Tremor in multiple sclerosis: neuroimaging perspective

Abstract

Multiple sclerosis (MS) is a common autoimmune disorder of the central nervous system (CNS), characterised by inflammation, demyelination and neurodegeneration. The clinical presentation and disease course of MS is heterogeneous, which reflects the multifocal nature of damage within the CNS. Almost half of the MS population experiences a tremor in the later stages of the disease. Tremor significantly increases disease severity and worsens patients’ quality of life. Current understanding of tremor pathophysiology in MS is incomplete and mostly based on treatment studies, clinical observation studies, or neuroimaging studies of parkinsonian tremor and essential tremor. Focused imaging assessments of defined neural pathways associated with tremor can help improve our understanding of complex pathophysiology of MS tremor. This could benefit the current lack of effective, noninvasive and long-term treatment options for tremor.

This thesis provides a comprehensive examination of the pathophysiology of tremor in MS. The first experimental chapter confirms the hypothesis that the cerebello-thalamo-cortical tract is involved in tremor pathophysiology. Specifically, the pilots study finds a positive correlation between thalamic and superior cerebellar peduncle atrophy and tremor severity. In the second experimental chapter, we aimed to develop a functional imaging task that will allow in vivo imaging of tremor pathology. We introduced a novel joystick task, which showed to elicit the MS-related tremor while playing the game. Furthermore, we showed good reproducibility, which is great for the longitudinal part of this thesis. In the third experimental chapter, we applied the joystick imaging task in a large sample of tremor and non-tremor MS patients. We supported that pathology along the cerebello-thalamo-cortical tract is instrumental in tremor pathology. Interestingly, we also found increased functional activation within sensorimotor integration and motor planning areas in MS tremor, which negatively correlated to tremor severity. In the final experimental chapter, we examined the central effects of onabotulinumtoxinA (BoNT-A) for the treatment of tremor in a randomized controlled trial. We found that patients that received BoNT-A had improved tremor and reduced activation within the sensorimotor integration regions. The change in tremor severity correlated with the change in activation, indicated that BoNT-A has a central effect as well as a local effect.

Collectively, these findings suggest that the clinical presentation of tremor in MS is influenced by a tremor network consisting of both structural and functional aspects. Specifically, atrophy and inflammation along the cerebello-thalamo-cortical tract is thought to be more causal to tremor. Contrarily, functional activation is thought to be compensatory to alleviate tremor severity. Intramuscular injection of BoNT-A reduced tremor severity and the activation within the sensorimotor integration area. The central effect of BoNT-A is thought to be due to the lower need for the compensatory functional activation. Together, both structural and functional aspects of the tremor network in MS need to be consider when trying to monitor tremor over time and to find effective treatments options.