Feeling the beat: The neurophysiology of cueing in Parkinson's disease

The proposed research addresses an emerging paradox in current views on
parkinsonian motor impairments. The paradox is that, on the one hand, it is
believed that movements guided by external cues are relatively preserved in
Parkinson*s disease (PD), providing a basis for the use of (rhythmic) cueing in
rehabilitation. On the other hand, there is growing evidence that PD patients
are not sensitive to temporal regularities in the environment and even have
difficulty perceiving such regularities. We will address this paradox in an
investigation into the neurophysiological basis of cueing. This may lead to
differently targeted or more selective use of cueing strategies.

We will investigate the neurophysiological basis of cueing in PD by examining
how patients differ from controls in spontaneous entrainment to environmental
regularities. Entrainment will be measured by means of slow brain oscillations
recorded with magnetoencephalography (MEG). According to recent
neurophysiological work in primates, endogenous slow brain oscillations
spontaneously adjust their phase and frequency to temporally regular
environmental events. The entrainment of slow oscillations, and nested faster
rhythms, enables sensory brain structures to optimise perceptual processing and
motor areas to adopt a predictive mode of control. We predict that the normal
pattern of entrainment is defective in patients with PD.

We already have evidence that slow preparatory brain potentials are abnormal in
PD, but do not know (i) whether this is due to lack of entrainment of slow
endogenous oscillations, (ii) whether nested faster rhythms are similarly
affected, and (iii) whether such abnormal oscillatory (re)activity contributes
to motor impairments and insensitivity to environmental regularities. These
questions are investigated in a series of experiments comparing PD patients
with healthy controls. The experiments will manipulate environmental
regularities in terms of relevance to task performance and by means of
perturbations. The results will be vital to assess the potential of cueing
strategies for rehabilitation, but are equally important to concepts of basal
ganglia function and the role of abnormal oscillatory synchronization in the
pathophysiology of Parkinson's disease.

Key hypothesis of the investigation is that Parkinson*s disease is
characterized by deficient entrainment of slow brain oscillations. Our previous
work already provides preliminary support for this hypothesis. In order to
evaluate to what extent this deficient entrainment limits the potential for
cueing strategies, and can be remediated or circumvented in the rehabilitation
of Parkinson patients, our objectives are to answer the following questions:
(i) Is deficient entrainment of slow brain oscillations due to abnormal
entrainment or due to defective generation of slow brain activity?
(ii) Does abnormal generation or deficient entrainment of slow oscillations to
regular environmental events carry over to nested faster oscillations
associated with the processing of and motor responses to those events?
(iii) Does such abnormal oscillatory (re)activity contribute to motor
impairments and insensitivity to environmental regularities?
(iv) What are the prospects of modifying the cueing approach such that, in
spite of reduced spontaneous entrainment, cues can be used to advantage?

Observational research. The study consists of 5 separate experiments:

Experiment 1: Spontaneous entrainment of slow brain oscillations to rhythmic
events
Experiment 2: Uncoupling of slow oscillations and faster rhythms
Experiment 3: Selective entrainment in the face of competing streams of
rhythmic events
Experiment 4: Oscillatory entrainment and instructed use of rhythmic event
structure
Experiment 5: Temporal coupling of deliberation and movement execution

There are no risks associated with the MEG measurements. Time burden is ~2 hrs
for the actual experiment (including preparation and debriefing), plus an
additional 0.5 hr for an head MRI scan if that has not been performed earlier
(for research or clinical purposes).