Dual long-axis reorganization of hippocampus in youth

1296 

Abstract Submission 

Debin Zeng¹, Qiongling Li², Deyu Li¹, Yirong He², Xiaoxi Dong², Shaoxian Li², Shenghan Bi², Yong He², Xi-Nian Zuo², Shuyu Li²

¹Beihang University, Beijing, China, ²Beijing Normal University, Beijing, China

Debin Zeng  
Beihang University
Beijing, China

Qiongling Li  
Beijing Normal University
Beijing, China

Deyu Li  
Beihang University
Beijing, China

Yirong He  
Beijing Normal University
Beijing, China

Xiaoxi Dong  
Beijing Normal University
Beijing, China

Shaoxian Li  
Beijing Normal University
Beijing, China

Shenghan Bi  
Beijing Normal University
Beijing, China

Yong He  
Beijing Normal University
Beijing, China

Xi-Nian Zuo  
Beijing Normal University
Beijing, China

Shuyu Li  
Beijing Normal University
Beijing, China

The reorganization of human hippocampus, especially its interaction with cortex, remains largely undefined in youth. The organization of a single hippocampal long-axis has been predominantly characterized as monotonic(Genon et al. 2021; Strange et al. 2014), despite recent indications of nonmonotonic features in neuron density(Gandolfi et al. 2023) and geometric eigenmodes(Pang et al. 2023). While the human cortical hierarchy has been well recognized for significant developmental and evolutionary advantages(Dong et al. 2021; Tong et al. 2022), hippocampus has been typically considered an evolutionarily conserved brain structure(Strange et al. 2014; Pandya et al. 2015), and overlooked regarding its integrative role of cortical hierarchical processing during development.

Our study utilized data from the Human Connectome Project Development (HCP-D) with 652 participants (5-21 years) and the Children School Functions and Brain Development Project (CBD, Beijing Cohort) with 300 children (6-13 years). We used the HippUnfold tool(DeKraker et al. 2022) to segment the hippocampus and generate mid-thickness surfaces. Hippocampal-cortical connectomes were created by correlating rs-fMRI time series between hippocampal vertices and cortical regions (defined by the Glasser atlas(Glasser et al. 2016)). A diffusion embedding method yielded the hippocampal functional gradient (Fig. 1a), and cortical projections were computed by taking the dot product between the gradient and the hippocampal functional connectivity for each cortical region. Geometric eigenmodes for each hippocampus were obtained through Laplace–Beltrami operator-based analysis. All developmental effects were studied using generalized additive models. Lastly, transcriptomic association and developmental enrichment analyses were conducted to explore the neurobiological basis of dual long-axis functional gradient development.

Here, we corroborated the presence and significance of a dual long-axis representation of the hippocampal connectome and geometry including both linear and quadratic gradients along its long-axis in youth (Fig. 1b and e). This finding was robust across two independent large-scale developmental cohorts. Projecting the connectome gradients onto the cortex, we clarified how distinct cortical hierarchies allocate functional connectivity differently along the long-axis, thus coding the hippocampus's intricate and multifaceted role in cortical hierarchical processing (Fig. 1c and d). These discoveries challenge classical views that propose a monotonic gradient of structural and functional differentiation along the hippocampal long-axis, and question the traditional notion of the hippocampus as being evolutionarily conserved in terms of its organization. We observed substantial developmental reorganization of dual long-axis gradients in supporting the maturation of the cortical hierarchy in youth (Fig. 2b). The reorganization further unfolds that the human hippocampus continues to loosen its geometric gradient constraints on functional gradients to support the executive function performance (Fig. 2c and d). Notably, we revealed that neurodevelopmental variability in the functional gradient profiles mirrors a gradient associated with a plasticity-limiting factor (myelin content, estimated by T1w/T2w ratio) (Fig. 2a). At micro-level, we found that neural growth, stress hormone regulation, and neuroactive signaling are involved in this geometry-function-cognition alignment, facilitating such reorganization of the dual hippocampal long-axis gradients in youth (Fig. 2e).

Our findings enrich the understanding of hippocampal-cortical reorganizational principles across structural, functional, and molecular dimensions as well as its maturation, and define the plasticity distribution within the human hippocampus at systems level, holding potentials to enhance and translate neurodevelopment and neuropsychiatric healthcare.

Transcriptomics

Executive Function, Cognitive Control and Decision Making

Working Memory

Normal Brain Development: Fetus to Adolescence ¹

fMRI Connectivity and Network Modeling ²

Cortex

Development

FUNCTIONAL MRI

Limbic Systems

Machine Learning

MRI

Multivariate

Myelin

NORMAL HUMAN

Open-Source Code