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Abstract Movement is accompanied by modulation of
oscillatory activity in different ranges over the sensorimotor
areas. This increase is more evident in normal subjects and less
with deficits in the formation of new motor skills. Here, we
investigated whether such EEG changes improved in a group of
PD patients, after two different treatments and whether this
relates to performance. Subjects underwent either a session of 5
Hz repetitive Transcranial Magnetic Stimulation (rTMS) over
the right posterior parietal cortex or a 4-week Multidisciplinary
Intensive Rehabilitation Treatment (MIRT). We used a reaching
task with visuo-motor adaptation to a rotated display in
incremental 10° steps up to 60°. Retention of the learned rotation
was tested before and after either intervention over two
consecutive days. High-density EEG was recorded throughout
the testing. We found that patients adapted their movements to
the rotated display similarly to controls, although retention was
poorer. Both rTMS and MIRT lead to improvement in retention
of the learned rotation. Mean beta modulation levels changed
significantly after MIRT and not after rTMS. These results
suggest that rTMS produced local improvement reflected in
enhanced short-term skill retention; on the other hand, MIRT
determined changes across the contralateral sensorimotor area,
reflected in beta EEG changes.
I. INTRODUCTION
neurodegenerative disorder characterized by motor and non-
motor symptoms. While diagnosis is made when motor signs,
such as tremor, rigidity, bradykinesia and postural instability
are present [1], deficits in learning and retention of new motor
skills can complicate the life of patients, impairing the
formation and implementation of novel routines [2,3,4]. This
failure in retention is likely linked to impairment of plasticity
processes, as evidenced by studies on long-term potentiation
(LTP)-like mechanisms in both patients with PD [5] and
animal models [6]. Briefly, in PD learning might fail to trigger
at some levels the appropriate mechanisms that are necessary
to promote LTP-related processes and thus, memory formation
and retention. Recent studies in animals and humans have
shown that 5Hz-repetitive Transcranial Magnetic Stimulation
(rTMS) promotes plastic changes, enhancing LTP [7]. Further,
*Equal contribution.
The study was supported by a grant from National Parkinson Foundation
(MFG ADR); NIH P01 NS083514-03 (MFG); NIH R01-NS54864 (MFG).
G. Marchesi is with the University of Genoa, DIBRIS, Genoa, Italy; (e-
mail: giorgia.marchesi@edu.unige.it)., G.A.Albanese was with University of
Genoa, DIBRIS, now is with Istituto Italiano di Tecnologia,, Genova, Italy;
S. Ricci is with both the University of Genoa, DIBRIS, Genoa, Italy and
retention of a motor skill in patients with PD can be enhanced
by local application of rTMS [8] to an area involved in that
specific learning [9,10]. Interestingly, in these last years, it is
becoming more clear that exercise improves plasticity: the
beneficial effect of exercise is likely linked to neurotrophic
factors and, in general, to the greater cerebral oxygenation that
promotes new cell growth and survival [11,12,13]. In addition,
exercise in PD stimulates dopamine synthesis in remaining
[14], suggesting a possible neuroprotective effect of aerobic
exercise [15]. A series of recent studies have shown that a
multidisciplinary intensive rehabilitation treatment (MIRT)
with aerobic, motor-cognitive and goal-based components can
[16]. MIRT has also a positive effect on sleep quality [17],
enhances the activity of BDNF levels [12, 13] and function
[17] in patients affected by PD.
Motor practice is related to increased modulation of beta
oscillatory activity (15-30 Hz) over sensory-motor areas that
accompanies each movement, as we have recently found in
normally aging subjects during a 40-minutes practice [18]
[19]. At re-test, 24 hours later, beta modulation returned to
baseline but the kinematic improvement achieved at the end of
the previous day was retained [19]. Such improvement
correlated with the increase of beta modulation during the
initial training. Thus, in agreement with other studies in
animals and humans, we interpreted this phenomenon as
expression of plasticity mechanism. Importantly, in patients
with PD, practice-related increase of beta modulation was
diminished during both initial testing and at re-test the
following day, with lack of retention of the motor
improvement.
In the present work, we tested the different effects of MIRT
and rTMS on skill learning and retention with reaching
movements. We used a visuo-motor adaptation task in which
subjects gradually and implicitly adapt their movements to a
visual rotation occurring in 10° steps for a total of 60° [20].
Adaptation was tested on the first day and retention the
following one. We first, compared the EEG and kinematic-
derived indices in both patients with PD and age-matched
controls. Then, we investigated in two separate groups of
CUNY School of Medicine, NY, USA; S. George, E. Tatti and M.F. Ghilardi
(e-mail: lice.mg79@gmail.com) are with CUNY School of Medicine, NY,
-
Gravedona ed Uniti, Italy; A. Quartarone is with Centro Neurolesi,
University of Messina, Messina, Italy; A. Di Rocco is with Northwell Health,
Department of Neurology, New York, NY, USA.
!
"
Giorgia Marchesi*, Giulia Aurora Albanese*, Davide Ferrazzoli, Shaina George, Serena Ricci, Elisa
Tatti, Alessandro Di Rocco, Angelo Quartarone, Giuseppe Frazzitta, M. Felice Ghilardi.
2019 IEEE 16th International Conference on Rehabilitation Robotics (ICORR)
Toronto, Canada, June 24-28, 2019
978-1-7281-2755-2/19/$31.00 ©2019 IEEE 1260
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patients with PD, the effects of two interventions: (i) a single
session of 5 Hz rTMS over the right posterior parietal cortex
or (ii) a 4-weeks Multidisciplinary Intensive Rehabilitation
Treatment (MIRT).
II. MATERIAL AND METHODS
A. Subjects
We tested 19 normally aging subjects (10 men, age: 59 ± 9
years) with normal neurological examination and 29 subjects
(23 men, age: 60 ± 6 years) with the diagnosis of PD. All
subjects were naïve to the motor task, had normal or corrected
vision and were right-handed as determined by the Edinburgh
inventory [21]. PD patients had mild to moderate PD (Hoehn-
Yahr Stage from 2 to 3; duration: 8 ± 4 years) and were treated
with dopaminergic drugs (Tables I and II). During the
experiment, patients were tested in their normal drug treatment
schedule and were in ON condition. The experiments were
conducted with the approval of the Institutional Review
Boards of the participating institutions and all participants
signed a written informed consent form.
B. Experimental Protocol
All subjects performed a 40-min reaching task over two
consecutive days. Subjects were trained in the week preceding
the testing to reach 95% accuracy.
The control group and 19 patients (14 men, mean age: 61
± 5 years; rTMS group) started the experiment around 9 am
(Fig. 1). PD subjects repeated the same session twice, one with
a 5-Hz repetitive TMS after the learning on day 1 and another
(SHAM session) after a SHAM stimulation. The two sessions
were randomized and were at least one week apart (Fig. 1b).
Both SHAM and rTMS were done after the initial learning in
the right posterior parietal cortex, over P6 (10-20 standard
EEG system). The 5 Hz stimulation frequency and the
stimulation parameters were known to induce LTP-like
plasticity [22]. The other group of 10 patients (9 men, mean
age: 58±7 years; MIRT group) performed the motor task over
two consecutive days. The sessions were performed before and
after 4-week MIRT (Fig. 1c). MIRT has been described in
detail in [14,15]. Briefly, this rehabilitative protocol targets
both cognitive and motor functions and is done by an
interdisciplinary team. In fact, it includes four daily
rehabilitative sessions: one-to-one treatment with physical
therapists; exercises to improve balance, postural control;
tasks for the autonomy in everyday activities; speech therapy.
Before every session, subjects of both the control and TMS
groups were outfitted a 256-channel EEG cap (Electrical
Geodesic Inc.), while the MIRT group used a 64-electrode cap
by Micromed.
C. Motor Task
All participants performed a reaction time reaching task
requiring planar movements without and with visuo-motor
rotation of different degrees, as previously described
[8,9,20,23]. Briefly, subjects in front of a computer screen
performed, with their right arm hidden, upper limb reaching
movements on a digitalizing tablet (GTCO CalComp, sample
rate: 166 Hz). The cursor position together with eight targets
(4 cm from the center) were displayed on the computer screen.
Subjects were instructed to move the cursor out and back
without correction as fast and accurately as possible after the
target appearance and to reverse sharply within the target
without stopping. Targets were randomly presented at a fixed
interval of 1.5 s. Each session was divided in 15 sets, of 56
movements (trials). Starting from the fourth set the screen was
rotated unbeknownst to the subjects in incremental steps of 10°
every two sets up to 60°.
For each movement, we measured the time interval from
the target appearance to the movement onset (reaction time);
TABLE I. PATIENTSCHARACTERISTICS OF RTMS GROUP
Patient
Age
Pd
duration
Hoehn-
Yahr
Stage
Levodopa
equivalent
1
67
14
2,5
990
2
58
11
2
875
3
63
17
2,5
750
4
68
4
2
595
5
64
4
2
650
6
56
3
2
400
7
61
5
2
550
8
62
6
2
475
9
59
11
3
1125
10
68
8
3
300
11
61
8
2
920
12
63
10
2
260
13
63
2
2
222,5
14
61
9
2,5
860
15
66
18
2
100
16
49
4
2
750
17
51
6
2
685
18
54
4
2
300
19
64
6
2
600
TABLE II. PATIENTSCHARACTERISTICS OF MIRT GROUP
Patient
Age
Pd
duration
Hoehn-
Yahr
Stage
Levodopa
equivalent
1
55
15
2
739
2
53
6
3
710
3
59
9
3
1260
4
48
5
3
1509
5
50
13
3
510
6
64
3
3
490
7
67
3
2
555
8
54
11
3
450
9
61
7
3
430
10
69
12
3
615
Figure 1b
experimental protocol; c
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the amplitude of peak velocity; the time from the movement
onset to the time point when the target was reached (movement
time) and the directional error at peak velocity. Moreover,
learning (1) and retention (2) were computed as such:
. 1 ###(
###'2 (1)
. 1 - / ###*)+,
"!$#!%%! $%&02 (2)
is the mean directional error of the last eight
movements of the last 60° rotational set of the first day, while
is the mean directional error of the first eight
movements of the first set (0° rotation) at the beginning of the
second day. $%&is the average directional error of the
second set of presentation of the degrees of rotation used in
that set.
D. EEG recording and analysis
EEG was recorded for the entire duration of the
experiments. For the controls and TMS group, data were
collected using the high impedance amplifier Net Amp 300
and Net Station 4.3 with a sampling rate of 500 Hz, then down
sampled to 250 Hz. For the MIRT group the Micromed system
(68 electrodes) with 256 Hz of sampling rate is used. Then,
data preprocessing and processing were performed using
EEGLAB [24] and Fieldtrip toolboxes [25] for MATLAB
(2017b version).
In this work, we focused on beta oscillations (15 to 30 Hz)
in the region where the strongest beta modulation occurs,
hence over the sensorimotor area contralateral to movements.
Indeed, EEG activity in the beta band is characterized by a
decrease that starts before movement onset with a minimum
during the execution, (Event Related Desynchronization,
ERD) and a rebound after the movement end (Event Related
Synchronization, ERS) [18]. In order to define the electrodes
with the strongest beta modulation and its closest neighbors,
we re-referenced data to the average across all electrodes, we
filtered the signal between 1 Hz and 80 Hz with a notch filter
and we divided the whole signal in temporal windows starting
until 3 s after.
We then rejected trials with sporadic noise artifacts by visual
inspection. Channels affected by an improper contact with the
scalp were removed and replaced with spherical spline
interpolation. Independent component analysis was used to
pick apart the different contributions to the signal and reject
stereotypical artifacts [26,27]. Then, after aligning data with
-frequency representations were
computed in the range from 15 to 30 Hz using a short-time
Fourier approach (Hanning taper, time step-size of 20 ms, 5
cycles adaptive window width, 0.5 Hz frequency step). EEG
activity changes were defined as percent change with respect
to the average. Beta ERS-ERD modulation was defined for
each trial as the difference between ERS and ERD magnitude
[19].
E. Statistical analysis
We excluded trials with both kinematic and EEG values
exceeding two standard deviations. Kinematic and
modulation indices were averaged across sets and then, set
and group differences were addressed with mixed model
ANOVAs. Moreover, we compared the effect of intervention
(rTMS or MIRT) with repeated measures ANOVA and two-
tailed paired t-tests.
III. RESULTS
A. Performance and beta modulation during simple motor
task
We first determined whether performance indices were
similar in patients with PD and normally aging controls. The
results of a mixed model ANOVA are reported in table III and
average results are illustrated in Fig. 2. The first three sets of
movements without rotation were slower in patients than in
controls, as attested by the significant group effect for
movement time (Fig. 2b) and mean velocity, even though
movement extent was similar in the two groups (Fig. 2c).
While we found no significant group difference for directional
errors (Fig. 2e), normalized area values were significantly
lower in patients than controls, suggesting that patients with
PD performed more accurate movements, with overlapping
trajectories, a sign of better interjoint timing. This greater
precision is probably due to the lower mean velocities, as at
lower speed the interaction torques are more easily
compensated by the proprioceptive signal [28]. Moreover,
controls (Fig. 2f). Interestingly, there were improvements
across sets for most of the kinematic parameters, as outlined
by the set-effect of normalized area, movement time, mean
velocity, directional error and movement extent (Table III),
suggesting that in both patients and controls some skill
learning occurred. Beta modulation increased across sets
without significant differences between groups. However, we
found a set by group interaction: in fact, beta modulation in set
three grew less in PD than in controls. This is in agreement
with the findings of a previous study [19] showing that by the
third set, beta modulation of PD patients reached a plateau and
stayed constant across the remaining twelve sets, while in
controls beta modulation kept increasing.
B. Retention of skills is lower in patients with PD
We then focused on the sets where a step-wise rotation was
applied. The results of mixed model ANOVAs (table IV)
revealed that all the kinematic parameters significantly
changed across sets. Also, significant differences between the
two groups and set by group interaction were present for
movement time, mean velocity and directional error. As
expected, for both groups, directional errors were greater in the
first set of imposed rotations and decreased during the second
exposure to the same rotation. However, differently from
TABLE III. MIXED MODEL ANOVA
Set 1-3
Set Group Set*Group
F(2,92)
p
F(1,46)
p
F(2,92)
p
Normalized Area
11.0 0.000
5.1 0.030
1.1 0.350
Movement Time
23.5 0.000
12.6 0.001
0.8 0.470
Direct ional Err or
5.8 0.005
0.3 0.599
1.4 0.245
Reaction Time
1.3 0.290
7.4 0.009
2.0 0.137
Movement Extent
4.9 0.010
1.5 0.224
0.6 0.564
Beta Modulation
18.1 0.000
0.0 0.993
5.9 0.004
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controls, adaptation on the second exposure had a greater
residual error (Fig. 2e), suggesting that patients adapted to the
imposed rotation, albeit less efficiently than controls (Fig. 2d).
Normalized area, for which we found a set by group
interaction but not a group difference, showed a similar trend:
however, for smaller rotations (10°) values were lower in
patients than in controls and the opposite was true for the
higher degree rotations (60°). Reaction times of patients with
PD were longer by an average of 20-30 ms than those of
controls and increased with the degree of imposed rotation; the
Movements of patients were significantly slower than those of
controls, with the slowness increasing with increasing the
degree of rotation. Altogether, these results suggest that
despite patients are slower, they adapt like normal subjects up
to 30°- 40° of imposed rotation.
Finally, we determined retention of adaptation by
measuring the after effects on day 2 during the performance in
the first set without imposed rotations. This trace of the learned
rotation was significantly greater in controls compared to
patients (p<0.000
adaptation at the end of the task performed on the first day was
only slightly lower than in controls, the degree of retention
tested the following day was greatly diminished in patients
compared to controls.
Next, we focused on the changes of beta modulation during
rotation. Beta modulation while adapting to a visuomotor
rotation remained stable across sets without significant
differences between the two groups (Table IV). Closer
inspection of the data in Fig. 2g shows that beta modulation
fluctuated within each rotation step, so that greater values were
found at the second exposure of the same rotation step,
similarly to the kinematic data. In other words, values of beta
modulation were on average lower in the first exposure of a
rotation step and constantly increased at the second exposure.
These fluctuations were more evident in normal controls and
not as prominent in patients with PD.
C. rTMS improves retention of new motor skills but does
not induce changes in beta power modulation
We then determined whether a SHAM session or rTMS
could change adaptation and after effects in a group of
patients with PD. We also measure beta modulation during
those recordings. The results of adaptation and after effects
confirm those of a previous study from our lab [8]. Briefly,
the analysis of step adaptation changes revealed that the
adaptation achieved at the end of the rTMS session on day 2
was significantly greater than that achieved on day 2 after the
SHAM session, while adaptation at the end of day 1 was
similar in the two sessions. Also, the retention index at the
beginning of day 2 was significantly greater after rTMS than
after SHAM stimulation (26.3% ± 9.3% versus 10.6% ± 7.8%,
t=-6.06, p<0.0001, Fig. 3b). The results of a repeated
measures ANOVA on beta modulation revealed no significant
effect of treatment in the first 3 sets (F(1,34)=0.5; p=0.509).
A borderline effect that however failed to achieve
significance was present during adaptation (F(1,204)=4.3;
p=0.058; Fig. 3a). Altogether, these results suggest that the
rTMS increased the rate of learning on the second day of task
TABLE IV. MIXED MODEL ANOVA
Set 4-15
Set Group Set*Group
F(13,
552)
p
F(1,46)
p
F(2,
92)
p
Normalized Area
54.0
0.000
0.154
0.696
6.6
0.000
Movement Time
25.2
0.000
16.2
0.000
7.0
0.000
Mean Velocity
13.2
0.000
13.7
0.001
2.8
0.002
Directional Error
150.1
0.000
385.1
0.000
7.5
0.000
Reaction Time
4.7
0.000
8.8
0.005
1.4
0.150
Movement Extent
1.9
0.039
2.5
0.121
1.1
0.392
Beta Modulation
4.0
0.000
0.434
0.514
1.0
0.482
Figure 2: Behavioral parameters for controls and PD patients: a) Normalized Area; b) Movement Time; c) Movement Extent; d) Pe
rcentage of adaptation;
e) Directional Error; f) Reaction Time; g) Beta Modulation; h) Percentage of after effects (p<0.001).
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and influenced the retention of the skills learned previously
but did not produce any significant effect on beta modulation.
Therefore, we thought it is likely that 5 Hz rTMS over the
right parietal area improved retention of adaptation, but the
benefits were only local and restricted to the stimulated area,
that is involved in visuo-motor adaptation. Indeed, they did
not extend to either other aspects of motor performance [8,29]
or to their neural correlates.
D. MIRT leads to more global changes
In this final part, we describe the effect of a four-week
intensive exercise program (MIRT) on adaptation, retention
and beta modulation. The indices of adaptation significantly
increased after MIRT from an average of 72.2% ± 10.2% to
74.5% ± 8.6% (t=-2.46, p=0.025). Most importantly, retention
of adaptation from day 1 to day 2 significantly improved after
MIRT (Fig. 4 bottom right): after MIRT, subjects retained an
average of 26.5% as compared to 13.1%, the retention average
before MIRT (t=-3.8, p=0.005, Fig. 4 bottom left). A repeated
measure ANOVA on beta modulation revealed a significant
effects of MIRT (both with and without rotation, respectively
F(1, 14)=15.1, p=0.005; F(1,84)=8.9, p=0.020). In conclusion,
MIRT has significant effects on the indices of adaptation and
retention. In addition, after MIRT, beta modulation values
decreased significantly.
IV. DISCUSSIO N
This is the first report investigating the EEG and kinematic
characteristics of patients with PD during the practice of
reaching movements with an imposed visuo-motor rotation
and the effects of two treatments: a session of 5 Hz rTMS and
a four-week MIRT.
Kinematic analyses show that patients with PD produce
slower but more accurate movements when the applied
rotation is absent or rather small. Indeed, directional error and
normalized area are lower in patients than controls when no or
small rotations are applied. This is not the case when the
degree of rotation increases. While patients can adapt to a
visuomotor rotation, their adaptation rate is lower than aged-
matched controls for rotations greater than 40°. Despite the
learning process is only slightly affected in PD, retention of
previously acquired skills is greatly diminished. In fact, the
percentage of after effects is somewhat affected in patients:
this retention index, which describes how much the rotation
imposed the previous day influences the initial movements the
day after, presents a value that is almost a quarter of those of
healthy subjects. This failure in retention can be caused by the
deficits in plasticity reported in PD [2]. In fact, PD affects at
some levels the mechanisms inducing processes related to LTP
[29,30], so learning might fail to trigger the appropriate
mechanisms that are necessary to promote memory formation
[31]. The analysis of movement-related beta modulation over
the sensorimotor region contralateral to the moving limb
showed that patients and controls have comparable values in
the first set of a that rotation, while on the second set the
control group shows a steady increase that is not so evident in
the PD group. This phenomenon, which might be related to
plasticity related mechanisms, needs to be confirmed in a
larger PD population.
Finally, we analyzed the effects of the two treatments on
two separate groups of patients. After both interventions,
indices of learning and retention improved. This could have
been driven by learning caused by a repetition of the same task.
However, previous work from our lab showed that, without
any intervention, PD patients did not show such improvements
[19]. Also, only rTMS and MIRT but not SHAM were able to
enhance learning and retention. The above-mentioned results
ensure that these improvements are not affected by learning
itself, but the interventions played a major role. Moreover, the
fact that these improvements were greater only after the TMS
intervention and not after the SHAM further supports these
results. Nevertheless, beta modulation presents a main effect
only after the MIRT. However, this result has been obtained in
a very small sample of patients indeed, the biggest limitation
of this study is the relatively small number of patients. In
addition, the two experiments were not designed to be
compared with each other, as they are part of exploratory
studies aimed to investigate possible solutions to improve
motor impairments in PD. Therefore, this preliminary work
explores different avenues to characterize the effects of novel
and effective strategies for improving the well-being of
patients with PD.
In summary, both interventions lead to an increase in
retention of the learned rotation but only MIRT seemed to
affect movement-related brain activity. In fact, beta
modulation may reflect the interplay of the activity of the
sensory and motor regions during motor performance [18]:
beta desynchronization likely reflects concomitantly
activation of the motor areas and attenuation of the sensory
afferences during movements, while beta synchronization or
rebound, instead, may reflect post-movement reactivation of
somatosensory areas and inhibition of the motor areas. Hence,
changes in beta modulation may be due to variations in the
sensorimotor integration processes, likely because intensive
motor exercise has an important aerobic component that may
Figure 3: In the first row, parameters post SHAM and post rTMS: b
eta
modulation; percentage of after effects; in the second row, parameters pre
and post MIRT: beta modulation; percentage of after effects.
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be beneficial in terms of neuroplasticity, such as by increasing
BDNF levels and activity [7,15] as well as cerebral blood flow
[11]. On the other hand, rTMS is a local treatment applied on
the area that facilitates learning and retention; in fact, it
produces only improvements in terms of skill retention since it
has only circumscribed effects on cortical plasticity and LTP-
like phenomena.
V. CONCLUSION
Movement-related brain activity changes after MIRT, a
multidisciplinary rehabilitative protocol but not after TMS
highlighted the importance of rehabilitative protocols targeting
have a positive effect on the sensorimotor integration process
occurring during movement executions and thus on the
everyday life of patients.
ACKNOWLEDGMENT
Kinematic data were collected with custom-designed
software, MotorTaskManager, produced by E.T.T. s.r.l.
(http://www. ettsolutions.com).
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