been shown to normalize dysfunctional connectivity. The authors should address whether medication status was controlled for or considered in the analysis and how it might have impacted the results.

8) The findings, while novel, are based on a single study with a specific sample. Replication in independent samples, particularly with larger and more diverse populations, is necessary to confirm the generalizability of the results. The authors should emphasize the need for replication in future research.

9) The study involves young children, and while informed consent was obtained, the manuscript does not discuss any potential ethical concerns related to the use of neuroimaging in this population. A brief discussion of ethical considerations, particularly regarding the use of fNIRS in children, would be beneficial.

10) The manuscript is generally well-written, but some sections could benefit from clearer organization and more concise language. For example, the introduction could be streamlined to focus more directly on the study's objectives and hypotheses. Additionally, the results section could be more clearly structured to highlight the key findings and their implications.

Author Response

Reviewer 1:  

1) The study includes a relatively small sample size, particularly for the hyperactive and inattentive ADHD subtypes. This limits the statistical power and generalizability of the findings. The authors acknowledge this limitation, but it remains a significant drawback, as it may affect the robustness of the results, especially when examining subtype-specific differences. The sample is predominantly composed of English-speaking, white, non-Hispanic/Latino children from high socioeconomic backgrounds. This lack of diversity limits the generalizability of the findings to more diverse populations, including children from different racial, ethnic, and socioeconomic backgrounds. Future studies should aim to include a more representative sample. 

 

Thank you for the insight. We understand that our sample size is relatively small and is primarily comprised of White and English-speaking children from upper socioeconomic backgrounds. We have discussed these two specific limitations in section 8.3, and we will further propose in the discussion of future plans the inclusion of more racially and socioeconomically diverse participants. 

 

2) While functional near-infrared spectroscopy (fNIRS) is a valuable tool for studying functional connectivity in young children, it has limited spatial resolution compared to other neuroimaging techniques like fMRI. This limitation may affect the precision of the connectivity patterns observed. The authors should discuss how this limitation might impact the interpretation of their findings and suggest future studies using higher-resolution imaging techniques to validate the results. The study excluded participants with significant motion artifacts, which is common in neuroimaging studies with children. However, this exclusion may introduce bias, as children with ADHD are more likely to exhibit movement during scanning. The authors should discuss how this might have affected the results and consider alternative methods for motion correction in future studies. 

 

 This study did not exclude children with significant motion artifacts, but instead corrected motion artifact using the PCA and TDDR methods as discussed in section 6.2. This combined approach accounts for FDR without overly cleaning the data. This also allowed children with severe ADHD symptoms, who are more likely to exhibit movement, to be scanned and their neural connectivity data to be analyzed. fNIRS’ capability to account and control for motion artifacts without total exclusion makes it a more wholistic neuroimaging technique for clinical populations as compared to others, such as fMRI. We now discuss this and further explain our rationale, as put forth here, in section 6.2.  

 

3) The study is cross-sectional, which limits the ability to draw conclusions about the developmental trajectories of functional connectivity in children with ADHD. Longitudinal data would provide more insight into how these neural profiles evolve over time and how they relate to symptom severity and treatment outcomes. The authors should acknowledge this limitation and suggest future longitudinal studies to address this gap. 

 

We appreciate this feedback and agree with the reviewers. Section 8.3 now includes a discussion of the limitations afforded by the cross-sectional design. We acknowledge that we were unable to see the profile change over time, and suggest future research include longitudinal studies that incorporate treatment plans to investigate the relationship between symptom severity and treatment outcomes. We are excited about data that is able to explore varying trajectories as a result of sex and subtype. This will better inform both behavioral and pharmacological intervention that takes into account the complexity of the individual across system levels (i.e., sex, behavioral subtype, age, etc.).  

 

4) The study does not extensively explore the impact of comorbidities (e.g., anxiety, depression, learning disabilities) on functional connectivity patterns. Given that ADHD often co-occurs with other psychiatric and developmental disorders, the presence of comorbidities could influence the observed neural profiles. The authors should consider controlling for or examining the effects of comorbidities in future research. 

 

Thank you for your comment. The introduction acknowledges that ADHD tends to have an increased co-morbidity rate with other psychiatric disorders, however, the current study did not aim to explore the impact of those comorbidities on ADHD's functional connectivity patterns specifically. Please refer to section 5.1 of the methods for inclusion and exclusion relative to co-occurring disorders in the current sample.  

 

 

 

5) The study involves multiple comparisons, particularly in the analysis of functional connectivity across different brain regions. While the authors use a false-discovery rate (FDR) correction, they should explicitly discuss the potential for Type I errors and how they addressed this issue in their analysis. Also, the manuscript does not consistently report effect sizes, which are important for understanding the magnitude of the observed differences. Including effect sizes would strengthen the interpretation of the results and provide a clearer picture of the clinical significance of the findings. 

 

We thank the reviewers for pointing this out. We have now included effect sizes. To our knowledge, the FDR corrections do not increase Type 1 errors as the robustness of the Analyzer Toolbox accounts for this within the GLM calculations now outlined in section 7.1. Please also see the reference below regarding this issue if the reviewer is interested or needs further clarification.  

 

Santosa H, Aarabi A, Perlman SB, Huppert TJ. Characterization and correction of the false-discovery rates in resting state connectivity using functional near-infrared spectroscopy. J Biomed Opt. 2017 May 1;22(5):55002. doi: 10.1117/1.JBO.22.5.055002. PMID: 28492852; PMCID: PMC5424771. 

 

 

6) While the study highlights sex and subtype differences in functional connectivity, the clinical implications of these findings are not fully explored. The authors should discuss how these neural differences might inform diagnostic practices, treatment strategies, and interventions for children with ADHD, particularly in terms of tailoring approaches based on sex and subtype. 

 

We appreciate this feedback and now have added clarifications on future implications of this work in discussion section 8.3. 

 

 

 

7) The study does not thoroughly discuss potential confounding factors, such as medication status, that could influence functional connectivity. Many children with ADHD are on stimulant medications, which have been shown to normalize dysfunctional connectivity. The authors should address whether medication status was controlled for or considered in the analysis and how it might have impacted the results. 

 

All children were medication naive and were recruited at the beginning of the referral pipeline through hospital records. That is, they had not started pharmaceutical interventions yet. We have now added those details to the participants section of the paper.  

 

8) The findings, while novel, are based on a single study with a specific sample. Replication in independent samples, particularly with larger and more diverse populations, is necessary to confirm the generalizability of the results. The authors should emphasize the need for replication in future research. 

 

In section 8.3, we have now included a note that further emphasizes that further replication of this study with increased sample sizes and diversity will be necessary to ensure generalizability of results. 

 

9) The study involves young children, and while informed consent was obtained, the manuscript does not discuss any potential ethical concerns related to the use of neuroimaging in this population. A brief discussion of ethical considerations, particularly regarding the use of fNIRS in children, would be beneficial. 

 

Thank you for your comment. We will add a brief discussion in the methods section about ethical considerations surrounding the safety of fNIRS on children. In addition, we will further emphasize that informed consent from parents was taken before any portion of the study was run with children. We will also emphasize that if the children showed any signs of discomfort or unwillingness to continue, the procedure was immediately terminated. However, we did not have to exclude any children from the presented data as a result of unwillingness to test during passive viewing. Thus, we support previous literature on passive viewing paradigms as ideal for capturing hard to test populations resting functional connectivity via fNIRS (see also work on toddlers at risk utilizing this paradigm in Kerr-German, A.N., et al., 2022). 

 

10) The manuscript is generally well-written, but some sections could benefit from clearer organization and more concise language. For example, the introduction could be streamlined to focus more directly on the study's objectives and hypotheses. Additionally, the results section could be more clearly structured to highlight the key findings and their implications. 

 

We thank the reviewer for this feedback and have made minor edits to the organization and language of the introduction section.  

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The paper addresses a very interesting topic for scholars and researchers of the relevant scientific community. The structure of the research methodology, the evaluation tools and the bibliographic references are coherent and effective. The results are significant and represent a starting point for future research in the sector.

Author Response

Reviewer 2:  

The paper addresses a very interesting topic for scholars and researchers of the relevant scientific community. The structure of the research methodology, the evaluation tools and the bibliographic references are coherent and effective. The results are significant and represent a starting point for future research in the sector. 

 

We thank the reviewer for their feedback and enthusiasm.  

Reviewer 3 Report

Comments and Suggestions for Authors

This study presents interesting findings regarding sex differences and subtype variations in functional connectivity in children with ADHD. The use of fNIRS is appropriate for this age group, and the focus on dimensional symptom severity is a strength. However, several areas need improvement before publication.

Key Strengths: The study addresses an important gap in the literature by investigating sex and subtype differences in ADHD using fNIRS. The use of fNIRS is well-justified, and the data analysis appears sound. The findings have potential implications for tailoring diagnostic and intervention strategies.

            Areas for Improvement

1. Introduction: Emphasize how this study builds upon and goes beyond previous research. Consider a slightly more explicit statement of the study's aims and hypotheses. Frame the limitations of previous research as opportunities that this study addresses.
2. Methods: Acknowledge the demographic limitations and discuss potential strategies for future research to address this. For example, "Future studies could benefit from oversampling underrepresented groups to ensure broader generalizability". Providing a bit more detail about the fNIRS data acquisition parameters would be helpful for readers interested in replicating the study. Consider briefly explaining the rationale behind the choice of PCA for motion correction. Reiterate why controlling for age is important in this type of study.
3. Results: The results section is well-organized, and the tables are helpful. Reporting exact p-values and effect sizes will allow readers to better assess the strength of the findings. The authors have clearly considered the issue of multiple comparisons. A brief justification for the chosen approach (q-values) is appreciated.
4. Discussion: The discussion does a good job of contextualizing the findings. Consider expanding on the potential clinical implications, while acknowledging the need for further research. The authors are commendably transparent about the limitations of the study. Perhaps framing these as avenues for future research would be a positive spin. The suggestions for future research are excellent. Consider adding a sentence or two about the potential impact of longitudinal studies.
5. Tables and Figures: The tables are generally well-formatted. Adding percentages to Table 1 would make it even easier to interpret.

Recommendation

This is a promising study that addresses an important question in the field of ADHD research. By addressing the suggestions outlined above, the authors can further strengthen their manuscript and increase its impact. I recommend that the authors revise the manuscript accordingly. This research has the potential to make a significant contribution to our understanding of ADHD.

Author Response

Reviewer 3:  

This study presents interesting findings regarding sex differences and subtype variations in functional connectivity in children with ADHD. The use of fNIRS is appropriate for this age group, and the focus on dimensional symptom severity is a strength. However, several areas need improvement before publication. 

Key Strengths: The study addresses an important gap in the literature by investigating sex and subtype differences in ADHD using fNIRS. The use of fNIRS is well-justified, and the data analysis appears sound. The findings have potential implications for tailoring diagnostic and intervention strategies. 

 

Areas for Improvement 

1. Introduction: Emphasize how this study builds upon and goes beyond previous research. Consider a slightly more explicit statement of the study's aims and hypotheses. Frame the limitations of previous research as opportunities that this study addresses. 

We thank the reviewer for their feedback and have now further emphasized the limitations of previous work, specifically as it pertains to subtype and sex exclusion in section 3. 

 

1.  Methods: Acknowledge the demographic limitations and discuss potential strategies for future research to address this. For example, "Future studies could benefit from oversampling underrepresented groups to ensure broader generalizability". Providing a bit more detail about the fNIRS data acquisition parameters would be helpful for readers interested in replicating the study. Consider briefly explaining the rationale behind the choice of PCA for motion correction. Reiterate why controlling for age is important in this type of study. 

 

We thank the reviewer for this feedback and have now added sections to the discussion section 8.3 as well as the methods section 6.2 to these aims.  

1. Results: The results section is well-organized, and the tables are helpful. Reporting exact p-values and effect sizes will allow readers to better assess the strength of the findings. The authors have clearly considered the issue of multiple comparisons. A brief justification for the chosen approach (q-values) is appreciated. 

We agree with the reviewers and have now more thoroughly explained the use of q-values.  

1. Discussion: The discussion does a good job of contextualizing the findings. Consider expanding on the potential clinical implications, while acknowledging the need for further research. The authors are commendably transparent about the limitations of the study. Perhaps framing these as avenues for future research would be a positive spin. The suggestions for future research are excellent. Consider adding a sentence or two about the potential impact of longitudinal studies. 

• This is a good point. We will emphasize that our limitations in this study could be great future directions in section 8.3, and how that could possibly further generalize our results even more. That would also be where we mention the potential use of longitudinal studies and how they could  

1. Tables and Figures: The tables are generally well-formatted. Adding percentages to Table 1 would make it even easier to interpret. 

• We feel the table would be more confusing with this addition.  

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Editors,

Thank you for granting me the opportunity to review this interesting study, which provides valuable insights into the neural underpinnings of ADHD, particularly regarding sex differences and symptom severity. This work has significant implications for future research and clinical practice, especially in improving early diagnosis and targeted interventions for ADHD.

I have only one minor concern about this manuscript. Sex differences in the presentation and neural activation patterns of ADHD as measured by functional near-infrared spectroscopy (fNIRS) have been observed in several studies, such as those referenced by PMID: 39696119 and PMID: 36937678. The authors should cite these studies and discuss the association between their findings and the results obtained from the current study.

Author Response

Reviewer 4:  

Dear Editors, 

Thank you for granting me the opportunity to review this interesting study, which provides valuable insights into the neural underpinnings of ADHD, particularly regarding sex differences and symptom severity. This work has significant implications for future research and clinical practice, especially in improving early diagnosis and targeted interventions for ADHD. 

 

I have only one minor concern about this manuscript. Sex differences in the presentation and neural activation patterns of ADHD as measured by functional near-infrared spectroscopy (fNIRS) have been observed in several studies, such as those referenced by PMID: 39696119 and PMID: 36937678. The authors should cite these studies and discuss the association between their findings and the results obtained from the current study. 

 

doi.org/10.1186/s12888-024-06350-6 

Doi.org/10.3389/fnins.2023.1119289 

 

Thank you for this feedback. We have now cited these articles and added additional clarification as to how our paper is novel relative to previous work.  

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

1) The discussion briefly mentions comorbidities (e.g., ADHD+ASD) but does not explore how these might confound or interact with the observed FC patterns. This could be expanded. 

2) Explicitly state how small subtype samples and demographic homogeneity affect conclusions.

3) Discuss fNIRS resolution limitations and potential biases in FC measurements. 

4) Add a cautionary note about interpreting subtype differences due to uneven group sizes.

5) Why there was no available link for supplementary materials? The link did not work...

Author Response

Please see attachment

Author Response File: Author Response.pdf