The noradrenergic basis of Parkinson*s tremor: a systems-level fMRI approach

Parkinson*s disease is the second most common neurodegenerative disease
worldwide. Clinically, Parkinson*s disease is characterized by motor slowing
(bradykinesia), stiffness (rigidity) and resting tremor. The pathological
hallmark of Parkinson*s disease is striatal dopamine depletion, but the
dopaminergic basis of resting tremor is disputed. For instance, striatal
dopamine depletion correlates with all motor symptoms except resting tremor.
Furthermore, resting tremor is often resistant to dopaminergic medication.
Instead, resting tremor worsens consistently during psychological stress, and
recent findings suggest that the noradrenergic (stress) system is hyperactive
in Parkinson*s disease. Based on empirical (fMRI) data, I have recently
proposed a new systems-level model of Parkinson*s tremor. According to this
model, tremor is initiated in the basal ganglia and amplified in the
cerebello-thalamo-cortical circuit. In this study, I will use this model as the
basis for understanding how the noradrenergic (stress) system amplifies
Parkinson tremor.

I will test the hypothesis that the noradrenergic system amplifies tremulous
activity in the cerebello-thalamo-cortical circuit. More specifically, I will
test how this modulation takes place (i.e. through which brain regions and
connections).

Cross-over intervention study.

The intervention only concerns the Parkinson patients with a tremor-dominant
phenotype (n=40). Parkinson patients with a non-tremor phenotype (n=30) will
undergo one session (without an intervention). They will serve as a control for
the tremor-dominant group, where we will compare the structural integrity of
the locus coeruleus between groups, and we will localize the locus coeruleus in
this group (using task fMRI).

To activate the noradrenergic system, I will use a validated and controlled
stress-induction task (cognitive-coactivation: alternating blocks of mental
arithmetic versus rest). This tasks consists of performing difficult
arithmetics under time pressure and under social pressure. The control task
will consist of performing easy arithmetics without any time pressure or social
pressure. Furthermore, I will test whether a pharmacological intervention
(propranolol 40 mg single dose) can counteract the effects of psychological
stress on the tremor circuitry. Propranolol is commonly used in clinical
practice to treat tremor. The control condition will be a placebo.

The burden of this study will be different for the two groups.

1. For the tremor-dominant Parkinson group (n=40):
The experimental protocol will consist of clinical measurements, and
performance of a simple cognitive task in the fMRI scanner. These measurements
will be performed on two mornings (duration: 4 hours per session). Patients
will arrive in a practically defined OFF state, i.e. at least 12 hours after
having taken their last dopaminergic medication. At the end of the measurement,
they will resume their normal medication regime. When OFF-medication, their
Parkinson symptoms may temporarily worsen, which can lead to discomfort. On one
session, patients will receive a single dose of propranolol (40 mg).
Propranolol is commonly used in clinical practice to treat tremor. This may
sometimes lead to temporary side effects such as dizziness, bradycardia, and
cold hands/feet. Patients will be extensively monitored during the measurements
(blood pressure, heart rate) to avoid any health risks. In addition, our task
is designed to induce psychological stress, and this may lead to some
discomfort. Finally, the noise in the fMRI scanner, and lying in a small space,
may lead to discomfort. If all security measures are fulfilled, then there is
not risk for the patients.

2. For the non-tremor group (n=30):
The experimental protocol will consist of clinical measurements, and
performance of a simple cognitive task in the fMRI scanner. These measurements
will be performed on one morning (duration: 4 hours per session). Patients will
arrive in a practically defined OFF state, i.e. at least 12 hours after having
taken their last dopaminergic medication. At the end of the measurement, they
will resume their normal medication regime. When OFF-medication, their
Parkinson symptoms may temporarily worsen, which can lead to discomfort.
Finally, the noise in the fMRI scanner, and lying in a small space, may lead to
discomfort. If all security measures are fulfilled, then there is not risk for
the patients.

Tremor is a common and debilitating symptom of Parkinson's disease. If tremor
does not respond to dopaminergic treatment, then there are only few therapeutic
options. Better pathophysiological insights are needed to provide a rational
basis for improved treatment strategies. This study aims at better
understanding the pathophysiology of Parkinson*s tremor, by focusing on the
noradrenergic system. Identifying the respective neural substrates could
potentially have great clinical and therapeutic implications and will also help
to better understand why tremor increases dramatically during stressful
circumstances. As such, this research may provide clues to target new therapies
in tremor-dominant Parkinson patients.