Clinical Prediction of Functional Decline in Multiple Sclerosis Using Volumetry-Based Synthetic Brain Networks

Background: Disability progression in multiple sclerosis (MS) is increasingly recognized as a consequence of large-scale brain network disruption rather than isolated regional damage. Although diffusion tensor imaging (DTI) is the reference method for assessing structural connectivity, its limited availability restricts widespread clinical application. There is therefore a critical need for alternative approaches capable of capturing network-level alterations using routinely acquired MRI data. Objective: This study aimed to determine whether synthetic structural connectivity matrices derived from standard regional volumetric MRI can capture clinically meaningful network alterations in MS and predict subsequent functional progression, particularly upper limb decline. Methods: Regional brain volumetry was obtained from routine T1-weighted MRI using an automated, clinically approved volumetric pipeline. Synthetic structural connectivity matrices were generated by integrating principles of structural covariance, distance-dependent connectivity, and disease-specific vulnerability patterns. Graph-theoretical network metrics were extracted to characterize global and regional topology. Machine learning models including logistic regression, support vector machines, random forests, and gradient boosting were trained to predict clinical progression defined by worsening on the 9-Hole Peg Test. Dimensionality reduction was performed using principal component analysis, and model performance was evaluated using balanced accuracy, AUC-ROC, and resampling-based validation. Feature importance analyses were conducted to identify network vulnerability patterns. Results: Synthetic connectivity networks exhibited biologically plausible properties, including preserved but attenuated small-world organization. Global efficiency showed a strong inverse correlation with disability severity (EDSS). Patients with clinical progression demonstrated marked reductions in network integration and segregation, alongside increased characteristic path length. Machine learning models achieved robust prediction of upper limb functional decline, with ensemble-based methods performing best (balanced accuracy > 80%, AUC-ROC up to 0.85). A limited subset of connections accounted for a disproportionate share of predictive power, predominantly involving frontoparietal associative networks, thalamocortical pathways, and inter-hemispheric connections. In a longitudinal subset, network-level alterations preceded measurable clinical deterioration by several months. Conclusions: Synthetic structural connectivity derived from routine volumetric MRI captures clinically relevant network-level disruption in multiple sclerosis and enables accurate prediction of functional progression. By bridging network neuroscience with widely accessible imaging data, this framework provides a pragmatic alternative for connectomic analysis when diffusion imaging is unavailable and supports a network-based understanding of disease evolution in MS.