The replication principle revisited: a shared functional organization between pulvinar-cortical and cortico-cortical connectivity and its structural and molecular imaging correlates

Reviewer #1 (Public review):

Summary:

The current work explored the link between the pulvinar intrinsic organisation and its functional and structural connectivity patterns of the cortex using different dimensional reduction techniques. Overall they find relationships between pulvinar-cortical organization and cortico-cortical organization, and little evidence for clustered organization. Moreover, they investigate PET maps to understand how neurotransmitter/receptor distributions vary within the pulvinar and along its structural and functional connectivity axes.

Strengths:

There is a replication dataset and different modalities are compared against each other to understand the structural and functional organisation of the pulvinar complex.

Weaknesses:

(1) What is the motivation of the study and how does this work extend previous assessments of the organization of the complete thalamus within the gradient framework?

(2) Why is the current atlas chosen for the delineation of the pulvinar and individualised maps not considered? Given the size of the pulvinar, more validation of the correctness of the atlas may be helpful.

(3) Overall the study feels a little incremental and a repetition of what others have done already in the thalamus. It would be good to know how focussing only on the pulvinar changes interpretation, for example by comparing thalamic and pulvinar gradients?

(4) Could it be that the gradient patterns stem from lacking anatomical and functional resolutions (or low SNR) therefore generating no sharp boundaries?

Reviewer #2 (Public review):

Summary:

The authors aimed to explore and better understand the complex topographical organization of the human pulvinar, a brain region crucial for various high-order functions such as perception and attention. They sought to move beyond traditional histological subdivisions by investigating continuous 'gradients' of cortical connections along the dorsoventral and mediolateral axes. Using advanced imaging techniques and a comprehensive PET atlas of neurotransmitter receptors, the study aimed to identify and characterize these gradients in terms of structural connections, functional coactivation, and molecular binding patterns. Ultimately, the authors targeted to provide a more nuanced understanding of pulvinar anatomy and its implications for brain function in both healthy and diseased states.

Strengths:

A key strength of this study lies in the authors' effort to comprehensively combine multimodal data, encompassing both functional and structural connectomics, alongside the analysis of major neurotransmitter distributions. This approach enabled a more nuanced understanding of the overarching organizational principles of the pulvinar nucleus within the broader context of whole-brain connectivity. By employing cortex-wide correlation analyses of multimodal embedding patterns derived from 'gradients,' which provide spatial maps reflecting the underlying connectomic and molecular similarities across voxels, the study offers a thorough characterization of the functional neuroanatomy of the pulvinar.

Weaknesses:

Despite its strengths, the current manuscript falls short in presenting the authors' unique perspectives on integrating the diverse biological principles derived from the various neuroimaging modalities. The findings are predominantly reported as correlations between different gradient maps, without providing the in-depth interpretations that would allow for a more comprehensive understanding of the pulvinar's role as a central hub in the brain's network. Another limitation of the study is the lack of clarity regarding the application of pulvinar and its subnuclei segmentation maps to individual brains prior to BOLD signal extraction and gradient reconstruction. This omission raises concerns about the precision and reproducibility of the findings, leaving their robustness less transparently evaluable.

Reviewer #3 (Public review):

Summary of the Study:

The authors investigate the organization of the human pulvinar by analyzing DWI, fMRI, and PET data. The authors explore the hypothesis of the "replication principle" in the pulvinar.

Strengths and Weaknesses of the Methods and Results:

The study effectively integrates diverse imaging modalities to provide a view of the pulvinar's organization. The use of analysis techniques, such as diffusion embedding-driven gradients combined with detailed interpretations of the pulvinar, is a strength.

Even though the study uses the best publicly available resolution possible with current MR-technology, the pulvinar is densely packed with many cell bodies, requiring even higher spatial resolution. In addition, the model order selection of gradients may vary with the acquired data quality. Therefore, the pulvinar's intricate organization needs further exploration with even higher spatial resolution to capture gradients closer to the biological organization of the pulvinar.

Appraisal of the Study's Aims and Conclusions:

The authors delineate the gradient organization of the pulvinar. The study provides a basis for understanding the pulvinar's role in mediating brain network communication.

Impact and Utility of the Work:

This work contributes to the field by offering insights into pulvinar organization.