Brain Connectome Modality

Resting-state functional magnetic resonance imaging (rs-fMRI) functional connectivity (FC) matrices are widely used for individual-level prediction, but strong performance within one cohort may not generalize to a new cohort. We ask whether within-dataset performance remains when the test data come from an entirely held-out rs-fMRI dataset. Each scan is represented as a regularized symmetric positive definite (SPD) correlation connectome, which allows methods to use the geometry of the SPD manifold. We introduce a reproducible age-prediction benchmark across six rs-fMRI datasets: COBRE, ADNIDOD, Cam-CAN, ABIDE, OASIS-3, and ADNI. The benchmark compares a vectorized correlation baseline, Tangent-Space Ridge, SPDNet, and split-wise Riemannian harmonization under within-dataset GroupKFold, pooled GroupKFold, and leave-one-dataset-out (LODO) evaluation. Within-dataset and pooled GroupKFold results are substantially more favorable than LODO results. When an entire dataset is held out, prediction error increases, differences among methods narrow, and performance is strongly affected by age-range mismatch and cohort heterogeneity. The benchmark provides common inputs, model settings, data splits, and analysis scripts so that future SPD matrix learning methods can be evaluated under the same external-validation protocol.

Cross-site identification of major depressive disorder (MDD) from resting-state functional magnetic resonance imaging (rs-fMRI) is hindered by inter-site distribution shifts and heterogeneous functional connectivity (FC) views. These views capture complementary neural relationships but exhibit distinct site biases and graph topologies, complicating alignment without sacrificing disease-relevant information or cross-view consistency. Existing studies largely treat multi-view connectome learning and cross-site adaptation separately. To the best of our knowledge, few studies have jointly modeled multiple FC views under multi-source unsupervised domain adaptation for cross-site rs-fMRI-based MDD classification. We construct Pearson correlation, sparse representation, and Granger causality graphs, each encoded by a view-specific graph attention network. Dual-stream adaptive fusion explicitly integrates pairwise cross-view interactions, followed by lightweight hyperbolic residual encoding for curvature-aware representation refinement. Class-wise Cauchy--Schwarz alignment reduces inter-source and source-target discrepancies, complemented by adversarial learning, information maximization, and confidence-aware pseudo-labeling. Across seven unlabeled target domains, our framework achieves 73.60% mean accuracy and 71.90% AUC, demonstrating effective generalization under heterogeneous acquisition conditions. These results highlight the effectiveness of unified heterogeneous-view modeling, curvature-aware refinement, and multi-source domain adaptation for cross-site MDD identification.The source code is at https://github.com/OPUS-Lightphenexx/MM-HyperGDA

The success of connectome mapping now shifts the challenge of understanding the nervous system to the interpretation of neural circuits. Here, we devise a new automated method, LLantia (LLM automated neural circuit inference and analysis), to systematically infer neural circuit function and the role of its component neural cell types. Our approach distills descriptions of cell type function from the literature and, in combination with the connectome, then infers the function for all other cell types, which serves as a basis for subsequent neural circuit function inference. Results are structured hierarchically, with different possible circuit functions organised under multiple possible behavioural and physiological contexts, and each circuit function composed of subcircuit descriptions alongside relevant cell types to facilitate both backtracking to known, published information and support further experimental research. We illustrate our method by inferring cell type function for all cell types of the adult fruit fly brain and for select broader circuits within, and validate our findings, including by cross-checking with literature published after the release date of our analysis.

Establishing large-scale, high-resolution neural connectivity maps is fundamental to elucidating the structural basis of brain function. However, when processing terabyte- or petabyte-scale electron microscopy data, over-segmentation inherent in automated reconstruction algorithms remains a critical bottleneck, requiring extensive manual proofreading spanning person-years. To alleviate the heavy reliance on annotated data and the limited flexibility of conventional tracing methods, we propose a training-free, targeted neuron tracing framework. Specifically, we introduce a skeleton-guided Heuristic Spatial Search paradigm that leverages geometric priors to iteratively reconstruct neuronal morphologies through a probing-verification cycle. To achieve robust zero-shot semantic verification, we further develop a Dimension-Aware Semantic Verification strategy built upon the foundation model NeuroSAM 2. This strategy resolves intra-slice splits via Planar Ensemble Consensus and inter-slice splits via Axial Spatio-Temporal Propagation. Notably, we integrate the proposed workflow into the Neuroglancer visualization platform, enabling an interactive human-in-the-loop proofreading system. Experimental results demonstrate that the proposed method outperforms supervised baselines and reduces manual proofreading time by 33.4%. The source code is publicly available at https://github.com/HeadLiuYun/Probe-EM.

A growing number of techniques leverage the spatial structures that underlie many real-world datasets. Despite these advances, the complementary task of estimating spatial structures and understanding their role within these techniques has often been overlooked. In neurophysiological data analysis specifically, numerous methods exist to estimate brain connectivity, but most are not explicitly model-based, dynamic, multivariate, or directed. To address these limitations, we previously introduced noise-driven heat modelling on graphs for neurophysiological connectivity estimation. In this study, we extend this framework by relaxing earlier noise assumptions and adding regularisation to improve robustness. We also develop a simulation procedure to characterise and evaluate our technique in a controlled setting. Finally, we demonstrate that the technique is able to capture meaningful spatial structure across two experiments, each using two real-world datasets. The explicit model formulation of our connectivity estimator has the potential to improve the interpretability of graph-based techniques across a wide range of applications. The code implementing our method is available at https://github.com/sgoerttler/Heat_Connectivity.

Recent breakthroughs in synaptic-resolution network connectomics have revealed that brain circuits feature fine-scale structural connectivity, such as pairs of correlated synaptic couplings known as second-order motifs. Large-scale recordings of neuronal activity in networks containing nonlinear neurons reveal macroscopic heterogeneous population dynamics throughout the brain. These findings rekindle the inquiry into this intriguing question: Can microscale synaptic structures contribute to macroscopic heterogeneous dynamics and computations in ways that canonical brain circuit models cannot? To answer this question, we create random RNNs with various cell types, nonlinear non-negative neural responses, and arbitrary marginal and second-order correlated synaptic statistics. We derive mean-field low-rank equations for P-population networks in which the pre- and postsynaptic neuronal population identities determine the synaptic and motif strengths. Our framework requires 2P latent dynamic variables with P variables describing mean population activity and P variables capturing within-population variability. Theoretical and simulational results demonstrate that chain motifs induce correlations in synaptic variability, enabling microscopic fluctuations to be integrated and influence mesoscopic mean population dynamics. We apply this framework to reverse engineer network connectivity that recapitulates the heterogeneous activity across the population in the mouse primary visual cortex. By bridging the gap between synaptic organization and nonlinear heterogeneous population dynamics, our results offer a principled approach and testable predictions regarding the relationship between fine-scale connectivity, heterogeneous dynamics, and functional computations.

While deep learning models achieve state-of-the-art performance in complex tasks, they remain brittle when faced with new environments or sensory deprivation. In contrast, biological systems exhibit remarkable tolerance to these challenges. We address this vulnerability by developing a recurrent neural network (RNN) whose architecture is directly derived from the synaptic-resolution brain connectome of the fruit fly Drosophila melanogaster. We demonstrate the feasibility of training the fly connectome neural network (FLYNN) to perform vision-based navigation in MuJoCo, achieving performance comparable to modern hand-crafted networks of similar parameter counts. Crucially, FLYNN exhibits superior resistance to out-of-distribution (OOD) data and tolerance to sensory loss without further training. It remained functional even under total vision loss while hand-crafted networks largely failed, even when specifically trained with camera dropout. Principal Component Analysis (PCA) of the internal state of FLYNN suggests that it exhibits a particularly high degree of representational modularity, which might be related to its robustness. Our work provides a new direction for designing resilient artificial agents following the topology of biological brains.

Understanding how a nervous system wires itself from birth to adulthood is a fundamental challenge in developmental neuroscience. We present DevoTG, a temporal graph framework that applies Temporal Graph Neural Networks (TGNs) to two complementary representations of C. elegans neural development: a Continuous-Time Dynamic Graph (CTDG) of cell division events derived from cell lineage data, and a Discrete-Time Dynamic Graph (DTDG) of the developing synaptic connectome spanning eight reconstructed electron-microscopy datasets. On the lineage prediction task, our TGN achieves a mean test AUC of 0.839 +/- 0.007 (5 seeds; validation AUC 0.937 +/- 0.001), outperforming a static GNN with the identical architecture by 26 AUC points (0.577 +/- 0.080), demonstrating that temporal memory is the decisive factor. Applied to the connectome DTDG, DevoTG identifies three connection stability classes (stable, developmental, and variable) across 225 neurons and 858 to 2,496 connections over development (L1 birth to adult), providing a temporal-graph-theoretic complement to the individual-variability classification of Witvliet et al. Analysis of hub command interneurons AVA, AVB, and AVE reveals their persistent centrality and how their integration roles are progressively reinforced across larval stages. Accompanying interactive visualizations (3D animated networks, centrality heatmaps, and a spatiotemporal lineage graph) make developmental dynamics accessible for biological hypothesis generation. DevoTG is open-source and designed for extension to other developing nervous systems. Code is publicly available at https://github.com/DevoLearn/DevoGraph/tree/main/DevoTG.

Proofreading--correcting segmentation errors in 3D brain reconstructions--is the rate-limiting step in synapse-resolution connectomics. We release ConnectomeBench2, a unified multi-species dataset of over 716,485 expert-labeled proofreading decisions with >4,500,000 associated images spanning four major open connectomes (mouse, human, zebrafish, fly), spanning both split and merge error correction. Trained on this dataset, a single Vision Transformer with shared encoders for mesh geometry and electron microscopy reaches human-level accuracy across species for split error correction and merge error identification, with performance scaling with data size and modality. Beyond accuracy, we show that the model is well-calibrated within distribution, that measures of distribution distance predict where calibration and accuracy will degrade on unseen data, and that connectomics-specific pretraining and active learning-based sample selection show potential to substantially reduce the labeling effort needed to extend to new species and brain regions. The benchmark provides the infrastructure to train and evaluate increasingly capable vision models for connectomic proofreading. Data and code availability. The ConnectomeBench2 dataset is released on Hugging Face at https://huggingface.co/datasets/jeffbbrown2/ConnectomeBench2. The accompanying codebase is available on GitHub at https://github.com/timfarkas/ConnectomeBench2.

This study examines how deficiencies in one brain connectome modality propagate to the other, using the Krakencoder as a simulation framework. Structural and functional connectomes from 702 healthy participants in the Human Connectome Project were analyzed, with the impact of each of the Yeo-7 functional networks assessed separately. Seven scenarios were considered, each involving the removal of a single network while the remaining networks were preserved. The resulting perturbations in cross-modal predictions were quantified using three complementary metrics: KL divergence on eigenvalue spectra, Frobenius norm, and Wasserstein distance. In addition, the persistence of sex-specific information within the predicted connectomes was evaluated. Across all metrics and both prediction directions, the Default Mode Network produced the largest perturbations, whereas the Somatomotor network yielded the smallest. Sex differences in network-level perturbation signatures were subtle, with the best result being an accuracy of 66.09% from connectomes predicted under network-removal conditions. In contrast, connectomes predicted from intact inputs achieved substantially higher sex classification accuracy, reaching up to 84.76%. These findings confirm that full predicted connectomes retain considerably more sex-discriminative information than perturbation-derived signatures alone.

Reservoir computing exploits the fixed dynamics of a recurrent network for temporal processing, requiring only a trained linear readout. Biological neural connectomes, shaped by millions of years of evolution, may encode computational structure beyond what random reservoirs provide, yet whether that structure can be further enhanced by principled optimisation remains an open question. We address it by applying four gradient-free, bio-inspired optimisers (Particle Swarm Optimisation, Differential Evolution, Grey Wolf Optimiser, and Whale Optimisation Algorithm) to the edge weights of connectome-based echo-state networks across six species spanning six orders of magnitude in neural complexity: C. elegans (279 neurons), Drosophila (49 nodes), mouse (112), rat (73), macaque (29 regions, continuous FLNe synaptic strengths), and human structural MRI connectivity (83 parcels). Each connectome is evaluated on four canonical reservoir computing benchmarks: Memory Capacity (MC), Lorenz attractor prediction, NARMA-10 system identification, and Mackey-Glass chaotic time-series prediction. All four optimisers consistently outperform unoptimised biological baselines across every task and species when initialised from biological weights. WOA achieves the largest gains on every task: up to a 17x MC improvement (C. elegans: 1.39 to 23.91) and up to 89% NRMSE reduction (Mackey-Glass, human), corresponding to an average 214% improvement across all species and tasks. Crucially, random initialisation on the same topology reliably underperforms biology, establishing biological weight values as an essential inductive bias that topology alone cannot recover. These results position bio-inspired, biologically-initialised optimisation as a principled and broadly effective strategy for connectome reservoir computing across the animal kingdom.

We introduce Convex Distance Operator Transport (CDOT), the first convex optimal transport framework that aligns distributions across heterogeneous domains by jointly preserving feature correspondence and intrinsic geometric structure. Specifically, CDOT employs an operator-based regularization that aligns aggregated distance structures by introducing distance and conditional expectation operators. Consequently, the proposed regularization improves the robustness to local geometric variations. We further prove that the resulting CDOT discrepancy is a valid pseudometric on the space of attributed compact metric-measure spaces. In addition, we characterize the relationship between CDOT and Gromov--Wasserstein (GW) through a new notion of dispersion gap, formally elucidating the geometric source of non-convexity in GW compared to the convexity of CDOT. In the finite-sample regime, we derive a non-asymptotic risk bound decomposed into optimization and statistical errors, establishing risk consistency under a globally convergent Frank--Wolfe algorithm. Experiments on synthetic point clouds, brain connectomes, and graph classification benchmarks demonstrate better performance over existing methods, with stable and reliable behavior in practice.

Mild cognitive impairment (MCI) and subjective cognitive decline (SCD) are closely associated with the early Alzheimer's disease continuum, where accurate and explainable diagnosis is important for early risk assessment and intervention. Existing connectome-based deep learning models can improve classification performance but often provide limited insight into disease-related functional and structural connectivity changes. This paper proposes an atlas-knowledge-guided Generative Counterfactual Attention-guided Network (GCAN) for explainable cognitive decline diagnosis using multimodal brain connectomes. GCAN formulates diagnosis as a source-to-target counterfactual generation problem, where target-label connectomes are generated from source-label inputs and their differences are used to construct counterfactual attention maps. To preserve connectome topology, an Atlas-aware Bidirectional Transformer (AABT) performs network-level token encoding and decoding under brain-atlas constraints. The framework is further extended from functional connectivity (FC) to joint functional and structural connectivity (SC) modeling, enabling counterfactual analysis of complementary functional reorganization and structural topology changes. Experiments on hospital-collected and ADNI datasets show that GCAN achieves competitive performance across HC vs. SCD, HC vs. MCI, and SCD vs. MCI classification tasks. Visualization, circular connectome analysis, CAM-based comparison, ablation studies, and confidence interval analysis further support the interpretability and reliability of the proposed framework. Modality-specific FC and SC pre-trained classifiers are used to provide target-state priors for counterfactual generation while being separated from the downstream diagnostic classifier to prevent data leakage.

Cortical surface registration is often driven by local geometric descriptors (e.g., sulcal depth and curvature). While this approach achieves geometric correspondence, it neglects the long-range wiring constraints imposed by white-matter anatomy. Diffusion MRI tractography offers these crucial constraints; however, prior connectivity-informed pipelines typically align precomputed connectivity matrices, making the optimization highly sensitive to connectivity estimation and its resolution. In this paper, we introduce a novel connectivity-based surface registration method that aligns cortical surfaces by operating directly on white-matter fiber-tract endpoints. We model tract endpoints as a point cloud on the product manifold $Ω\times Ω$, where $Ω$ represents the spherical domain of the inflated cortical hemispheres. Our alignment method iteratively (i) computes a small diffeomorphic warp for $Ω$ by minimizing connectivity mismatch, and (ii) updates the endpoints based on this warp. The method relies on a geometric framework that ensures output warps are diffeomorphisms and has a final goal that optimizes the matching of well-known fiber bundles. Experiments on Human Connectome Project (HCP) data demonstrate improved tract-level correspondence, achieving higher connectivity-level overlap coefficients on major fiber bundles and stronger robustness across grid resolutions for $Ω$ compared to state-of-the-art methods such as ENCORE and MSMAll.

Acquisition differences across sites, scanners, and protocols in dMRI introduce variability that complicates structural connectome analysis. This motivates deep learning models that can represent high-dimensional connectomes in a low-dimensional space while explicitly separating acquisition-related effects from biological variation. Conventional dimensionality reduction methods model all variance as continuous, so acquisition effects often get absorbed into a continuous latent space. Recent hybrid latent-space models combine discrete and continuous components to address this, but typically require manual capacity tuning to ensure the discrete component captures the intended variability. We introduce an unsupervised framework that removes this manual tuning by architecturally annealing encoder outputs before decoding, allowing the model to adaptively balance discrete and continuous latent variables during training. To evaluate it, we curated a dataset of N=7,416 structural connectomes derived from dMRI, spanning ages 2 to 102 and 13 studies with 25 unique acquisition-parameter combinations. Of these, 5,900 are cognitively unimpaired, 877 have mild cognitive impairment (MCI), and 639 have Alzheimer's disease (AD). We compare against a standard VAE, PCA with k-means clustering, and hybrid models that anneal only through the loss function. Our architectural annealing produces stronger site learning (ARI=0.53, p<0.05) than these baselines. Results show that a hybrid continuous-discrete latent space, with architectural rather than loss-based annealing, provides a useful unsupervised mechanism for capturing acquisition variability in dMRI: by jointly modeling smooth and categorical structure, the Joint-VAE recovers clusters aligned with scanner and protocol differences.