How precisely does circuit wiring specify function? This fundamental question is particularly relevant for modern neuroscience, as large-scale electron microscopy now enables the reconstruction of neural circuits at single-synapse resolution across many organisms. To interpret circuit function from such datasets, we must understand the extent to which the measured structure constrains dynamics. We investigate this question in the Drosophila head direction (HD) circuit, which maintains an internal heading estimate through attractor dynamics that integrate self-motion velocity cues. This circuit serves as a sensitive assay for functional specification: continuous attractor networks are theoretically known to require finely tuned wiring symmetries, whereas connectomes omit key cellular parameters such as synaptic gains, neuronal thresholds, and time constants, and reveal that biological wiring can be heterogeneous. We introduce a method that combines selfsupervised and unsupervised learning objectives to estimate unknown parameters at the level of cell types, rather than individual neurons and synapses. Starting from the raw connectivity matrix, our approach recovers a network that exhibits continuous attractor dynamics and accurately integrates a range of velocity inputs, despite minimal parameter tuning on a connectome that notably departs from the symmetric regularity of an idealized ring attractor. We characterize how deviations from the original connectome shape the space of viable solutions. We also perform in-silico ablation experiments to probe the distinct functional roles of specific cell types in the circuit, demonstrating how connectome-derived structure, when augmented with minimal, biologically grounded tuning, can replicate known physiology and elucidate circuit function.

Spatial location and molecular interactions have long been linked to the connectivity patterns of neural circuits. Yet, at the macroscale of human brain networks, the interplay between spatial position, gene expression, and connectivity remains incompletely understood. Recent efforts to map the human transcriptome and connectome have yielded spatially resolved brain atlases, however modeling the relationship between high-dimensional transcriptomic data and connectivity while accounting for inherent spatial confounds presents a significant challenge. In this paper, we present the first deep learning approaches for predicting whole-brain functional connectivity from gene expression and regional spatial coordinates, including our proposed Spatiomolecular Transformer (SMT). SMT explicitly models biological context by tokenizing genes based on their transcription start site (TSS) order to capture multi-scale genomic organization, and incorporating regional 3D spatial location via a dedicated context [CLS] token within its multi-head self-attention mechanism. We rigorously benchmark context-aware neural networks, including SMT and a single-gene resolution Multilayer-Perceptron (MLP), to established rules-based and bilinear methods. Crucially, to ensure that learned relationships in any model are not mere artifacts of spatial proximity, we introduce novel spatiomolecular null maps preserving key transcriptomic autocorrelation structure. Context-aware neural networks outperform linear methods, significantly exceed our stringent null map estimates, and generalize across diverse connectomic datasets and parcellation resolutions. Together, these findings demonstrate a strong, predictable link between the spatial distributions of gene expression and functional brain network architecture, and establish a rigorously validated deep learning framework for decoding this relationship.

Connectomics--the mapping of neural connections in an organism's brain--currently requires extraordinary human effort to proofread the data collected from imaging and machine-learning assisted segmentation. With the growing excitement around using AI agents to automate important scientific tasks, we explore whether current AI systems can perform multiple tasks necessary for data proofreading. We introduce ConnectomeBench, a multimodal benchmark evaluating large language model (LLM) capabilities in three critical proofreading tasks: segment type identification, split error correction, and merge error detection. Using expert annotated data from two large open-source datasets--a cubic millimeter of mouse visual cortex and the complete Drosophila brain--we evaluate proprietary multimodal LLMs including Claude 3.7/4 Sonnet, o4-mini, GPT-4.1,

Major leap towards reanimation after death as mammal's brain preserved A pig's brain has been frozen with its cellular activity locked in place and minimal damage. Could our brains one day be preserved in a way that locks in our thoughts, feelings and perceptions? An entire mammalian brain has been successfully preserved using a technique that will now be offered to people who are terminally ill. The intention is to preserve all the neural information thought necessary to one day reconstruct the mind of the person it once belonged to. "They would need to donate their brain and body for scientific research," says Borys Wróbel at Nectome in San Francisco, California, a research company focused on memory preservation.

Based on the fact that these connectivities build a network, graph-based approaches for analyzing the brain connectome have provided insights into the functionsofthehumanbrain.

ARXIV PREPRINT 1 Attention-Based V ariational Framework for Joint and Individual Components Learning with Applications in Brain Network Analysis Yifei Zhang, Meimei Liu, and Zhengwu Zhang Abstract Brain organization is increasingly characterized through multiple imaging modalities, most notably structural connectivity (SC) and functional connectivity (FC). Integrating these inherently distinct yet complementary data sources is essential for uncovering the cross-modal patterns that drive behavioral phenotypes. However, effective integration is hindered by the high dimensionality and non-linearity of connectome data, complex non-linear SC-FC coupling, and the challenge of disentangling shared information from modality-specific variations. To address these issues, we propose the Cross-Modal Joint-Individual Variational Network (CM-JIVNet), a unified probabilistic framework designed to learn factorized latent representations from paired SC-FC datasets. Our model utilizes a multi-head attention fusion module to capture non-linear cross-modal dependencies while isolating independent, modality-specific signals. V alidated on Human Connectome Project Y oung Adult (HCP-Y A) data, CM-JIVNet demonstrates superior performance in cross-modal reconstruction and behavioral trait prediction. By effectively disentangling joint and individual feature spaces, CM-JIVNet provides a robust, interpretable, and scalable solution for large-scale multimodal brain analysis.

Structural connectomes are detailed graphs that map how different brain regions are physically connected, offering critical insight into aging, cognition, and neurodegenerative diseases. However, these connectomes are high-dimensional and densely interconnected, which makes them difficult to interpret and analyze at scale. While low-dimensional spaces like PCA and autoencoders are often used to capture major sources of variation, their latent spaces are generally continuous and cannot fully reflect the mixed nature of variability in connectomes, which include both continuous (e.g., connectivity strength) and discrete factors (e.g., imaging site). Motivated by this, we propose a variational autoencoder (VAE) with a hybrid latent space that jointly models the discrete and continuous components. We analyze a large dataset of 5,761 connectomes from six Alzheimer's disease studies with ten acquisition protocols. Each connectome represents a single scan from a unique subject (3579 females, 2182 males), aged 22 to 102, with 4338 cognitively normal, 809 with mild cognitive impairment (MCI), and 614 with Alzheimer's disease (AD). Each connectome contains 121 brain regions defined by the BrainCOLOR atlas. We train our hybrid VAE in an unsupervised way and characterize what each latent component captures. We find that the discrete space is particularly effective at capturing subtle site-related differences, achieving an Adjusted Rand Index (ARI) of 0.65 with site labels, significantly outperforming PCA and a standard VAE followed by clustering (p < 0.05). These results demonstrate that the hybrid latent space can disentangle distinct sources of variability in connectomes in an unsupervised manner, offering potential for large-scale connectome analysis.

Diffusion-weighted MRI allows us to estimate structural brain connections in-vivo by measuring the diffusion of water molecules at different spatial directions.

Efficient deployment of machine learning models ultimately requires taking hardware constraints into account. The binary logic gate is the fundamental building block of all digital chips. Designing models that operate directly on these units enables energy-efficient computation. Recent work has demonstrated the feasibility of training randomly connected networks of binary logic gates (such as OR and NAND) using gradient-based methods. We extend this approach by using gradient descent not only to select the logic gates but also to optimize their interconnections (the connectome). Optimizing the connections allows us to substantially reduce the number of logic gates required to fit a particular dataset. Our implementation is efficient both at training and inference: for instance, our LILogicNet model with only 8,000 gates can be trained on MNIST in under 5 minutes and achieves 98.45% test accuracy, matching the performance of state-of-the-art models that require at least two orders of magnitude more gates. Moreover, for our largest architecture with 256,000 gates, LILogicNet achieves 60.98% test accuracy on CIFAR-10 exceeding the performance of prior logic-gate-based models with a comparable gate budget. At inference time, the fully binarized model operates with minimal compute overhead, making it exceptionally efficient and well suited for deployment on low-power digital hardware.

Understanding the interactions between biomarkers among brain regions during neurodegenerative disease is essential for unravelling the mechanisms underlying disease progression. For example, pathophysiological models of Alzheimer's Disease (AD) typically describe how variables, such as regional levels of toxic proteins, interact spatiotemporally within a dynamical system driven by an underlying biological substrate, often based on brain connectivity. However, current methods grossly oversimplify the complex relationship between brain connectivity by assuming a single-modality brain connectome as the disease-spreading substrate. This leads to inaccurate predictions of pathology spread, especially during the long-term progression period. Meanhwile, other methods of learning such a graph in a purely data-driven way face the identifiability issue due to lack of proper constraint. We thus present a novel framework that uses Large Language Models (LLMs) as expert guides on the interaction of regional variables to enhance learning of disease progression from irregularly sampled longitudinal patient data. By leveraging LLMs' ability to synthesize multi-modal relationships and incorporate diverse disease-driving mechanisms, our method simultaneously optimizes 1) the construction of long-term disease trajectories from individual-level observations and 2) the biologically-constrained graph structure that captures interactions among brain regions with better identifiability. We demonstrate the new approach by estimating the pathology propagation using tau-PET imaging data from an Alzheimer's disease cohort. The new framework demonstrates superior prediction accuracy and interpretability compared to traditional approaches while revealing additional disease-driving factors beyond conventional connectivity measures.