Structural connectivity-based segmentation of the human entorhinal cortex

Abstract

The medial (MEC) and lateral entorhinal cortex (LEC), widely studied in rodents, are well defined and characterized. In humans, however, the exact locations of their homologues remain uncertain. Previous functional magnetic resonance imaging (fMRI) studies have subdivided the human EC into posterior-medial (pmEC) and anterior-lateral (alEC) parts, but uncertainty remains about the choice of imaging modality and seed regions, in particular in light of a substantial revision of the classical model of EC connectivity based on novel insights from rodent anatomy. Here, we used structural, not functional imaging, namely diffusion tensor imaging (DTI) and probabilistic tractography to segment the human EC based on differential connectivity to other brain regions known to project selectively to MEC or LEC. We defined MEC as more strongly connected to presubiculum and retrosplenial cortex (RSC), and LEC as more strongly connected to distal CA1 and proximal subiculum (dCA1pSub) and orbitofrontal cortex (OFC). Although our DTI segmentation had a larger medial-lateral component than in previous fMRI studies, our results show that the human MEC and LEC homologues have a border oriented both towards the posterior-anterior and medial-lateral axes, supporting the differentiation between pmEC and alEC.

Functional connectivity and information pathways in the human entorhinal-hippocampal circuitry

“…These findings provide clear evidence for a long hypothesized transversal gradient in contextual information processing within the subiculum. Our data also replicate the earlier functional and structural connectivity reports in humans as well as anatomical findings of a route between posterior-medial EC and distal subiculum (Maass et al, 2015;Syversen et al, 2021;Witter et al, 2000). The spatial or contextual information processing bias has, however, mainly been reported for the EC (in rodents: Neunuebel et al, 2013;Knierim et al, 2014;Keene et al, 2016;in humans: Schultz et al, 2012;Navarro Schröder et al, 2015;Berron et al, 2018).…”

“…In addition, we expand the functional investigation of entorhinal-hippocampal communication towards the human CA1 region to bring knowledge from animal research together with human research. Our unbiased functional connectivity approach likewise extends recent structural data (Syversen et al, 2021). Finally, we advance earlier findings by investigating functional connectivity together with associated biases for scene and object information processing in the same dataset (as aspects of contextual and item information processing, respectively).…”

“…First, we provide initial human evidence for an information pathway between the anterior-lateral EC and the subiculum/CA1 border. Non-primate and primate anatomical data as well as ex-vivo and in vivo structural connectivity data in humans show the possibility of information flow along that route (Syversen et al, 2021;Witter et al, 2017;Witter & Amaral, 1991. Our results now underpin a functional relevance of that connection beyond the subiculum (for the subiculum see Maass, Berron et al, 2015).…”

“…Third, it remains elusive in how far a transversal functional segregation can be extended towards the human CA1 region in analogy to rodent literature. Note that a recent structural connectivity study is among the first studies in humans that examines retrosplenial input towards the EC (Syversen et al, 2021). This is to our knowledge also the first study that investigates the connectivity profile of the distal CA1 and thus suggests an expansion of the transversal connectivity pattern in the human brain as well.…”

“…The four entorhinal subregions that we later used as seeds to determine the topography of entorhinal-hippocampal connectivity are based on intrinsic functional connectivity preferences with either the parahippocampal cortex, the retrosplenial cortex, Area 36 or Area 35. These cortical regions are in general concordance with Maass, Berron et al (2015) but consider recent emphasis on the retrosplenial cortex as a source that conveys contextual information from the posterior-medial stream (Nilssen et al, 2019;Syversen et al, 2021) as well as potential clinical implications for anatomical Alzheimer's tau pathology progression (Jacobs et al, 2018;Ziontz et al, 2021).…”