Background: In people with multiple sclerosis (pwMS), disease progression and accumulation of clinical disability correlates only modestly with standard radiological parameters of inflammatory activity. This clinico-radiological dissociation could partially be attributable to functional compensatory changes in response to structural damage. In this study, we examined the structural and functional changes associated with the clinical phenotype of upper limb tremor in pwMS.

Methods: Forty-two pwMS (46.6±11.5y, Expanded Disability Status Scale [EDSS] 4±5.5) with unilateral upper limb tremor and 27 pwMS without tremor (46.7±11.6y, EDSS 3±3.5) were included in a cross-sectional study. Tremor was quantified using the BAIN score (0 to 10) for overall severity, handwriting and Archimedes spiral drawing on a pre-drawn pattern. Functional MRI activations were compared between patient groups during performance of a joystick task designed to isolate tremulous movement. Lesion load and atrophy of cerebello-thalamo-cortical brain structures was quantified. Structural and functional MRI measures were correlated with tremor severity.

Results: Tremor-affected pwMS were found to have bilateral atrophy of the cerebellum and thalamus (p< 0.01), and higher ipsilateral cerebellar lesion load (p=0.018) compared to pwMS without tremor. Tremor-affected PwMS displayed higher activation in the inferior parietal lobule, the premotor cortex, and supplementary motor area (SMA) compared to pwMS without tremor during performance of the joystick task. Stronger activation in those areas was associated with lower tremor severity (Bain severity ρ=-0.393, p=0.016; Bain handwriting ρ=-0.401, p=0.014; Bain Archimedes ρ=-0.347, p=0.036).

Conclusion: Cortical functional neuroplasticity, and subcortical neurodegeneration and inflammation are concomitant in the pathophysiology of tremor in MS patients. Future longitudinal and treatment studies are warranted to further understand the relationship of both processes to tremor in MS, and the effect of drugs on tremor pathophysiology.