Functional Determinants of Parkinson*s Bradykinesia; A Kinematic, Neurophysiological and Psychophysical Study

Parkinson*s Disease (PD) is a neurodegenerative disorder with a clinical
hallmark consisting of tremor, rigidity, postural instability and bradykinesia.
Besides the prominent motor symptoms, also non-motor symptoms, including
sensory processing and sensorimotor integration, are affected in PD. In this
respect, PD symptoms may not only be due to impaired motor or sensory
processing but may be a consequence of intrinsically disturbed sensorimotor
integration. With regard to actions in external space, especially visuomotor
integration is important.

Visuomotor integration includes the temporal adjustment of movements to sensory
events. Our previous functional Magnetic Resonance Imaging (fMRI) experiment
showed a crucial role for the Basal Ganglia (BG) in the temporal processing of
velocity estimation. Further evidence for basal ganglia involvement in velocity
estimation came from a subsequent behavioural experiment in which PD patients
showed a selective disturbance in velocity estimation of a moving object seen
on a screen. In our last experiment, we found that the severity of bradykinesia
correlated with the magnitude of perceived accelerations. In the present
experiment this latter issue will be further studied.

More specifically, in our previous experiment the degree to which a
deceleration of the observed ball was judged as accelerating negatively
correlated with the degree of bradykinesia, i.e. the judgment of the more
bradykinetic patients was actually closer to the physical reality than that of
the less bradykinetic patients. An explanation for this *acceleration bias*
might be that *real-time* motor control requires feed-forward based processing
to overcome intrinsic cerebral processing speed limitations. Such acceleration
bias appears to be consistent with the *flash-lag* illusion in which the
position of a moving stimulus is projected ahead compared to a stationary
landmark. Up to now, no unifying neural mechanism underlying the flash-lag
illusion has been postulated. However, a recent study indicated that TMS of
area MT+, and not V1/2, reduced the perceived flash lag illusion.
Interestingly, in a recent fMRI study by our group, area MT+ appeared to show
specific disturbances in visual motion processing in PD.

In accordance with the flash-lag illusion the functional basis of bradykinesia
not fully elucidated either. One hypothesis is that the dopamine depleted BG
fail to reinforce cortical mechanisms that prepare and execute commands to
move. This might be due to pathological synchronisation in the BG, more
specifically the subthalamic nucleus (STN). In one study, 20 Hz stimulation of
the STN turned out to specifically increase bradykinesia in one study but not
in a subsequent study.

Next to these deviant sub-cortical oscillations in bradykinesia, less is known
about cortical oscillations (assessed with EEG) in PD*s bradykinesia. Despite
sporadic reports, it was assumed until recently that non-demented PD patients
do not show slowing of occipital background activity. However, recent evidence
showed diffuse EEG slowing in PD patients without remarkable dementia.
Regarding bradykinesia, one study reported a statistically significant
association between the degree of motor disability and the dominant frequency
of occipital background activity in PD patients without remarkable dementia.
However, this study didn*t specifically look at bradykinesia per se. Although
there is a lack of knowledge on the frequency of background activity in
bradykinetic patients, attenuation of background activity during movements does
correlate negatively with bradykinesia.

Bradykinesia is clinically tested by assessment of the bradykinesia items of
the Unified Parkinson*s Disease Rating Scale (UPDRS). However, these items have
the lowest reliability among all UPDRS items. For this reason, more
quantitative measures using motion sensors are currently developed but not
validated yet.

Primary Objective:

1. Test whether the flash lag illusion is decreased in PD and more specifically
whether the decrease is associated with bradykinesia.

Secondary Objective(s):

2. Quantify bradykinesia by means of motion sensors and validate this
quantitative measurement by clinical bradykinesia judgement by a movement
disorders specialist.
3. Correlating quantitative and qualitative bradykinesia scores with the
dominant EEG background frequency.

A prospective cohort study will be conducted at the department of neurology of
the University Medical Center Groningen.
For the experiment subjects will come to the outpatient department and
will successively undergo:

1. A brief neurological examination (the UPDRS III) in which characteristic PD
motor features will be investigated. Patients will be videoed during the
examination and movement sensors will be attached on the relevant body parts.
2. A keyboard task quantifying bradykinesia (the BRAIN task [20] lasting
approximately 5 minutes), will be conducted.
3. A subjective rating (1-10) to which degree patients experience bradykinesia
will be obtained.
4. A psychophysical experiment in which subjects have to judge whether a moving
ball stops simultaneously with a flash or not. This experiment presented on a
laptop and responses will be given using a mouse. The task will last
approximately 35 minutes consisting of 3 runs of 8 minutes with pauses of 5
minutes.
5. A 5 minute EEG registration in laying position with eyes closed will be
conducted.
6. A brief cognitive screening task, the SCOPA-COG [21] will be performed.
7. Items 1 -3 will be repeated.

- patients will be planned to be tested at the end of their regular dose of
Parkinsonian medication
- after item 2 of the experiment, patients will take their medication
- control subjects will only undergo steps 1, 2 and 5

There are no risks involved for the participating patients and controls. The
experiment will require approximately 2 hours of the patients time in which the
subjects will conduct a behavioural experiment, undergo a brief neurological
examination and EEG and fill in a short cognitive task. There are no potential
benefits for the participating patients.