Neuroimaging Models

Neuroimaging foundation models pretrained on large, predominantly western cohorts are increasingly proposed as general-purpose backbones for brain MRI analysis. Yet, their ability to generalize to underrepresented clinical populations remains largely untested. We evaluate four recent foundation models (BrainIAC, Neuro-JEPA, NeuroVFM, and Primus) on a three-way diagnostic classification task (Control, Dementia, Parkinson's disease) using a cohort of 88 subjects from a Nigerian clinical brain MRI dataset, across four modality configurations (T1w, T2w, T1w+T2w, FLAIR), and compare against an end-to-end trained ViT3D baseline. The frozen backbones collapse to majority-class predictions, while Neuro-JEPA on FLAIR shows modest but still limited discrimination. In contrast, the end-to-end trained ViT3D achieves higher accuracy and MCC on every task (up to 53.4% accuracy, MCC=0.27) and is the only model with non-trivial recall. Our findings suggest that these frozen neuroimaging foundation models are insufficient for fine-grained diagnostic classification in small, non-western clinical cohorts, motivating parameter-efficient adaptation and broader multi-site external validation for equitable deployment in global health settings.

Dementia is a major and growing global health burden, with Alzheimer's disease (AD) accounting for most cases. Timely and accurate diagnosis is central to managing this burden and increasingly depends on integrating complementary clinical and imaging information. Multimodal deep learning can combine these modalities for AD diagnosis, but how its explanations behave across modalities, fusion strategies, and cohorts remains unclear. We developed an explainable multimodal framework pairing a 3D CNN encoder for T1-weighted MRI with a feedforward network for harmonized clinical and demographic data, comparing varied model setups on three-way and pairwise diagnostic tasks using 6,479 internal records from the ADNI and 1,703 independent records from the OASIS-3. On ADNI, the tabular-only model achieved the highest three-class AUC-ROC of 0.879 and best discriminated cognitively normal (CN) versus mild cognitive impairment (MCI; 0.903), while cross-attention performed best for MCI versus AD (0.861); CN versus AD was highly discriminative overall. On OASIS-3, the vision-only model performed best (three-class AUC-ROC 0.910); CN versus MCI remained difficult, and no fusion strategy consistently outperformed single modalities across tasks and cohorts. SHAP and Integrated Gradients identified the MMSE as the dominant tabular feature in both cohorts, with global feature rankings agreeing strongly in ADNI ($\rho=0.94$) and OASIS-3 ($\rho=0.96$); CAM-based explanations, however, changed with model configuration and cohort. These findings show that multimodal performance and explanations are task, modality, fusion, and cohort-dependent: a dominant cognitive signal persisted across cohorts, but feature contributions and CAM explanations did not, underscoring the need to evaluate explainability under cohort shift rather than as a stable, intrinsic property.

Age-related Macular Degeneration (AMD) is the major cause of blindness in the Western world. Its late dry phase is characterised by irreversible atrophic areas, namely Geographic Atrophy (GA). Longitudinal Fundus Autofluorescence (FAF) image acquisitions are currently the main tool for assessing lesion growth over time at the image level. However, due to its highly individualised progression, the evolution of late AMD remains poorly understood. In this work, we propose using Implicit Neural Representations (INRs) to model GA progression at the individual level in a low-data setting. Our approach generates both FAF and GA segmentation at both past and future time points. Among the comparison models, our method achieves competitive segmentation quality across different scenarios, yielding the lowest Mean Absolute Error (MAE) for the GA lesion area and the highest DICE score, without sacrificing FAF image quality. The code is available at https://github.com/SimoneSarrocco/ga-progression-with-inrs.

Neuroimaging and genetic testing are two important clinical references for nervous system diseases, offering complementary diagnostic information. However, integrating genomic and neuroimaging data for precise disease diagnosis is challenging due to cross-modality heterogeneity. Existing imaging-genetics approaches mainly encode genetic information as hard-coded labels, which lose the local sequence context around disease-associated variants. To address this limitation, we propose GeneFuse, a multimodal learning framework that aligns genetic representations from pre-trained Genomic Language Models (GLMs) with features extracted from images. GeneFuse integrates two components: (1) Genotype-Conditioned Feature Modulation (GCFM), a FiLM-inspired module that uses genomic embeddings to modulate image feature maps; and (2) Uncertainty-aware Genomic Residual Fusion (U-GRF), a fusion strategy that uses imaging-derived predictive uncertainty to gate the contribution of genotypic features. We evaluate GeneFuse on early cognitive decline identification (NC vs. MCI) and dementia screening (NC vs. AD). In the APOE-centered setting, GeneFuse achieves AUROCs of 0.77 and 0.83, outperforming existing imaging-genetics fusion methods. These results indicate that GLM-derived genomic embeddings provide additional information to imaging.

Alzheimer's disease (AD) progression is a longitudinal process with subtle pathological cues in the early stages. Yet, computational constraints have limited most neuroimaging models to either compromise spatial information or limit the number of longitudinal scans. We aim to overcome this bottleneck and fully leverage high-resolution, variable-length T1w structural MRI (4D sMRI) scan sequences. We introduce Parcel2Progression (P2P), a Longitudinal Transformer Framework which tackles this challenge using an Atlas-guided Parcel Encoder that tokenizes 3D scans into a set of richer anatomically grounded representations. A Longitudinal Transformer then integrates irregular, arbitrary-length longitudinal visits with patient age. This synergy delivers two key advantages: (1) parcel-specific interpretability, and (2) computational tractability for long-term analysis, which scales linearly with the number of scans compared to a naive quadratic 4D ViT cost. P2P outperforms prior works and baselines in both MCI (Mild Cognitive Impairment) to AD conversion prediction and AD vs. CN (Cognitively Normal) classification tasks across ADNI, AIBL, and MIRIAD datasets. Leveraging longitudinal scans boosts performance over single-scan baselines by up to 5% and 7% in balanced accuracy for AD classification and MCI conversion prediction tasks, respectively. Interpretability analysis using parcel saliencies and attention rollouts reveals clinically consistent atrophy patterns in AD and MCI subjects. We also demonstrate the frameworks' reliability in anomaly detection using a synthetic dataset, and test the model's generalizability for other neurodegenerative diseases like Frontotemporal Dementia.

Stochastic cortical self-reconstruction (SCSR) enables personalized mapping of gray matter atrophy, a hallmark of neurodegenerative disorders such as Alzheimer's disease (AD), onto high-resolution cortical surfaces. Unlike conventional normative modeling approaches, which typically operate at a coarse regional level and remain inherently constrained by the covariates included during training, SCSR estimates an individualized healthy reference directly from the observed cortical thickness at the vertex level. This allows the detection of subtle, subject-specific deviations from healthy cortical shape. In this work, we investigate the generalization and transferability of SCSR, originally trained on UK Biobank (UKB) data, to an independent Chinese population dataset. Specifically, we evaluate the ability of SCSR-derived Z-scores to discriminate between healthy scans, individuals with mild cognitive impairment (MCI), and patients with AD, while also assessing model robustness across the lifespan. We compare four training strategies: direct application of the UKB-trained model, fine-tuning on Chinese data, training from scratch, and joint training on UKB and Chinese cohorts. As reconstruction backbones, we consider both a multilayer perceptron (MLP) and a Spherical UNet (SUNet). Our results demonstrate that SCSR provides robust detection of cortical atrophy in the Chinese population across all evaluated models. The highest discriminative performance was achieved by the fine-tuned SUNet model (average pairwise AUC = 0.848), followed closely by the UKB-trained SUNet. Moreover, reconstruction errors remained low across the lifespan, even when the training population exhibited a substantially narrower age distribution, indicating strong cross-population transferability.

Multimodal medical large language models remain structurally weak for neuro-oncology because volumetric evidence is compressed into generic visual tokens and diagnostic conclusions often lack an auditable link to MRI regions. We present NeuroMosaic, a 3D multimodal language model that converts multi-sequence brain MRI into anatomy-indexed regional tokens, aligns them with clinical narrative and molecular concepts, and generates evidence-linked outputs. The architecture combines a multi-resolution volumetric tokenizer, a neuroanatomical graph router, a molecular concept memory, and selective risk control. Across four glioma cohorts, NeuroMosaic achieved an internal subtype macro-F1 of 0.827 and external macro-F1 values of 0.784, 0.761, and 0.742. On UPenn-GBM, it improved over the strongest matched-input baseline by 3.6 percentage points (95% CI: 1.8 to 5.4, adjusted p = 0.0018), with IDH, 1p/19q, and MGMT AUROCs of 0.918, 0.861, and 0.781. Evidence pointing accuracy reached 0.703, and targeted evidence deletion reduced correct-answer probability by 0.187, compared with 0.046 for random deletion. These results establish anatomy-indexed routing as a measurable mechanism for accurate, grounded, and calibrated volumetric medical-language reasoning.

Functional near-infrared spectroscopy (fNIRS) is a promising modality for autism spectrum disorder (ASD) classification, yet existing approaches assume temporally aligned evaluation. In practice, the optimal observation window varies across subjects due to differences in hemodynamic delay and neurovascular coupling, creating a temporal distribution shift that degrades performance. We formalize this as a \textit{cross-time-window transfer problem}, introducing a protocol that varies window length (2.5--10,s) and offset within biological motion trials. Using topographic map representations of fNIRS recordings, we benchmark three vision architectures under two zero-shot baselines and eight adaptation strategies under leave-one-subject-out cross-validation ($N{=}124$). Key findings: (1) zero-shot cross-window accuracy is near chance (54--69%); (2) ${\approx}5\%$ subject-specific fine-tuning recovers 90--96%, while a subject-specific upper bound reaches 97--100%, identifying inter-subject variability as the dominant barrier; (3) domain-adversarial and self-supervised strategies achieve 78--90% without target-subject data; and (4) discriminative information is recoverable from windows as short as 2.5,s. These findings provide a practical roadmap for deploying fNIRS-based ASD classifiers under realistic temporal variability.

Despite tremendous success in neuroimaging methodology, making large-scale, high-dimensional datasets ready for AI/ML applications remains a critical operational bottleneck. Conventional workflows require extensive manual effort across metadata curation, pipeline execution, post-processing quality control, and data management, a burden that disproportionately excludes laboratories with limited manpower and computational infrastructure. To address this real-world barrier, there is an urgent need for scalable, cost-effective computational platforms that democratize advanced neuroimaging analytics and accelerate discoveries in mental health and clinical translation. Capitalizing on multi-agent LLM breakthroughs, we introduce CyberNeuro, an agentic workbench with a tailored local LLM-model ('WandaMind') for automated neuroimaging and health-data analysis. Driven by four dedicated agents (Planner, Validator, Dispatcher, and Reporter) communicating via a secure MCP bridge and a pinned execution layer, CyberNeuro enables researchers to execute complex workflows using natural language while maintaining clinical-grade data privacy. On the public NeuroBench suite, CyberNeuro increases held-out domain accuracy from 40% to 69% over the baseline model. Beyond automated metrics, the platform integrates a human-in-the-loop verification panel to ensure rigorous biomedical quality control. Across the same end-to-end 10-batch cohort workflow suite, the local WandaMind configuration completed all tasks with an estimated aggregate token count of about 10.6% using WandaMind and 61.7% using cloud providers of token usage, compared to Neuroclaw, respectively. The platform and its production-ready modules are available at https://wanda-cyberbench.com.

Transforming raw neuroimage archives into analysis-ready derivatives relies on three brittle stages: data standardization, modality-specific preprocessing, and quality control (QC). While individual neuroimaging tools are well developed, their orchestration requires project-specific scripts, environment-adaptive tuning, and labor-intensive manual QC. To address this, we introduce NeuroPilot, a multi-agent system that digitalizes the expertise of neuroimage processing, QC, and data management into three LLM-invocable skills: dcm2bids-skill, neuroimage-pre-skill, and qc-agent-skill. The LLM-driven agent autonomously orchestrates workflows, generalizing various infrastructure settings into a single configuration to achieve the highest scalability. Demonstrating the system's generalizability, we deployed NeuroPilot across 17 cohorts (>123,000 subjects) spanning infant to aging populations and multiple MRI modalities (structural, diffusion, functional). In practice, after standardizing data via the dcm2bids-skill, the agent dynamically routes datasets to the optimal neuroimage-pre-skill based on available modalities and cohort traits (e.g., dispatching T1w and fMRI data to fMRIPrep, or selecting specialized pipelines for infant cohorts). The qc-agent-skill then drives an evidence-based, semi-automated QC via a 3-D browser dashboard, utilizing a multi-tiered verification system to optimize failed cases and escalate complex issues for supervisor inspection. Quantitatively, our QC agent screened 558 production subjects, validating its automated flags against FreeSurfer's topology-defect metrics. The infant processing pipeline achieved a 100% (201/201) completion rate on QC-validated inputs. Importantly, NeuroPilot compresses the traditional 2--3 month timeline for training staff and processing complete datasets into a single week. NeuroPilot is deployed in https://wanda-cyberbench.com/.

Medical foundation models (FMs) are increasingly used for brain MRI analysis. However, their evaluation remains dominated by high-resource datasets, leaving generalization to African cohorts underexplored. We assess whether FMs generalize equally to African and non-African brain MRI data across two tasks: dementia classification using a Nigerian dataset and brain tumor segmentation using BraTS-Africa. We evaluate two generalist FMs (BrainIAC, 3DINO) and two segmentation-specific FMs (MedSAM2, Medical-SAM2) against a from-scratch baseline. For classification, FMs provide limited gains (highest ROC-AUC of 0.86 with BrainIAC), whereas for segmentation they consistently improve performance, reaching up to 0.86 Dice with MedSAM2. Performance differences between African and non-African cohorts are inconsistent and appear more related to dataset size than data origin. These results suggest that FMs do not exhibit an inherent bias against African cohorts, and highlight the limited availability and diversity of African neuroimaging datasets as the main barrier to robust evaluation and deployment.

Although artificial intelligence (AI) has shown promising performance in several medical tasks, accurate dementia etiology diagnosis with AI remains challenging due to complex overlapping symptoms among diseases. Scaling up the dataset size by combining the cross-center samples may bring a gain in the pursuit of performance, while the inherent data heterogeneity across centers or populations induces the conflict. Conventional multi-task learning paradigms offer a promising framework; however, they fail to consider critical meta information (e.g., site-specific acquisition and modality availability) to combat the heterogeneity. To address this challenge, we propose a Collaborative Meta Knowledge Enhancement (COME) framework for dementia etiology diagnosis, which injects multi-center acquisition semantics, source identifiers, and modality indicators as heterogeneity-aware embeddings into a unified Transformer architecture for scale-up training, enabling explicit modeling of heterogeneity. Besides, a trust-region constrained optimization scheme is designed to regularize the model from spurious correlations during training through a reference model. Across seven independent cohorts, our method achieves state-of-the-art in-domain performance with a mean macro-averaged AUC of 85.62% and a 4.29-point gain over the strongest baseline, while maintaining superior out-of-domain generalization under both cross-center and cross-sequence evaluations. Extensive validation also confirms the alignment between model predictions and established biomarkers (amyloid, tau) and clinical severity, highlighting the potential of COME to enable robust and interpretable dementia diagnostics in real-world settings.

Foundation models pretrained using self-supervised learning have transformed computer vision by learning transferable representations from large-scale unlabeled data. However, existing foundation models for neuroimaging remain limited by task-specific training, slice-based learning strategies, or relatively small pretraining datasets, restricting their generalizability across diverse brain MRI applications. In this work, we present BrainNext, a general-purpose self-supervised foundation model for volumetric brain MRI analysis. BrainNext combines masked autoencoder (MAE) pretraining with a native three-dimensional Bi-Directional xLSTM-UNet architecture to learn rich anatomical representations from 60,551 unlabeled brain MRI examinations spanning multiple MRI modalities. The pretrained model is subsequently adapted to downstream tasks through lightweight task-specific fine-tuning. We evaluate BrainNext on the Foundation Models for Medical Imaging (FOMO) 2025 Method Track, encompassing classification, segmentation, and brain-age estimation, where it achieved second place overall and ranked first in the meningioma segmentation task on the official FOMO 2025 challenge leaderboard, demonstrating strong transferability across heterogeneous neuroimaging tasks. These results highlight the potential of large-scale self-supervised pretraining to learn robust and transferable volumetric representations, establishing BrainNext as a scalable foundation model for diverse brain MRI applications.

Accurate diagnostic classification and disease-severity prediction for Alzheimer's disease are hampered by the incompleteness and heterogeneity of real-world clinical data. Left unaddressed, these barriers prevent reliable disease modelling and hinder effective clinical evaluation. Conventional imputation strategies introduce systematic bias, distort inter-feature relationships, and yield overconfident predictions, limitations especially consequential in diagnostic settings. Here, we propose NITROGEN, an imputation-free transformer that jointly models within-patient feature dependencies and between-patient relational structure through masked and intersample attention, enabling robust multimodal learning directly from partially observed records. We trained NITROGEN on ADNI (N=7858 scans), and evaluated it on two independent cohorts: OASIS-3 (N=2675 scans) and AIBL (N=1286 scans). Across cohorts and diagnostic and cognitive score prediction tasks, NITROGEN showed robust calibration and uncertainty quantification advantages over tree-based ensemble methods, while maintaining competitive discriminative performance. Cross-cohort and cross-method analyses identified cortical thickness in the temporal pole, age, and APOE genotype as important, though not individually sufficient, features for AD classification. We further introduced a modality-aware uncertainty adjustment that augments predictive uncertainty proportionally to the importance of absent modalities, enabling calibrated confidence when diagnostic information is unavailable. Together, our results show that imputation-free attention learning preserved meaningful discrimination under cohort shift, revealing expected degradation on more distributionally different cohorts, and demonstrate that evaluating models along calibration, interpretability, and cross-cohort reliability, not accuracy alone, is essential for clinical deployment.

Large-scale, multi-subject widefield calcium imaging provides unprecedented access to brain-wide cortical dynamics. However, the high dimensionality, complex spatiotemporal structure, and substantial task-irrelevant activity in widefield recordings have largely restricted modeling efforts to single-session analyses, limiting scalability and generalization. While multi-subject pretrained models have been explored for some neural modalities, multi-subject models for widefield calcium imaging have not yet been demonstrated; further, subject-invariant zero-shot behavior decoding remains elusive for multi-subject models across neural modalities more broadly. As a first step toward foundation modeling of widefield data, we introduce WiCAT, a multi-subject model that leverages self-supervised pretraining to both outperform single-session models and enable zero-shot behavior decoding on unseen subjects. WiCAT introduces an atlas-grounded tokenization scheme without session-specific components and learns globally shared spatiotemporal representations. Across multiple widefield datasets, the pretrained model supports lightweight downstream decoding, transfers across subjects, tasks, and datasets, and outperforms baseline models. Notably, the model also achieves robust zero-shot continuous behavior decoding and left-out brain region reconstruction on unseen subjects.

Neuroimaging research requires manipulating heterogeneous data structures, including raw MRI volumes, volumetric parcellations, cortical surface meshes, tractograms, and connectivity matrices, across tools with incompatible interfaces and file formats, forcing researchers to repeatedly re-implement routine but technically demanding operations. We present CLABTOOLKIT, an open-source Python package that consolidates these operations into a single, coherent framework by representing volumetric, surface, and streamline data as interoperable Python objects. Five core data structures (Parcellation, Surface, AnnotParcellation, Tractogram, and Connectome) encapsulate common neuroanatomical entities and provide consistent methods for loading, processing, and exporting data across standard neuroimaging formats (e.g., NIfTI, GIFTI, FreeSurfer annotations, TCK/TRK), including connectome generation from a parcellation and scalar-map projection onto tractogram streamlines. Complementary modules support BIDS dataset management, FreeSurfer integration, diffusion MRI processing, morphometric analysis, graph-theoretical network analysis, and GPU-accelerated multi-panel visualization via PyVista. The toolkit comprises 19 modules organised into six layers, exposing 13 object-oriented classes with 234 methods and 207 standalone functions, and a JSON-based configuration system enables workflow customization without code changes. Unlike existing neuroimaging libraries, which typically address these tasks separately, CLABTOOLKIT combines color and lookup-table management, parcellation manipulation, multi-surface visualization, and tractography utilities within a single framework. CLABTOOLKIT is compatible with Python 3.9-3.12 and released under the Apache 2.0 license. Source code, documentation, and example workflows are available at https://github.com/connectomicslab/clabtoolkit.

INTRODUCTION: Accurate MRI-based identification of Alzheimer's disease (AD), mild cognitive impairment (MCI), and related dementias remains challenging because disease-related structural changes are often subtle and heterogeneous. We developed NeuroBridge, a clinically guided multi-task MRI framework for neurodegenerative disease diagnosis. METHODS: NeuroBridge integrates large-scale self-supervised MRI pretraining with hippocampal segmentation, hippocampal atrophy classification, and reconstruction objectives, followed by gated fusion fine-tuning. Performance was evaluated across ADNI and OASIS cohorts, including cross-cohort transfer, probability-based analysis, and opportunistic screening. RESULTS: NeuroBridge achieved the highest performance across evaluated classification tasks, reaching 88.17% accuracy for AD versus cognitively normal controls in ADNI and 82.78% in OASIS. The largest gains occurred in MCI-related and mixed-diagnosis settings. The framework demonstrated strong cross-cohort generalization, systematic associations between predicted-class probability and accuracy, and the feasibility of probability-based opportunistic screening. DISCUSSION: Clinically guided multi-task representation learning improves neurodegenerative MRI diagnosis beyond conventional single-task approaches. NeuroBridge provides a robust and scalable framework for dementia assessment and MRI-based opportunistic screening.

Artificial intelligence is transforming our capability to solve biological challenges. In dimensionality bottleneck regimes exacerbated by high-dimensional biological data, neural networks force distinct concepts into the lower dimensions known as superposition. Although this superposition is widely known to hinder interpretability, its impact on corrupting the geometry of latent spaces remains critically overlooked. Here, we utilized sparse autoencoders (SAEs) trained on over 100,000 multiplexed images of patient-derived Parkinson's disease and healthy neurons to resolve superposition. This approach bypasses the mathematical non-uniqueness of feature attribution by shifting to interpretable latent representation analysis. We theoretically and empirically demonstrate that superposition contaminates representational metric spaces, and thereby SAEs successfully recover geometric fidelity. By treating these geometrically purified representations as single-cell state vectors, we adapted single-cell RNA sequencing (scRNA-seq) data analysis methodologies directly to the image domain. Finally, we introduce GW-map, utilizing Gromov-Wasserstein optimal transport to align these image representations with authentic scRNA-seq data de novo. This coupling reconstructs hierarchical neuronal pathology pathways such as Calcium-AIS scaffold, without reference spatial transcriptomics, establishing a scalable foundation for spatial biology. Code is available at https://github.com/jijihihi/Bio\_superposition

Longitudinal glioblastoma response assessment requires comparing subtle tumor changes across MRI time points using structured clinical criteria such as RANO. However, most deep learning methods predict response labels directly from imaging features, which limits clinical inspection, verification, and correction. We introduce TRACE, a RANO 2.0-aligned concept bottleneck model for interpretable 4-class glioblastoma response classification on longitudinal 3D MRI. TRACE processes paired baseline and follow-up multimodal MRI scans with a shared 3D vision encoder, predicts clinically meaningful tumor measurements as root concepts, computes downstream RANO-derived concepts through deterministic rules, and incorporates scan interval and new-lesion information as passthrough concepts. This design frames response assessment as structured concept reasoning rather than direct image-to-label prediction. Using 5-fold patient-wise cross-validation on the LUMIERE dataset, TRACE achieves a 4-class macro F1 of 0.4769 and a binary progression-versus-non-progression macro F1 of 0.7085. It improves over a concept bottleneck baseline and remains within the range of published non-interpretable deep learning approaches. Ablation studies show that the expert RANO graph and intervention-consistency training are important for performance, while intervention experiments demonstrate that correcting concepts can improve downstream predictions. These results suggest that structured concept bottlenecks offer a transparent and clinically aligned direction for longitudinal glioblastoma response assessment, while highlighting the need for larger protocol-aligned datasets and external validation.

Neurological disorders involve diverse pathologies of the brain and nervous system, making early and accurate detection essential. While many deep CNNs have been developed for MRI-based classification of neurological disorders, most are optimized for binary tasks and often fail to capture the multi-class features needed to distinguish subtle anatomical differences across conditions. This study proposes the Enhanced Neurological Disorder Detection Network (End-Net) for multi-class MRI classification of neurological disorders. End-Net includes 24 convolutional layers, beginning with convolutional blocks followed by 21 optimized inception modules. These modules extract multiscale features via parallel 1 x 1, 3 x 3, and factorized 5 x 5 convolutional branches, along with max pooling, enabling the model to capture complementary texture, edge, shape, and contextual information. A global average pooling head, compact fully connected classifier, and dropout reduce parameters, limit overfitting, and improve robustness. End-Net was evaluated on the Multi-Class Neurological Disorder dataset, comprising MRI scans from patients with Alzheimer's disease, brain tumors, multiple sclerosis, and healthy controls. Severe class imbalance was addressed by augmenting minority classes with WGAN-GP and randomly undersampling the majority class. The results show that End-Net outperforms existing architectures in both accuracy and generalization. The model is also integrated into an online system for real-time web-based inference and accessibility.

Causally linking disease-related factors to image-derived biomarkers provides a powerful pathway to understanding disease mechanisms. Despite growing interest in applying causal artificial intelligence (AI) approaches for this task, these methods still need to be adapted for complex medical images, and especially, neuroimaging. However, the lack of ground-truth data presents a barrier to development. To bridge this gap, we developed and tested a method for generating synthetic neuroimages, which adhere to a user-specified causal structure describing the non-image to image variable relationships, permitting the creation of ground-truth neuroimaging datasets. In the simulated T1-weighted magnetic resonance images, anatomical variability is modeled by sampling from a subspace estimated from real data and deforming a template image to create unique simulated subjects. Causal relationships are encoded via precise volumetric changes of any region-of-interest without unwanted global artifacts. We achieved relative volume errors of 0.3-2.66% for the targeted regions-of-interest and demonstrate their statistically significant causal relationships, while maintaining mean absolute errors for non-target brain regions between 0.034-0.397ml. An initial evaluation of causal discovery methods exposes their limited ability to suppress spurious connections, highlighting the need for image-appropriate methods. Our framework is the first to enable the generation of realistic synthetic 3D neuroimages with explicit causal control that can serve as the missing ground-truth data necessary for the objective benchmarking and development of causal AI methods.

We introduce SMART, a framework for learning a flexible, interpretable, and scalable spatio-temporal brain atlas from longitudinal high-resolution 3D medical images. Existing approaches to spatio-temporal atlas construction rely on black-box generative models that lack flexibility, limit interpretability, and struggle to scale to high-dimensional data. SMART addresses these challenges by learning a continuous disease-time atlas that decouples global group-wise disease dynamics from their patient-specific anatomical manifestation. Guided by anatomically inspired priors, SMART models interpretable global trajectories of regional progression along a shared disease timeline through region-specific differential equations. Global trajectories are further personalized to individual anatomies via dense diffeomorphic displacements parameterized by a flexible and scalable multi-scale Neural Cellular Automata. Evaluated on five longitudinal MRI datasets in Alzheimer's disease (ADNI-1/GO/2, OASIS-3, AIBL; > 1,300 subjects), SMART produces anatomically meaningful predictions of disease progression and achieves state-of-the-art forecasting accuracy and improved temporal consistency over adversarial and diffusion baselines. Our approach establishes a new paradigm for flexible, interpretable, and scalable modeling of spatio-temporal change in high-dimensional medical image time-series.

Deep neural networks have achieved strong performance in medical image classification, but often work like black-box. Commonly used post-hoc interpretation methods often provide heuristic visualizations whose relationship to the classifier's predictive distribution is indirect. This work introduces a local sensitivity analysis framework based on the input-dependent Fisher Information Matrix (iFIM) of a trained classifier. The iFIM characterizes how the classifier's predictive distribution changes under infinitesimal perturbations of the input image. By using a Gram-matrix formulation, the nonzero eigenspectrum of the iFIM can be recovered without explicitly forming the full image-dimensional Fisher matrix. The leading iFIM eigenspace is then used to project an input image into a high local-sensitivity component and its orthogonal component. These components provide a model-intrinsic description of local predictive sensitivity, rather than a conventional pixel-wise attribution heatmap or a causal segmentation of task-relevant anatomy. The framework is evaluated on controlled and clinical medical image classification tasks using multiple classifier architectures. Perturbation-based experiments show that high-sensitivity iFIM components are more strongly coupled to changes in predictive confidence and classification performance than lower-sensitivity complementary components. The results support the iFIM framework as a principled tool for analyzing local decision sensitivity and for complementing existing attribution-based interpretability methods in medical imaging.

Alzheimer's disease (AD) progression is often described through the amyloid-tau-neurodegeneration, or AT(N), cascade. However, most longitudinal models represent this cascade either as a fixed sequence of biomarkers or as a black-box forecasting task. This makes it difficult to determine when biologically guided biomarker relationships influence future regional pathology. In this study, we introduce Bayesian Networks with Latent Time Embedding (BN-LTE), a Bayesian structural framework for stage-aware modeling of AD progression. BN-LTE estimates disease pseudotime from baseline biomarker profiles and constrains directed dependencies according to biologically plausible AT(N) ordering. Posterior spline-varying structural equations are then used to link initial multimodal measurements with future annualized regional tau-PET change. Across repeated subject-disjoint evaluations using ADNI data, BN-LTE shows strong spatial reconstruction of tau progression compared with the included forecasting baselines. Beyond spatial reconstruction, BN-LTE recovers posterior stage-varying AT(N)-constrained effects and identifies a mid-pseudotime window of amyloid sensitivity. This window is supported by model-implied g-formula contrasts, root-adjusted AIPW, mechanism-sensitive ablations, and robustness analyses across spline and prior specifications. Overall, these findings position BN-LTE as a Bayesian structural framework for forecasting tau progression while examining stage-dependent AT(N)-cascade mechanisms in observational longitudinal neuroimaging data. Our code is available at https://github.com/danleneurocom/BN-LTE.

Brain MRIs are routinely acquired as multiple complementary sequences with unique contrast weighting, including T1-weighed imaging (T1w) anatomic and fluid-sensitive T2-weighted (T2w) contrasts. However, methods for learning unified representations across the multitude of MRI contrast mechanisms at health-system scale are lacking. In this study, we introduce Neuro-JEPA, a sparse multimodal neuroimaging foundation model that combines a latent predictive objective with a Mixture-of-Experts architecture to encode brain MRI across core T1w, T2w, and fluid-suppressed FLAIR imaging (FLAIR). We further provide a systematic methodological study of architectural, masking, objective, and sparsity design choices beneficial for robust neuroimaging multimodal representation learning. Neuro-JEPA was pretrained on 1,551,862 scans from 428,647 studies after modality-specific preprocessing with data curation across three core structural brain MRI sequences. We evaluated the learned representations across clinical and research settings, including 25 tasks from three health systems: NYU Langone, NYU Long Island, and Massachusetts General Hospital, and 22 tasks from 12 public datasets, covering unimodal, multimodal and cross-domain evaluation configurations. Across these benchmarks, existing neuroimaging foundation models showed inconsistent gains over a simple convolutional neural network (CNN) baseline, whereas Neuro-JEPA achieved stronger and more consistent performance across all evaluated settings. These results establish a scalable methodological framework for multimodal neuroimaging representation learning and highlight the need for foundation model evaluation protocols that include simple baselines, clinically heterogeneous cohorts and controlled multimodal comparisons.

Neurodegenerative diseases such as Alzheimer's disease (AD) require accurate and scalable tools for assessing disease severity, yet current clinical staging remains time-intensive and prone to variability. We propose an attention-enhanced multimodal machine learning framework with ordinal regression for automated and interpretable AD severity staging. The framework integrates T1-weighted MRI with demographic and genetic variables and compares unimodal and multimodal architectures using ordinal and non-ordinal prediction heads. Models were trained and validated using cohort-stratified splits derived from the ADNI, AIBL, and NIFD datasets. A strictly held-out test set was constructed using subjects excluded from all training, validation, preprocessing, and hyperparameter tuning procedures, with subject-level splitting employed throughout to prevent data leakage. Among unimodal approaches, the T1-weighted MRI model achieved slightly higher adjacent-stage accuracy (0.963) and agreement with clinical staging (QWK 0.444) than the tabular model (QWK 0.433). Integrating imaging, demographic, and genetic information improved overall performance. The multimodal non-ordinal baseline achieved the lowest prediction error (MAE 0.340), whereas the ordinal multimodal model achieved the highest adjacent-stage accuracy (0.970) and strongest agreement with clinical staging (QWK 0.549). These findings indicate that ordinal formulations better capture the ordered structure of the CDR scale and yield predictions more consistent with clinical staging. Explainability analyses using Grad CAM++ and SHAP demonstrated anatomically and clinically plausible model behavior, supporting transparent decision-making. Overall, attention-based multimodal learning with ordinal regression represents a robust, interpretable, and scalable approach for automated AD severity staging and AI-assisted clinical decision support.

Multimodal neuroimaging, integrating functional connectivity from fMRI and structural connectivity from DTI, enables non-invasive analysis of brain networks using graph neural networks. However, demographic factors such as age and sex systematically confound the relationship between brain connectivity and clinical outcomes, causing GNNs to exploit spurious shortcuts rather than learning causally invariant representations. While recent causal GNN methods introduce causality at the graph-modeling level, their causal mechanisms remain domain-agnostic without accounting for the real-world confounders inherent in clinical neuroimaging data. Moreover, brain networks are constructed from atlas-based parcellations where each region exhibits distinct sensitivity to demographic factors, necessitating region-aware adjustment. We propose Artemis, a region-level causal framework that bridges this gap with causal intervention at each brain region independently by learning region-specific confounder representations with lightweight parameters. Our adjustment comprehensively utilized the multimodal functional and structural features for graph reasoning as a plug-in module compatible with arbitrary GNN backbones. Experiments on three benchmarks, ADNI for disease diagnosis, OASIS for dementia staging, and HCP for sex classification, demonstrate consistent improvements over representative GNN-based baselines. Multiple supporting experiments further demonstrate statistical significance and neuroscientific interpretability.

Classical sparse Type-II Bayesian methods for M/EEG brain imaging support joint estimation of source and noise hyperparameters, but rely on fixed iterative update rules. Although these updates are principled and interpretable, their dynamics cannot be adapted from data. We propose to learn the update mechanism itself while preserving the underlying Bayesian structure by unfolding a classical joint hyperparameter-learning solver into a trainable neural architecture whose layers mirror the original iterations. The resulting framework is initialized to recover the classical solver exactly before training and is enriched through progressively more expressive correction-learning mechanisms, ranging from learnable biases to adaptive MLP and attention-based contextual refinements. In this way, training does not replace Bayesian inference with a black-box predictor, but instead learns structured correction terms while retaining the interpretability and model-based character of the original update dynamics. Structured correction learning therefore aims to improve empirical reconstruction performance without replacing the original model-based inference mechanism. Experimental results show that the learned correction variants improve reconstruction performance and convergence behavior over the baseline unfolded solver while preserving its algorithmic transparency.

Ischemic stroke is a major global disease. Treatment decisions are highly time-sensitive, as eligibility for reperfusion therapies relies on the interval between stroke onset and intervention. However, the true onset time is often uncertain in clinical practice, necessitating imaging-based assessment of tissue age as a surrogate marker. Early ischemic changes on routinely acquired non-contrast CT (NCCT) are often subtle, and real-world clinical datasets exhibit pronounced onset-time class imbalance and center-scanner-related heterogeneity. In this work, we propose StrokeTimer, a fully automated framework for onset-time estimation in acute ischemic stroke. StrokeTimer integrates self-supervised disentanglement learning with energy-guided contrastive learning to capture subtle ischemic patterns while addressing long-tailed data distributions under acquisition variability. Onset time is categorized into three clinically relevant windows: <4.5 h, 4.5-6 h, and >6 h. Experimental results on a large multi-center NCCT dataset from two national cohorts, MR CLEAN Registry and MR CLEAN LATE, show that StrokeTimer achieves a macro AUC of 0.69 and a macro F1-score of 0.57, improving the strongest baseline by nearly 50% (p < 0.005). In this realistic, challenging setting, representative baseline approaches exhibit near-chance macro performance. Model explanations further highlight subtle gray-white matter blurring and hypodense regions consistent with established radiological biomarkers. These findings demonstrate the potential of StrokeTimer to support treatment decision-making in acute ischemic stroke. Code is available at https://github.com/BrainVas/StrokeTimer.

Early and accurate detection of Alzheimer's disease (AD) is important for timely intervention and disease management. Generalized Eigenvalue Proximal Support Vector Machine (GEPSVM) and its Universum-based variants have shown promising results for AD classification. However, existing methods treat Universum samples as independent points and do not consider the geometric relationships among them. This paper proposes two graph-guided Universum learning models, namely UG-GEPSVM and IUG-GEPSVM, for AD versus cognitively normal (CN) classification using structural MRI data. In the proposed framework, mild cognitive impairment (MCI) subjects are used as Universum data to provide intermediate information between AD and CN classes. A graph is constructed over the Universum samples using Gaussian similarity, Minimum Spanning Tree connectivity, and multi-hop propagation. From this graph, a Laplacian matrix is derived that captures the geometric structure of the MCI samples. This Laplacian-based regularization is incorporated into the learning process in place of the conventional independent Universum penalty term. UG-GEPSVM integrates this regularization into the generalized eigenvalue formulation, while IUG-GEPSVM extends the numerically stable improved GEPSVM framework using a standard eigenvalue formulation. Experiments on ADNI MRI dataset variants using ICA- and PCA-based features at five different noise levels show that both proposed models consistently outperform existing GEPSVM and Universum-based methods. UG-GEPSVM achieves the highest average AUC of 88.07% and maintains stable performance under increasing noise levels. Statistical tests further confirm the significance of the observed improvements.

Multimodal neuroimaging fusion of functional MRI (fMRI) and diffusion tensor imaging (DTI) provides complementary information for cognitive impairment analysis, but remains challenged by heterogeneous feature spaces and misaligned representations. We propose \textit{NeuroAlign}, a hierarchical framework for structured multimodal fusion. It introduces (1) \textit{Dual-Modal Hierarchical Alignment} (DMHA), which models multi-scale dynamic connectivity and aligns dynamic-static and functional-structural embeddings; and (2) \textit{Dual-Domain Hierarchical Interaction} (DDHI), which enables fine-grained modulation and global interaction between connectivity- and region-level features. To support feature-level inspection, we design \textit{Synergistic Activation Mapping} (SAM), a gradient-free, marker-oriented attribution method for DFC, SFC, ALFF, and FA. Evaluated on GUTCM, ADNI, and OASIS under five-fold validation, NeuroAlign achieves competitive MCI/SCD detection and preliminary cross-dataset transferability. Attribution analyses reveal modality-specific and partially consistent brain patterns, providing model-derived evidence for multimodal representation analysis.

Forecasting the progression of neurodegenerative diseases, such as Parkinson's disease, is essential for effective long-term planning and personalized therapeutic intervention. Existing systems typically produce scalar clinical scores that ignore the rich structure of longitudinal neuroimaging, while traditional generative approaches suffer from a loss of anatomical details and blurring subtle progression patterns. To address this, we introduce a novel treatment-conditioned diffusion framework that predicts high-fidelity future brain states by conditioning the generative process on patients' screening DaTscan images and levodopa equivalent daily dose over one year. The pipeline uses a Transformer-based encoder to represent non-linear, time-dependent pharmacological dynamics and optimizes generation through a multi-weight region-of-interest mask that focuses on biologically critical areas. Experimental evaluation shows that our framework maintains sharp anatomical boundaries and significantly improves clinical fidelity relative to the baseline, achieving 14.0% lower MSE, 7.2% lower MAE, and 4.9% higher SSIM.

Recent progress in task-optimized neural networks has established encoding models as a powerful tool for predicting brain responses to naturalistic stimuli, yet most existing approaches rely on unimodal representations. The emergence of omni-modal foundation models and rich multimodal neural datasets enables encoding models that jointly integrate visual, auditory, and linguistic information across subjects. We introduce MIRAGE, a brain encoding framework for predicting whole-brain fMRI responses to naturalistic audiovisual stimuli. MIRAGE achieves state-of-the-art performance via a native multimodal backbone and adaptive feature gating across layers. These representations are then combined with a transformer-based brain encoder and a subject-specific linear head over the cortical parcels. Controlled comparisons show that natively multimodal features consistently outperform post-hoc aggregation of independent unimodal features, across architectural levels and backbones. Beyond predictive accuracy, the learned attention weights are directly inspectable to interpret the modality-specific gating profile over the backbone, and each modality traces a distinct anatomical pattern across cortex. Together, these results propose adaptive layer-wise aggregation of natively multimodal features as a generalizable, interpretable, and accurate approach for whole-brain encoding.

Functional magnetic resonance imaging (fMRI) is a powerful tool for investigating human brain function. However, the high cost of data acquisition and the inherent subjectivity of psychiatric rating scales often lead to datasets with small sample sizes and variable label quality, especially when targeting a specific neurological condition. Combined with the inherently high dimensionality of fMRI data, these limitations substantially increase the risk of model overfitting. Recent years have seen growing interest in developing fMRI foundation models by combining multiple datasets; however, the computational resources needed for pretraining and fine-tuning are often prohibitive. We show that a lightweight self-supervised framework yields representations that generalize across diverse downstream tasks, outperforming fully supervised baselines and approaching the performance of large-scale models. We introduce BrainSimSiam, a data-efficient self-supervised representation learning framework that leverages positive-only data pairs to learn robust and generalizable features. We demonstrate that the learned representations achieve strong performance across multiple downstream classification and regression tasks, highlighting the potential of BrainSimSiam for data-limited neuroimaging applications.

Cross-subject brain-to-visual decoding remains a core challenge in brain-computer interfaces due to severe inter-individual variability that induces systematic subject-specific functional misalignment. To address this issue, we propose MindAdapter, a parameter-efficient few-shot calibration framework for pretrained brain-to-visual decoding models. MindAdapter adopts a decoupled linear-residual cascade alignment paradigm by freezing a pretrained explicit brain functional alignment backbone (coarse) and introducing a lightweight nonlinear residual adapter (fine), thereby disentangling global cross-subject correspondence from subject-specific residual corrections for fine-grained spatial and semantic calibration. To further preserve global representational stability, we design a topology-anchored dual-stream manifold constraint, where a small set of shared stimuli serves as topological pins with voxel-level paired supervision, while a semantic stream enforces consistency through a frozen vision-language decoder on unpaired brain data. Together, MindAdapter efficiently injects subject-specific corrections while maintaining the global representational geometry learned during pretraining. Experiments on the Natural Scenes Dataset (NSD) demonstrate that MindAdapter substantially improves cross-subject visual reconstruction and retrieval accuracy using only a few shared stimuli, offering a practical and data-efficient solution for personalized brain-to-visual decoding.

Ultra-low-field (ULF) MRI offers portable and accessible neuroimaging but suffers from reduced signal-to-noise ratio and limited spatial resolution compared to high-field (HF) systems. Acquiring paired ULF-HF data for supervised enhancement is often difficult, particularly in resource-limited settings. We introduce ULF-Synth, a framework that combines: (i) acquisition-based synthesis of realistic ULF images from HF volumes to create large-scale paired training data, (ii) a spatial-frequency domain objective that prioritizes recovery of high-frequency anatomical detail. This formulation is architecture-agnostic, consistently improving structural similarity and perceptual fidelity across encoder-decoder, adversarial, and diffusion-based translation models. When trained exclusively on synthetic data, the resulting models generalize effectively to real 64mT ULF acquisitions, improving downstream multiclass brain segmentation and achieving higher radiologist preference and diagnostic acceptability in a blinded reader study. These findings demonstrate that synthetic paired supervision provides a practical and scalable pathway for enhancing ULF MRI without requiring real paired acquisitions. Code, Models and Dataset: https://github.com/toufiqmusah/ULF-Synth

Many modern datasets are large and carry complex structural relationships. Graph-based methods have traditionally been used to represent networked data, modeling individual elements as nodes and pairwise interactions as edges. Furthermore, Graph Signal Processing (GSP) has been developed to analyze signals on graph nodes, such as temperature measurements (node signals) across different regions of a country represented as a graph. Topological Signal Processing (TSP) is an emerging field that generalizes GSP, enabling the analysis of signals defined not only on nodes but also on edges, triangles, and higher-dimensional network elements, modeled as simplicial complexes and related topological structures. This makes TSP naturally well-suited for studying higher-order interactions in complex systems by extending classical signal processing concepts, such as filtering and Fourier transforms, to the topological level. Despite its versatility, TSP remains challenging for many practitioners. Therefore, we present an accessible overview of TSP foundations while drawing connections with application-oriented settings. We focus on processing techniques based on the combinatorial Hodge Laplacian, which generalizes the graph Laplacian to simplicial complexes. In particular, we review key TSP concepts, relate them to real-world examples, and discuss how higher-order structures and signals can be derived from datasets. For instance, we introduce an edge-level signal capturing lagged interactions between nodal signals, and demonstrate its use in a case study on TSP-based analysis of brain imaging data, revealing nontrivial interactions between sets of brain regions. Overall, we aim to promote a broader adoption of TSP by bridging methodological developments with applications, fostering its use among a wide community of theoretical and applied researchers.

While AI-generated hallucinations pose considerable risks, the underlying cognitive mechanisms by which humans can successfully recognize or be misled by these hallucinations remain unclear. To address this problem, this paper explores humans' neural dynamics to characterize how the brain processes hallucinated content. We record EEG signals from 27 participants while they are performing a verification task to judge the correctness of image descriptions generated by a multi-modal large language model (MLLM). Based on an averaged event-related potential (ERP) study, we reveal that multiple cognitive processes, e.g., semantic integration, inferential processing, memory retrieval, and cognitive load, exhibit distinct patterns when humans process hallucinated versus non-hallucinated content. Notably, neural responses to hallucinations that were misjudged versus correctly judged by human participants showed significant differences. This indicates that misjudged AI-generated hallucinations failed to trigger the standard neurocognitive fact verification pathway.

Clinical diagnostic workups typically follow a modality escalation pathway: after initial clinical evaluation, clinicians begin with routine structural imaging (e.g., MRI), selectively add sequences such as FLAIR or T2 to refine the differential, and reserve molecular imaging (e.g., amyloid-PET) for cases that remain uncertain after standard evaluation. Consequently, patients are observed with heterogeneous and often incomplete modality subsets. However, most current AI models assume fixed data modalities as the model inputs. In this paper, we present BrainAnytime, a unified pretraining framework pretrained on 34,899 3D brain scans from five datasets that support brain image analysis under arbitrary modality availability spanning multi-sequence MRI and amyloid-PET. A single model accepts whatever imaging is available, from a lone T1 scan to a full multimodal workup. Pretraining learns structural-molecular correspondences between MRI and PET via cross-modal distillation (RCMD) and prioritizes disease-vulnerable anatomy via atlas-guided curriculum masking (PACM), all within a shared 3D masked autoencoder (Multi-MAE3D). Across four downstream tasks and five clinically motivated modality settings, BrainAnytime largely outperforms modality-specific models, missing-modality baselines, and large-scale brain MRI pretrained foundation models on most modality settings. Notably, it surpasses the strongest missing-modality baselines with relative improvements of 6.2% and 7.0% in average accuracy on CN vs. AD and CN vs. MCI classification, respectively. Code is available at https://github.com/SDH-Lab/BrainAnytime.

Transforming neuroimaging data into clinically actionable biomarkers is a knowledge-intensive and labor-intensive process. Standardized workflows such as fMRIPrep have improved robustness and efficiency, but they are statically configured and cannot reason about downstream objectives, deliberate over alternative strategies, or close the loop between intermediate evidence and subsequent decisions in the way a human researcher would. This lack of closed-loop adaptation often leaves domain experts trapped in a cycle of manual trial-and-error to tune parameters and remediate pipeline failures, severely constraining the scalability of clinical biomarker development. To bridge this gap, we introduce NEXUS, an autonomous multi-agent framework that integrates neuroimaging workflow execution with scientific-objective understanding. Unlike conventional flat toolcalling agents, NEXUS adopts a code-centric execution paradigm where specialist agents collaboratively synthesize and optimize executable programs over composable domain-specific primitives. This design enables robust, long-horizon workflow construction that adapts dynamically to runtime observations. Furthermore, we propose a hierarchical verification framework for autonomous quality control, integrating cohort-level metric screening with agentic visual inspection to drive evidence-grounded workflow remediation. Experiments on ADHD-200 and ADNI demonstrate that NEXUS outperforms standard workflow-based baselines in predictive performance while exhibiting sophisticated agentic behaviors, including strategy exploration and adaptive refinement. The code is available at https://github.com/LearningKeqi/Virtual-Neuroscientist-NEXUS.

Deep vision models degrade sharply in low-data regimes, particularly in medical imaging where labeled samples are scarce. We show this arises not merely from overfitting but from a geometric failure: finite-sample noise corrupts the embedding covariance, collapsing the eigengap and limiting the number of recoverable signal-bearing modes. We develop a spectral theory of finite-sample representation learning that quantifies the recoverable dimension K(N), the number of eigenmodes that can be stably estimated from N samples. Using perturbation theory and concentration bounds, we show that only modes with eigenvalues above the noise floor $\|\hatΣ - Σ\|_{\mathrm{op}} \sim \sqrt{D/N}$ are reliable, yielding a truncated Mahalanobis energy that governs classification performance. Under a power-law spectral model, this energy can be approximated by a truncated Riemann zeta function, linking eigenvalue decay to data efficiency and AUC. Within this framework, multimodal learning acts as spectral stabilization: vision-language models impose low-rank constraints that suppress noise-dominated directions and preserve the eigengap, increasing K(N) under data scarcity. Across MNIST and multi-disease neuroimaging, we show that multimodal training maintains more stable modes and improves class separation, even when unimodal models achieve comparable few-shot accuracy. These results identify spectral collapse as a fundamental bottleneck in low-data learning. We use truncated Mahalanobis energy and K(N) to diagnose encoder quality, and introduce zeta-based spectral filtering as a principled approach to improve data efficiency.

Deep learning models in medical imaging typically operate as parametric memory, diagnosing patients by recalling fixed knowledge learned during training. This contrasts sharply with clinical practice, where physicians employ analogical reasoning to diagnose new cases by referencing similar records from past exemplars. While In-Context Learning (ICL) frameworks such as Tabular Prior-Fitted Networks (TabPFN) offer a promising diagnosis-by-reference paradigm, they are designed with tabular-specific inductive priors and rely on non-differentiable preprocessing pipelines, leading to manifold mismatch and gradient fracture when applied to heterogeneous multimodal data. To address these limitations, we propose PromptDx, a novel diagnosis-by-reference framework that leverages a pre-trained TabPFN as an ICL engine while enabling seamless integration with multimodal representations. Our core contribution is a Differentiable Prompt Tuning (DPT) mechanism that aligns a Masked Multimodal Modeling module with the pre-trained ICL engine. By training a lightweight adapter as a differentiable surrogate for the engine's non-differentiable preprocessors, we enable an end-to-end optimization of multimodal prompts within the ICL paradigm. We validate our method on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset using 3D MRI and tabular biomarkers. Experiments demonstrate that our approach outperforms traditional parametric baselines. Notably, our method achieves superior performance using only 1% context samples compared to 30% in standard ICL, demonstrating exceptional manifold condensation ability. We further validate the generalizability of our DPT framework across six tabular datasets with diverse scales. Overall, our method offers a more data-efficient and clinically aligned paradigm for Alzheimer's Disease diagnosis.

Deep learning and large public datasets have recently catalyzed the proliferation of AI models for processing brain recordings. However, systematically evaluating these models remains a challenge: not only do the preprocessing pipelines, training and finetuning approaches largely vary across studies, but their downstream evaluation is often limited to small sets of tasks and/or datasets. Here, we present NeuralBench: a unified framework for benchmarking AI models of brain activity. We accompany this framework with NeuralBench-EEG v1.0 -- a large EEG benchmark that includes 36 electroencephalography (EEG) tasks and 14 deep learning architectures, and is evaluated on 94 datasets accessed through a standardized interface. This first EEG-focused release already highlights two main findings. First, current foundation models only marginally outperform task-specific models. Second, a large set of tasks (e.g. cognitive decoding, clinical predictions) remain highly challenging, even for the best models. Critically, NeuralBench is designed for the integration of new tasks, datasets, models, and neuroimaging modalities, as illustrated by preliminary extensions to MEG and fMRI datasets and models. Through this white paper, we invite the community to expand this open-source framework and work together toward a unified benchmarking standard for neuroimaging models.

Recent advances in neuroimaging have deepened our understanding of the brain's complex functional and structural organization. Among these, functional Magnetic Resonance Imaging (fMRI) - particularly resting-state fMRI (rs-fMRI) - has emerged as a tool for identifying biomarkers of intrinsic brain connectivity and delineating large-scale neural networks. These networks are typically represented as volumetric spatial maps that capture functionally coherent brain regions and reflect individual differences in brain activity and structure. The spatial resolution of these maps plays an important role, as it determines the ability to localize functional units with precision, perform reliable brain parcellation, and detect subtle, spatially specific neurobiological alterations associated with development, aging, or disease. Therefore, improving the effective resolution of neuroimaging-derived maps holds significant promise for enabling more detailed insights into brain architecture and its relationship to behavior and pathology. To address this need, we propose NeuroGAN-3D, a novel 3D generative super-resolution model tailored to the computational demands of volumetric neuroimaging. Our model leverages a generative adversarial network architecture to enhance the spatial resolution of rs-fMRI spatial maps, significantly outperforming a conventional baseline.

Multimodal neuroimaging analysis often involves complex, modality-specific preprocessing workflows that require careful configuration, quality control, and coordination across heterogeneous toolchains. Beyond preprocessing, downstream statistical analysis and disease classification commonly require task-specific code, evaluation protocols, and data-format conventions, creating additional barriers between raw acquisitions and reproducible scientific analysis. We present NeuroAgent, an LLM-driven agentic framework that automates key preprocessing and analysis steps for heterogeneous neuroimaging data, including sMRI, fMRI, dMRI, and PET, and supports interactive downstream analysis through natural-language queries. NeuroAgent employs a hierarchical multi-agent architecture with a feedback-driven Generate-Execute-Validate engine: agents autonomously generate executable preprocessing code, detect and recover from runtime errors, and validate output integrity. We evaluate the system on 1,470 subjects pooled across all ADNI phases (CN=1,000, AD=470), where all subjects have sMRI and tabular data, with subsets also having Tau-PET (n=469), fMRI (n=278), and DTI ($n=620$). Pipeline ablation studies across multiple LLM backends show that capable models reach up to 100% intent-parsing accuracy, with the strongest backend (Qwen3.5-27B) reaching 84.8% end-to-end preprocessing step correctness. Automated recovery limits manual intervention to edge cases where human review is required via the Human-In-The-Loop interface. For Alzheimer's Disease classification using automatically preprocessed multimodal data, our agent ensemble achieves an AUC of 0.9518 with four modalities, outperforming all single-modality baselines. These results show that NeuroAgent can reduce the manual effort required for neuroimaging preprocessing and enable end-to-end automated analysis pipelines for neuroimaging research.

Brain MRI underpins a wide range of neuroscientific and clinical applications, yet most learning-based methods remain task-specific and require substantial labeled data. Here we show that a single self-supervised representation can generalize across heterogeneous brain MRI endpoints. We trained BrainDINO, a self-distilled foundation model, on approximately 6.6 million unlabeled axial slices from 20 datasets encompassing broad variation in population, disease, and acquisition setting. Using a frozen encoder with lightweight task heads, BrainDINO supported transfer across tumor segmentation, neurodegenerative and neurodevelopmental conditions classification, brain age estimation, post-stroke temporal prediction, molecular status prediction, MRI sequence classification, and survival modeling. Across tasks and supervision regimes, BrainDINO consistently equaled or exceeded natural-image and MRI-specific self-supervised baselines, with particularly strong advantages under label scarcity. Representation analyses further showed anatomically organized and pathology-sensitive feature structure in the absence of task-specific supervision. Our findings indicate that large-scale slice-wise self-supervised learning can yield a unified brain MRI representation that supports diverse neuroimaging tasks without volumetric pretraining or full-network fine-tuning, establishing a scalable foundation for robust and data-efficient brain imaging analysis. Code is available at https://github.com/mclwu22/BrainDINO

Cognitive decline is highly heterogeneous across individuals, which complicates prognosis, trial design, and treatment planning. We present the Personalized Cognitive Decline Assessment Digital Twin (PCD-DT), a multimodal and uncertainty-aware framework for modeling patient-specific disease trajectories from sparse, noisy, and irregular longitudinal data. The framework combines three methodological components: (1) latent state-space models for individualized temporal dynamics, (2) multimodal fusion for clinical, biomarker, and imaging features, and (3) uncertainty-aware validation and adaptive updating for robust digital twin operation. We also outline how conditional generative models can support data augmentation and stress testing for underrepresented progression patterns. As a preliminary feasibility study, we analyze longitudinal TADPOLE trajectories and show clear separation between cognitively normal and Alzheimer's disease cohorts in ADAS13, ventricle volume, and hippocampal volume over five years. We further conduct a multimodal next-visit prediction ablation using an LSTM sequence model on 3{,}003 visit-pair sequences derived from TADPOLE, where the combined cognitive plus MRI configuration achieves the lowest standardized RMSE for both ADAS13 (0.4419) and ventricle volume (0.5842), outperforming a Last Observation Carried Forward baseline. A Bayesian tensor modeling component for high-dimensional imaging fusion is also discussed. These results support the feasibility of the proposed architecture while also highlighting the need for stronger uncertainty calibration and longer-horizon predictive evaluation. The PCD-DT framework provides a principled starting point for personalized in silico modeling in neurodegenerative disease. This work positions PCD-DT as a foundational step toward clinically deployable, uncertainty-aware digital twin systems.

Despite being resource-intensive to train, 3D convolutional neural networks (CNNs) have been the standard approach to classify CT and MRI scans. Recent work suggests that deep multiple instance learning (MIL) may be a more efficient alternative for 3D brain scans, especially when the pre-trained image encoder used to embed each 2D slice is frozen and only the pooling operation and classifier are trained. In this paper, we provide a systematic comparison of simple MIL, attention-based MIL, 3D CNNs, and 3D ViTs across three CT and four MRI datasets, including two large datasets of at least 10,000 scans. Our goal is to help resource-constrained practitioners understand which neural networks work well for 3D neuroimages and why. We further compare design choices for attention-based MIL, including different encoders, pooling operations, and architectural orderings. We find that simple mean pooling MIL, without any learnable attention, matches or outperforms recent MIL or 3D CNN alternatives on 4 of 6 moderate-sized tasks. This baseline remains competitive on two large datasets while being 25x faster to train. To explain mean pooling's success, we examine per-slice attention quality and a semi-synthetic dataset where we can derive the best possible classifier via a Bayes estimator. This analysis reveals the limits of existing MIL approaches and suggests routes for future improvements.

Accurate brain lesion segmentation in MRI is vital for effective clinical diagnosis and treatment planning. Due to high annotation costs and strict data privacy regulations, universal models require employing Continual Learning (CL) to adapt to evolving clinical tasks without losing previously acquired knowledge. However, existing CL paradigms often suffer from capacity limits or redundant parameter growth, and even advanced dynamic methods rely mostly on image-perception strategies that struggle to handle the substantial pathological and multimodal heterogeneity inherent in brain imaging. To address this issue, we propose Concept-Reasoning Expansion (CoRE) framework, which establishes a joint decision-making mechanism by integrating visual features with structured concepts. Through the alignment of image tokens with a hierarchical concept library, CoRE simulates clinical reasoning to guide both interpretable expert routing and demand-based model growth. This collaborative process ensures model evolution is grounded in clinical priors, preventing redundant parameter expansion while maximizing knowledge reuse. Extensive evaluations across 12 sequential brain lesion MRI tasks demonstrate that CoRE achieves state-of-the-art performance and provides a high knowledge starting point for efficient future adaptation. Its superior few-shot transferability and clinical interpretability further validate its effectiveness in managing non-stationary clinical data streams. Our code will be released soon.

Clinical abnormality grounding for rare diseases is often hindered by data scarcity, making supervised fine-tuning impractical and single-pass inference highly unstable. We propose Dynamic Decision Learning (DDL), a framework that enables frozen large vision-language models (LVLMs) to refine their decisions across both language and visual spaces by optimizing instructions and consolidating predictions under visual perturbations. This process improves localization quality and produces a consensus-based reliability score that quantifies model confidence. Results on brain imaging benchmarks, including a rare-disease dataset with 281 pathology types across models ranging from 3B to 72B parameters, show that DDL improves mAP@75 by up to 105% on rare-disease cases and outperforms adaptation baselines and supervised fine-tuning. Furthermore, DDL demonstrates stronger calibration between reliability scores and localization accuracy under severe distribution shifts and increasing task difficulty. Code is available at: https://lijunrio.github.io/DDL/

Agentic artificial intelligence systems promise to accelerate scientific workflows, but neuroimaging poses unique challenges: heterogeneous modalities (sMRI, fMRI, dMRI, EEG), long multi-stage pipelines, and persistent reproducibility risks. To address this gap, we present NeuroClaw, a domain-specialized multi-agent research assistant for executable and reproducible neuroimaging research. NeuroClaw operates directly on raw neuroimaging data across formats and modalities, grounding decisions in dataset semantics and BIDS metadata so users need not prepare curated inputs or bespoke model code. The platform combines harness engineering with end-to-end environment management, including pinned Python environments, Docker support, automated installers for common neuroimaging tools, and GPU configuration. In practice, this layer emphasizes checkpointing, post-execution verification, structured audit traces, and controlled runtime setup, making toolchains more transparent while improving reproducibility and auditability. A three-tier skill/agent hierarchy separates user-facing interaction, high-level orchestration, and low-level tool skills to decompose complex workflows into safe, reusable units. Alongside the NeuroClaw framework, we introduce NeuroBench, a system-level benchmark for executability, artifact validity, and reproducibility readiness. Across multiple multimodal LLMs, NeuroClaw-enabled runs yield consistent and substantial score improvements compared with direct agent invocation. Project homepage: https://cuhk-aim-group.github.io/NeuroClaw/index.html

Understanding and predicting the progression of neurodegenerative diseases remains a major challenge in medical AI, with significant implications for early diagnosis, disease monitoring, and treatment planning. However, most available longitudinal neuroimaging datasets are temporally sparse with a few follow-up scans per subject. This scarcity of temporal data limits our ability to model and accurately capture the continuous anatomical changes related to disease progression in individual subjects. To address this problem, we propose a novel 4D (3DxT) diffusion-based generative framework that effectively models and synthesizes longitudinal brain anatomy over time, conditioned on available clinical variables such as health status, age, sex, and other relevant factors. Moreover, while most current approaches focus on manipulating image intensity or texture, our method explicitly learns the data distribution of topology-preserving spatiotemporal deformations to effectively capture the geometric changes of brain structures over time. This design enables the realistic generation of future anatomical states and the reconstruction of anatomically consistent disease trajectories, providing a more faithful representation of longitudinal brain changes. We validate our model through both synthetic sequence generation and downstream longitudinal disease classification, as well as brain segmentation. Experiments on two large-scale longitudinal neuroimage datasets demonstrate that our method outperforms state-of-the-art baselines in generating anatomically accurate, temporally consistent, and clinically meaningful brain trajectories. Our code is available on Github.

Predicting individual cognitive decline in Alzheimer's disease (AD) is difficult due to the heterogeneity of disease progression. Reliable clinical tools require not only high accuracy but also fairness across demographics and robustness to missing data. We present CognitiveTwin, a digital twin framework that predicts patient-specific cognitive trajectories. The model integrates multi-modal longitudinal data (cognitive scores, magnetic resonance imaging, positron emission tomography, cerebrospinal fluid biomarkers, and genetics). We use a Transformer-based architecture to fuse these modalities and a Deep Markov Model to capture temporal dynamics. We trained and evaluated the framework using data from 1,666 patients in the TADPOLE (Alzheimer's Disease Neuroimaging Initiative) dataset. We assessed the model for prediction error, demographic fairness, and robustness to missing-not-at-random (MNAR) data patterns. ognitiveTwin provides accurate and personalized predictions of cognitive decline. Its demonstrated fairness across patient demographics and resilience to clinical dropout make it a reliable tool for clinical trial enrichment and personalized care planning.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a major cause of dementia. Structural MRI is widely used to analyze AD-related brain atrophy; however, most deep learning methods rely on computationally expensive 3D convolutional neural networks (CNNs), limiting deployment in resource-constrained settings. This work introduces two main contributions. First, we propose a pipeline that converts T1-weighted MRI into anatomically informed 2D point clouds using Anatomical Priority Sampling (APS), producing ADNI-2DPC, the first neuroanatomically labeled MRI-derived point cloud dataset. Second, we present NeuroAPS-Net, a lightweight geometric deep learning model that incorporates anatomical priors via region-aware feature encoding and ROI token aggregation. Experiments on ADNI-2DPC demonstrate that NeuroAPS-Net achieves competitive classification accuracy while significantly reducing inference latency and GPU memory compared to state-of-the-art point cloud methods. These results highlight the potential of anatomically guided point cloud learning as an efficient and interpretable alternative to voxel-based CNNs for AD classification.

Linear models are widely used in computational neuroimaging to identify biomarkers associated with brain pathologies. However, interpreting the learned weights remains challenging, as they do not always yield clinically meaningful insights. This difficulty arises in part from the inherent correlation between brain regions, which causes linear weights to reflect shared rather than region-specific contributions. In particular, some groups of regions, including homologous structures in the left and right hemispheres, are known to exhibit strong anatomical correlations. In this work, we leverage this prior neuroanatomical knowledge to introduce a whitening approach applied to groups of regions with known shared variance, designed to disentangle overlapping information across correlated brain measures. We additionally propose a regularized variant that allows controlled tuning of the degree of decorrelation. We evaluate this method using region-of-interest features in two psychiatric classification tasks, distinguishing individuals with bipolar disorder or schizophrenia from healthy controls. Importantly, unlike PCA or ICA which use whitening as a dimensionality reduction step, our approach decorrelates anatomically informed pairs of neuroanatomical regions while retaining the full input signal, making it specifically suited for feature interpretation rather than feature selection. Our findings demonstrate that whitening improves the interpretability of model weights while preserving predictive performance, providing a robust framework for linking linear model outputs to neurobiological mechanisms.

State-of-the-art large language models (LLMs) show high performance in general visual question answering. However, a fundamental limitation remains: current architectures lack the native 3D spatial reasoning required to directly analyze volumetric medical imaging, such as CT or MRI. Emerging agentic AI offers a new solution, eliminating the need for intrinsic 3D processing by enabling LLMs to orchestrate and leverage specialized external tools. Yet, the feasibility of such agentic frameworks in complex, multi-step radiological workflows remains underexplored. In this work, we present a training-free agentic pipeline for automated brain MRI analysis. Validating our methodology on several LLMs (GPT-5.4, Gemini 3.1 Pro, Claude Sonnet 4.6) with off-the-shelf domain-specific tools, our system autonomously executes complex end-to-end workflows, including preprocessing (skull stripping, registration), pathology segmentation (glioma, meningioma, metastases), and volumetric reasoning. We evaluate our framework across increasingly complex radiological tasks, from single-scan tumor and anatomy analysis to longitudinal response assessment requiring multi-timepoint comparisons. We analyze the impact of architectural design by comparing single-agent models against multi-agent "domain-expert" collaborations. To support rigorous evaluation of future agentic systems, we release a benchmark dataset of image-prompt-answer tuples derived from public data. Our results demonstrate that agentic AI can solve highly neuro-radiological image analysis tasks through tool use without the need for training or fine-tuning.

Portable CT scanners may support earlier stroke assessment, but reduced photon counts introduce noise that affects image quality and may alter automated classification. We compared direct classification of simulated low-dose slices with residual U-Net denoising followed by the same fixed classifier. Poisson noise was generated at photon-count scaling factors of 1, 5, 10, 20, and 40 using three deterministic seeds. The held-out set contained 809 slices, including 242 positive and 567 negative slices. Direct classification reached its highest mean ROC-AUC at a scaling factor of 20 (0.937 +/- 0.002). Denoising followed by classification reached 0.842 +/- 0.005 at a scaling factor of 1 and declined to 0.655 +/- 0.002 at a scaling factor of 40. Meanwhile, reconstruction quality rose steadily from 21.92 to 40.91 dB PSNR and from 0.761 to 0.987 SSIM. Both pathways had poor sensitivity at a fixed 0.5 cutoff because their classification scores were concentrated near zero. Patient-level analysis was limited by the test-set composition: all 10 patients were positive under the mask-derived patient label, preventing estimation of patient-level AUC and specificity. Overall, higher reconstruction fidelity did not translate into better discrimination by the fixed classifier except at the lowest photon-count setting.

Accurate compensation of brain deformation is critical for reliable image-guided neurosurgery. Surgical manipulation and tumor resection induce tissue motion, causing preoperative planning images to become misaligned with the intraoperative anatomy. In this systematic review, we examine data-driven methods developed between 2020 and 2025 for brain deformation registration and modeling, with a particular focus on learning-based approaches. A comprehensive literature search was conducted in PubMed, IEEE Xplore, Scopus, and Web of Science using predefined inclusion and exclusion criteria for computational methods addressing brain deformation in neurosurgical imaging, resulting in 46 eligible studies. We provide a unified analysis of methodological strategies, including deep learning-based image registration, direct deformation field regression, synthesis-driven multimodal alignment, resection-aware architectures for handling missing correspondences, and hybrid models integrating biomechanical priors. We also examine dataset utilization, evaluation metrics, validation protocols, and the assessment of uncertainty and generalization across studies. While learning-based methods demonstrate promising accuracy and computational efficiency, current approaches remain limited by out-of-distribution robustness, standardized benchmarking, interpretability, and readiness for clinical deployment. Our review highlights these gaps and outlines future directions toward more robust, generalizable, and clinically translatable solutions for neurosurgical guidance. By organizing recent advances and critically assessing evaluation practices, this work provides a comprehensive reference for researchers and clinicians working on data-driven registration and modeling of brain deformation.

Parallel imaging techniques reduce magnetic resonance imaging (MRI) scan time but image quality degrades as the acceleration factor increases. In clinical practice, conservative acceleration factors are chosen because no mechanism exists to automatically assess the diagnostic quality of undersampled reconstructions. This work introduces a general framework for pixel-wise uncertainty quantification in parallel MRI reconstructions, enabling automatic identification of unreliable regions without access to any ground-truth reference image. Our method integrates conformal quantile regression with image reconstruction methods to estimate statistically rigorous pixel-wise uncertainty intervals. We trained and evaluated our model on Cartesian undersampled brain and knee data obtained from the fastMRI dataset using acceleration factors ranging from 2 to 10. An end-to-end Variational Network was used for image reconstruction. Quantitative experiments demonstrate strong agreement between predicted uncertainty maps and true reconstruction error. Using our method, the corresponding Pearson correlation coefficient was higher than 90% at acceleration levels at and above four-fold; whereas it dropped to less than 70% when the uncertainty was computed using a simpler a heuristic notion (magnitude of the residual). Qualitative examples further show the uncertainty maps based on quantile regression capture the magnitude and spatial distribution of reconstruction errors across acceleration factors, with regions of elevated uncertainty aligning with pathologies and artifacts. The proposed framework enables evaluation of reconstruction quality without access to fully-sampled ground-truth reference images. It represents a step toward adaptive MRI acquisition protocols that may be able to dynamically balance scan time and diagnostic reliability.

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.