Developmental Alterations in Brain Network Asymmetry in 3- to 9-Month Infants with Congenital Sensorineural Hearing Loss

Reviewer #1 (Public Review):

Liu et al. investigated the brain functional lateralization in typically developing infants and infants with congenital sensorineural hearing loss (SNHL) to understand how early auditory deprivation disrupts the development of functional network organization using resting-state fNIRS imaging and the graph theory approach. They found that hemispheric asymmetry formed in early life and the initial lack of auditory exposure affected the typical development of functional network asymmetry in infants with hearing loss. Although the infants with hearing loss exhibited a balance between information segregation and integration within two hemispheres, consistent with the typically developing (TD) controls, the development of the leftward hemispheric asymmetry in network efficiency measures was disrupted. At the regional level, infants with hearing loss exhibited aberrant development of hemispheric network asymmetry especially in frontal regions.

Strengths:
The strengths of this study include its focus on a relatively understudied area of research, namely the impact of hearing loss on brain network asymmetry in infants. The study used advanced neuroimaging techniques to examine the development of cerebral asymmetry in infants with hearing loss and compared their results to typically developing controls. The study's findings provide valuable insights into the importance of early auditory exposure for typical brain development. Overall, this study contributes to our understanding of the brain functional network changes underlying hearing loss and has important implications for early intervention and treatment strategies.

Weaknesses:
Although this study does have strengths in principle, the weaknesses of this work are that the key claims cannot be fully supported due to inappropriate statistical analyses, the theoretical significance and the narrative logic are not well presented. In particular:

Theoretical significance: In the Introduction, the authors did not nicely explain why it is important to investigate how the brain functional network asymmetry develops in SNHL infants, and what new knowledge this analytical approach can tell the readers. It is insufficient to merely state that few studies have focused on this. The authors did not elaborate on the broader significance of studying the hemispherical asymmetry in SNHL infants.

Narrative logic: The organization of the Results part needs substantial improvement. The authors did not provide an overview of the analysis at the beginning of each results section, including the relationships between different measurements, the purpose of each analysis, the specific methods employed, and the meaning of the neural index used. It is therefore very difficult to understand why the authors conducted each analysis and how it contributes to the main narrative of the study. For instance, what is the relationship between the small-world properties within the hemisphere and the hemispherical asymmetry of network efficiency? What is the relationship between global/local efficiency and regional nodal efficiency? What global efficiency and local efficiency reflect? It is crucial to clarify and justify the analysis.

Problems on the statistics:

1. To support the major claim that the left hemisphere dominance of the functional network organization was significantly disrupted in SNHL infants, the authors should also report a statistically significant interaction (between leftward hemispheric asymmetry and type of infants), but instead they only reported that one effect (the leftward hemispheric asymmetry in the TD infants) was statistically significant, whereas the other effect (the leftward hemispheric asymmetry in the infants with SNHL) was not. And why not directly use asymmetry index and compare it between groups?
2. The necessary statistical values to support the conclusions are missing in several places. For example, Lines 111 - 113 and section 2.4.
3. The authors conducted multiple comparisons without correction in section 2.3 and section 2.5. It is likely that some of these comparisons would not survive the multiple comparison correction; therefore, the results need to be rephrased and the findings reinterpreted accordingly.
4. Inconsistent results exist. If "a significant group × age interaction effect on the mean AI of nodal efficiency was observed only in the frontal cortex, while other regions did not exhibit such an interaction" (Line 170-172), and the authors "investigated the group × age interaction effect on the mean nodal efficiencies of the frontal regions for each hemisphere" (Line 178-179), why "a significant interaction effect was observed in the frontal, temporal, parietal, and occipital regions of the left hemisphere" (Line 179-182)?

Reviewer #2 (Public Review):

Using fNIRS and resting state recordings of brain activity, authors have compared functional network organization in infants with congenital sensorineural hearing loss (SNHL) as well as typically developing infants. The manuscript reports a disruption in the development of leftward hemispheric lateralization in SNHL infants as compared to typically developing infants, across several network measures. The study used an adapted methodology for infants, and involved an adequate number of infants for cross-sectional studies and the findings are valuable. However, a number of methodological points and controls need to be taken into account to better explain the results and to remove redundancy. Moreover, the discussion can be improved by a more detailed comparison between the current work and the past literature.

- My major concern is that functional connectivity patterns change importantly depending on the sleep stage (Uchitel et al., 2021 Pediatric Research; Tóth et al., 2017 Human Brain mapping), it is therefore not enough to have all infants sleep, but to have them on the same sleep stage. Therefore, authors need to re-analyze their dataset taking into account sleep stage as a factor, i.e. grouping infants based on the sleep stage (otherwise it can be a confounding factor - as one can imagine that infants with sensorineural hearing loss may enter "quiet sleep" faster in a short recording session - given the environmental noise does not bother them etc.). This could completely change the interpretation of the results. Do authors have a mean in the data or via additional recordings (respiration, EMG, ECG?) to separate the sleep stages?

- Several statistical analyses are performed with redundancy, i.e. several effects are looked at in more than one test: for example one ANOVA analysis with several factors including group (SNHL/typical) as a factor, is followed by two other separate ANOVAs with the same variables as before but redone for each group separately. The latter tests are redundant. This has happened across different sections, making the manuscript unnecessarily long while also reporting effects that are redundant.

- Given the number of statistical comparisons performed, it would be helpful that authors better explain how corrections are performed: number of comparisons for each correction or which tests are considered independent (i.e. across which correction of multiple comparisons are not performed).

- The discussion generally needs to be improved: both for the position of the current study/novelty/strength and its limitations with respect to the previous works (Cui et al 2022- also looking into early functional organization in SNHL, etc) and also in terms of the differences in findings (i.e. associations of functional connectivity measures to hearing loss severity)