Author response:
Reviewer #1 (Public Review):
Summary:
The present study evaluates the role of visual experience in shaping functional correlations between extrastriate visual cortex and frontal regions. The authors used fMRI to assess "resting-state" temporal correlations in three groups: sighted adults, congenitally blind adults, and neonates. Previous research has already demonstrated differences in functional correlations between visual and frontal regions in sighted compared to early blind individuals. The novel contribution of the current study lies in the inclusion of an infant dataset, which allows for an assessment of the developmental origins of these differences.
The main results of the study reveal that correlations between prefrontal and visual regions are more prominent in the blind and infant groups, with the blind group exhibiting greater lateralization. Conversely, correlations between visual and somato-motor cortices are more prominent in sighted adults. Based on these data, the authors conclude that visual experience plays an instructive role in shaping these cortical networks. This study provides valuable insights into the impact of visual experience on the development of functional connectivity in the brain.
Strengths:
The dissociations in functional correlations observed among the sighted adult, congenitally blind, and neonate groups provide strong support for the study's main conclusion regarding experience-driven changes in functional connectivity profiles between visual and frontal regions.
In general, the findings in sighted adult and congenitally blind groups replicate previous studies and enhance the confidence in the reliability and robustness of the current results.
Split-half analysis provides a good measure of robustness in the infant data.
Weaknesses:
There is some ambiguity in determining which aspects of these networks are shaped by experience.
This uncertainty is compounded by notable differences in data acquisition and preprocessing methods, which could result in varying signal quality across groups. Variations in signal quality may, in turn, have an impact on the observed correlation patterns.
The study's findings could benefit from being situated within a broader debate surrounding the instructive versus permissive roles of experience in the development of visual circuits.
Reviewer #2 (Public Review):
Summary:
Tian et al. explore the developmental organs of cortical reorganization in blindness. Previous work has found that a set of regions in the occipital cortex show different functional responses and patterns of functional correlations in blind vs. sighted adults. In this paper, Tian et al. ask: how does this organization arise over development? Is the "starting state" more like the blind pattern, or more like the adult pattern? Their analyses reveal that the answer depends on the particular networks investigated; some functional connections in infants look more like blind than sighted adults; other functional connections look more like sighted than blind adults; and others fall somewhere in the middle, or show an altogether different pattern in infants compared with both sighted and blind adults.
Strengths:
The question raised in this paper is extremely important: what is the starting state in development for visual cortical regions, and how is this organization shaped by experience? This paper is among the first to examine this question, particularly by comparing infants not only with sighted adults but also blind adults, which sheds new light on the role of visual (and cross-modal) experience. Another clear strength lies in the unequivocal nature of many results. Many results have very large effect sizes, critical interactions between regions and groups are tested and found, and infant analyses are replicated in split halves of the data.
Weaknesses:
A central claim is that "infant secondary visual cortices functionally resemble those of blind more than sighted adults" (abstract, last paragraph of intro). I see two potential issues with this claim. First, a minor change: given the approaches used here, no claims should be made about the "function" of these regions, but rather their "functional correlations". Second (and more importantly), the claim that the secondary visual cortex in general resembles blind more than sighted adults is still not fully supported by the data. In fact, this claim is only true for one aspect of secondary visual area functional correlations (i.e., their connectivity to A1/M1/S1 vs. PFC). In other analyses, the infant secondary visual cortex looks more like sighted adults than blind adults (i.e., in within vs. across hemisphere correlations), or shows a different pattern from both sighted and blind adults (i.e., in occipito-frontal subregion functional connectivity). It is not clear from the manuscript why the comparison to PFC vs. non-visual sensory cortex is more theoretically important than hemispheric changes or within-PFC correlations (in fact, if anything, the within-PFC correlations strike me as the most important for understanding the development and reorganization of these secondary visual regions). It seems then that a more accurate conclusion is that the secondary visual cortex shows a mix of instructive effects of vision and reorganizing effects of blindness, albeit to a different extent than the primary visual cortex.
Relatedly, group differences in overall secondary visual cortex connectivity are particularly striking as visualized in the connectivity matrices shown in Figure S1. In the results (lines 105-112), it is noted that while the infant FC matrix is strongly correlated with both adult groups, the infant group is nonetheless more strongly correlated with the blind than sighted adults. I am concerned that these results might be at least partially explained by distance (i.e., local spread of the bold signal), since a huge portion of the variance in these FC matrices is driven by stronger correlations between regions within the same system (e.g., secondary-secondary visual cortex, frontal-frontal cortex), which are inherently closer together, relative to those between different systems (e.g., visual to frontal cortex). How do results change if only comparisons between secondary visual regions and non-visual regions are included (i.e., just the pairs of regions within the bold black rectangle on the figure), which limits the analysis to long-rang connections only? Indeed, looking at the off-diagonal comparisons, it seems that in fact there are three altogether different patterns here in the three groups. Even if the correlation between the infant pattern and blind adult pattern survives, it might be more accurate to claim that infants are different from both adult groups, suggesting both instructive effects of vision and reorganizing effects of blindness. It might help to show the correlation between each group and itself (across independent sets of subjects) to better contextualize the relative strength of correlations between the groups.
It is not clear that differences between groups should be attributed to visual experience only. For example, despite the title of the paper, the authors note elsewhere that cross-modal experience might also drive changes between groups. Another factor, which I do not see discussed, is possible ongoing experience-independent maturation. The infants scanned are extremely young, only 2 weeks old. Although no effects of age are detected, it is possible that cortex is still undergoing experience-independent maturation at this very early stage of development. For example, consider Figure 2; perhaps V1 connectivity is not established at 2 weeks, but eventually achieves the adult pattern later in infancy or childhood. Further, consider the possibility that this same developmental progression would be found in infants and children born blind. In that case, the blind adult pattern may depend on blindness-related experience only (which may or may not reflect "visual" experience per se). To deal with these issues, the authors should add a discussion of the role of maturation vs. experience and temper claims about the role of visual experience specifically (particularly in the title).
The authors measure functional correlations in three very different groups of participants and find three different patterns of functional correlations. Although these three groups differ in critical, theoretically interesting ways (i.e., in age and visual/cross-modal experience), they also differ in many uninteresting ways, including at least the following: sampling rate (TR), scan duration, multi-band acceleration, denoising procedures (CompCor vs. ICA), head motion, ROI registration accuracy, and wakefulness (I assume the infants are asleep).
Addressing all of these issues is beyond the scope of this paper, but I do feel the authors should acknowledge these confounds and discuss the extent to which they are likely (or not) to explain their results. The authors would strengthen their conclusions with analyses directly comparing data quality between groups (e.g., measures of head motion and split-half reliability would be particularly effective).
Response #1: We appreciate the reviewer’s comments. In response, we have revised the paper to provide a more balanced summary of the data and clarified in the introduction which signatures the paper focuses on and why. Additionally, we have included several control analyses to account for other plausible explanations for the observed group differences. Specifically, we randomly split the infant dataset into two halves and performed split-half cross-validation. Across all comparisons, the results from the two halves were highly similar, suggesting that the effects are robust (see Supplementary Figures S3 and S4).
Furthermore, we compared the split-half noise ceiling across the groups (infants, sighted adults, and blind adults) and found no significant differences between them (details in response #6). Finally, we repeated our analysis after excluding infants with a radiology score of 4 or 5, and the results remained consistent, indicating that our findings are not confounded by potential brain anomalies (details in response #2).
We hope these control analyses help strengthen our conclusions.
Reviewer #3 (Public Review):
Summary:
This study aimed to investigate whether the differences observed in the organization of visual brain networks between blind and sighted adults result from a reorganization of an early functional architecture due to blindness, or whether the early architecture is immature at birth and requires visual experience to develop functional connections. This question was investigated through the comparison of 3 groups of subjects with resting-state functional MRI (rs-fMRI). Based on convincing analyses, the study suggests that: 1) secondary visual cortices showed higher connectivity to prefrontal cortical regions (PFC) than to non-visual sensory areas (S1/M1 and A1) in sighted infants like in blind adults, in contrast to sighted adults; 2) the V1 connectivity pattern of sighted infants lies between that of sighted adults (stronger functional connectivity with non-visual sensory areas than with PFC) and that of blind adults (stronger functional connectivity with PFC than with non-visual sensory areas); 3) the laterality of the connectivity patterns of sighted infants resembled those of sighted adults more than those of blind adults, but sighted infants showed a less differentiated fronto-occipital connectivity pattern than adults.
Strengths:
The question investigated in this article is important for understanding the mechanisms of plasticity during typical and impaired development, and the approach considered, which compares different groups of subjects including, neonates/infants and blind adults, is highly original.
-Overall, the analyses considered are solid and well-detailed. The results are quite convincing, even if the interpretation might need to be revised downwards, as factors other than visual experience may play a role in the development of functional connections with the visual system.
Weaknesses:
While it is informative to compare the "initial" state (close to birth) and the "final" states in blind and sighted adults to study the impact of post-natal and visual experience, this study does not analyze the chronology of this development and when the specialization of functional connections is completed. This would require investigating when experience-dependent mechanisms are important for the setting- establishment of multiple functional connections within the visual system. This could be achieved by analyzing different developmental periods in the same way, using open databases such as the Baby Connectome Project. Given the early, "condensed" maturation of the visual system after birth, we might expect sighted infants to show connectivity patterns similar to those of adults a few months after birth.
The rationale for mixing full-term neonates and preterm infants (scanned at term-equivalent age) from the dHCP 3rd release is not understandable since preterms might have a very different development related to prematurity and to post-natal (including visual) experience. Although the authors show that the difference between the connectivity of visual and other sensory regions, and the one of visual and PFC regions, do not depend on age at birth, they do not show that each connectivity pattern is not influenced by prematurity. Simply not considering the preterm infants would have made the analysis much more robust, and the full-term group in itself is already quite large compared with the two adult groups. The current study setting and the analyses performed do not seem to be an adequate and sufficient model to ascertain that "a few weeks of vision after birth is ... insufficient to influence connectivity".
In a similar way, excluding the few infants with detected brain anomalies (radiological scores higher or equal to 4) would strengthen the group homogeneity by focusing on infants supposed to have a rather typical neurodevelopment. The authors quote all infants as "sighted" but this is not guaranteed as no follow-up is provided.
Response #2: We appreciate the reviewer’s suggestion. We re-analyzed the infant cohort after excluding all cases with radiological scores ≥4 (n =39 infants excluded). The revised analysis confirmed that the connectivity patterns reported in the main text remain statistically unchanged (see Supplementary Fig. S11). This demonstrates the robustness of our findings to potential confounding effects from potential brain anomalies. We have explicitly clarified this in the revised Methods section (page 14, line 391in the manuscript).
In our dataset, newborns (average age at scan = 2.79 weeks) have very limited and immature vision. We agree with the reviewer that long-term visual outcomes cannot be guaranteed without follow-up data. The term "sighted infants" was used operationally to distinguish this cohort from congenitally blind populations.
The post-menstrual age (PMA) at scan of the infants is also not described. The methods indicate that all were scanned at "term-equivalent age" but does this mean that there is some PMA variability between 37 and 41 weeks? Connectivity measures might be influenced by such inter-individual variability in PMA, and this could be evaluated.
The rationale for presenting results on the connectivity of secondary visual cortices before one of the primary cortices (V1) was not clear to understand. Also, it might be relevant to better justify why only the connectivity of visual regions to non-visual sensory regions (S1-M1, A1) and prefrontal cortex (PFC) was considered in the analyses, and not the ones to other brain regions.
In relation to the question explored, it might be informative to reposition the study in relation to what others have shown about the developmental chronology of structural and functional long-distance and short-distance connections during pregnancy and the first postnatal months.
The authors acknowledge the methodological difficulties in defining regions of interest (ROIs) in infants in a similar way as adults. The reliability and the comparability of the ROIs positioning in infants is definitely an issue. Given that brain development is not homogeneous and synchronous across brain regions (in particular with the frontal and parietal lobes showing delayed growth), the newborn brain is not homothetic to the adult brain, which poses major problems for registration. The functional specialization of cortical regions is incomplete at birth. This raises the question of whether the findings of this study would be stable/robust if slightly larger or displaced regions had been considered, to cover with greater certainty the same areas as those considered in adults. And have other cortical parcellation approaches been considered to assess the ROIs robustness (e.g. MCRIB-S for full-terms)?
Recommendations for the Authors:
Reviewer #1(Recommendations for the authors):
Further consideration should be given to the underlying changes in network architecture that may account for differences in functional correlations across groups. An increase (or decrease) in correlation between two regions could signify an increase (decrease) in connection or communication between those regions. Alternatively, it might reflect an increase in communication or connection with a third region, while the physical connections/interactions between the two original regions remain unchanged. These possibilities lead to distinct mechanistic interpretations. For example, there are substantial changes in connectivity during early visual (e.g. Burkhalter A. 1993, Cerebral Cortex) and visuo-motor development (e.g., Csibra et al. 2000 Neuroreport). It's not clear whether increases in communication within the visual network and improvements in visuo-motor behavior (e.g., Yizhar et al. 2023 Frontiers in Neuroscience) wouldn't produce a qualitatively similar pattern of results.
Relatedly, the within-network correlation patterns between visual ROIs and frontal ROIs appear markedly different between sighted adults and infants (Supplementary Figure S1). To what extent do the differences in long-range correlations between visual and frontal regions reflect these within-network differences in functional organization?
Response #3: The reviewer is raising some interesting questions about possible mechanisms and network changes. Resting state studies are indeed always subject to possibility that some effects are mediated by a third, unobserved region. Prior whole-cortex connectivity analyses have observed primarily changes in occipito-frontal connectivity in blindness, so there is not a clear cortical ‘third region’ candidate (Deen et al., 2015). However, some thalamic affects have also been observed and could contribute to the phenomenon (Bedny et al., 2011). Resting state changes in correlation between two areas do not imply changes in strength of long-range anatomical connectivity. Indeed, in the current case they may well reflect differential functional coupling, rather than strengthening or weakening of anatomical connections. We now discuss this in the Discussion section on page 12, line 301 as follows:
“Despite these insights, many questions remain regarding the neurobiological mechanisms underlying experience-based functional connectivity changes and their relationship to anatomical development. Long-range anatomical connections between brain regions are already present in infants—even prenatally—though they remain immature (Huang et al., 2009; Kostović et al., 2019, 2021; Takahashi et al., 2012; Vasung, 2017). Functional connectivity changes may stem from local synaptic modifications within these stable structural pathways, consistent with findings that functional connectivity can vary independently of structural connection strength (Fotiadis et al., 2024). Moreover, functional connectivity has been shown to outperform structural connectivity in predicting individual behavioral differences, suggesting that experience-based functional changes may reflect finer-scale synaptic or network-level modulations not captured by macrostructural measures (Ooi et al., 2022). Prior studies also suggest that, even in adults, coordinated sensory-motor experience can lead to enhancement of functional connectivity across sensory-motor systems, indicating that large-scale changes in functional connectivity do not necessarily require corresponding changes in anatomical connectivity (Guerra-Carrillo et al., 2014; Li et al., 2018).”
It is not clear how changes in correlation patterns among visual areas would produce the connectivity between visual areas and prefrontal areas reported in the current study. Activity in visual areas drives correlations both among visual areas and between visual and prefrontal areas and the same is true of prefrontal corticies.
The findings from this study should be more closely linked to the extensive literature surrounding the debate on whether experience plays an instructive or permissive role in visual development (e.g., Crair 1999 Current Opin Neurobiol; Sur et al. 1999 J Neurobiol; Kiorpes 2016 J Neurosci; Stellwagen & Shatz 2002 Neuron; Roy et al. 2020 Nature Communications).
Response #4: The instructive role suggests that specific experiences or patterns of neural activity directly shape and organize neural circuitry, while the permissive role indicates that such experiences or activity merely enable other factors, such as molecular signals, to influence neural circuit formation(Crair, 1999; Sur et al., 1999). To distinguish whether experience plays an instructive or permissive role, it is essential to manipulate the pattern or information content of neural activity while maintaining a constant overall activity level (Crair, 1999; Roy et al., 2020; Stellwagen & Shatz, 2002). However, both the sighted and blind adult groups have had extensive experience and neural activity in the visual cortices. For the sighted group, activity in the visual cortex is partly driven by bottom-up input from the external environment, through the retina, LGN, and ultimately to the cortex. In contrast, the blind group’s visual cortex activity is partially driven by top-down input from non-visual networks. The precise role of this activity in shaping the observed connectivity patterns remains unclear. Although our study cannot speak to this issue directly, we now link to the relevant literature on page 12,line 320 of the manuscript in the Discussion section as follows:
“The current findings reveal both effects of vision and effects of blindness on the functional connectivity patterns of the visual cortex. A further open question is whether visual experience plays an instructive or permissive role in shaping neural connectivity patterns. An instructive role suggests that specific sensory experiences or patterns of neural activity directly shape and organize neural circuitry. In contrast, a permissive role implies that sensory experience or neural activity merely facilitates the influence of other factors—such as molecular signals—on the formation and organization of neural circuits (Crair, 1999; Sur et al., 1999). Studies with animals that manipulate the pattern or informational content of neural activity while keeping overall activity levels constant could distinguish between these hypotheses (Crair, 1999; Roy et al., 2020; Stellwagen & Shatz, 2002).”
The assertion that a few weeks of vision after birth is insufficient to influence connectivity is provocative. Though supported by the study's results, it would benefit from integration with research in animal models showing considerable malleability of networks from early experience (e.g., Akerman et al. 2002 Neuron; Li et al. 2006 Nature Neuroscience; Stacy et al. 2023 J Neuroscience).
Response #5: We thank the reviewer for their suggestion. The present study found that several weeks of postnatal visual experience is insufficient to significantly alter the long-term connectivity patterns of the visual cortices. While animal studies have shown that acute visual experience, or even exposure to visual stimuli through unopened eyelids, can robustly influence visual system development(Akerman et al., 2002; Li et al., 2008; Van Hooser et al., 2012). We think this discrepancy may be attributed to the substantial differences in developmental timelines between species. The human lifespan is much longer, and so is the human critical period, making it unclear how to map duration from one species to another. We briefly touched upon the time course issue in page 11 line 289 in the Discussion section as follows:
“The present results reveal the effects of experience on development of functional connectivity between infancy and adulthood, but do not speak to the precise time course of these effects. Infants in the current sample had between 0 and 20 weeks of visual experience. Comparisons across these infants suggests that several weeks of postnatal visual experience is insufficient to produce a sighted-adult connectivity profile. The time course of development could be anywhere between a few months and years and could be tested by examining data from children of different ages.”
Substantial differences between the groups are evident in several key aspects of the study, including the number of subjects, brain sizes, imaging parameters, and data preprocessing, all of which are likely to have an impact on the overall signal quality. To clarify how these differences might have impacted correlation differences between groups, it would be essential to include information on the noise ceilings for each correlation analysis within each group.
Response #6: We thank the reviewer for their suggestion. We now report the split-half noise ceiling for adult and infant groups. For each participant, we first split the rs-fMRI time series into two halves, then calculated the ROI-wise rsFC pattern from the two splits. The split-half noise ceiling was estimated according to Lage-Castellanos et al (2019). The noise ceilings of the three groups (infants: 0.90 ± 0.056,blind adults: 0.88 ± 0.041, sighted adults: 0.90 ± 0.055) showed no significant difference (One-way ANOVA, F(2,552) = 2.348, p = 0.097). Therefore, we believe that overall signal quality is unlikely to impact our results. We also add the relevant context in the Method section in page 16 Line 447 as follows:
“Substantial differences between the groups exist in this study, including the number of subjects, brain sizes, imaging parameters, and data preprocessing, all of which are likely to have an impact on the overall signal quality. To address this concern, we compared the split-half noise ceiling across the groups (infants, sighted adults, and blind adults). For each participant, we first split the rs-fMRI time series into two halves, then calculated the ROI-wise rsFC pattern from the two splits. The split-half noise ceiling was estimated according to Lage-Castellanos et al (Lage-Castellanos et al., 2019). The noise ceilings of the three groups (infants: 0.90 ± 0.056, blind adults: 0.88 ± 0.041, sighted adults: 0.90 ± 0.055) showed no significant difference (One-way ANOVA, F (2,552) = 2.348, p = 0.097). Therefore, overall signal quality is unlikely to impact our results.”
In general, it appears that the infant correlations are stronger compared to the other groups. While this could reflect increased coherence or lack of differentiation, it is also possible that it is simply due to the presence of a non-neuronal global signal. Such a signal has the potential to substantially limit the effective range of functional correlations and comparisons with adults. To address this, it is advisable to conduct control analyses aimed at assessing and potentially removing global signals.
Response #7: We agree with the reviewer that global signal regression (GSR) may help reduce non-neuronal artifacts, such as motion, cardiac, and respiratory signals, which are known to correlate with the global signal. However, the global signal also contains neural signals from gray matter, and removing it can introduce unwanted artifacts, especially for the current study. First, GSR can reduce the physiological accuracy of functional connectivity (FC); second, GSR may have differential effects across groups, potentially introducing additional artifacts in between-group comparisons, as noted by Murphy et al (Murphy & Fox, 2017). The CompCor method (Behzadi et al., 2007; Whitfield-Gabrieli & Nieto-Castanon, 2012) is capble to estimate the global non-neuronal artifacts like the GSR method. Meanwhile as it estimate global non-neuronal artifacts from signals within the white matter (WM) and cerebrospinal fluid (CSF) masks, but not the gray matter (GM), CompCor could introduce minimal unwanted bias to the GM signal.
Was there a difference in correlations for preterm vs term neonates? Recent research has suggested that preterm births can have an impact on functional networks, particularly in frontal cortices. e.g., Tokariev et al. 2019, Li et al. 2021 elife; Zhang et al. 2022 Fronteirs in Neuroscience.
Response #8: We have compared preterm and term neonates for all the main results, including the connectivity from the secondary visual cortex/V1 to non-visual sensory cortices versus prefrontal cortices, the laterality of occipito-frontal connectivity, and the specialization across different fronto-occipital networks. This information is reported in Page 6 line 169 and Supplementary Figure S7. The connectivities of full-term infants are generally higher than those of preterm infants. However, the connectivity patterns of term and preterm infants are very similar.
The consistency between the current results and prior work (e.g., Burton et al. 2014) is notable, particularly in the observed greater correlations in prefrontal regions and weaker correlations in somato-motor regions for early blind individuals compared to sighted. However, almost all visual-frontal correlations in both groups were negative in that prior study. Some discussion on why positive correlations were found in the current study could help to clarify.
Response #9: Many other papers have reported positive correlations similar to those found in our study (e.g., Deen et al., 2015; Kanjlia et al., 2021). In contrast, Burton's study identified predominantly negative visual-frontal correlations, we think this is likely because the global signal was regressed out during preprocessing. This methodological choice can lead to an increase in negative connections (Murphy & Fox, 2017).
The term "secondary visual areas" used throughout the paper lacks specificity, and its usage in terms of underlying anatomical and functional areas has been inconsistent in the literature. It would be advisable to adopt a more precise characterization based on functional and/or anatomical criteria.
Response #10: We specified in the article that Tthe occipital ROIs were defined in the current study are functional areas in people born blind identified in prior studies as regions that respond to three non-visual tasks such as language, math, or executive function, and show functional connectivity changes in blind adults in previous studies (Kanjlia et al., 2016, 2021; Lane et al., 2015). These regions respond to language, math and executivie function in the congenitally blind population (see Figure 1.) The are refered collectively as ‘secondary visual areas’ to destinguish them from V1. Anatomically, these three regions cover the majority of the lateral occipital cortex and part of the ventral occipital cortex, providing a good sample of the connectivity profile of higher-order visual areas. Thus, we are using the term "secondary visual areas" to refer to these regions. In blind individuals, although these regions respond to non-visual tasks, their exact functions are unknown.
The inclusion of the ventral temporal cortex in the visual ROIs is currently only depicted in Supplementary Figure S7. To enhance the clarity of the areas of interest analyzed, it would be advisable to illustrate the ventral temporal areas in the main text. Were there notable differences in the frontal correlations between the lateral occipital visual areas and ventral temporal areas?
Response #11: We thank the reviewer for pointing out this issue. We added a statement about the ventral visual cortex in describing the location of the ROI and added the ventral view of ROIs in the Figure 1. The language-responsive and math -responsive ROIs covers both the lateral and ventral visual cortex, whereas executive function (response-conflict) regions cover only the lateral visual cortex. We compared the connectivity patterns of these three regions and found no differences (see supplementary Fig S2).
The blind group results are characterized as reflecting a reorganization in comparison to sighted adults while the results for sighted adults compared to infants are discussed more as a maturation ("adult pattern isn't default but requires experience to establish"). Both the sighted and blind adult groups showed differences from the infant group, and these differences are attributed to the role of experience. Why use "reorganization" for one result and maturation for another?
Response #12: We agree with the reviewer that both of the adult groups should be thought of as equal in relation to the infants. In other words, the brain develops under one set of experiential conditions or another. We do not think that the adult sighted pattern reflects maturation. Rather, the sighted adult pattern reflects the combined influence of maturation and visual experience. The adult blind pattern reflects the combined influence of maturation and blindness. We use the term ‘reorganization’ to label differences in the blind adults relative to sighted infants. We do so for the purpose of clarity and to remain consistent with terminology in prior liaterature. However, we agree with the reviewer that the blind group does not reflect ‘reorganization’ intrinsically any more than the sighted adult group.
The statement that "visual experience is required to set up long-range functional connectivity" is unclear, especially since the infant and blind groups showed stronger long-range functional correlations with PFC.
Response #13: We revised this sentence to specifically as “visual experience establishes elements of the sighted-adult long-range connectivity” in tha Abstract line 17.
The statement that the visual ROIS roughly correspond to "the anatomical location of areas such as V5/MT+, LO, V3a, and V4v" appears imprecise. From Supplementary Figure S7, these areas cover anterior portions of ventral temporal cortex (do these span the anatomical location of putative category-selective areas?) and into the intraparietal sulcus.
Response #14: Thanks to the reviewer for the clarification. The ventral ROIs cover the middle and part of the anterior portion of the ventral temporal lobe, including the putative category-selective areas. Additionally, the dorsal ROIs extend beyond the occipital lobe to the intraparietal sulcus and superior parietal lobule. We have added a more detailed description of the anatomical location of the ROI in the Methods section Page 17 line 489 as follows:
“Each functional ROI spans multiple anatomical regions and together the secondary visual ROIs tile large portions of lateral occipital, occipito-temporal, dorsal occipital and occipito-parietal cortices. In sighted people, the secondary visual occipital ROIs include the anatomical locations of functional regions such as motion area V5/MT+, the lateral occipital complex (LO), category specific ventral occipitotemporal cortices and dorsally, V3a and V4v. The occipital ROI also covers the middle of the ventral temporal lobe. Dorsally, it extended to the intraparietal sulcus and superior parietal lobule.”
The motivation for assessing correlations with motor and frontal regions was briefly discussed in the introduction. It would be helpful to reiterate this motivation when first introducing the analyses in the results.
Response #15: Thank you for the thoughtful suggestion. Upon reflection, we chose to substantially revise the Introduction to more clearly and comprehensively explain the rationale for examining the couplings with motor and frontal regions, rather than reiterating it in the Results section. We believe this revised framing provides a stronger foundation for the analyses that follow, while avoiding redundancy across sections. We hope this addresses the reviewer’s concern.
Reviewer #2 (Recommendations for the authors):
Congratulations on a well-written paper and an interesting set of results.
Reviewer #3 (Recommendations for the authors):
Abstract:
Mentioning "sighted infants" does not seem adequate.
Response #16: In our dataset, newborns (average age at scan = 2.79 weeks) have very limited and immature vision. We agree with the reviewer that long-term visual outcomes cannot be guaranteed without follow-up data. The term "sighted infants" was used operationally to distinguish this cohort from congenitally blind populations.
In sentences after "Specifically...", it was not clear whether the authors referred to V1 connectivity.
Response #17: We thank the reviewer for this comment. In the revised abstract, we have removed the original "Specifically..." phrasing and clarified the results.
Introduction
Talking about the "instructive effects" of vision might be confusing or misleading. Visual experiences like exposure to oral language are part of the normal/spontaneous environment that allows the infant behavioral acquisitions (contrarily with learnings that occur later during development with instruction like for reading).
Response #18: We appreciate the reviewer’s concern and would like to clarify that the term “instructive effect” is used here derived from neurodevelopmental studies (Crair, 1999; Sur et al., 1999). In this context, “instructive” refers to activity-dependent mechanisms where patterns of neural activity actively guide the organization of synaptic connectivity, emphasizing that spontaneous or sensory-driven activity (e.g., retinal waves, visual experience) can directly shape circuit refinement, as seen in ocular dominance column formation. In the context of our study, we emphasize that vision plays an instructive role in setting up the balance of connectivity between occipital cortex and non-visual networks.
For references on the development of connectivity, I would advise citing MRI studies but also studies based on histological approaches (see for example the detailed review by Kostovic et al, NeuroImage 2019).
Response #19: We thank the reviewer for this suggestion. We have incorporated a discussion on the long-range anatomical connections that emerge as early as infancy, referencing studies that employed diffusion MR imaging and histological methods, as detailed below.
“Many long-range anatomical connections between brain regions are already established in infants, even before birth, although they are not yet mature (Huang et al., 2009; Kostović et al., 2019, 2021; Takahashi et al., 2012; Vasung, 2017).” (Page 12, line 303 in the manuscript)
Results
P7 l170: It might be helpful to be precise that this is "compared with inter-hemispheric connectivity".
Response #20: We thank the reviewer for this suggestion. To align with our established terminology, we have revised the statement to explicitly contrast within-hemisphere connectivity with between-hemisphere connectivity. The modified text now reads (page 7, line 183 in the manuscript):
“Compared to sighted adults, blind adults exhibited a stronger dominance of within-hemisphere connectivity over between-hemisphere connectivity. That is, in people born blind, left visual networks are more strongly connected to left PFC, whereas right visual networks are more strongly connected to right PFC.
L176-181: It was not clear to me what was the difference between "across" and "between hemisphere connectivity". Would it be informative to test the difference between blind and sighted adults?
Response #21: We clarify that there is no distinction between the terms “across” and “between hemisphere connectivity”—they refer to the same concept. To ensure consistency, we have revised the text to exclusively use “between hemisphere connectivity” throughout the manuscript. Regarding the comparison between blind and sighted adults, we conducted statistical comparisons between these groups in our analysis, and the results have been incorporated into the revised version (Page 7, line 187 in the manuscript).
Adding statistics on Figure 3, but also on Figures 1 and 2 might help the reading.
Response #22: We have added the statistics in Figure 1-4.
Adding the third comparison in Figure 4 would be possible in my view.
Response #23: We explored integrating the response-conflict region into Figure 4, but this would require a 3x3 bar chart with pairwise statistical significance markers, which introduced excessive visual complexity that hindered readers’ ability to grasp our intended message. To ensure clarity, we retained the original Figure 4 while providing the complete three-region analysis (including all statistical comparisons) in Supplementary Figure S8 to ensure completeness.
Methods
The authors might have to specify ages at birth, and ages at scan (median + range?).
Response #24: We have added that information in the Methods section as follows:
“The average age from birth at scan = 2.79 weeks (SD = 3.77, median = 1.57, range = 0 – 19.71); average gestational age at scan = 41.23 weeks (SD = 1.77, median = 41.29, range = 37 – 45.14); average gestational age at birth = 38.43 weeks (SD = 3.73, median = 39.71, range = 23 – 42.71).” (Page 14, line 379 in the manuscript)
It might be relevant to comment on the range of available fMRI volumes, and the fact that connectivity measures might then be less robust in infants.
Response #25: We report the range of fMRI volumes in the Methods section (Page 16, Line 449). Adult participants (blind and sighted) underwent 1–4 scanning sessions, each containing 240 volumes (mean scan duration: 710.4 seconds per participant). For infants, all subjects had 2300 fMRI volumes, and we retained a subset of 1600 continuous volumes per subject with the minimum number of motion outliers. While infant connectivity measures may inherently exhibit lower robustness due to developmental and motion-related factors, our infant cohort’s large sample size (n=475) and stringent motion censoring criteria enhance the reliability of group-level inferences. We have integrated this clarification into the Methods section (Page 16, Line 444) as follows:
"While infant connectivity estimates may be less robust at the individual level compared to adults due to shorter scan durations and higher motion, our cohort’s large sample size (n=475) and rigorous motion censoring mitigate these limitations for group-level analyses. "
The mention of dHCP 2nd release should be removed from the paragraph on data availability.
Response #26: We have removed it.
