Explorations into the cerebral mechanisms of dopa-responsive and dopa-resistant Parkinson*s resting tremor

Resting tremor is a core symptom of Parkinson*s disease (PD). Unlike other
motor symptoms, the response of tremor to levodopa varies greatly between PD
patients. The reason for this variability is unclear, preventing treatment and
development of new therapies. Using concurrent fMRI and EMG recordings, we have
previously developed a new technique to localize brain regions involved in
tremor. This approach allows us to detect differences in cerebral activity
between patients with dopa-resistant and dopa-responsive tremor. Furthermore,
we will investigate the role of GABA in both tremor types, since GABA is the
most important inhibitory neurotransmitter in the human brain, and since
inhibition of the thalamus is strongly linked to the expression of tremor.
Finally, we investigate differences in the structural integrity of the brain
stem (using DTI) between Parkinson patients with a dopamine-responsive and
dopamine-resistant tremor.

We hypothesize that PD patients with dopa-responsive and dopa-resistant tremor
have different tremor-related brain activity, different inter-regional
functional connectivity, and different GABA-ergic tone in the thalamus.
Furthermore, we expect that both groups have different cerebral responses to
levodopa.

This research takes place in two phases. In phase 1, we will measure tremor
severity before and after dopaminergic treatment (i.e. Levodopa-Benserazide 250
mg) in 80 patients with Parkinson's disease. From this group we will select 25
patients Parkinson with dopa-responsive tremor and 25 patients with
dopa-resistant tremor, who will take part in phase 2. We will also include 25
healthy controls. In all 3 groups, we will measure brain activity using fMRI,
and tremor variations with EMG. This allows us to test for tremor-related
activity. We will test all patients twice: without their normal medication, and
after having taken Levodopa-Benserazide 250 mg. We will also measure GABA
concentrations in the thalamus using magnetic resonance spectroscopy (MRS), and
structural integrity of the brain stem using DTI.

All Parkinson patients (n=80) will be tested without dopaminergic medication
(their own medication stopped for at least 12 hours). On one day they will
receive a placebo (with 10 mg Domperidon), on the other day dopaminergic
medication (250 mg Levodopa-Benserazide and 10 mg Domperidone). The goal of the
intervention is to distinguish patients with a dopamine-responsive tremor from
patients with a dopamine-resistant tremor, and to test if tremor-related brain
regions in both groups are dopamine-responsive. This is not a randomized
research. The controls will not get an intervention.

The experimental protocol will consist of clinical measurements, and
performance of a simple motor and cognitive task in the fMRI scanner. These
measurements will be performed on 3 mornings (duration: 4-4.5 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 two sessions, patients will receive a standard dose of
Levodopa-Benserazide (250 mg) that may (or may not) be higher than the
patient's own usual dose. This may sometimes lead to side effects such as
nausea or dizziness. For this reason, patients will receive 10 mg Domperidone,
which is a standard clinical treatment to avoid such side effects. 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.