Neuroproprioceptive Facilitation and Inhibition Physical Therapy Activates Adaptive and Plastic Changes in the Central Nervous System
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: Charles University, Czech Republic

Official Title: Neuroproprioceptive Facilitation and Inhibition Physical Therapy 
Activates Adaptive and Plastic Changes in the Central Nervous System 
Brief Title:Neuroproprioceptive "Facilitation, Inhibition" and Brain Plasticity (NEFAI) 
Unique Protocol ID: VP/22/0/2014 
Identifiers:NCT04355663 
Date: 19.2. 2014 
 
 
 

 
Methods 
1.1. 
Study design 
The Multi-Arm Parallel-Group Exploratory Trial (NCT04355663) was realized between 
May 2015 and May 2017. MS patients were divided into three groups by an 
independent study coordinator according to availability of each therapist (in Groups 1 
and 2) and amount of FES devices to borrow (in Group 3), and underwent three kinds 
of PT. At baseline and after the end of the two months' therapeutic program, white 
matter integrity was estimated from DTI and a blinded assessor evaluated clinical 
outcomes. 
 
1.2. 
Participants 
Patients with defined MS (13) were recruited from the MS Centers of Hospitals in the 
Czech Republic in accordance with the following inclusion criteria: prevailed spastic 
paraparesis, stable clinical status and treatment in the preceding 3 months determined 
by neurologist, Expanded Disability Status Scale score (EDSS) £7.5 (14). The study 
was powered in order to provide 80% power for weak to moderate effect size (Cohen's 
d=0.2-0.5). 120 people were initially assessed for eligibility, 92 were allocated into 
three groups; from these 71 participants finished their therapeutic programs. Data of 
ten patients were discarded upon the visual control, due to the low quality of DTI 
acquisition resulting in 61 participants entering the central analysis. This sample 
provides 80% power to detect at p<0.05 effects of minimal size d=0.36 (weak to 
moderate effect size). For distribution of participants into groups during the study see 
Figure 1, for their baseline characteristics see Table 1. All subjects signed an informed 

consent form approved by the Ethics Committee of Kralovske Vinohrady University 
Hospital in Prague (full trial protocol EK-VP/22/0/2014 is available there). 
 
1.3. 
Interventions 
All groups underwent two months’ ambulatory neuroproprioceptive PT led by well-
educated (MSc.), experienced (at least two years’ practice with pwMS) therapists 
specially trained in each method. Treatments were individually designed according to 
patient status. The therapists offered their full help and adopted the schedule, so 
each patient was able to complete the whole program. To increase adherence, 
therapists provided effective reminders and established confidential relationships. 
Group 1 underwent 16 face-to-face sessions (1 hour, twice a week for two months) of 
MPAT (10), method developed and verified by our team. In this therapy, patients are 
corrected into a postural position where the joints are functionally centered. Afferent 
stimuli are then applied to activate motor programs in the brain, which then lead to 
the co-contraction of the patient's whole body when lying, sitting, standing up or 
moving forward. Activated programs are repeated under various conditions and in 
different situations and environments to teach the patients to automatically use the 
acquired motor skills in daily life. Therapy was realized at Faculty Hospital Royal 
Vineyard. 
Group 2 underwent 16 face-to-face sessions (1 hour, twice a week for two months) of 
VRL (15), which is a standard approach for patients with MS in the Czech Republic. 
During the therapy, global patterns of the reflex locomotion are activated by 
stimulation of specific zones, with the individual placed in a precisely determined 
initial position (supine, prone and side laying, low kneeling position). These 
movement patterns have the qualities of the forward movement (locomotion) and the 

movement responses are precisely defined. Reflex locomotion (reflex turning and 
reflex creeping) is used in therapy to activate involuntarily responses of muscle 
function, which are necessary for spontaneous movements. Therapy was realized at 
Motol University Hospital. 
Group 3 underwent FES in PCP (16), a method developed at our workplace. 
Participants first underwent individual two-hour session consisting of postural 
correction using MPAT and the device (The WalkAide® System, Innovative 
Neurotronics Inc., 4999 Aircenter Circle, Suite 103 Reno, NV 89502, USA) 
programming. Patients received the device to be used use as much as they felt able 
to during their normal daily activities.. After fourteen days, the patients received the 
second individual two-hour session. The patients then continued to use the device daily 
for the next six weeks. 
 
1.4. 
Clinical outcomes 
Demographic and anamnestic data were collected by a neurologist, namely gender, 
age, length of disease, type of MS (relapsing-remitting, primary or secondary 
progressive) and EDSS. 
The balance [Berg Balance Scale, BBS (17) and Timed up and go – TUG (18)] was 
examined and patient-reported outcomes [the 12-item Multiple Sclerosis Walking 
Scale, MSWS-12 (19) and MS impact with the 29-item Multiple Sclerosis Impact Scale, 
MSIS-29 (20)] were collected. 
1.5. 
White matter integrity 
All participants underwent magnetic resonance imaging on a 3T magnetic resonance 
scanner (Siemens Trio Tim, Erlangen, Germany) using a 12-channel phased-array 
head coil. The acquisition protocol consisted of T1-weighted and T2-weighted 

anatomical scans, and diffusion weighted imaging using spin echo epi sequence with 
following parameters TR=9100 ms, TE=96 ms, FOV=260x211 mm, 64 contiguous 
axial slices with 2 mm thickness, b=0 and 1100 s/mm2, 64 gradient directions. 
For the DTI pre-processing, a combination of FSL tools (FMRIB Software Library, 
http://www.fmrib.ox.ac.uk/fslwiki, version 5.0) and MRtrix3 was used. The data was 
initially de-noised and corrected by applying the MRtrix dwidenoise function (21) and 
Gibbs ringing correction (22). The resulting images were visually controlled, and the 
volumes with low quality were discarded. The 'Eddy current correction' was 
subsequently applied (23). 
In the context of neuroproprioceptive PT, we did not expect changes in a particular 
area; hence we analyzed FA across the white matter using a global changes of FA as 
well as FA changes in 48 white matter regions. 
FA global change and changes in 48 regions of interest 
A diffusion tensor was fitted to each voxel of the brain, and a fractional anisotropy (FA) 
map was created for each subject (24). The images were further analyzed using tract-
based spatial statistics (TBSS) (25). The TBSS routine consisted of three steps: 1) 
non-linear registration of all FA images to a chosen template – we chose the 
FMRIB58_FA standard-space image as a target; 2) application of the non-linear 
registration identified in the first step, affine registration of each subject to MNI152 
space and skeletonization of the mean image; 3) thresholding of the mean skeleton 
(we used 0.3 as a threshold) and a projection of individual subjects FA maps onto the 
mean skeleton. Primarily, the (global) mean of the projected FA values over the whole 
skeleton were compared among subjects. 

The resulting skeletonized images were parcellated using the ICBM-DTI-81 white- (26) 
matter labels atlas consisting of 48 regions, and the mean FA value for each region 
was computed (regions are listed in Table 3). 
1.6. 
Statistical analysis 
The resulting dataset was further analyzed using the non-parametric Wilcoxon test for 
assessing the difference between visits. Differences between the treatment groups 
were identified using the Kruskal-Wallis test. All statistical analyses were performed 
using Matlab (MATLAB version R2018b). Note that the region-wise analysis was 
considered exploratory so that there was used an uncorrected significance threshold 
of 0.05 to select the strongest effects for description. Due to the multiple undertaken 
tests, many of the presented localized effect results can constitute false positive 
findings, and thus the observed effects serve rather as initial findings calling for 
independent validation in a follow-up study. The conservative Bonferroni-corrected 
threshold across 48 regions would correspond to 0.05/48~=0.0001, which was not 
reached by any single one of the effects. However, this is to be expected, as the study 
sample size was not designed for confirmatory testing of such a large set of 
hypotheses, but rather for global effect testing. This additional exploratory analysis is 
intended to provide the reader with further information on the presence/absence and 
spatial distribution of any potential localized effects outside the global hypotheses 
testing.