Yang, Y.; Woollams, A.; Lipp, I.; Haigh, J.; Kouwenhoven, R.-M.; Tomassini, V.; Trujillo-Barreto, N. J.; Muhlert, N.

Background: The thalamus has emerged as a key region involved in cognitive dysfunction in multiple sclerosis (MS). While previous studies have identified associations between thalamic structural damage, altered functional connectivity, and cognitive performance, the specific contributions of individual thalamic nuclei and the added value of integrating structural and functional metrics remain poorly understood. Methods: T1-weighted MRI, diffusion MRI, resting-state fMRI, and neuropsychological data were collected from 102 individuals with MS and 27 healthy controls. Thalamic grey matter volume, white matter microstructural integrity, and functional controllability were calculated for each nucleus and compared between individuals with MS and healthy controls, as well as between MS cognitive subgroups. Partial Spearman correlations were used to examine the relationship between imaging metrics across the three modalities, and also between imaging metrics and cognitive performance in MS. Sparse canonical correlation analysis models were used to examine the covariance between thalamic imaging metrics and cognitive performance in MS. Results: Widespread atrophy and microstructural damage were observed across all thalamic nuclei in individuals with MS, regardless of cognitive status. In contrast, alterations in functional controllability were more spatially specific, primarily affecting the medial dorsal anterior nuclei, and were most pronounced in cognitively impaired individuals. These functional controllability metrics were independent of grey matter volume, white matter integrity, and lesion load. Combining thalamic functional controllability with structural metrics yielded a stronger association with cognitive performance in MS than either modality alone. Conclusion: This study provides novel evidence that functional controllability in the thalamus, particularly within the medial dorsal anterior nuclei, plays a critical role in cognitive impairment in MS. By applying a network control framework, our findings offer a dynamic systems perspective that extends beyond traditional connectivity analyses, capturing the thalamus's role in supporting flexible cognitive transitions. The integration of structural and functional controllability metrics enhances the ability to characterise individual differences in cognitive performance and may inform future efforts to identify biomarkers of cognitive dysfunction in MS.