Brain Age

Brain age estimation has become a popular research proxy for assessing brain health and disease, yet longitudinal trajectories of brain ageing are still poorly defined, and clinical use is limited. Building on existing Siamese longitudinal frameworks, we develop Brain-Predicted Age Acceleration (Brain-PACE) to directly estimate the pace of structural brain ageing from paired T1-weighted MRI. Brain-PACE identified accelerated ageing in $42.6$% of participants with mild cognitive impairment. Faster Brain-PACE was associated with greater functional and cognitive impairment (FAQ; $r=0.35$, ADAS13; $r=0.30$, CDR-SB; $r=0.32$) and greater regional tau burden in the posterior cingulate ($r=0.59$), precuneus ($r=0.47$), and entorhinal cortex ($r=0.37$). These associations were stronger than those observed when pace was calculated indirectly from repeated cross-sectional brain age estimates, suggesting that direct longitudinal modelling captures complementary information relevant to ongoing pathological change. Methodologically, Brain-PACE extends the LILAC framework by combining spatial attention with soft label distribution learning and a Cram'er distance objective, improving probabilistic performance and reducing prediction bias while providing measures of predictive uncertainty. Together, these findings support Brain-PACE as a complementary longitudinal imaging phenotype with sensitivity to relevant clinical and biological changes in early neurodegeneration.

Brain-age prediction models are commonly evaluated by predictive accuracy, yet accurate predictions alone do not establish that a model relies on reproducible or neurobiologically supported mechanisms. Post-hoc explanation methods can expose these mechanisms, but existing workflows typically stop at diagnosis or require correction targets to be specified before model analysis. We propose XAI-Refine, an automated explanation-knowledge loop for brain-age prediction from resting-state functional connectivity. At each iteration, XAI-Refine consolidates complementary post-hoc analyses across repeated training runs into reliable, structured model explanations. It converts each reliable explanation into a neutral neurobiological question, retrieves and verifies relevant literature, and compiles the verified evidence into an admissible set in the same typed explanation space. The target for refinement is defined as the minimal projection of the current model explanation onto the admissible set induced by applicable verified knowledge. This revised explanation is then translated into a differentiable constraint while preserving the originating model variable, measurement operator, and applicable scope. Candidate updates are promoted only when multi-seed validation confirms target-directed explanatory movement, predictive performance remains within a prespecified guardrail, and non-target explanatory drift remains bounded. Experiments on functional-connectivity-based brain-age prediction evaluate predictive performance, explanation reliability, literature alignment, and target-specific model revision, illustrating a structured route from post-hoc analysis to evidence-guided model refinement.

Brain age - the age inferred from a physiological recording - is an emerging biomarker whose deviation from chronological age tracks neurological and psychiatric burden, and EEG is an attractive substrate for it because it is cheap, portable, and temporally rich. Yet EEG brain-age models must contend with cross-site montage heterogeneity, small labelled cohorts, and dominant subject-level non-stationarity, and few EEG foundation models have been shown to deliver competitive age regression across the full pediatric to older adult range in which such a biomarker would actually be deployed. We introduce STST-JEPA, a self-supervised transformer for resting-state and task EEG, pretrained on 47,703 sessions spanning ages 5-81 from the brain.space and Healthy Brain Network (HBN) corpora. The model combines a latent-prediction objective - predicting masked-token representations against an EMA-of-tokenizer target - with an auxiliary signal-reconstruction term, applied to 30-second multi-channel windows under spatiotemporal block masks. A lightweight attentive probe trained on frozen pretrained embeddings achieves a best held-out-validation mean absolute error of 3.06 years (r = 0.924) for age regression on 3,367 sessions, against a predict-the-mean baseline of approximately 10 years MAE. With light task-specific finetuning of the model's final layers, the same pretrained encoder achieves rank-1 placements - with the model's native 30-second windows - on the public NeuralBench x brain.space EEG leaderboard for sex classification (balanced accuracy 0.911), age prediction (r = 0.749), and psychopathology composite regression (r = 0.215). We further show that the model's age-prediction residual is negatively correlated with cognitive efficiency over several tasks we examined.

Large and demographically balanced datasets are essential for reliable neuroimaging biomarkers. Full-resolution 3D brain MRI synthesis can support data augmentation in this setting, but existing approaches either incur prohibitive computational cost at volumetric scale or rely on lossy latent compression that may compromise anatomical detail. As a result, practical 3D generative augmentation often requires specialized compute infrastructure. We propose WaveDiT, a conditional flow matching framework operating in the coefficient space of a 3D Haar Discrete Wavelet Transform. The model combines factorized spatio-depth attention with band-wise heteroscedastic uncertainty modeling derived from higher-order wavelet statistics. Predicted log-variance is integrated directly into both the flow objective and conditioning pathway, enabling adaptive precision consistent with the heavy-tailed and input-dependent variance structure of anatomical detail. This formulation supports full-resolution 3D synthesis under practical memory and time constraints on a single modern GPU. Evaluation on a multi-site cohort demonstrates improved alignment between generated and real MRI distributions, together with enhanced downstream brain age prediction and region-level anatomical agreement relative to diffusion, latent, and wavelet-based baselines. Code is available at https://github.com/sisinflab/WaveDiT

The study of brain morphology changes in normal individuals may capture aspects of functionally-relevant brain aging not fully indicated by gross volumetry. Despite the important role of subcortical brain structures in cognition, the associations between their morphological trajectories and cognitive changes in aging have not been documented. We use neuroimaging, demographic, and cognitive data from a large longitudinal study of cognitive aging, the Lothian Birth Cohort 1936, to explore shape changes in subcortical brain structures of community-dwelling individuals across their 8th decade of life. We investigate the association of these changes with cognitive aging using ANCOVA and mixed linear model analyses. Subcortical shape changes were heterogeneous, with varied atrophy patterns across whole period. The hippocampus and the ventral DC experienced varied morphological deformations (from its baseline point) different in left and right hemispheres, while the thalami and globus pallidi shapes, for example, experienced a more uniform volume contraction, nearly symmetrical throughout different timelines. Changes in general cognition were mainly associated with inwards and outwards vertex displacements between the time-points.

Defining vascular age in terms of physiological function has become one focal point of the extensive studies to categorize and track chronological age. Transcranial Doppler (TCD) is a method by which cerebral blood flow velocity is measured along the major arteries feeding the human brain. This study aims to use features extracted from TCD to estimate chronological age and assess accelerated aging in subjects with various brain diseases. We predict subjects with various brain diseases to present with accelerated cerebrovascular aging when tested on various regression models trained by healthy subjects. 168 healthy subjects and 277 diseased subjects with bilateral TCD recordings of the middle cerebral artery were analyzed using the Morphological Analysis and Clustering of Intracranial Pressure (MOCAIP) algorithm. MOCAIP-generated features and heart rate variability features were used as input features for regression models to predict the brain vascular age. 66 subjects with acute stroke, 27 subjects with post stroke, 26 subjects with Alzheimer's disease, 23 subjects with mild cognitive impairment, and 135 established subjects were tested against the machine learning model to assess for accelerated cerebrovascular age. The trained model, on average, predicted healthy subjects' cerebrovascular age to be 3.69 years above their chronological age. Subjects with different disease conditions exhibited varying levels of age acceleration. The differences in healthy and diseased subjects' performances suggest that features generated using TCD may be relevant when evaluating accelerated cerebrovascular aging. Moreover, imbalanced datasets have been observed to affect the performance of machine-learning-based brain age prediction models.

Foundation models (FMs) promise to extract unified representations that generalize across downstream tasks. They have emerged across fields, including electroencephalography (EEG), but it is less clear how effective they are in this particular field. Published evaluations differ in datasets, in the EEG-specific preprocessing that might influence reported results, and in the reported metrics, frequently obscuring the clinical relevance in EEG. We introduce NeuroAtlas, the largest EEG benchmark to date: 42 datasets and 260k hours covering clinical EEG (epilepsy, sleep medicine, brain age estimation) and brain-computer interfaces, and include multiple datasets per task along with bespoke clinical evaluation metrics. Besides evaluating EEG-FMs with respect to supervised baselines, we present results from generic time-series FMs. We report three findings. First, EEG-specific FMs do not consistently outperform time-series FMs, which have neither EEG-focused architectures nor been pretrained on EEG. Second, standard machine learning metrics are insufficient to assess clinical utility: thus, we thoroughly evaluate more appropriate measures such as the quality of event-level decision-making, hypnogram-derived features, and the brain-age gap in the domains of epilepsy, sleep, and brain age, respectively. Third, model rankings and performance can vary substantially within domains. We conclude that pretrained models perform largely on par, with only narrow advantages for a few, and that current models do not yet deliver on the promise of an out-of-the-box unified EEG model. NeuroAtlas exposes this gap and provides the datasets and metrics for the next generation of unified EEG FMs.

The accurate quantification of brain age from MRI has emerged as an important biomarker of brain health. However, existing approaches are often restricted to narrow age ranges and single-modality MRI data, limiting their capacity to capture the coordinated macro- and microstructural changes that unfold across the human lifespan. To address these limitations, we develop a multi-modal brain age framework to characterize the integrated evolution of brain morphology and white matter organization. Our model adopts a two-stage architecture, where modalities are processed independently and integrated via late fusion in both stages: first to estimate a probability distribution over six developmental stages, and then to predict age via probability-weighted stage-specialized experts. Experiments on nine datasets spanning fetal to elderly stages demonstrate competitive in-domain performance and out-of-domain generalization, with our method reducing MAE by 13% and 78% over existing baselines and multi-modal integration yielding 12-13% gains. Analysis of ADNI clinical groups further suggests the potential of the predicted brain age gap to characterize Alzheimer's-related brain aging.

Deep learning (DL) has transformed neuroimaging by delivering state-of-the-art performance with reduced computation times. Yet, the numerical uncertainty inherent to DL training remains largely underexplored despite its potential to significantly impact the reliability of model outcomes. We show that training the FastSurfer segmentation model introduces substantial numerical uncertainty that exceeds its non-DL counterpart (FreeSurfer 7.3.2) in cortical regions, potentially impacting downstream clinical results. We also characterize this training-time uncertainty using random seed perturbations and demonstrate that seed-induced variability is structurally comparable to numerical variability. We then show that seed variability can be leveraged as a data augmentation technique through ensembling to improve downstream brain age regression performance. These findings position numerical uncertainty during DL training as a substantive factor in neuroimaging reliability, with measurable consequences for downstream tasks, and demonstrate that it can simultaneously be harnessed as a data augmentation technique.

$\textbf{Objective:}$ Brain-predicted age difference (BrainAGE) is a neuroimaging biomarker reflecting brain health. However, training robust BrainAGE models requires large datasets, often restricted by privacy concerns. This study evaluates the performance of federated learning (FL) for BrainAGE estimation in ischemic stroke patients treated with mechanical thrombectomy, and investigates its association with clinical phenotypes and functional outcomes. $\textbf{Methods:}$ We used FLAIR brain images from 1674 stroke patients across 16 hospital centers. We implemented standard machine learning and deep learning models for BrainAGE estimates under three data management strategies: centralized learning (pooled data), FL (local training at each site), and single-site learning. We reported prediction errors and examined associations between BrainAGE and vascular risk factors (e.g., diabetes mellitus, hypertension, smoking), as well as functional outcomes at three months post-stroke. Logistic regression evaluated BrainAGE's predictive value for these outcomes, adjusting for age, sex, vascular risk factors, stroke severity, time between MRI and arterial puncture, prior intravenous thrombolysis, and recanalisation outcome. $\textbf{Results:}$ While centralized learning yielded the most accurate predictions, FL consistently outperformed single-site models. BrainAGE was significantly higher in patients with diabetes mellitus across all models. Comparisons between patients with good and poor functional outcomes, and multivariate predictions of these outcomes showed the significance of the association between BrainAGE and post-stroke recovery. $\textbf{Conclusion:}$ FL enables accurate age predictions without data centralization. The strong association between BrainAGE, vascular risk factors, and post-stroke recovery highlights its potential for prognostic modeling in stroke care.

BrainAGE is a promising imaging-derived biomarker of neurobiological ageing and disease risk, yet current approaches rely predominantly on T1-weighted structural MRI, overlooking functional vascular changes that may precede tissue damage and cognitive decline. DeepCBV maps, synthesized from non-contrast MRI, offer a scalable alternative to contrast-enhanced perfusion imaging by capturing vascular information relevant to early neurodegeneration. We developed a multimodal BrainAGE framework that combines predictions from two separate three-dimensional convolutional neural networks: one trained only on structural MRI scans and another trained only on DeepCBV maps. Each model was trained and validated on 2851 scans from 13 open-source datasets and was evaluated for concordance with MCI and AD. The combined model achieved the most accurate brain age gap for CN controls, with a mean absolute error of 3.95 years, outperforming models trained on MRI or DeepCBV alone. Saliency maps revealed complementary modality contributions: MRI emphasized white matter and cortical atrophy, while DeepCBV highlighted vascular-rich and periventricular regions implicated in hypoperfusion and early cerebrovascular dysfunction, consistent with known patterns of normal ageing. Next, we observed that BrainAGE increased stepwise across diagnostic strata (CN < MCI < AD) and correlated with cognitive impairment. DeepCBV-based BrainAGE showed a particularly strong separation between stable versus progressive MCI, suggesting sensitivity to prodromal vascular changes that precede overt atrophy. Integrating structural MRI with deep learning-derived vascular measures substantially enhances BrainAGE estimation and improves sensitivity to MCI and AD progression, supporting its potential role in risk stratification, early detection and monitoring of therapeutic response.