The effects of Transcranial Magnetic Stimulation on freezing in Parkinson's Disease patients with Freezing of Gait

Freezing of gait (FOG) is one of the most disabling features in Parkinson*s
Disease (PD). It can be described as short involuntary stops during gait and a
feeling of *being glued to the floor*. FOG has an episodic character that is
usually experienced during step initiation or turning. It occurs in 20-80 % of
the PD patients depending on the disease stage and treatment and it is one of
the most common causes of falling and mobility problems in PD.

Nevertheless, the brain mechanism behind the occurrence of FOG is still not
completely clear. The fronto-striatal circuitry is probably involved. Our
recent study showed patients with FOG had a decreased Supplementary Motor Area
(SMA) activity and an increased activity in the mesencephalic locomotor region
in the brainstem (CMO nr. 2004/150).
In addition, there may also be a role for the cerebello-cortical circuitry,
although this has never been investigated extensively. In PD patients without
FOG, hypoactivity in the putamen, SMA and pre-SMA and hyperactivity in the
motor cortex and left and right cerebellum has been found during a hand task.
It has been hypothesized that this hyperactivation in the ipsilateral
cerebellum is a compensatory mechanism for the defective basal ganglia.

We now hypothesize that patients with FOG are less able to recruit the
cerebellum to compensate for the dysfunction in frontro-striatal circuitry.

For a possible (better) treatment of FOG a better understanding of the
brainmechanism behind this phenomenon is needed. Previous studies showed some
brain areas that are possibly involved in FOG.The aim of this study is to see
whether we can induce a positive effect on freezing by stimulating the
hypoactive Supplementary Motor Area (SMA) in the fronto-striatal or the
compensatory cerebellum in the cerebello-cortical pathway in PD patients with
FOG.

The primary research question is:

1. What is the effect of TBS over the SMA and the cerebellum on the total
freezing time (duration of all freezing episodes combined) in PD patients with
FOG?

The secondary research question's are:

1. What is the effect of TBS over the SMA and the cerebellum on the frequency
and average duration of freezing in PD patients with FOG?

2. Is there a difference in effect between TBS over the SMA and cerebellum on
freezing in PD patients?

3. Does TBS over the SMA and cerebellum have a similar effect on upper limb
freezing and FOG in PD patients?

4. What stimulation protocol over the cerebellum has the most beneficial effect
on freezing? Inhibitory (cTBS) or excitatory (iTBS)?

5. Does TBS over the SMA and cerebellum have an effect on the motor evoked
potentials measured over the motor cortex?

The study is an intervention study consistsing of four sessions. During each of
these sessions a different stimulation condition is used. The four possible
conditions are iTBS over the SMA, cTBS over the cerebellum, iTBS over the
cerebellum and cTBS over the SMA. The order of the stimulation conditions in
time is randomized. Two consecutive sessions are separated by at least one week.

The protocol for session 1 consists of four major parts, which in total last
approximately 3 hours. The four major parts are:
1. Instruction and clinical measures
2. Baseline measurements
3. Determination threshold and TMS intervention
4. Post-intervention measurements

Sessions 2, 3 and 4 are similar in set up to session 1. During these sessions
the baseline measurements, an intervention and the outcome measurements are
performed. The difference with session 1 is that less clinical measures are
performed and the determination of the threshold are not repeated. This means
that the total time needed is approximately between one and a half and two
hours.

The intervention used in this study is Theta Burst Stimulation (TBS), which is
a repetitive form of Transcranial Magnetic Stimulation. In total four
stimulions will be given seperated over four different days.
The Supplementary Motor Area (SMA) and the cerebellum will be stimulated with
both Continuous Theta Burst stimulation (cTBS) and Intermittent Theta Burst
Stimulation (iTBS).

CTBS consists of 3 pulses at 50 Hz repeated every 200 ms for 40 seconds (600
pulses). This kind of stimulation has a transitory inhibiting effect on the
stimulated brain area. ITBS consists of 3 pulses at 50 Hz repeated every 200
ms in trains of 2 seconds. These trains are repeated every 10 seconds for a
total of 190 seconds (600 pulses). This kind of stimulation has a transitory
excitatory effect on the stimulated brain area. The stimulation intensity of
the TBS will be 70 % of the resting motor threshold (RMT) found over the motor
cortex. During TBS the subjects are instructed to relax their whole body as
much as possible.

Concerning the risks two major points have to be addressed, namely
1. Withdrawal of morning medication till the end of the experiments
2. Application of TBS

We will not go into the safety aspects concerning MRI. For it has been well
established that this is a safe technique, which brings no disadvantageous
effects to the patients.

1. To study the phenomenon of FOG the patients have to be in the *off* state
concerning their medication. A widely accepted and used method to do this is to
ask patients to postpone their morning medication uptake until after the
experiments. This way the risk is minimal because the patients are allowed to
take their medication directly after the experiments. However, there is a
temporary increase of PD symptoms during the experiment. This is by no means
harmful over a longer period of time. The responsible neurologist involved has
a lot of experience with this method.
During the gait task, there are some additional risks of falling caused by the
withdrawal of the patients morning drugs. Therefore a researcher will accompany
the patient while performing the gait task.

2. Repetitive Transcranial Magnetic Stimulation is a non-invasive technique
that is considered reasonably save. In the last couple of years thousands of
papers with TMS and rTMS are produced with minimal reports of serious adverse
events. These concern studies with healthy subjects and patients (e.g.
parkinson). However, there are some potential risks involved that require some
attention. The most important risk to take into account is unintended epileptic
seizure, although even this risk is certainly very low. Concerning the specific
application of TBS only 1 case with seizure is reported out of 741 participants
that have undergone TBS till mid 2009. This specific case concerned a healthy
man who underwent a 100 % resting motor threshold TBS stimulation. A physical
exam, detailed neurological exam and mental status exam 45 minutes after the
end of the stimulation showed normal results, and they stayed normal later on.
In addition to the seizure risk, a small percentage of participants (10-30 %)
experience some discomfort due to scalp or facial muscle twitches or headaches
from rTMS. The headaches are transitory and can be treated with aspirin or
acetaminophen (c.q. Paracetamol).