GABA-ergic inhibition in human hMT+ predicts visuo-spatial intelligence mediated through the frontal cortex

  1. Department of Neurosurgery of the Second Affiliated Hospital and Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou 310029, China
  2. Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou 310028, China
  3. Key Laboratory of Biomedical Engineering of Ministry of Education, Qiushi Academy for Advanced Studies, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310027, China
  4. College of Intelligence Science and Technology, National University of Defense Technology, Changsha 410073, China
  5. Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310013, China
  6. University of Ottawa Institute of Mental Health Research, University of Ottawa; Ottawa, ON, K1Z 7K4, Canada
  7. MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, Hangzhou 311121, China

Peer review process

Revised: This Reviewed Preprint has been revised by the authors in response to the previous round of peer review; the eLife assessment and the public reviews have been updated where necessary by the editors and peer reviewers.

Read more about eLife’s peer review process.

Editors

  • Reviewing Editor
    Xilin Zhang
    South China Normal University, Guangzhou, China
  • Senior Editor
    Yanchao Bi
    Beijing Normal University, Beijing, China

Reviewer #1 (Public Review):

Summary:

The study of human intelligence has been the focus of cognitive neuroscience research, and finding some objective behavioral or neural indicators of intelligence has been an ongoing problem for scientists for many years. Melnick et al, 2013 found for the first time that the phenomenon of spatial suppression in motion perception predicts an individual's IQ score. This is because IQ is likely associated with the ability to suppress irrelevant information. In this study, a high-resolution MRS approach was used to test this theory. In this paper, the phenomenon of spatial suppression in motion perception was found to be correlated with the visuo-spatial subtest of gF, while both variables were also correlated with the GABA concentration of MT+ in the human brain. In addition, there was no significant relationship with the excitatory transmitter Glu. At the same time, SI was also associated with MT+ and several frontal cortex FCs.

Strengths:

(1) 7T high-resolution MRS is used.

(2) This study combines the behavioral tests, MRS, and fMRI.

Weaknesses:

Major:

(1) In Melnick (2013) IQ scores were measured by the full set of WAIS-III, including all subtests. However, this study only used visual spatial domain of gF. I wonder why only the visuo-spatial subtest was used not the full WAIS-III? I am wondering whether other subtests were conducted and, if so, please include the results as well to have comprehensive comparisons with Melnick (2013).

Minor:

(1) Table 1 and Table supplementary 1-3 contain many correlation results. But what are the main points of these values? Which values do the authors want to highlight? Why are only p-values shown with significance symbols in Table supplementary 2??

(2) Line 27, it is unclear to me what is "the canonical theory".

(3) Throughout the paper, the authors use "MT+", I would suggest using "hMT+" to indicate the human MT complex, and to be consistent with the human fMRI literature.

(4) At the beginning of the results section, I suggest including the total number of subjects. It is confusing what "31/36 in MT+, and 28/36 in V1" means.

(5) Line 138, "This finding supports the hypothesis that motion perception is associated with neural activity in MT+ area". This sentence is strange because it is a well established finding in numerous human fMRI papers. I think the authors should be more specific about what this finding implies.

(6) There are no unit labels for all x- and y-axies in Figure 1. I only see the unit for Conc is mmol per kg wet weight.

(7) Although the correlations are not significant in Figure supplement 2&3, please also include the correlation line, 95% confidence interval, and report the r values and p values (i.e., similar format as in Figure 1C).

(8) There is no need to separate different correlation figures into Figure supplementary 1-4. They can be combined into the same figure.

(9) Line 213, as far as I know, the study (Melnick et al., 2013) is a psychophysical study and did not provide evidence that the spatial suppression effect is associated with MT+.

(10) At the beginning of the results, I suggest providing more details about the motion discrimination tasks and the measurement of the BDT.

(11) Please include the absolute duration thresholds of the small and large sizes of all subjects in Figure 1.

(12) Figure 5 is too small. The items in plot a and b can be barely visible.

Reviewer #3 (Public Review):

(1) Throughout the manuscript, hMT+ connectivity with the frontal cortex has been treated as an a priori hypothesis/space. However, there is no such motivation or background literature mentioned in the Introduction. Can the authors clarify the necessity of functional connectivity? In other words, can BOLD activity of hMT+ in the localizer task substitute for functional connectivity between hMT+ and the frontal cortex?

(2) There is an obvious mismatch between the in-text description and the content of the figure:

"In contrast, there was no correlation between BDT and GABA levels in V1 voxels (figure supplement 1a). Further, we show that SI significantly correlates with GABA levels in hMT+ voxels (r = 0.44, P = 0.01, n = 31, Figure 3d). In contrast, no significant correlation between SI and GABA concentrations in V1 voxels was observed (figure supplement 1b)."

(3) The authors' response to my previous round of review indicated that the "V1 ROIs" covered a substantial amount of V3 (32%). Therefore, it would no longer be appropriate to call these "V1 ROIs". I'd suggest renaming them as "Early Visual Cortex (EVC) ROIs" to be more accurate. Can the authors justify why choosing the left hemisphere for visual intelligence task, which is typically believed to be right lateralized?

(4) "Small threshold" and "large threshold" are neither standard descriptions, and it is unclear what "small threshold" refers to in the following figure caption. Additionally, the unit (ms) is confusing. Does it refer to timing?

"(f) Peason's correlation showing significant negative correlations between BDT and small threshold."

(5) In the response letter, the authors mentioned incorporating the neural efficiency hypothesis in the Introduction, but the revised Introduction does not contain such information.

Author response:

The following is the authors’ response to the original reviews.

Public Reviews:

Reviewer #1 (Public Review):

Summary:

The study of human intelligence has been the focus of cognitive neuroscience research, and finding some objective behavioral or neural indicators of intelligence has been an ongoing problem for scientists for many years. Melnick et al, 2013 found for the first time that the phenomenon of spatial suppression in motion perception predicts an individual's IQ score. This is because IQ is likely associated with the ability to suppress irrelevant information. In this study, a high-resolution MRS approach was used to test this theory. In this paper, the phenomenon of spatial suppression in motion perception was found to be correlated with the visuo-spatial subtest of gF, while both variables were also correlated with the GABA concentration of MT+ in the human brain. In addition, there was no significant relationship with the excitatory transmitter Glu. At the same time, SI was also associated with MT+ and several frontal cortex FCs.

Strengths:

(1) 7T high-resolution MRS is used.

(2) This study combines the behavioral tests, MRS, and fMRI.

Weaknesses:

(1) In the intro, it seems to me that the multiple-demand (MD) regions are the key in this study. However, I didn't see any results associated with the MD regions. Did I miss something?

Thank you to the reviewer for pointing this out. After careful consideration, we agree with your point of view. According to the results of Melnick 2013, the motion surround suppression (SI) and the time thresholds of small and large gratings representing hMT+ functionality are correlated with Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed Indicators, with correlation coefficients of 0.69, 0.47, 0.49, and 0.50, respectively. This suggests that hMT+ does have the potential to become the core of MD system. However, due to our results only delving into “the GABA-ergic inhibition in human MT predicts visuo-spatial intelligence mediated through the frontal cortex”, it is not yet sufficient to prove that hMT+is the core node of the MD system, we have adjusted the explanatory logic of the article. Briefly, we emphasize the de-redundancy of hMT+ in visual-spatial intelligence and the improvement of information processing efficiency, while weaken the significance of hMT+ in MD systems.

(2) How was the sample size determined? Is it sufficient?

Thank you to reviewer for pointing this out. We use G*power to determine our sample size. In the study by Melnick (2013), they reported a medium effect between SI and Perception Reasoning sub-ability (r=0.47). Here we use this r value as the correlation coefficient (ρ H1), setting the power at the commonly used threshold of 0.8 and the alpha error probability at 0.05. The required sample size is calculated to be 26. This ensures that our study has reasonable power to yield valid statistical results. Furthermore, compared to earlier within-subject studies like Schallmo et al.'s 2018 research, which used 22 datasets to examine GABA levels in MT+ and the early visual cortex (EVC), our study includes an enough dataset.

(3) In Schallmo elife 2018, there was no correlation between GABA concentration and SI. How can we justify the different results different here?

Thank reviewer for pointing this out. There are several differences between us:

a. While the earlier study by Schallmo et al. (2018) employed 3T MRS, we utilize 7T MRS, enhancing our ability to detect and measure GABA with greater accuracy.

b. Schallmo elife 2018 choose to use the bilateral hMT+ as the MRS measurement region while we use the left hMT+. The reason why we focus on left hMT+ are describe in reviewer 1. (6). Briefly, use of left MT/V5 as a target was motivated by studies demonstrating that left MT/V5 TMS is more effective at causing perceptual effects (Tadin et al., 2011).

c. The resolution of MRS sequence in Schallmo elife 2018 is 3 cm isotropic voxel, while we apply 2 cm isotropic voxel. This helps us more precisely locate hMT+ and exclude more white matter signal.

(4) Basically this study contains the data of SI, BDT, GABA in MT+ and V1, Glu in MT+ and V1-all 6 measurements. There should be 6x5/2 = 15 pairwise correlations. However, not all of these results are included in Figure 1 and supplementary 1-3. I understand that it is not necessary to include all figures. But I suggest reporting all values in one Table.

We thank the reviewer for the good suggestion, we have made a correlation matrix to reporting all values in Figure Supplementary 9.

(5) In Melnick (2013), the IQ scores were measured by the full set of WAIS-III, including all subtests. However, this study only used the visual spatial domain of gF. I wonder why only the visuo-spatial subtest was used not the full WAIS-III?

We thank the reviewer for pointing this out. The decision was informed by Melnick’s findings which indicated high correlations between Surround suppression (SI) and the Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed Indexes, with correlation coefficients of 0.69, 0.47, 0.49, and 0.50, respectively. It is well-established that the hMT+ region of the brain is a sensory cortex involved in visual perception processing (3D perception). Furthermore, motion surround suppression (SI), a specific function of hMT+, aligns closely with this region's activities. Given this context, the Perception Reasoning sub-ability was deemed to have the clearest mechanism for further exploration. Consequently, we selected the most representative subtest of Perception Reasoning—the Block Design Test—which primarily assesses 3D visual intelligence.

(6) In the functional connectivity part, there is no explanation as to why only the left MT+ was set to the seed region. What is the problem with the right MT+?

We thank the reviewer for pointing this out. The main reason is that our MRS ROI is the left hMT+, we would like to make different models’ ROI consistent to each other. Use of left MT/V5 as a target was motivated by studies demonstrating that left MT/V5 TMS is more effective at causing perceptual effects (Tadin et al., 2011).

(7) In Melnick (2013), the authors also reported the correlation between IQ and absolute duration thresholds of small and large stimuli. Please include these analyses as well.

We thank the reviewer for the good advice. Containing such result do help researchers compare the result between Melnick and us. We have made such figures in the revised version (Figure 3f, g).

Reviewer #2 (Public Review):

Summary:

Recent studies have identified specific regions within the occipito-temporal cortex as part of a broader fronto-parietal, domain-general, or "multiple-demand" (MD) network that mediates fluid intelligence (gF). According to the abstract, the authors aim to explore the mechanistic roles of these occipito-temporal regions by examining GABA/glutamate concentrations. However, the introduction presents a different rationale: investigating whether area MT+ specifically, could be a core component of the MD network.

Strengths:

The authors provide evidence that GABA concentrations in MT+ and its functional connectivity with frontal areas significantly correlate with visuo-spatial intelligence performance. Additionally, serial mediation analysis suggests that inhibitory mechanisms in MT+ contribute to individual differences in a specific subtest of the Wechsler Adult Intelligence Scale, which assesses visuo-spatial aspects of gF.

Weaknesses:

(1) While the findings are compelling and the analyses robust, the study's rationale and interpretations need strengthening. For instance, Assem et al. (2020) have previously defined the core and extended MD networks, identifying the occipito-temporal regions as TE1m and TE1p, which are located more rostrally than MT+. Area MT+ might overlap with brain regions identified previously in Fedorenko et al., 2013, however the authors attribute these activations to attentional enhancement of visual representations in the more difficult conditions of their tasks. For the aforementioned reasons, It is unclear why the authors chose MT+ as their focus. A stronger rationale for this selection is necessary and how it fits with the core/extended MD networks.

We really appreciate reviewer’s opinions. The reason why we focus on hMT+ is following: According to the results of Melnick 2013, the motion surround suppression (SI) and the time thresholds of small and large gratings representing hMT+ functionality are correlated with Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed Indicators, with high correlation coefficients of 0.69, 0.47, 0.49, and 0.50, respectively. In addition, Fedorenko et al. 2013, the averaged MD activity region appears to overlap with hMT+. Based on these findings, we assume that hMT+ does have the potential to become the core of MD system.

(2) Moreover, although the study links MT+ inhibitory mechanisms to a visuo-spatial component of gF, this evidence alone may not suffice to position MT+ as a new core of the MD network. The MD network's definition typically encompasses a range of cognitive domains, including working memory, mathematics, language, and relational reasoning. Therefore, the claim that MT+ represents a new core of MD needs to be supported by more comprehensive evidence.

Thank reviewer for pointing this out. After careful consideration, we agree with your point of view. Due to our results only delving into visuo-spatial intelligence, it is not yet sufficient to prove that hMT is the core node of the MD system. We will adjust the explanatory logic of the article, that is, emphasizing the de-redundancy of hMT+in visual-spatial intelligence and the improvement of information processing efficiency, while weakening the significance of hMT+ in MD systems.

Reviewer #3 (Public Review):

Summary:

This manuscript aims to understand the role of GABA-ergic inhibition in the human MT+ region in predicting visuo-spatial intelligence through a combination of behavioral measures, fMRI (for functional connectivity measurement), and MRS (for GABA/glutamate concentration measurement). While this is a commendable goal, it becomes apparent that the authors lack fundamental understanding of vision, intelligence, or the relevant literature. As a result, the execution of the research is less coherent, dampening the enthusiasm of the review.

Strengths:

(1) Comprehensive Approach: The study adopts a multi-level approach, i.e., neurochemical analysis of GABA levels, functional connectivity, and behavioral measures to provide a holistic understanding of the relationship between GABA-ergic inhibition and visuo-spatial intelligence.

(2) Sophisticated Techniques: The use of ultra-high field magnetic resonance spectroscopy (MRS) technology for measuring GABA and glutamate concentrations in the MT+ region is a recent development.

Weaknesses:

Study Design and Hypothesis

(1) The central hypothesis of the manuscript posits that "3D visuo-spatial intelligence (the performance of BDT) might be predicted by the inhibitory and/or excitation mechanisms in MT+ and the integrative functions connecting MT+ with the frontal cortex." However, several issues arise:

(1.1) The Suppression Index depicted in Figure 1a, labeled as the "behavior circle," appears irrelevant to the central hypothesis.

We thank the reviewer for pointing this out. In our study, the inhibitory mechanisms in hMT+ are conceptualized through two models: the neurotransmitter model and the behavioral model. The Suppression Index is essential for elucidating the local inhibitory mechanisms within the behavioral model. However, we acknowledge that our initial presentation in the introduction may not have clearly articulated our hypothesis, potentially leading to misunderstandings. We have revised the introduction to better clarify these connections and ensure the relevance of the Suppression Index is comprehensively understood.

(1.2) The construct of 3D visuo-spatial intelligence, operationalized as the performance in the Block Design task, is inconsistently treated as another behavioral task throughout the manuscript, leading to confusion.

We thank the reviewer for pointing this out. We acknowledge that our manuscript may have inconsistently presented this construct across different sections, causing confusion. To address this, we ensured a consistent description of 3D visuo-spatial intelligence in both the introduction and the discussion sections. But we maintained ‘Block Design task score' within the results section to help readers clarify which subtest we use.

(1.3) The schematics in Figure 1a and Figure 6 appear too high-level to be falsifiable. It is suggested that the authors formulate specific and testable hypotheses and preregister them before data collection.

We thank the reviewer for pointing this out. We have revised the Figure 1a and made it less abstract and more logical. For Figure 6, the schematic represents our theoretical framework of how hMT+ contributes to 3D visuo-spatial intelligence, we believe the elements within this framework are grounded in related theories and supported by evidence discussed in our results and discussions section, making them specific and testable.

(2) Central to the hypothesis and design of the manuscript is a misinterpretation of a prior study by Melnick et al. (2013). While the original study identified a strong correlation between WAIS (IQ) and the Suppression Index (SI), the current manuscript erroneously asserts a specific relationship between the block design test (from WAIS) and SI. It should be noted that in the original paper, WAIS comprises Similarities, Vocabulary, Block design, and Matrix reasoning tests in Study 1, while the complete WAIS is used in Study 2. Did the authors conduct other WAIS subtests other than the block design task?

Thank you for pointing this out. Reviewer #1 also asked this question, we copy the answers in here “The decision was informed by Melnick’s findings which indicated high correlations between Surround suppression (SI) and the Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed Indexes, with correlation coefficients of 0.69, 0.47, 0.49, and 0.50, respectively. It is well-established that the hMT+ region of the brain is a sensory cortex involved in visual perception processing (3D perception). Furthermore, motion surround suppression (SI), a specific function of hMT+, aligns closely with this region's activities. Given this context, the Perception Reasoning sub-ability was deemed to have the clearest mechanism for further exploration. Consequently, we selected the most representative subtest of Perception Reasoning—the Block Design Test—which primarily assesses 3D visual intelligence.”

(3) Additionally, there are numerous misleading references and unsubstantiated claims throughout the manuscript. As an example of misleading reference, "the human MT ... a key region in the multiple representations of sensory flows (including optic, tactile, and auditory flows) (Bedny et al., 2010; Ricciardi et al., 2007); this ideally suits it to be a new MD core." The two references in this sentence are claims about plasticity in the congenitally blind with sensory deprivation from birth, which is not really relevant to the proposal that hMT+ is a new MD core in healthy volunteers.

Thank you for pointing this out. We have carefully read the corresponding references and considered the corresponding theories and agree with these comments. Due to our results only delving into “the GABA-ergic inhibition in human MT predicts visuo-spatial intelligence mediated by reverberation with frontal cortex”, it is not yet sufficient to prove that hMT+ is the core node of the MD system, we will adjust the explanatory logic of the article, that is, emphasizing the de redundancy of hMT+in visual-spatial intelligence and the improvement of information processing efficiency, while weakening the significance of hMT+ in MD systems. In addition, regarding the potential central role of hMT+ in the MD system, we agree with your view that research on hMT+ as a multisensory integration hub mainly focuses on developmental processes. Meanwhile, in adults, the MST region of hMT+ is considered a multisensory integration area for visual and vestibular inputs, which potentially supports the role of hMT+ in multitasking multisensory systems (Gu et al., J. Neurosci, 26(1), 73–85, 2006; Fetsch et al., Nat. Neurosci, 15, 146–154, 2012.). Further research could explore how other intelligence sub-ability such as working memory and language comprehension are facilitated by hMT+'s features.

Another example of unsubstantiated claim: the rationale for selecting V1 as the control region is based on the assertion that "it mediates the 2D rather than 3D visual domain (Born & Bradley, 2005)". That's not the point made in the Born & Bradley (2005) paper on MT. It's crucial to note that V1 is where the initial binocular convergence occurs in cortex, i.e., inputs from both the right and left eyes to generate a perception of depth.

Thank you for pointing this out. We acknowledge the inappropriate citation of "Born & Bradley, 2005," which focuses solely on the structure and function of the visual area MT. However, we believe that choosing hMT+ as the domain for 3D visual analysis and V1 as the control region is justified. Cumming and DeAngelis (Annu Rev Neurosci, 24:203–238.2001) state that binocular disparity provides the visual system with information about the three-dimensional layout of the environment, and the link between perception and neuronal activity is stronger in the extrastriate cortex (especially MT) than in the primary visual cortex. This supports our choice and emphasizes the relevance of hMT+ in our study. We have revised our reference in the revised version.

Results & Discussion

(1) The missing correlation between SI and BDT is crucial to the rest of the analysis. The authors should discuss whether they replicated the pattern of results from Melnick et al. (2013) despite using only one WAIS subtest.

We thank for the reviewer’s suggestion. We have placed it in the main text (Figure 3e).

(2) ROIs: can the authors clarify if the results are based on bilateral MT+/V1 or just those in the left hemisphere? Can the authors plot the MRS scan area in V1? I would be surprised if it's precise to V1 and doesn't spread to V2/3 (which is fine to report as early visual cortex).

We thank for the reviewer’s suggestion. We have drawn the V1 ROI MRS scanning area (Figure supplement 1). Using the template, we checked the coverage of V1, V2, and V3. Although the MRS overlap regions extend to V2 (3%) and V3 (32%), the major coverage of the MRS scanning area is in V1, with 65% overlap across subjects.

(3) Did the authors examine V1 FC with either the frontal regions and/or whole brain, as a control analysis? If not, can the author justify why V1 serves as the control region only in the MRS but not in FC (Figure 4) or the mediation analysis (Figure 5)? That seems a little odd given that control analyses are needed to establish the specificity of the claim to MT+

We thank for the reviewer’s suggestion. We have done the V1 FC-behavior connection as control analysis (Figure supplement 7). Only positive correlations in the frontal area were detected, suggesting that in the 3D visuo-spatial intelligence task, V1 plays a role in feedforward information processing. However, hMT+, which showed specific negative correlations in the frontal, is involved in the inhibition mechanism. These results further emphasize the de-redundancy function of hMT+ in 3D visuo-spatial intelligence.

Regarding the mediation analysis, since GABA/Glu concentration in V1 has no correlation with BDT score, it is not sufficient to apply mediation analysis.

(4) It is not clear how to interpret the similarity or difference between panels a and b in Figure 4.

We thank the reviewer for pointing this out. We have further interpreted the difference between a and b in the revised version. Panels a represents BDT score correlated hMT+-region FC, which is obviously involved in frontal cortex. While panels b represents SI correlated hMT+-region FC, which shows relatively less regions. The overlap region is what we are interested in and explain how local inhibitory mechanisms works in the 3D visuo-spatial intelligence. In addition, we have revised Figure 4 and point out the overlap region.

(5) SI is not relevant to the authors‘ priori hypothesis, but is included in several mediation analyses. Can the authors do model comparisons between the ones in Figure 5c, d, and Figure S6? In other words, is SI necessary in the mediation model? There seem discrepancies between the necessity of SI in Figures 5c/S6 vs. Figure 5d.

We thank the reviewer for highlighting this point. The relationship between the Suppression Index (SI) and our a priori hypotheses is elaborated in the response to reviewer 3, section (1). SI plays a crucial role in explicating how local inhibitory mechanisms, on the psychological level, function within the context of the 3D visuo-spatial task. Additionally, Figure 5c illustrates the interaction between the frontal cortex and hMT+, showing how the effects from the frontal cortex (BA46) on the Block Design Task are fully mediated by SI. This further underscores the significance of SI in our model.

(6) The sudden appearance of "efficient information" in Figure 6, referring to the neural efficiency hypothesis, raises concerns. Efficient visual information processing occurs throughout the visual cortex, starting from V1. Thus, it appears somewhat selective to apply the neural efficiency hypothesis to MT+ in this context.

We thank the reviewer for highlighting this point. There is no doubt that V1 involved in efficient visual information processing. However, in our result, the V1 GABA has no significant correlation between BDT score, suggesting that the V1 efficient processing might not sufficiently account for the individual differences in 3D visuo-spatial intelligence. Additionally, we will clarify our use of the neural efficiency hypothesis by incorporating it into the introduction of our paper to better frame our argument.

Transparency Issues:

(1) Don't think it's acceptable to make the claim that "All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary information". It is the results or visualizations of data analysis, rather than the raw data themselves, that are presented in the paper/supp info.

We thank the reviewer for pointing this out. We realized that such expression would lead to confusion. We have deleted this expression.

(2) No GitHub link has been provided in the manuscript to access the source data, which limits the reproducibility and transparency of the study.

We thank the reviewer for pointing this out. We have attached the GitHub link in the revised version.

Minor:

"Locates" should be replaced with "located" throughout the paper. For example: "To investigate this issue, this study selects the human MT complex (hMT+), a region located at the occipito-temporal border, which represents multiple sensory flows, as the target brain area."

We thank the reviewer for pointing this out. We have revised it.

Use "hMT+" instead of "MT+" to be consistent with the term in the literature.

We thank the reviewer for pointing this out. We agree to use hMT+ in the literature.

"Green circle" in Figure 1 should be corrected to match its actual color.

We thank the reviewer for pointing this out. We have revised it.

The abbreviation for the Wechsler Adult Intelligence Scale should be "WAIS," not "WASI."

We thank the reviewer for pointing this out. We have revised it.

Recommendations for the authors:

Reviewer #1 (Recommendations For The Authors):

(1) The figures and tables should be substantially improved.

We thank the reviewer for pointing this out. We have improved some of the figures’ quality.

(2) Please explain the sample size, and the difference between Schallmo eLife 2018, and Melnick, 2013.

We thank the reviewer for pointing this out. These questions are answered in the public review. We copy the answer in the public review.

(2.1) How was the sample size determined? Is it sufficient??

Thank you to the reviewer for pointing this out. We use G*power to determine our sample size. In the study by Melnick (2013), they reported a medium effect between SI and Perception Reasoning sub-ability (r=0.47). Here we use this r value as the correlation coefficient (ρ H1), setting the power at the commonly used threshold of 0.8 and the alpha error probability at 0.05. The required sample size is calculated to be 26. This ensures that our study has adequate power to yield valid statistical results. Furthermore, compared to earlier within-subject studies like Schallmo et al.'s 2018 research, which used 22 subjects to examine GABA levels in MT+ and the early visual cortex (EVC), our study includes an enough dataset.

(2.2) In Schallmo elife 2018, there was no correlation between GABA concentration and SI. How can we justify the different results different here?

Thank you to the reviewer for pointing this out. There are several differences between the two studies, ours and theirs:

a. While the earlier study by Schallmo et al. (2018) employed 3T MRS, we utilize 7T MRS, enhancing our ability to detect and measure GABA with greater accuracy.

b. Schallmo elife 2018 choose to use the bilateral hMT+ as the MRS measurement region while we use the left hMT+. The reason why we focus on left hMT+ are described in review 1. (6). Briefly, use of left MT/V5 as a target was motivated by studies demonstrating that left MT/V5 TMS is more effective at causing perceptual effects (Tadin et al., 2011).

c. The resolution of MRS sequence in Schallmo elife 2018 is 3 cm isotropic voxel, while we apply 2 cm isotropic voxel. This helps us more precisely locate hMT+ and exclude more white matter signal.

(3) Table 1 and Table Supplementary 1-3 contain many correlation results. But what are the main points of these values? Which values do the authors want to highlight? Why are only p-values shown with significance symbols in Table Supplementary 2?

(3.1) what are the main points of these values?

Thank you to the reviewer for pointing this out. These correlations represent the relationship between behavior task (SI/BDT) and resting-state functional connectivity. It indicates that left hMT+ is involved in the efficient information integration network when it comes to the BDT task. In addition, left hMT+’s surround suppression is involved in several hMT+ - frontal connectivity. Furthermore, the overlapping regions between two tasks indicate a shared underlying mechanism.

(3.2) Which values do the authors want to highlight?

Table 1 and Table Supplementary 1-3 present the preliminary analysis results for Table 2 and Table Supplementary 4-6. So, we generally report all value. Conversely, in the Table 2 and Table Supplementary 4-6, we highlight (bold font) indicating the significant correlations survived from multi correlation correction.

(3.3) Why are only p-values shown with significance symbols in Table Supplementary 2?

Thank you for pointing this out, it is a mistake. We have revised it and delete the significance symbols.

(4) Line 27, it is unclear to me what is "the canonical theory".

We thank the reviewer for pointing this out. We have revised “the canonical theory" to “the prevailing opinion”.

(5) Throughout the paper, the authors use "MT+", I would suggest using "hMT+" to indicate the human MT complex, and to be consistent with the human fMRI literature.

We thank the reviewer for pointing this out. We have revised them and used "hMT+" to be consistent with the human fMRI literature.

(6) At the beginning of the results section, I suggest including the total number of subjects. It is confusing what "31/36 in MT+, and 28/36 in V1" means.

We thank the reviewer for pointing this out. We have included the total number of subjects in the beginning of result section.

(7) Line 138, "This finding supports the hypothesis that motion perception is associated with neural activity in MT+ area". This sentence is strange because it is a well-established finding in numerous human fMRI papers. I think the authors should be more specific about what this finding implies.

We thank the reviewer for pointing this out. We have deleted the inappropriate sentence "This finding supports the hypothesis that motion perception is associated with neural activity in MT+ area".

(8) There are no unit labels for all x- and y-axies in Figure 1. I only see the unit for Conc is mmol per kg wet weight.

We thank the reviewer for pointing this out. Figure 1 is a schematic and workflow chart, so labels for x- and y-axes are not needed. I believe this confusion might pertain to Figure 3. In Figures 3a and 3b, the MRS spectrum does not have a standard y-axis unit as it varies based on the individual physical conditions of the scanner; it is widely accepted that no y-axis unit is used. While the x-axis unit is ppm, which indicate the chemical shift of different metabolites. In Figure 3c, the BDT represents IQ scores, which do not have a standard unit. Similarly, in Figures 3d and 3e, the Suppression Index does not have a standard unit.

(9) Although the correlations are not significant in Figure Supplement 2&3, please also include the correlation line, 95% confidence interval, and report the r values and p values (i.e., similar format as in Figure 1C).

We thank the reviewer for pointing this out. We have revised them.

(10) There is no need to separate different correlation figures into Figure Supplementary 1-4. They can be combined into the same figure.

We thank the reviewer for the suggestion. However, each correlation figure in the supplementary figures has its own specific topic and conclusion. The correlation figures in Supplementary Figure 1 indicate that GABA in V1 does not show any correlation with BDT and SI, illustrating that inhibition in V1 is unrelated to both 3D visuo-spatial intelligence and motion suppression processing. The correlations in Supplementary Figure 2 indicate that the excitation mechanism, represented by Glutamate concentration, does not contribute to 3D visuo-spatial intelligence in either hMT+ or V1. Supplementary Figure 3 validates our MRS measurements. Supplementary Figure 4 addresses potential concerns regarding the impact of outliers on correlation significance. Even after excluding two “outliers” from Figures 3d and 3e, the correlation results remain stable.

(11) Line 213, as far as I know, the study (Melnick et al., 2013) is a psychophysical study and did not provide evidence that the spatial suppression effect is associated with MT+.

We thank the reviewer for pointing this out. It was a mistake to use this reference, and we have revised it accordingly.

(12) At the beginning of the results, I suggest providing more details about the motion discrimination tasks and the measurement of the BDT.

We thank the reviewer for pointing this out. We have included some brief description of task at the beginning of the result section.

(13) Please include the absolute duration thresholds of the small and large sizes of all subjects in Figure 1.

We thank the reviewer for the suggestion. We have included these results in Figure 3.

(14) Figure 5 is too small. The items in plot a and b can be barely visible.

We thank the reviewer for pointing this out. We increase the size and resolution of Figure 5.

Reviewer #2 (Recommendations For The Authors):

Recommendations for improving the writing and presentation.

I highly recommend editing the manuscript for readability and the use of the English language. I had significant difficulties following the rationale of the research due to issues with the way language was used.

We thank the reviewer for pointing this out. We apologize for any shortcomings in our initial presentation. We have invited a native English speaker to revise our manuscript.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation