Regional Brain Volume Patterns Relative to Global Brain Volume in Multiple Sclerosis: Associations with Disability and Exploratory Implications for Depression-Relevant Regions

Background/Objectives: Regional atrophy of frontal, temporal, hippocampal and thalamic structures has been linked to depression in multiple sclerosis (MS), but it is unclear whether such regional loss exceeds what global atrophy predicts. This study characterized atrophy in these depression-relevant regions relative to global brain volume and examined its clinical correlates. Methods: In this single-center observational study, 83 patients with MS underwent automated MRI volumetry. Bilateral frontal and temporal percentiles were averaged into a relative frontotemporal atrophy, and hippocampal and thalamic percentiles into a hippocampal–thalamic domain. Relative atrophy was defined as the residual of each domain regressed on total brain volume percentile. Associations with baseline Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT), and lesion count were tested with regression models adjusted for age, sex, and lesion count. Results: The median total brain volume percentile was 6.5 (IQR, 1.3–30.4). Total brain volume explained 48.8% and 32.7% of the variance in the frontotemporal and relative hippocampal–thalamic atrophy, respectively, and the two relative atrophy measures were weakly correlated (r = −0.130, p = 0.241). Greater relative frontotemporal atrophy was associated with higher EDSS (β = 0.024 per percentile point, 95% CI 0.006–0.042; p = 0.011), with a consistent result in ordinal regression; this association did not remain significant after false discovery rate correction across the multivariable models (adjusted p = 0.066). Neither measure was associated with SDMT or lesion count. Conclusions: Atrophy in depression-relevant regions partly departs from global brain atrophy and may relate to disability. Because depression was not assessed, these regional patterns are candidate substrates of affective vulnerability that require testing in prospective studies with standardized depression measures.