0264

Investigating structural and functional connectivity of human entorhinal subregions using DTI and fMRI
Ingrid Framås Syversen1,2, Daniel Reznik3, Tobias Navarro Schröder1, and Christian F. Doeller1,3,4
1Kavli Institute for Systems Neuroscience, NTNU - Norwegian University of Science and Technology, Trondheim, Norway, 2Department of Diagnostic Imaging, Akershus University Hospital, Lørenskog, Norway, 3Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, 4Institute of Psychology, Leipzig University, Leipzig, Germany

Synopsis

Despite previous attempts to localize the human homologues of the medial (MEC) and lateral entorhinal cortex (LEC) using fMRI and DTI separately, there are still uncertainties related to the choice of imaging modality and seed regions used. In this study, we investigated both structural connectivity from DTI and functional connectivity from fMRI between the EC and associated brain regions. Differential EC connectivity to these regions was then used to predict the locations of the human homologues of MEC and LEC. Our results from both DTI and fMRI showed a qualitatively similar subdivision into posteromedial and anterolateral EC, supporting previous studies.

Introduction

The entorhinal cortex (EC), a part of the hippocampal formation in the medial temporal lobe of the brain, is central in cognitive processes such as memory formation, spatial navigation and time perception1-4. Its two main subregions – the ‘medial’ (MEC) and ‘lateral’ entorhinal cortex (LEC) – differ in both functional properties and connectivity to other brain regions5-7. However, while the locations of MEC and LEC have been identified in other species such as rodents, their human homologues remain unclear. Despite previous studies using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to investigate this, there are still uncertainties related to the choice of imaging modality and seed regions for connectivity analysis8-12. Identifying the locations of MEC and LEC in humans has importance both in cognitive neuroscience and in translational studies on e.g. Alzheimer’s disease, which partially starts in the EC13. The purpose of this study was to compare using structural connectivity from DTI with functional connectivity from fMRI for predicting the locations of the human homologues of MEC and LEC.

Methods

T1-weighted, diffusion-weighted and resting-state functional MRI data from 81 participants were obtained from the WU-Minn Human Connectome Project (http://db.humanconnectome.org)14,15, acquired on a 3T Siemens Connectome Skyra scanner and a 7T Siemens Magnetom scanner (Siemens Medical Systems, Erlangen, Germany). Diffusion-weighted images were acquired at 3T and 7T, respectively, using spin-echo EPI sequences with 1.25 and 1.05 mm isotropic resolution, and with b-values of 1000, 2000, 3000 s/mm2 and 1000, 2000 s/mm2 in addition to a set of b = 0 images16,17. fMRI data were acquired at 7T using a gradient-echo EPI sequence with 1.6 mm isotropic resolution18-20. There were two resting-state runs with posterior-anterior (PA) and two runs with anterior-posterior (AP) phase encoding direction, and in each run 900 image volumes were acquired over 16 minutes.

Regions of interest (ROIs) of the EC, presubiculum, distal CA1 + proximal subiculum (dCA1pSub), retrosplenial cortex (RSC) and posterolateral orbitofrontal cortex (OFC) were obtained from automated cortical parcellation12,21,22. Probabilistic tractography between the EC and the other four ROIs was then performed on the 3T and 7T DTI data23-27. From this, structural connectivity maps representing the probability of each voxel in the EC to be connected to the other ROIs were created. Seed-based functional connectivity analysis was performed on the PA and AP fMRI data, by calculating the Pearson correlation between the time series of each voxel in the EC and the four other ROIs – creating functional connectivity maps as well.

The structural and functional connectivity maps were used separately to segment the EC into the human MEC and LEC homologues. We defined MEC as being more strongly connected to presubiculum and RSC, whereas LEC was defined as being more strongly connected to dCA1pSub and OFC12,28-36. The segmentation was performed as a “hard segmentation”37,38 based on numerical preference to the connectivity maps, although while scaling the maps iteratively until the sizes of the resulting MEC and LEC were approximately equal. At last, total MEC and LEC probability maps were created by combining the structural and functional segmentation results.

Results

The structural connectivity maps and segmentation from using DTI are shown in Figure 1, while the functional connectivity maps and segmentation from using fMRI are shown in Figure 2. Figure 3 shows the total combined probability of MEC and LEC locations. Both the structural and functional connectivity approaches show relatively distinguishable differences between posteromedial and anterolateral parts of the EC.

Discussion

Structural and functional connectivity analyses resulted in qualitatively similar patterns of connectivity to the other ROIs within the EC. While presubiculum and RSC were more strongly connected to posterior and medial EC, dCA1pSub and OFC were more strongly connected to anterior and lateral EC. Using DTI and fMRI to segment the EC subregions resulted in similar locations of the MEC and LEC homologues, namely posteromedial (pmEC) and anterolateral EC (alEC), respectively. This is qualitatively similar to the results from previous fMRI and DTI studies10-12.

The fMRI-based segmentation showed a slightly higher degree of posterior-anterior subdivision of the EC than the DTI results, and a correspondingly lower degree of medial-lateral subdivision. It is uncertain whether these differences are a result of actual biological differences in structural vs. functional connectivity, or if they are caused by inherent differences or limitations in the modalities and analysis methods. Future studies should map the EC connectivity to even more brain regions, and optimize the DTI and fMRI acquisition protocols and analysis pipelines in order to reduce such uncertainties.

Conclusion

The results from this study show that both DTI and fMRI yield qualitatively similar subdivisions of the EC, and support the subdivision of the human EC into pmEC and alEC as suggested in previous studies. The MEC and LEC homologues defined in this study can be applied to cognitive and translational MRI studies, although they should be further validated across cohorts, imaging modalities and with a larger number of seed regions.

Acknowledgements

We want to thank Menno P. Witter and Asgeir Kobro-Flatmoen for anatomical advice regarding the choices and delineations of ROIs, as well as topography of connections. We also want to thank Pål Erik Goa for assistance on MRI physics and image quality.

Data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University.

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Figures

Figure 1: Group-averaged structural connectivity maps and MEC and LEC segmentations from DTI. Results are shown on selected sagittal (left) and coronal (right) brain slices. A: EC connectivity to presubiculum+RSC, B: EC connectivity to dCA1pSub+OFC. C: Segmentation of MEC (blue) and LEC (red) homologues based on the structural connectivity maps, shown both on coronal and sagittal slices and in 3D (bottom row). S = superior, I = inferior, A = anterior, P = posterior, R = right, L = left.

Figure 2: Group-averaged functional connectivity maps and MEC and LEC segmentations from fMRI. Results are shown on selected sagittal (left) and coronal (right) brain slices. A: EC connectivity to presubiculum+RSC, B: EC connectivity to dCA1pSub+OFC. C: Segmentation of MEC (blue) and LEC (red) homologues based on the functional connectivity maps, shown both on coronal and sagittal slices and in 3D (bottom row).

Figure 3: Total combined probability of MEC and LEC homologue locations based on both structural and functional connectivity maps. Results are shown on selected sagittal (left) and coronal (right) brain slices. A: Probability of MEC location, B: Probability of LEC location, C: Total combined probability of MEC vs. LEC locations.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)
0264
DOI: https://doi.org/10.58530/2022/0264