A feasibility study of fMRI-neurofeedback in Parkinson*s disease

Parkinson*s disease (PD) is associated with progressive neurodegeneration of
dopaminergic neurons of the substantia nigra. It is characterized by both motor
and non-motor systems and affects predominantly people over 60. Although motor
symptoms, which include the classic triad of limb tremor, limb rigidity and
slowness of movement, can be treated with dopaminergic drugs, some patients
have insufficient clinical responses, and for many treatment effects de-crease
over time. Furthermore, non-motor symptoms are difficult to manage in many
patients.

This feasibility study aims to investigate and develop a new protocol for a
non-invasive treat-ment modality for PD, based on self-regulation of brain
circuits with neurofeedback (NF). Neurofeedback entails training of
self-regulation of brain regions or networks via real-time feedback of neural
signals, for example obtained by functional MRI (fMRI). NF enables patients to
develop personal strategies that are most effective in self-regulating brain
areas and net-works associated with mental imagery. Thereby, it can provide an
individually tailored inter-vention(Esmail & Linden, 2014; Johnston et al.,
2010; Linden, 2014). NF is a highly sustainable form of non-invasive
neuromodulation because, once learnt, the self-regulation strategies can be
applied by patients whenever needed to overcome disease symptomology. The PI*s
group has shown proof-of-concept of fMRI-neurofeedback in Parkinson*s disease
(PD) (Subrama-nian et al., 2011; 2016) but target selection has so far been
rather generic, such as activation level of the supplementary motor area (SMA).
Our aim with this feasibility study is to evaluate a new neurofeedback protocol
that entails upregulation training of specific parts of the basal ganglia, the
subcortical circuit that is primarily affected by PD and also targeted by deep
brain stimulation, the most successful (but invasive) neuromodulation treatment
developed for PD thus far. We therefore want to investigate whether patients
with PD can learn self-regulation of basal ganglia activation with
fMRI-neurofeedback.

Primary objective: Identify feasibility of basal-ganglia regions as NF targets
in PD patients
Secondary objective: Document short-term changes in brain resting-state
activation

This is single-group feasibility study of PD patients receiving NF training
using SMA and basal ganglia as target areas. NF training will be delivered in
up to three sessions, modelled on our previous work (Mehler et al., 2019).
Following initial contact with patients through one of the collaborating
clinical teams, a suitably qualified member of the study team will provide
patients with information about the study and a date for the screening session
is scheduled (at the earliest 7 days after participants received the study
information). At the start of the screening session consent is taken.
Subsequently, the screening assessment is performed to determine inclusion and
exclusion criteria.

Study participants will then be invited for up to three further separate visits
for fMRI-NF sessions in approximately weekly intervals. At the last NF session,
a post-training assessment will be conducted.

The fMRI neurofeedback (NF) sessions will include anatomical scans, an fMRI
localizer (inactive bar thermometer shown whilst patients move the dominant
hand, alternating with rest periods) and neurofeedback runs during which
participants see an active thermometer on a screen and are instructed to
upregulate activation in brain regions, alternating with rest periods. These
regions are assigned according to the NF condition, either SMA or basal
ganglia, and further individualized using the localizer measurement. Success of
this upregulation is signaled by the level of the thermometer. Participants
will receive some guidance from the investigator as to potential mental
strategies, for example mental imagery of swimming or playing a musical
instrument. If necessary, auditive cueing can be provided. Localization and
neurofeedback training will be performed with TurboBrainVoyager
(BrainInnovation B.V., Maastricht, The Netherlands). The principle of
neurofeedback training is that participants optimize the strategies for
self-regulation themselves. After each run, patients will be debriefed about
their strategy. Before the first and after the final fMRI-NF run we will also
acquire a resting state scan to determine any connectivity changes in the
patients* brain.

The overall time commitment (excluding travel) will be appr. 2.5 hours.
Patients will be compensated for their time (10¤ / hour) and travel costs.
Expected benefits are creation of a feeling of control as well as an
interesting methodological paradigm. There are no known safety issues arising
from fMRI-neurofeedback over and above general MRI safety requirements (for
which strict guidelines implemented at Scannexus will be followed). The risk of
adverse effects of the fMRI-neurofeedback procedure on patients* wellbeing is
minimal and will be monitored through debriefing.