Characterizing the cerebello-thalamo-cortical tracts in the pathophysiology of adult-onset idiopathic dystonia
Creators: name: Sondergaard, Rachel Elisa
Publisher: name: Graduate Studies
Year: 2023
Subjects: subject: Dystonia
subject: Movement disorders
subject: Transcranial magnetic stimulation
subject: Cerebellum
subject: Neuroscience

description: Adult-onset idiopathic dystonia (AOID) is a movement disorder causing painful and disabling muscular contractions. The pathophysiology of AOID has evolved over time from original consideration as a purely functional neurological condition to its present understanding as a disorder of the motor network. What is presently unknown within the network model is the relative contribution of specific cerebellar outflow pathways, despite several lines of evidence in support of a role for these tracts. In this thesis, I attempt to characterize the anatomy, function, and response to intervention of the cerebello-thalamo-cortical pathway, a cerebellar outflow pathway subserving motor processes, in AOID. First, tractographic measures of the bilateral dentato-rubro-thalamic tracts were computed in patients with cervical dystonia (CD) and healthy controls. We identified bilateral reductions in diffusion tractography metrics in CD metrics relative to controls. We also computed the degree of lateralization of these tractographic measures and found that it was related to the severity of CD in subgroups of patients with similar motor phenotype. Second, I sought evidence that functions subserved by the cerebello-thalamo-cortical tracts may also be abnormal. Using a transcranial magnetic stimulation (TMS) protocol called cerebellar brain inhibition (CBI) I found that CD severity increased in association with a breakdown in normal CBI. I suspected that proprioception, another function subserved by this pathway might be abnormal and could be rescued by changing activity along this pathway using repetitive TMS. I was unable to find evidence of either in a small pilot study. I was also unable to find evidence that a single session of repetitive TMS targeting the cerebellar cortex induced changes in local field potential activity at the level of the thalamus in movement disorder patients treated with deep brain stimulators for their movement disorders. Third, I indirectly examined the response to intervention subserved by the cerebello-thalamo-cortical tracts by comparing TMS motor maps of hand representations in focal hand dystonia patients produced at peak botulinum toxin treatment effect and following washout. I examined technical factors contributing to the modest or absent changes in hand representation between conditions in these patients in an additional pilot study and structured review. Overall, I found evidence supporting abnormal anatomy and function of the cerebello-thalamo-cortical tracts in dystonia. Taken together, the findings establish structural and functional features of the cerebello-thalamo-cortical tracts in the pathophysiology of dystonia. The specific pattern of microstructural abnormalities observed and its relationship with severity also provides a plausible new target for non-invasive repetitive TMS targeting the cerebellum for therapeutic effect in AOID.