fMRI-based Neurofeedback of the basal ganglia 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 system manifestations. Dopamine replacement therapy or
dopaminergic medication are the key therapeutic strategies, but deep brain
stimulation (DBS) is increasingly being used in cases where drug response is/
has become insufficient or hampered by unacceptable side effects (Hartmann et
al., 2019; Lee et al., 2018).

Neurofeedback (NF) entails training of self-regulation of brain regions or
networks via mental imagery and 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
networks. Thereby, it can provide an individually tailored intervention
(Linden, 2014). NF is a highly sustainable form of non-invasive neuromodulation
because, once learnt, the self-regulation strategies can in principle be
applied by patients whenever needed to overcome disease symptomology.

NF can be used to train patients to change their brain activity in different
directions, or to modulate patterns of co-activation between regions. Mental
imagery of moving one*s own body (also called kinaesthetic imagery) can
potentially be used to improve motor functions and neuroplasticity in PD
(Sarasso et al., 2023). Kinaesthetic imagery is also a suitable strategy for
increasing activation in the brain*s motor network, and motor imagery training
can be reinforced through combination with NF. A NF paradigm involving
upregulation training of motor areas through kinaesthetic imagery thus has good
plausibility for PD. The PI*s group has shown proof-of-concept of such an
fMRI-NF training (targeting the supplementary motor area, SMA) in PD
(Subramanian et al., 2011, 2016) and is currently conducting a feasibility
study of fMRI-NF targeting the putamen in 12 PD patients (METC study number
NL82024.068.22 / METC22-052). FMRI-NF targeting of the putamen has become
available in a medical product, the software TurboBrainVoyager MED (TBV-MED),
and the aim of the current investigator-initiated study is to investigate the
effects of putamen upregulation training on motor function in PD.

Primary Objective:

Assess the effect of mental imagery with fMRI-neurofeedback-based upregulation
of the putamen on motor symptoms of PD


Secondary Objective(s):

-Assess changes in whole brain activation patterns over the course of the NF
training

-Assess effects on non-motor symptoms

-Assess correlations between NF success and additional behavioral parameters

-Explore potential predictors of NF success

This is a randomized controlled trial for the application of fMRI-neurofeedback
targeting subcortical regions of the motor control network during mental
imagery in patients with PD. The primary outcome measure will be the
post-interventional change in the MDS-UPDRS (Unified Parkinson's Disease Rating
Scale) motor scale widely used in the clinic to assess the motor symptoms of
PD.

Following initial contact with patients through one of the collaborating
clinical teams, a suitably qualified member of the study team or patient
representatives will provide patients with information about the study. The
patients can then contact the study team to schedule a date for the screening
session (at the earliest 7 days after participants received the study
information). At the start of the screening session consent will be taken. The
patients will be randomly allocated into either the experimental or the control
group. In both groups, patients will perform an approximately 10 week-long
mental training including motor imagery. During this period, patients in the
experimental group will be subjected to four weekly MRI sessions where they
will learn to upregulate the activity of the putamen during motor imagery via
fMRI neurofeedback. In the control group, motor imagery is also performed
during the MRI sessions, but no feedback is provided to the patient. After the
last fMRI session and at 1 month follow-up, a post-training assessment of the
symptoms will be conducted. The study will test the hypothesis that the
experimental group will experience a larger improvement in the MDS-UPDRS part
III: Motor Examination scale after the last MRI session compared to the control
group.

The patients will be randomly allocated into either the experimental or the
control group. Both groups will be asked to take part in a total of four fMRI
sessions. The first MRI measurement session will be scheduled approximately one
week after screening. This provides some further delay for the patients to be
able to reconsider their agreement and withdraw their consent before the actual
start of the intervention if desired. Both groups will then be invited for
another three fMRI measurement sessions in approximately weekly intervals.
After the last NF session, a post-training assessment of clinical measures will
be conducted. The intervention will thus be concluded after approximately 5-6
weeks. One further follow-up assessment (1 month after the last MRI-session)
will conclude the trial. Therefore, the total on-site visits in the trial will
be six; one for the initial screening and baseline assessment, four for the MRI
measurements and one meeting for the follow-up assessment. All patients of this
group will be asked to practice the motor imagery they have been doing in the
scanner also on the days between the fMRI-sessions and to keep a diary of this
practice (suggested time minimally 10 minutes per day). A diary template will
be offered (see appendix F2 Patient Diaries).

No risks or harm were identified in relation to the neurofeedback procedure, no
risk control measures were defined and implemented that are specific to the
neurofeedback treatment. However, we have implemented general risk management
procedures as appropriate for this population, including accessibility of
clinical professionals if needed. There are no known safety issues arising from
fMRI-based neurofeedback over and above general MRI safety requirements (for
which strict guidelines implemented at Scannexus will be followed).

The overall time commitment (excluding travel) will be approximately 11 hours.
Patients will be compensated for their time (10¤ / hour) and travel costs.
Previous work (Subramanian et al., 2011; 2016) has shown that fMRI-NF may have
a clinically relevant effect (improvement of 5 points on the MDS-UPDRS part
III: Motor Examination). The participants stand to potentially benefit from
therapeutic effects due to the neurofeedback intervention. Non-clinical
benefits include creation of a feeling of control as well as learning about
non-invasive methodologies for self-regulation that the participants can
implement outside the scanner at a later time.