Rest tremor in
Parkinson's disease is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. Clinically, there is strong interindividual variation in the therapeutic response of
tremor to dopaminergic medication. This observation casts doubt on the idea that Parkinson's
tremor has a dopaminergic basis. An interesting alternative explanation is that interindividual differences in the pathophysiology of
tremor may underlie this clinical heterogeneity. Previous work showed that dopaminergic medication reduces Parkinson's
tremor by inhibiting tremulous activity in the pallidum and thalamus, and this may explain why some
tremors are
dopamine-responsive. Here we test the hypothesis that
dopamine-resistant
resting tremor may be explained by increased contributions of non-dopaminergic brain regions, such as the cerebellum. To test this hypothesis, we first performed a
levodopa challenge test in 83 tremulous
Parkinson's disease patients, and selected 20 patients with a markedly
dopamine-responsive
tremor (71% reduction) and 14 patients with a markedly
dopamine-resistant
tremor (6% reduction). The
dopamine response of other core motor symptoms was matched between groups. Next, in all 34 patients, we used combined EMG-functional MRI to quantify
tremor-related brain activity during two separate sessions (crossover, double-blind, counterbalanced design): after placebo, or after 200/50 mg dispersible
levodopa/
benserazide. We compared
tremor-related brain activity between groups and medication sessions. Both groups showed
tremor amplitude-related brain activity in a cerebello-thalamo-cortical circuit.
Dopamine-resistant
tremor patients showed increased
tremor-related activity in non-dopaminergic areas (cerebellum), whereas the
dopamine-responsive group showed increased
tremor-related activity in the thalamus and secondary somatosensory cortex (across medication sessions).
Levodopa inhibited
tremor-related thalamic responses in both groups, but this effect was significantly greater in
dopamine-responsive patients. These results suggest that
dopamine-resistant
tremor may be explained by increased cerebellar and reduced somatosensory influences onto the cerebellar thalamus, making this region less susceptible to the inhibitory effects of
dopamine.