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  1. Evaluation Summary:

    This is an interesting quantitative study of the anatomical connections of a region of prefrontal cortex that has often been overlooked - the Ventrolateral Prefrontal Cortex. The idea that this is a special region that is different to both the rest of ventrolateral prefrontal cortex and probably the rest of orbitofrontal cortex is important because it helps us understand some otherwise puzzling results. The quantitative analysis of connections is an unusual strength of the study as is the comparison of tracer data in macaques, fMRI connectivity data in macaques, and human fMRI connectivity data.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    This paper addresses an important gap in the literature, namely testing the role of the ventrolateral prefrontal cortex (vlPFC) in large-scale networks and in particular in the salience network (SN). A translational and multimodal approach was chosen in which tract-tracing in non-human primates (NHP) was used to quantify the anatomic connectivity strength between the different vlPFC areas and frontal and insular cortices. Next, seed-based functional connectivity analyses in NHP and human resting-state functional connectivity MRI (fcMRI) were used to validate the tract-tracing results. In sum, this study shows that the vlPFC contains nodes for all three tested networks, the VAN, DAN, and SN and the authors conclude that it may play a key role as an attentional hub.

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  3. Reviewer #2 (Public Review):

    Trambaiolli and colleagues combine ground-truth tract tracing experiments in macaques with translationally-relevant resting-state functional connectivity analyses of fMRI data collected from both macaques and humans. Analysing these data, they comprehensively show that the ventrolateral prefrontal cortex (vlPFC) is a hub connected with two regions that are part of the salience network (SN): the anterior insular cortex (AI) and dorsal anterior cingulate cortex (dACC). The methods are state of the art and combining multiple approaches means that the limitations of one method can compensate for the limitations of the other. The main result they report is the strong connection of the vlPFC region, area 47/12, with both dACC and AI. Then using fMRI functional connectivity analyses from a single macaque they show that anatomical connections identified using tract tracing are mirrored by activity correlations between 47/12, AI and ACC. Extending this work to resting-state fMRI data collected from 1000 humans, the authors show that there is a coupling between 47/12, ACC and AI. Based on these findings, the authors suggest vlPFC should be included as one node of the SN alongside the other two regions. These results are relevant as vlPFC is already part of the dorsal and ventral attentional network that have been identified in humans. Its inclusion as one of the nodes of the SN as well therefore has important implications for cognitive neuroscience and basic understanding of functional networks and their hubs. Based on this, vlPFC would appear to be a major hub as it links multiple functional networks.

    Despite the importance of the work and generally solid methods, there are a number of issues with the current work that need to be addressed. Most notably some additional analyses are required to ensure the validity and reliability of the results that are reported, especially in the macaque imaging data where analyses appear to have been conducted on a high-quality dataset from a single macaque.

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  4. Reviewer #3 (Public Review):

    This is an interesting quantitative study of the anatomical connections of a region of prefrontal cortex that has often been overlooked because it is at the border of what is typically called ventrolateral prefrontal cortex and orbitofrontal prefrontal cortex (the unusual location is apparent in figure 2b). Sometimes it is included as part of ventrolateral prefrontal cortex, sometimes as part of orbitofrontal cortex and sometimes it is simply given little attention because ventrolateral prefrontal cortex studies focus on the inferior convexity and orbital studies focus on the region between the orbitofrontal sulci. The idea that this is a special region that is different to both the rest of ventrolateral prefrontal cortex and probably the rest of orbitofrontal cortex is important because it helps us understand some otherwise puzzling reports about the orbitofrontal and ventrolateral prefrontal cortex.

    To investigate the connections of the caudal and orbital part of 47/12, Trambaiolli report the distribution of tracer labels across ventralateral prefrontal, insular, and cingulate cortex when tracer injections were made in a number of these areas. This provides the initial key evidence for specialized sub-regions in 47/12. Second, they follow this up with an examination of the patterns of correlation in activity between sub-divisions of area 47/12 and other brain regions that are apparent in analysis of resting state functional magnetic resonance imaging (fMRI) MION contrast data taken from a macaque. Finally, they report an analogous analysis of resting state fMRI BOLD contrast data from human participants that leads them to infer similar patterns of interconnections between the cytoarchitectural similar areas of the human brain.

    The quantitative analysis of connections was an unusual strength of the study as was the comparison of tracer data in macaques, fMRI connectivity data in macaques, and human fMRI connectivity data.

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