Figures and data
Conceptional overview: Youth development of the hippocampal triple gradient organization, underpinned by multiscale traits including gene expression, myelination and geometry.
This reorganization during youth actively contributes to cortical hierarchy maturation and facilitates the development of episodic memory and executive functions.
Triple gradient organization of the hippocampus.
a, Methodological overview for identifying hippocampal functional gradients. The two intrinsic orthogonal geodesic axes, namely posterior-anterior (P-A) and proximal-distal (P-D) are displayed on this panel. The coordinates on the P-D axis indicate the geodesic distance to the neocortex (isocortex), thus reflecting the iso-allocortical axis. b, c, and d, Topography of the first three hippocampal functional gradients at the overall group level and their associations with anatomical positions denoted by P-A and P-D coordinates. e and f, Development of explained variance and standard deviation of the triple gradients (i.e. ILG, qLG, and clG). ILG, linear long-axis gradient; qLG, quadratic long-axis gradient; clG, cubic iso-allocortical gradient.
Reorganization of the hippocampal triple gradients in youth is linked to the cortical hierarchy maturation and cognitive functions.
a, Methodological overview for projecting the hippocampal gradient to the cortex and analyzing its development. b, The cortical functional hierarchy map derived from the corticocortical connectome gradient49. c, Group-averaged cortical projection of the triple hippocampal gradients for left hippocampus. d, development of the coupling between the hippocampal gradient projections and the cortical functional hierarchy (FH). e, f, and g, Region-specific developmental effects on cortical projections of the triple hippocampal gradients, showing only regions that remained significant after FDR correction. Left, cortical distribution of significant effects (FDR-corrected p<0.05) for ILG, qLG, and cIG, respectively. Right, distribution of these effects across seven intrinsic functional systems defined by Yeo et al.50. h, Scatter plots showing the relationship between predicted and actual cognitive performance. Predictions for episodic memory and three executive function components were derived from cortical projections of the triple hippocampal gradients. The dashed box in each column highlights the strongest significant correlation (FDR-corrected p < 0.05) for that cognitive measure. The magnitude of the correlation coefficient (r) is represented by a consistent color scheme applied to the scatter points and the circle in the lower-left corner of each panel.
Geometric constraints on hippocampal triple gradient development in youth.
a, b, and c, Group-averaged first three geometric eigenmodes obtained through the Laplace–Beltrami operator and their associations with hippocampal principal gradients. d, e, and f, Developmental trajectories of structure-function coupling (Pearson correlation) between geometric eigenmodes and the corresponding hippocampal functional gradients.
Development of hippocampal triple gradients parallel myelin maturation.
a and b, Group-averaged T1w/T2w intensity map and its association with the triple functional gradients. c, Developmental trajectories and age effects (Δ Adjusted R2) of the average T1w/T2w intensity within each of the nine uniform bins along the group-averaged T1w/T2w intensity. Similarly, d depicts the corresponding developmental patterns for triple hippocampal functional gradients within the same nine bins, respectively. All the developmental trajectories are zero-centered to facilitate comparison between them. To distinguish the direction of age effects, Δ Adjusted R2 values for trajectories that decreased with age are shown as negative. Note: * p<0.05, ** p<0.01, *** p<0.001, FDR corrected.
Transcriptomic association analysis of the hippocampal triple gradients.
a, The hippocampal triple gradients were predicted using ten separate 10-fold cross-validated LASSO-PCR models based on transcriptomic data from the Allen Human Brain Atlas. The relationship between these predicted and the actual gradients was then evaluated. b, c and d, Left, an enrichment network was generated from the enriched biological pathways and Gene Ontology terms identified for the key gene sets predicting hippocampal gradients. Each term is represented as a node, and edges were drawn between nodes with Kappa similarity above 0.3. Node colors denote cluster memberships, which correspond to the same-colored bars in the adjacent plot. The length of each bar indicates the statistical significance (−log10[FDR-corrected p-value]) of the associated enriched terms; Right, developmental enrichment analysis for the above identified important gene sets, illustrating the FDR-corrected p values for the hippocampus within specific developmental stages.
Δ Adjusted R2 and FDR-corrected p value for three bins along the group-averaged T1w/T2w axis
Δ Adjusted R2 and FDR-corrected p value for six bins along the group-averaged T1w/T2w axis
Δ Adjusted R2 and FDR-corrected p value for twelve bins along the group-averaged T1w/T2w axis
Δ Adjusted R2 and FDR-corrected p value for fifteen bins along the group-averaged T1w/T2w axis
a, the explained variance plot of the top 20 hippocampal functional gradients for left and right hemisphere, respectively. b, Topography of the 4rd and 5th hippocampal functional gradient.
The relationship between the triple hippocampal gradients and the alternative anatomical axis.
Topographic pattern (a) and the density estimation (b) of first three gradients presented within four age-specific groups defined by equal intervals (5-9, 10-13, 14-17, and 18-21 years, with 111, 201, 188, and 152 participants, respectively).
Development of the range, skewness, and kurtosis of the hippocampal triple gradients.
Group-averaged cortical projection of the hippocampal gradients in youth.
a, Group-averaged cortical projection of the triple hippocampal gradients for right hippocampus. b & d, Relationship between triple hippocampal gradients and the cortical-hippocampal FCs for cortical regions with the top and bottom 5% projection values for left and right hippocampus, respectively. c & e, Correlation between projection patterns and cortical functional topographies for left and right hippocampus, respectively. RMG denotes representation-mediation gradient, FH denotes functional hierarchy, and IEG denotes internal-external gradient. f, Region-specific trajectories of hippocampal projections, with each line representing a cortical region defined by the Glasser atlas. The color of these trajectories was assigned based on the absolute age effect.
Spatial and temporal correspondence between the refinement of myelin content and the maturation of hippocampal functional gradients is replicated with various bins (3, 6, 12 and 15) used for partitioning the hippocampal mid-thickness surface.
Replication results of the hippocampal triple gradient organization.
a, Topography of the first three hippocampal gradients on CBD and NKI datasets respectively, and their associations with the HCP-D dataset. b, First three geometric eigenmodes obtained from CBD and NKI datasets respectively, and their associations with HCP-D dataset. c & d, Development of explained variance and standard deviation of the triple gradients in NKI dataset, respectively. e, Development of the association between the hippocampal gradient projections and the cortical functional hierarchy (FH) in NKI dataset.
Δ Adjusted R2 and FDR-corrected p value for nine bins along the group-averaged T1w/T2w axis
Demographic information of the CBD and NKI-RS samples: age information for each scan of all participants.
Sagittal and coronal view of the inner, outer, and mid-thickness surface (I-O axis).
The associations between hippocampal projection maps and cortical functional gradients.
