Is step initiation during improbable events affected in PD with or without FOG? An explorative study.

Introduction
Parkinson*s disease (PD) is a progressive neurological condition that affects
movement as well as behavior. It is typically characterized by slowness in
initiating movement, muscular rigidity, and tremor (Rodriguez-Oroz et al.,
2009). It is more common in the elderly (over 65) (Ma et al., 2014), and with
an ageing population in Europe (EuropeanCommission, 2012) an increasing number
of people will become affected by the condition.
The nature of their condition causes people with PD to make short shuffling
steps when walking, making them more likely to experience a fall (Latt et al.,
2009). Additionally, they take longer to perform everyday activities, and
eventually are unable to care for themselves. Around a third of people with PD
experience *freezing* when trying to initiate a forward stepping movement (Nutt
et al., 2011, Schaafsma et al., 2003, Chee et al., 2009) - known as freezing of
gait (FOG). They describe this transient phenomenon (typically lasting <1
minute) as *being glued to the floor* (Schaafsma et al., 2003).
The difficulties in initiating a movement, such as a step, that people with PD
face means that they have difficulty navigating their environment. For people
with PD who also have FOG, initiating a step is even more of a challenge (Tard
et al., 2014), as they experience *freezing* when they turn, go through doors
or encounter obstacles (Schaafsma et al., 2003). The mechanisms underlying the
movement difficulties observed in PD, with and without FOG, when initiating a
step are still not well understood.

Rationale
To navigate an environment, we must be able to continually adapt to it. When
faced with an improbable obstacle we have to suddenly adapt to it to, for
example, prevent falling. To adapt, the brain selects the *best-at-the-time*
action from a set of possible actions within a given environment - a process
known as Action Selection (Cisek, 2007). Dopamine, a neurotransmitter in the
brain, is thought to be critically involved in this process (Galea et al.,
2012, Friston et al., 2012).
There is a severe loss of the brain cells that produce dopamine in people with
PD (Lees et al., 2009). Their symptoms, including slowness in initiating
movement and FOG episodes, worsen when off their dopaminergic medication
(Giladi, 2008, Schaafsma et al., 2003). We propose that their ability to select
the *best-at-the-time-action* is affected, and contributes to the difficulties
observed, in PD, in initiating a step.
The importance of dopamine in Action Selection has already been shown for
initiating finger movements in PD (Galea et al., 2012). During the task people
with PD on and off dopaminergic medication, and controls, were asked to press
four different buttons each of which corresponded to a picture on the screen.
In a predictable context pictures appeared in sequence, however the sequence
was at times interrupted, when a picture out of sequence appeared - an
improbable picture. Participants had to suddenly adapt to this. In an
unpredictable context pictures appeared in a random order. People with PD, off
their dopaminergic medication, were unable to react (press the correct button)
fast enough to the improbable pictures in a predictable context.
The improbability of an event has also been shown to precipitate *freezing*
episodes in people with PD and FOG. When confronted with an improbable obstacle
while walking on a treadmill people with PD and FOG, off their dopaminergic
medication, are unable to initiate a forward stepping movement (Snijders et
al., 2010).
To explore how initiating a step is affected in PD, action selection during
step initiation will be investigated in PD and PD with FOG. The work on finger
movements in people with PD will be translated to a stepping task.
Participants, including age-matched controls, will be asked to make four
different steps each of which corresponds to a picture on the screen, in both a
predictable and unpredictable context (as explained above).
Measuring participants with PD, and PD with FOG off their dopaminergic
medication will allow us to investigate whether there is an action selection
deficit, i.e. whether they are able to initiate the correct step in response to
a sudden change (improbable picture in a predictable context). By measuring
them also on their dopaminergic medication we can compare performance in *on*
and *off* to investigate whether it is indeed dopamine that is contributing to
the action selection deficit observed.
Our aim is to understand whether action selection contributes to the
difficulties in stepping seen in PD with and without FOG.

Hypothesis
We hypothesize that action selection is affected in PD both with and without
FOG, when off their dopaminergic medication. This means that they will be
unable to make the right step fast enough in response to the improbable
pictures in a predictable context, when compared to healthy age-matched
controls. Additionally, we expect that action selection is more severely
affected in PD with FOG, off their dopaminergic medication, when compared to PD
without FOG in *off*. As dopamine is critical for action selection we do not
expect the deficit to be present when subjects are tested *on* their
dopaminergic medication.

Main objective
To investigate whether dopamine affects the ability to initiate the correct
step in response to a sudden change (improbable picture in a predictable
context) in PD with and without FOG.

Secondary objective
To investigate whether dopamine affects step length and step duration, and
anticipatory postural adjustments, in PD with and without FOG, when they
attempt to make the correct step in response to a sudden change (improbable
picture in a predictable context).

An experimental study analysing three parallel groups (PD-NFOG, PD-FOG,
controls), for their movement performance to probable and improbable
environmental cues (stimuli). More importantly this study does not involve any
intervention.
Participants will be allocated to either of three groups: Controls, PD without
FOG (PD-NFOG), PD with FOG (PD-FOG). PD participants will be tested in ON and
OFF states (dopaminergic medication), preferably one week apart. Days for ON
and OFF dopaminergic medication will be randomly assigned. After training,
participants will undergo the Main Experiment Task. This will consist of 2
Unpredictable blocks, and 2 Predictable blocks. The order of the blocks will be
randomised.

As this is not an interventional study, no immediate benefits are expected.
Benefit comes from the impact that the results from this study will have on
therapeutic strategies for people with Parkinson*s disease.
There are no expected risks during this study. Note however that some
discomfort is expected from resurgence of the parkinsonian symptoms following
withdrawal of antiparkinsonian medication during the OFF measurement.