Guiding personalized treatments for Parkinson*s tremor with individual neuroimaging * an exploratory study

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. Parkinson*s tremor has
a variable and inconsistent response to available medication, and only very few
patients proceed to invasive treatments such as deep brain surgery. This is
caused by pathophysiological heterogeneity between patients, which is currently
not taken into account. Non-invasive treatments * and individual predictors of
treatment success * are therefore very much needed. Using combined EMG-fMRI, we
have previously shown that Parkinson*s tremor is associated with increased
activity in a cerebello-thalamo-cortical tremor circuit. However, it is unclear
to what extent inter-individual variability between patients in the
architecture of the tremor circuit is unique and reliable (between-sessions
replicability) and whether this variability can explain relevant clinical
information (such as treatment success).

The main goal of this study is to use individual pathophysiological
characteristics (pattern of activity and connectivity within a patient*s tremor
network; *tremor fingerprint*) to predict the effect of a new and non-invasive
anti-tremor treatment (transcranial alternating current stimulation, TACS, over
the motor cortex) in individual patients. Furthermore, we aim to unravel
through which mechanisms TACS over the motor cortex influences the tremor
circuitry.

This is a combined observational and intervention study. First, we will
localize tremor-related activity using concurrent EMG-fMRI scanning on two
separate days (to determine replicability). Second, we will apply network
analyses (dynamic causal modelling) on tremor-related activity in order to
compute tremor network parameters for each individual patient (e.g. effective
connectivity). Third, we will test for the effects of transcranial alternation
current stimulation (TACS) over the motor cortex on tremor severity and on
tremor-related activity and connectivity. This leads to individual tremor
*fingerprints* that predict treatment effects.

The intervention involves TACS, which is a non-invasive, non-painful way of
stimulating underlying cortical brain tissue through electrodes applied to the
scalp. When applied rhythmically at the frequency of cortical oscillatory
activity, it can exert excitatory or inhibitory (depending on the phase)
effects on brain function. In this research, we will apply TACS over the motor
cortex contralateral to the tremulous hand, in the same frequency, and
phase-locked to, the ongoing tremor. There are three conditions: inhibitory
TACS (anti-phase), stimulating TACS (in-phase), and sham (no/fake stimulation).
TACS will be applied both outside and inside the MRI scanner, to test for the
effect on the tremor circuitry.

This research involves capacitated adults. This research has no direct benefit
for the participants. The scientific benefit of this study is to achieve a
better understanding of the pathophysiology of a severe symptom (Parkinson*s
tremor). The outcomes of this study may give rise to future new treatments for
Parkinson*s tremor. The burdens of this study are relatively small: there are
no invasive procedures, and the time asked from each participant is two
day-parts of approximately 3 hours.

Considering the exclusion criteria, the screening procedure and constant
monitoring of the subjects we do not expect (S)AE side effects. MRI
measurements themselves do not pose any risk, if appropriate precautions are
made. However, the noise and the relative confined space of the MRI scanner may
cause discomfort to some subjects. Like for MRI, risks of TACS are considered
negligible. Participants may experience mild tingling, itching, or burning
sensations on the skin under the electrode which usually disappear after a
while. In any case, the experimenter will make sure that the stimulation is
fully tolerable at the beginning as well as throughout the experiment. The most
common side effects are a transient mild headache which is short lasting and
responds well to light painkillers like paracetamol, as well as a mild feeling
of fatigue. In rare cases, nausea and vertigo have been reported. Measurements
will always be stopped whenever the participant wants to or whenever the
participant does not tolerate any measurement. Finally, some patients may
experience discomfort due to resurgence of the parkinsonian symptoms following
withdrawal of anti-parkinsonian medication. This is, however, in no way
dangerous for the patient. Patients will be asked to bring their own medication
to the laboratory, so that they can take their medication immediately after the
experiment.