Circuit-level mechanisms of cerebral compensation in Parkinson's disease

The brain is adaptable, and numerous brain regions can change their neural
signal patterns following neurodegeneration in Parkinson's disease (PD).
However, it is not clear whether these changes are pathological, or, if they
represent compensatory mechanisms to help maintain function. We will explore
possible compensatory brain changes in the parietal-occipital cortex in
Parkinson's disease, which we hypothesize could relate to patients utilizing
visual information to guide movements. This hypothesis is grounded on clinical
and neuroimaging evidence: first, Parkinson*s patients show increased use of
visual cues when initiating movement, but also freeze their motion when the
visual environment changes (known as freezing of gait); second, in neuroimaging
studies, visuo-motor portions of the parietal-occipital cortices show increased
activity when Parkinson*s patients need to move. It is important to test
whether this *hyperactivity* is actually beneficial to movement initiation,
because, an over-reliance on visual information could also contribute to
freezing of gait in PD. Knowledge from this experiment will be directly useful
to clinicians and the scientific community in understanding the neural
mechanism behind compensatory strategies used by people with Parkinson*s
disease.

Our objective is to perturb neural activity in the parietal-occipital cortex in
PD patients (and age-matched control subjects) to determine if the activity
contributes to better visually-guided behaviour, but at the same time, to
diminished voluntary control. We will also perturb this activity in healthy
young adult subjects to more precisely explore the nature of parietal-occipital
hyperactivity.

This study has two arms, because it requires the participation of people with
Parkinson*s disease and age-matched control subjects in a patient-control
design, but in addition, the participation of healthy young adults who will
undergo different experimental procedures. This is necessary because we have a
specific hypothesis that cannot be addressed by only performing at
patient-control study. In brief, one arm will directly test for compensatory
changes in the brains of people with Parkinson*s disease by measuring behavior
along with functional magnetic resonance imaging; the second arm will more
precisely examine the functional relevance of this activity in a
behavioral-only study where fMRI cannot be collected, and which would be an
unnecessary extra burden on the patients to perform. In Arm 1 we will apply a
form of repetitive Transcranial Magnetic Stimulation (rTMS), known as
continuous theta-burst stimulation (cTBS) to the parietal-occipital cortex in
Parkinson's patients and control subjects to see how this changes behaviour and
neural activity measured with functional magnetic resonance imaging (fMRI).
In Arm 2, we will apply cTBS to the frontal cortex in healthy young adults
because we have previous evidence for parietal-occipital compensation following
frontal cortex cTBS. We will then use single pulse TMS at different times to
the parietal-occipital cortex, to test more precisely how the
parietal-occipital cortex might compensate for motor system impairments by
enhancing visual processing. (This will be a behavior-only study, as we do not
possess the ability to perform single pulse TMS while scanning with fMRI).

All participants will receive single-pulse transcranial magnetic stimulation
(TMS), and continuous theta-burst transcranial magnetic stimulation (cTBS).

Each participant will receive no direct benefit from participating in the
study, but will receive a compensatory (financial) incentive. Transcranial
magnetic stimulation (TMS) is a widely used non-invasive brain stimulation
technique, based on the principle of electromagnetic induction. During
stimulation the participant will likely hear the clicks of the TMS pulses and
experience stimulation of nerves and muscles of the head. The most common side
effect is a light transient headache (2-4% occurrence). A severe headache is
uncommon (0.3-0.5% occurrence). In TMS studies of patient populations (e.g.
epilepsy) or that exceeded the standard protocols (e.g. in intensity or
frequency) epileptic seizures have been reported in rare cases. In the current
study all participants will be stimulated with protocols that fall within the
safety guidelines. All subjects are screened for their relevant medical history
and other TMS safety aspects (e.g. presence of metal parts in the head). In
summary, because the risk and burden associated with participation can be
considered negligible-to-minimal, we do not expect serious adverse events
during the project.
The noise in the fMRI scanner, and lying in a small space, may lead to
discomfort in some subjects. If all security measures are fulfilled, then there
is no risk for the subjects. Parkinson*s patients will be asked to withhold
dopaminergic medications for at least 12 hours to be in a practically defined
off-state (Langston et al., Movement Disorders, 7(1) 2-13, 1992). When
OFF-medication, their Parkinson symptoms may temporarily worsen, which can lead
to discomfort. At the end of the measurement, they will resume their normal
medication regime.