Objective: Parkinson's disease (PD) resting tremor is thought to be initiated in the basal ganglia and amplified in the cerebello-thalamo-cortical circuit. Since stress worsens tremor, the noradrenergic system may play a role in amplifying tremor. We tested if and how propranolol, a non-selective beta-adrenergic receptor antagonist, reduces PD tremor, and whether or not this effect is specific to stressful conditions. Methods: In a cross-over, double-blind intervention study, participants with PD resting tremor received propranolol (40mg, single dose) or placebo (counter-balanced) on two different days. During both days, we assessed tremor severity (with accelerometry) and tremor-related brain activity (with functional Magnetic Resonance Imaging; fMRI), as well as heart rate and pupil diameter, while subjects performed a stressful cognitive load task that has been linked to the noradrenergic system. We tested for effects of drug (propranolol vs. placebo) and stress (cognitive load vs. rest) on tremor power and tremor-related brain activity. Results: We included 27 PD patients with clear resting tremor. Tremor power significantly increased during cognitive load vs. rest (F(1,19)=13.8; p=.001; ηp2=0.42) and decreased by propranolol vs. placebo (F(1,19)=6.4; p=.02; ηp2=0.25), but there was no interaction. We observed task-related brain activity in a stress-sensitive cognitive control network, and tremor power-related activity in the cerebello-thalamo-cortical circuit. Propranolol significantly reduced tremor-related activity in the motor cortex compared to placebo (F(1,21)=5.3; p=.03; ηp2=0.20), irrespective of cognitive load. Interpretation: Our findings indicate that the noradrenergic system has a general, context-independent role in amplifying PD tremor at the level of the primary motor cortex.

The authors have declared no competing interest.

The EudraCT number is 2016-004629-18, and the study was also registered in the ISRCTN registry (ISRCTN89589002).

This study was funded by a VENI grant to RH (grant ID #91617077) from the Netherlands Organization for Scientific Research (Netherlands).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Medisch-ethische toetsingscommissie (METC) Oost-Nederland (reference 2016-3101; NL59724.091.16) gave ethical approval for this work.

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All derived and anonymized individual data supporting these findings are openly available at the Donders Repository at https://data.ru.nl/collections/di/dccn/DSC_3024005.02_550. All scripts used to generate the analyses presented in this paper are publicly archived at https://github.com/AnoukvanderHeide/Propranolol_PD_tremor.

https://data.ru.nl/collections/di/dccn/DSC_3024005.02_550