Spatially Periodic Computation in the Entorhinal-Hippocampal Circuit During Navigation

Reviewer #1 (Public review):

Summary:

Zhang and colleagues examine neural representations underlying abstract navigation in the entorhinal cortex (EC) and hippocampus (HC) using fMRI. This paper replicates a previously identified hexagonal modulation of abstract navigation vectors in abstract space in EC in a novel task involving navigating in a conceptual Greeble space. In HC, the authors claim to identify a three-fold signal of the navigation angle. They also use a novel analysis technique (spectral analysis) to look at spatial patterns in these two areas and identify phase coupling between HC and EC. Finally, the authors propose an EC-HPC PhaseSync Model to understand how the EC and HC construct cognitive maps. While the wide array of techniques used is impressive and their creativity in analysis is admirable, overall, I found the paper a bit confusing and unconvincing. I recommend a significant rewrite of their paper to motivate their methods and clarify what they actually did and why. The claim of three-fold modulation in HC, while potentially highly interesting to the community, needs more background to motivate why they did the analysis in the first place, more interpretation as to why this would emerge in biology, and more care taken to consider alternative hypotheses seeped in existing models of HC function. I think this paper does have potential to be interesting and impactful, but I would like to see these issues improved first.

General comments:

(1) Some of the terminology used does not match the terminology used in previous relevant literature (e.g., sinusoidal analysis, 1D directional domain).

(2) Throughout the paper, novel methods and ideas are introduced without adequate explanation (e.g., the spectral analysis and three-fold periodicity of HC).

Reviewer #2 (Public review):

The authors report results from behavioral data, fMRI recordings, and computer simulations during a conceptual navigation task. They report 3-fold symmetry in behavioral and simulated model performance, 3-fold symmetry in hippocampal activity, and 6-fold symmetry in entorhinal activity (all as a function of movement directions in conceptual space). The analyses are thoroughly done, and the results and simulations are very interesting.

Author response:

Reviewer #1, Comment (1): Terminology

We fully acknowledge the importance of terminological consistency and will align our usage with established literature. Specifically, we will revise as follows,

(1) Replace “sinusoidal analysis” with either “sinusoidal modulation” (Doeller et al., 2010; Bao et al., 2019; Raithel et al., 2023) or “GLM with sinusoidal (cos/sin) regressors” (Constantinescu et al., 2016).

(2) Replace “1D directional domain” with either “angular domain of movement directions (0–360°)” or “directional modulation analysis”.

Reviewer #1, Comment (2): Spectral analysis and 3-fold periodicity

We agree that the presentation of our spectral analysis and the theoretical motivation underlying our expectation of a three-fold periodicity within hippocampal data requires further clarification.

In our revised manuscript, we will:
(1) Clearly articulate the theoretical motivation for anticipating a three-fold signal, explicitly linking it to the known hexagonal grid structure encoded by the entorhinal cortex.

(2) Clarify our methodological rationale for using Fourier analysis (FFT).

a) FFT allows unbiased exploration of multiple candidate periodicities (e.g., 3–7-fold) without predefined assumptions.

b) FFT results cross-validate our sinusoidal modulation results, providing complementary evidence supporting the 6-fold periodicity in EC and 3-fold periodicity in HPC.

c) FFT uniquely facilitates analysis of periodicities in behavioral performance data, which is not feasible via standard sinusoidal GLM approaches. This consistency allows us to directly compare periodicities across neural and behavioral data.

(3) Further, we will expand our discussion to provide:

a) A deeper interpretation of potential biological bases for the observed hippocampal three-fold periodicity.

b) A careful examination of alternative explanations within existing hippocampal modeling frameworks.

Reference:

Doeller, C. F., Barry, C., & Burgess, N. (2010). Evidence for grid cells in a human memory network. Nature, 463(7281), 657-661.

Constantinescu, A. O., O'Reilly, J. X., & Behrens, T. E. J. (2016). Organizing conceptual knowledge in humans with a gridlike code. Science, 352(6292), 1464-1468.

Bao, X., Gjorgieva, E., Shanahan, L. K., Howard, J. D., Kahnt, T., & Gottfried, J. A. (2019). Grid-like neural representations support olfactory navigation of a two-dimensional odor space. Neuron, 102(5), 1066-1075.

Raithel, C. U., Miller, A. J., Epstein, R. A., Kahnt, T., & Gottfried, J. A. (2023). Recruitment of grid-like responses in human entorhinal and piriform cortices by odor landmark-based navigation. Current Biology, 33(17), 3561-3570