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  1. Evaluation Summary:

    Grande and colleagues provide new insights into how different regions of the entorhinal cortex functionally interact with specific cortical brain areas and how, in turn, subregions of the entorhinal cortex interact with the hippocampus during 'scene' and 'object' processing. This paper is relevant to cognitive neuroscientists with an interest in the entorhinal cortex - hippocampal pathways and 'scene' and 'object' representation in the medial temporal lobe. The study is well-motivated, well-designed and appropriately analysed to address the research questions. Most conclusions of the paper are well supported by the 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 and Reviewer #2 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    Grande et al report the results of a series of functional connectivity experiments that build upon and extend results reported in Maass et al. (2015). The authors conducted three separate but interrelated analyses with a primary aim of characterising entorhinal-hippocampal processing pathways in the human brain.

    The first analysis served to identify subregions within the entorhinal cortex (EC) that preferentially connect with the retrosplenial cortex (RSC), posterior parahippocampal cortex (PHC) and perirhinal areas 35 (A35) and 36 (A36). The results of this analysis revealed that the RSC and PHC preferentially connect with the anterior medial EC and posterior medial EC respectively while A35 and A36 preferentially connect with the anterior lateral EC and posterior lateral EC respectively. In a second analysis, the authors evaluated patterns of functional connectivity between the four entorhinal subregions identified in Analysis 1 and specific subfields of the hippocampus, namely the subiculum and CA1. The authors provide evidence that each EC subregion preferentially connects with specific regions along the transverse (medial-lateral) axis of the subiculum and CA1.

    In a third analysis, the authors investigated whether 'object' and 'scene' information is differentially processed within EC subregions and along the transverse axis of the subiculum and CA1. Results revealed that the posterior medial EC and distal (medial) subiculum were preferentially engaged by 'scene' stimuli. In contrast, anterior regions of the EC and the CA1/subiculum border were equally engaged by 'object' and 'scene' stimuli. The authors propose that the posterior medial EC and distal subiculum may represent a unique route for scene/contextual information flow while anterior regions of the EC and the CA1/subiculum border may be involved in integrating both 'scene' and 'object' information.

    Overall, the study was well-motivated, well-designed and appropriately analysed to address the research questions. The conclusions of the paper are well supported by the data.

    The primary novelty of these results relate to the characterisation of how the RSC, PHC, A35 and A36 functionally connect with different portions of the EC and how, in turn, these EC subregions preferentially connect along the medial-lateral axis of the subiculum and CA1. These new and detailed insights will have an impact on and advance current theoretical models of entorhinal-hippocampal functional organisation in the human brain with implications for our understanding of human memory processing and its dysfunction.

    The study also provides new evidence regarding the functional organisation of EC-hippocampal circuitry as it relates to 'object' and 'scene' processing. Results of this component of the analysis support accumulating evidence that medial portions of the hippocampus and EC are preferentially engaged during scene-based cognition.

    Taken together, the results of this study inform and extend current theoretical models of entorhinal-hippocampal information processing pathways in the human brain.

    A major strength of the study is the detailed approach used to investigate each cortical region of interest (ROI), to characterise their functional connectivity with subregions of the EC and, in turn, how these EC subregions functionally relate to hippocampal subfields. The authors take advantage of the rich dataset acquired at 7T to gain new insights into entorhinal-hippocampal functional interactions.

    While the detailed approach noted above is a major strength of the study, it is also the source of some weaknesses. For example, when manually segmenting small ROIs (such as hippocampal subfields), quality assurance measures are important to give the reader confidence that the ROI masks are, as accurately as possible, measuring what we think they are measuring. A weakness of this study in its current form is that no quality assurance measures have been presented for the ROIs. The authors provide no metrics relating to intra- or inter-rater reliability (e.g., DICE metrics) for the manually segmented ROIs. Also, it can be difficult to warp small ROIs such as hippocampal subfields to EPI images with sufficient accuracy. No data is presented to assure readers that the ROIs (manually segmented on structural images and then warped to EPI space) were well aligned with the EPI images.

    It is also important to note that the subiculum mask used in this study appears to encompass the entire 'subicular complex' inclusive of the subiculum, presubiculum and parasubiculum. Importantly, the pre- and parasubiculum are located on the medial most aspect of the 'subicular complex' but this region is referred to throughout the current study as the 'distal subiculum'. Therefore, results attributed to the distal subiculum likely also reflect functional activation of the pre- and parasubiculum. Indeed, this makes sense considering accumulating evidence that the pre- and parasubiculum are preferentially engaged during scene-based cognition. Interpretation of results relating to the 'distal subiculum' should, therefore, be interpreted with this in mind.

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  3. Reviewer #2 (Public Review):

    In the paper, the authors re-visit the important and still debated concept of functionally different cortical processing streams into the hippocampal memory system. Based on an elegant merger of functional connectivity analyses with functional activation data they convincingly argue the presence of two functionally different streams, one preferentially dealing with scene information, and the second dealing with a mixture of scene and object information. Traditionally, these two parallel cortical streams have been associated with on the one hand scenes, context or spatial representations, and on the other hand with objects and more recently with information about sequences. What the authors conclude, although this could have been formulated more explicitly, is that in contrast to the traditional idea that the convergence between these two different cortical streams takes place in the hippocampal formation, it actually takes place in the entorhinal cortex. In the discussion this new concept, which is in line with a recent proposal based on animal data, is put into the context of functional deficits seen in early stage Alzheimer's dementia.

    The combination of the different imaging modalities makes this a very strong paper, not just since it further details the organization of the human medial temporal lobe memory system in terms of functional input streams, showing that animal experimental data cannot easily be translated to use on the human brain. It also puts these findings into the context of an important disease opening up new avenues for more focused clinical studies on Alzheimer's disease. This is presented in a clear and convincing way. A further strength of the study is that the authors discuss potential shortcomings of the methods used and thus where conclusions are still open to debate.

    The paper has one main weakness in my view, and this is that the language to describe the data is often complex, some underlying important concepts are not well explained, and in the description of the data and the discussion, clearly defined concepts and descriptors would help immensely.

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  4. Reviewer #3 (Public Review):

    Grande and colleagues used high-resolution 7 Tesla fMRI to investigate the topographical distribution of functional connectivity, and sensitivity to scene and object stimuli, across subregions of the entorhinal-hippocampal circuitry. They report scene-specific activations in functionally connected voxels of the posterior-medial entorhinal cortex (EC) and the distal subiculum. In contrast, no specific preference for object stimuli was detected.

    The authors managed to characterize functional connectivity patterns in the entorhinal-hippocampal circuitry to an impressive level of detail. The division of the subiculum and CA1 region in 5 and 3 segments, respectively, extends the very sparse body of literature on the organization of connectivity across the transversal axis of the hippocampal formation in humans. Notably, the authors replicate findings by Maass et al. 2015 of a dissociation of functional connectivity preference between voxels in anterior-lateral and posterior-medial EC with voxels in proximal and distal subiculum (informed by the well-described connectivity architecture of the hippocampal formation in rodents; see e.g. Witter et al. 2000). In addition, they report the novel finding of specific functional connectivity preference of voxels in anterior-medial and anterior-lateral EC seed regions with distal CA1 (again consistent with previous findings in rodents, as well as diffusion MRI findings in humans; Syversen et al. 2021).

    After having established 4 different clusters of entorhinal voxels based on functional connectivity to 4 'source' regions, the authors report specific scene sensitivity in a posterior-medial cluster, partially replicating previous studies. In addition, they describe another novel finding of specific scene sensitivity in the two most distal segments of the subiculum.

    I agree with the authors that understanding the connectivity of hippocampal subregions and their functional preferences is an important goal with relevance for many research disciplines, such as on episodic memory, spatial navigation, or Alzheimer's disease.

    While the paper makes a number of important contributions to help understand entorhinal-hippocampal function and connectivity, I feel that the premise and research question is somewhat unclear and potentially misleading. Most notably, I don't think the conclusions pertaining to processing of object (item) information are supported by the results. An absence of a difference does not provide evidence for similar levels of processing of object and scene information.

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