Connectome

Randomised copies of a connectome are the usual baseline for asking whether measured wiring matters, and the answer depends on what the randomisation preserves. We evolved embodied foraging agents whose brains are a compressed adult Drosophila connectome (FlyWire v783; 512 cell-type groups and 1,000 Kenyon cells) alongside agents built on randomised wiring, in pre-registered experiments with ten seeds, four ecologies and 600 generations. Two standard randomisations, a column shuffle and degree-preserving edge swaps, route 10.6 to 10.7 % of olfactory output directly onto descending motor groups, against 0.012 % in the connectome. On the registered primary endpoint, fitness averaged over the run, no difference was detected; at the last common-garden probe the connectome was behind both controls (-0.22 and -0.20 fitness units on seed means). Against controls that keep every sensory-output and motor-input edge and rewire only the interior, the seed-mean difference lay within a +/-0.10 equivalence bound (+0.002 and -0.074, unchanged under a calibration that also matches activity spread), although per ecology the interior column shuffle was ahead by 0.26 in one of four ecologies at ten seeds, a lead that ten further pre-registered seeds did not replicate. Rewiring the connectome so that it acquires the shortcut raised its fitness by 0.44 (10 of 10 seeds) and its dependence on olfaction from 0.15 to 0.99; graded doses raised both in step; at comparable swap counts the full dose was ahead of an interior-only sham by 0.53 (10 of 10 seeds); and a sham that rewired the same boundary edges without creating shortcuts matched the connectome (+0.007) while the full dose was ahead of it by 0.60. What a null preserves at the sensory-motor boundary can decide an evolutionary connectome comparison, and sensory-to-motor path statistics belong next to the degree statistics a null is said to preserve.

Brain networks characterize structural and functional relationships among brain regions and support research on cognition, brain disorders, and brain-computer interfaces. Their time-varying topology and higher-order spatiotemporal dependencies are not adequately represented by conventional static networks. Existing tools primarily focus on static connectomes and provide limited integration of dynamic network modeling with modern graph and sequence learning methods. We present BrainNet Studio, an integrated toolkit for static and dynamic brain network analysis. It provides a unified workflow encompassing network construction, feature extraction, predictive modeling, candidate biomarker identification, visualization, and assisted interpretation. The toolkit integrates 27 algorithms, including deep learning, graph neural networks, and spatiotemporal sequence models, to support classification and the identification of discriminative brain regions and connections. A large language model generates researcher-verifiable summaries of functional connectivity, structural connectivity, and structure-function coupling at individual and group levels. Within a consistent computational framework, users can configure analytical tasks, compare methods, inspect outputs, and extend functionality without repeatedly assembling application-specific pipelines. BrainNet Studio provides a practical and extensible platform for connectome analysis in cognitive neuroscience, exploratory studies of brain disorders, and brain-computer interfaces. The toolkit is publicly available at https://github.com/xbrainnet/Brainnet-Studio.

Self-supervised pretraining reshaped prediction in language and vision, and brain foundation models (BFMs) inherited its promise. Representations learned from large unlabelled corpora should capture individual functional dynamics and generalise across cohorts. However, kernel ridge regression (KRR) fitted on functional connectivity (FC) matrices still predicts individual phenotypes more accurately than any BFM we tested. In this paper, we show that KRR is weighted by the eigenvalues of the FC which are miscalibrated for phenotype prediction. We apply an efficient spectral filter to recalibrate the eigenvalues of each subject's FC matrix, enabling the model to exploit more inter-individual variance. Across the 5 datasets, 11 parcellations and 6 prediction targets we tested, we match or exceed the KRR baseline. Based on this finding, we then pretrain a small encoder model on about 4,000 hours of fMRI from 162 open datasets, whereby we align the pairwise similarities between the embeddings of recording snippets with those between the recalibrated connectomes. Our model performs on par with the best of the 6 published BFMs we tested while having an order of magnitude fewer parameters. Our encoder performs better than FC on short scans and in smaller cohorts, especially in fingerprinting. We release the pretrained model weights, the code and the pretraining data, preprocessed and parcellated.

We benchmarked vision-language models (VLMs) on the decisions annotators take when inspecting electron microscopy images in connectomics: synapse detection (presence and polarity) and proofreading (split errors and merge errors). For synapse detection, we evaluated 19 open and 2 closed models across various architectures and sizes under zero-shot, four-shot in-context learning and LoRA settings, against specialist models, on datasets constructed by us using public resources. For proofreading, we evaluated 3 open and 2 closed models on the ConnectomeBench2 dataset, with cross-species transfer from fly and mouse to human and zebrafish. Most models were at chance zero-shot; a few examples helped mainly the closed and largest open ones. LoRA on a few thousand labels brought open models level with specialist models. When evaluated on unseen species, the best adapted VLMs outperformed specialist models trained on the same data in identifying merge errors. The project will be publicly available upon acceptance.

Nanoscale imaging of mammalian brains is critical for connectomics. X-ray laminography enables high-throughput imaging of extended, plate-like biological specimens. However, the tilted acquisition geometry leads to incomplete Fourier-space coverage, giving rise to a missing-cone of information. Conventional reconstruction methods cannot recover unmeasured information within the cone, resulting in artifacts that distort fine brain structures. While resolving these requires modeling 3D structure, direct 3D deep learning approaches are limited by data scarcity and computational cost. Here we introduce LUCID (Laminography with Unified Consistent Diffusion), a framework that combines multi-view diffusion priors with projection-domain data consistency. LUCID integrates complementary 3D structural information while enforcing strict alignment with the laminography forward model. On simulated datasets, LUCID substantially improves spatial fidelity and restores missing Fourier components, outperforming baseline methods. Applied to experimental laminography data, LUCID generalizes robustly despite being trained exclusively on fully sampled tomographic volumes, and effectively recovers unmeasured Fourier information.

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.

Photonic reservoir computing has attracted increasing attention as a fast and low-cost approach for time-series prediction. Photonic reservoir computing utilizes the high speed, broad bandwidth, and spatial parallelism of light. However, the effect of the internal connection structure (network topology) on the computing performance has not been investigated for large-scale photonic reservoirs. In this study, we experimentally and numerically demonstrate photonic reservoir computing using a spatial light modulator to systematically evaluate the relationship between the network topology and the performance of reservoir computing. We introduce complex network structures such as small-world and scale-free network topologies of the internal nodes in the reservoir. We perform the memory capacity measurement and the one-step-ahead prediction task of the chaotic time series to compare the performance. We found that the small-world network exhibits the maximum memory capacity and the best prediction performance. Our numerical calculations reveal that the performance of the time-series prediction can be optimized by changing the rewiring probability of the network and the leak rate of the reservoir. We also implement photonic human brain network as a reservoir, which is designed by the connectomes of human brain activities. We found that the network topology strongly affects the performance of reservoir computing, and the small-world network structure outperforms the other configurations.

Brain network analysis is crucial for understanding cognition and neurological disorders, yet existing deep learning methods mainly treat connectome analysis as a graph-to-logit classification problem, offering limited explanatory reasoning. Large language models (LLMs) provide a promising interface for knowledge-intensive scientific analysis, but directly applying general-purpose LLMs to brain networks remains challenging due to the structure-language gap, limited neuroscience grounding, and overconfident positive predictions. In this paper, we propose \textbf{BrainAgent}, an agentic LLM framework for knowledge-enhanced brain network analysis. BrainAgent reformulates connectome classification as an iterative process of topology-aware understanding, external retrieval, reasoning, and reflection. Specifically, it first converts raw brain networks into compact multi-level structural descriptions through brain-specific analysis tools, then retrieves relevant neuroscience knowledge and task-specific cases to ground the reasoning process, and finally generates structured predictions with reflective verification. Experiments on four public rs-fMRI datasets show that BrainAgent consistently improves different closed-source and open-source LLM backbones over direct prompting and standard reasoning baselines. Further ablation and interpretability analyses demonstrate the effectiveness of each component and show that BrainAgent produces more comprehensive, multi-level, and verifiable explanations.These results indicate that agentic LLMs provide a practical route toward interpretable and knowledge-grounded brain network analysis.

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.

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.

Longitudinal neuroimaging is essential for modeling disease progression in Alzheimer's disease (AD), yet irregular sampling and missing visits pose substantial challenges for learning reliable temporal representations. To address this challenge, we propose SDE-HGNN, a stochastic differential equation (SDE)-driven spatio-temporal hypergraph neural network for irregular longitudinal fMRI connectome modeling. The framework first employs an SDE-based reconstruction module to recover continuous latent trajectories from irregular observations. Based on these reconstructed representations, dynamic hypergraphs are constructed to capture higher-order interactions among brain regions over time. To further model temporal evolution, hypergraph convolution parameters evolve through SDE-controlled recurrent dynamics conditioned on inter-visit intervals, enabling disease-stage-adaptive connectivity modeling. We also incorporate a sparsity-based importance learning mechanism to identify salient brain regions and discriminative connectivity patterns. Extensive experiments on the OASIS-3 and ADNI cohorts demonstrate consistent improvements over state-of-the-art graph and hypergraph baselines in AD progression prediction. The source code is available at https://anonymous.4open.science/r/SDE-HGNN-017F.

Biophysical diffusion MRI models like Neurite Exchange Imaging (NEXI) are essential for probing gray matter microstructure, estimating compartment diffusivities, neurite fraction, and exchange time. However, NEXI's multi-shell, multi-diffusion-time requirements cause prohibitively long acquisitions. Leveraging the Connectome 2.0 ultra-high gradient scanner, we developed a time-efficient protocol using an Explainable AI (XAI) framework. Combining XGBoost, SHAP, and Recursive Feature Elimination trained on synthetic signals, XAI identified an optimal 8-feature subset, cutting scan time from 27 to 14 minutes. Validated in vivo in seven healthy participants, the XAI protocol was benchmarked against the full 15-feature acquisition, a Cram'er-Rao Lower Bound (CRLB) theoretical optimum, and two heuristics ("Mid-Range" and "Corner"). It robustly reproduced parameter estimates and maintained test-retest reproducibility. Remarkably, the XAI selection converged to the CRLB optimum. This validates XAI's optimality while highlighting its main advantage: achieving gold-standard optimization without complex analytical Jacobians, making it easily adaptable to numerical models or complex noise where CRLB is intractable. Furthermore, XAI showed superior in vivo robustness over heuristics: "Mid-Range" sampling yielded biased exchange time estimates from insufficient temporal diversity, while "Corner" sampling gave unstable intra-neurite diffusivity estimates (5-fold higher CV) due to noise sensitivity. Ultimately, this robust 14-minute protocol accelerates exchange-sensitive microstructural mapping, establishing a model-agnostic optimization framework adaptable to future ultra-high gradient systems and existing clinical scanners.