Dopa-responsive and dopa-resistant tremor in PD

Resting tremor is a core symptom of Parkinsons disease (PD), occurring in 75% of patients. Unlike rigidity and bradykinesia, resting tremor has a variable response to levodopa. There are two clinical expressions of PD resting tremor: dopa-responsive and dopa-resistant resting tremor. Here, we aim to demonstrate electrophysiological and cerebral differences between dopa-responsive and dopa-resistant resting tremor, as well as different tremor-related responses to dopaminergic treatment between these two groups. We will exploit two clinical triggers of PD resting tremor: the typical increase in tremor amplitude during cognitive co-activation, and the re-emergence of resting tremor, typically emerging several seconds after adopting a new posture. Using functional magnetic resonance imaging (fMRI), we will investigate whether both tremor-types are triggered by the same neural mechanisms in those two contexts, capitalizing on the recently developed dimmer-switch- model. According to this model, PD resting tremor results from the combined action of two distinct cerebral circuits: the basal ganglia and the cerebello-thalamo-cortical-circuit. These circuits were identified previously in tremor-dominant PD patients using concurrent electromyography (EMG) and fMRI. The basal ganglia appear to act as the tremor-trigger (on/off switch). Conversely, the cerebello-thalamo-cortical-circuit may regulate the amplitude of tremor (dimmer). Here, we hypothesize to find differences between both tremor-groups in the switch-location (identified as activity related to tremor onset). Specifically, we expect finding onset-related activity in the basal ganglia of patients with dopa-responsive tremor, and activity in other (presumably non-dopaminergic i.e. serotonergic or noradrenergic) regions in patients with dopa-resistant tremor. Furthermore, we expect a similar location of the dimmer in both groups. We will also test the alternative hypothesis that tremor amplitude-related cerebral activity differs between patients with dopa-responsive and dopa-resistant tremor, and that this may be reflected in specific electrophysiological differences between those two PD tremor forms. To test these hypotheses, we will first perform extensive laboratory-based tremor assessment (using surface EMG and accelerometry) in 80 PD-patients ON and OFF levodopa (before and after a standardized dose of 250mg dispersible levodopa-benserazide). Specifically, we will investigate tremor frequency and tremor amplitude in different contexts. Based on the dopa-response we will select two groups out of these initial 80 patients (n=20 in each group)-given a >20% improvement of limb bradykinesia- with either relatively dopa-responsive tremor (= 60% limb resting tremor improvement) or relatively dopa-resistant tremor (=20% improvement). Second, we will study these groups in more detail using concurrent EMG-fMRI, and also compare them with 20 healthy controls. Specifically, we will investigate tremor onset-and amplitude-related activity, inter-regional connectivity, as well as the levodopa-effect. This design will allow us to investigate the electrophysiological phenotype and neural basis of dopa-responsive and dopa-resistant PD resting tremor. A better understanding of the cerebral mechanisms involved in dopa-resistant tremor may provide a basis for future treatment of this debilitating symptom.