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Robot Training of Upper Limb in Multiple Sclerosis: Comparing Protocols

With or WithoutManipulative Task Components

Article  in  IEEE transactions on neural systems and rehabilitation engineering: a publication of the IEEE Engineering in Medicine and Biology Society · May 2012
DOI: 10.1109/TNSRE.2012.2187462 · Source: PubMed

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IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 20, NO. 3, MAY 2012
Robot Training of Upper Limb in Multiple
Sclerosis: Comparing Protocols With or
WithoutManipulative Task Components
Ilaria Carpinella, Davide Cattaneo, Rita Bertoni, and Maurizio Ferrarin, Member, IEEE
Abstract—In this pilot study, we compared two protocols for
robot-based rehabilitation of upper limb in multiple sclerosis
(MS): a protocol involving reaching tasks (RT) requiring arm
transport only and a protocol requiring both objects’ reaching
and manipulation (RMT). Twenty-two MS subjects were assigned
to RT or RMT group. Both protocols consisted of eight sessions.
During RT training, subjects moved the handle of a planar robotic
manipulandum toward circular targets displayed on a screen.
RMT protocol required patients to reach and manipulate real
objects, by moving the robotic arm equipped with a handle which
left the hand free for distal tasks. In both trainings, the robot
generated resistive and perturbing forces. Subjects were evaluated
with clinical and instrumental tests. The results confirmed that
MS patients maintained the ability to adapt to the robot-gener-
ated forces and that the rate of motor learning increased across
sessions. Robot-therapy significantly reduced arm tremor and
improved arm kinematics and functional ability. Compared to
RT, RMT protocol induced a significantly larger improvement
in movements involving grasp (improvement in Grasp ARAT
sub-score: RMT 77.4%, RT 29.5%, p=0.035) but not precision
grip. Future studies are needed to evaluate if longer trainings and
the use of robotic handles would significantly improve also fine
manipulation.
Index Terms—Motor learning, multiple sclerosis, robot-therapy,
upper limb function.
I. INTRODUCTION
A LTHOUGH multiple sclerosis (MS) is the most common
cause of chronic neurological disability in young adults,
current pharmacological therapies are so far not able to sub-
stantially improve motor functionality [1]. Although no firm
conclusions can be drawn, a recent review suggests that reha-
bilitation may be useful to maximize the functional status of
these subjects [2]. Most studies about motor rehabilitation in
MS are focused on walking and mobility [3], but, as the dis-
ease progresses, nearly 75% of MS subjects experience also
upper limb dysfunction [4], mainly related to tremor [5], co-
ordination deficit [6] and muscle weakness [7]. Although arm
impairment highly contributes to reduce the quality of life of
Manuscript received July 14, 2011; revised October 20, 2011; accepted Jan-
uary 29, 2012. Date of current version May 18, 2012. This work was supported
in part by FISM—Fondazione Italiana Sclerosi Multipla.
I. Carpinella and M. Ferrarin are with the Biomedical Technology Depart-
ment, Don Carlo Gnocchi Foundation Onlus IRCCS, 20148 Milan, Italy (e-mail:
icarpinella@dongnocchi.it).
D. Cattaneo and R. Bertoni are with the Department of Neurorehabilitation,
Don Carlo Gnocchi Foundation Onlus IRCCS, 20148 Milan, Italy (e-mail: dcat-
taneo@dongnocchi.it).
Digital Object Identifier 10.1109/TNSRE.2012.2187462
1534-4320/$31.00 © 2012 IEEE
351
MS subjects [8], only few studies exist about neuromotor reha-
bilitation of upper limb in MS [7], [9], [10]. The results emerged
from these works showed that physical rehabilitation generated
an improvement in arm strength [7], in the execution of the ac-
tivities of daily living (ADL) [10] and a tendency to an improved
manual dexterity, although not significant [9]. Given the paucity
of existing studies, more research is needed to explore the ef-
fects of neuro-rehabilitation on upper limb dysfunction in MS
subjects.
In the last decade, robotic devices for upper limb motor
rehabilitation have been increasingly studied, becoming a
promising complement to traditional therapy, as they can pro-
vide high-intensity, repetitive and interactive treatment of the
impaired upper limb and, inherently, an objective, quantitative
measurement of patient’s progress. Although robotic systems
are mostly used in rehabilitation of stroke patients [11], they
appear good candidates also for the treatment of tremor and
incoordination due to MS. At present, three studies have ad-
dressed the application of robot-based treatment of upper limb
in MS [12]–[14]. Gijbels et al. [14] used a gravity-supporting
exoskeleton which allowed the subject to execute 3-D tasks
simulated in a virtual environment on a computer screen.
Carpinella et al. [12] and Vergaro et al. [13] used a planar
robotic system and adaptive training protocols, in which the
robot did not assist subjects during the execution of the move-
ment, but, rather it provided unfamiliar dynamic environments
to which subjects were required to adapt, by learning to predict
the effects of perturbing forces [15], [16]. A common finding
of these studies was the post-treatment improvement in the
execution of functional tasks implying distal movements not
directly involved in the training. In particular, robotic training
consistently improved manual dexterity, as shown by the Nine
Hole Peg Test score [17] which significantly decreased from
157 to 109 s in severe MS subjects [14] and from nearly 60
to 48 s in mild/moderate patients [12], [13]. These results
indicated that, even though the mean improvement was signifi-
cant, the post-treatment score was still consistently higher than
the threshold value typical of healthy adults with comparable
age, that is 19 [18]. Starting from these results, one
may wonder if the implementation of a functional-based robot
training, which involves not only the movement of proximal
joints but also the use of distal arm and the manipulation of real
objects should even improve the rehabilitation outcome and
facilitate the skill transfer from the experimental setting to the
ADL [19]. This approach has been recently applied to stroke
patients [20], not yet to MS subjects.
352 IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 20, NO. 3, MAY 2012

In the present study we designed a robot-based functional TABLE I

training which combines a typical adaptive paradigm, previ- DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF TREATED MS SUBJECTS
ously applied to stroke [21] and MS subjects [12], [13], [22],
with two main principles of motor learning: 1) the use of real
objects during purposeful and challenging functional tasks in-
volving whole arm, to enhance motor performance and maxi-
mize subjects’ active participation [19] and 2) the execution of
different types of exercises during each session, that has been
shown to promote motor learning [23]. A robot-based protocol
incorporating these two concepts was applied to a group of MS
subjects and the results were compared to those obtained by
a second group of MS patients treated with a more traditional
robot-based protocol involving reaching tasks [12], [13]. Goal
of this pilot study was to evaluate if a robot therapy approach in-
volving both objects’ reaching and manipulation leads to better
outcomes than training involving only the transport of the arm.

II. METHODS

A. Subjects
A consecutive sample of 22 MS subjects were enrolled in
the study within a period of one year and a half. Their demo-
graphic and clinical characteristics are shown in Table I. All sub-
jects signed an informed consent to the protocol which was con-
formed to the standards for human experiments set by the Decla-
ration of Helsinki. Subjects fulfilled the following inclusion cri-
teria: a definite diagnosis of MS according to McDonald criteria
[24], Expanded Disability Status Scale [25] , Nine Hole Peg
Test [17] score between 30 and 300 s, Mini-Mental State Exam-
ination [26] , willing to follow the rehabilitation program.
Subjects were excluded if they had reduced and not amendable
visual acuity and/or ocular motility which interfere with the exe-
cution of the training tasks. Each subject was allocated to one of
the following groups: a group receiving a robot-based
rehabilitation program involving the execution of reaching tasks
Fig. 1. (a) Experimental set-up. (b) The “traditional” handle. (c) The “func-
(RT) and a group receiving a robot-based rehabil- tional” handle. (d) Example of a subject executing a functional task, i.e., insert
itation program involving both objects’ reaching and manipu- a key in a padlock.
lation (RMT). Group allocation was performed following mini-
mization method [27], that is a widely acceptable alternative ap-
proach to randomization in small trials, as it ensures excellent manipulate real objects [Fig. 1(d)]. The “functional” handle
balance between groups, even in small samples. In particular, is fixed to the robotic arm through a 12-cm-long vertical rod
each subject was allocated to one group or the other, depending that supports a cylindrical ball bearing which can rotate around
on the baseline clinical characteristics of those participants al- the rod and translate in vertical direction with low friction. A
ready enrolled, in order to minimize the imbalance between the forearm splint made of thermoplastic material is fixed to the
two groups. As shown in Table I, demographic and clinical char- ball bearing. The inner surface of the splint is covered with
acteristics were similar in both groups. foam rubber coat to guarantee subject’s comfort.

B. Experimental Equipment C. Robot-Based Rehabilitation Protocols

The apparatus consists of a planar robotic manipulandum
[Fig. 1(a)] with two back-driveable degrees-of-freedom
(Braccio di Ferro, Celin srl, La Spezia, Italy), which has been
fully described elsewhere [28]. It has an 80 40 cm elliptic
workspace and is smoothly impedance-controlled in order to
generate continuous forces up to 25 . Subjects can interact
with the robotic arm through two handles: a “traditional” handle
grasped by the patient [Fig. 1(b)] and a customized “functional”
handle [Fig. 1(c)] wrapped around the forearm of the subject
and fastened through velcro stripes leaving the hand free to
Both RT and RMT protocols were composed of eight ses-
sions. The number of sessions was chosen on the basis of the
results obtained by Vergaro et al. [13]. Each session consisted
of eight epochs of 20 movements each, for a total of 160 move-
ments and a duration of 30–45 min. The most affected arm of
each subject was treated.
In the RT protocol (see also [12], [13], and [22]), subjects sat
on a chair behind a table and grasped the “traditional” handle of
the robot [Fig. 1(b)]. A 19-in LCD screen, positioned in front
of the subject, was used to display the current position of the
CARPINELLA et al.: ROBOT TRAINING OF UPPER LIMB IN MULTIPLE SCLEROSIS
end-effector and the target (circles with a diameter of 1.5 cm
and 3 cm, respectively). Subjects performed center-out reaching
movements from the same center position to peripheral targets
(directions: 45 and 135 with respect to the horizontal axis)
and then they returned to the center (directions: 225 and 315 ).
The amplitude of the nominal reaching trajectory was 25 cm. All
subjects were able to fulfill the task. The movements were ex-
ecuted at self-selected speed and the targets were presented in
a random order. Each training session consisted of two phases
[13], [22]: 1) null field phase (2 epochs, 40 movements) and 2)
force field phase (6 epochs, 120 movements). During the null
field phase, subjects executed the reaching task while the robot
did not generate forces. Null field trials had the purpose to mon-
itor the progress of unperturbed reaching movement and the re-
tention of the effects of each training session on arm kinematics.
During the force field phase, subjects executed the reaching task
while the robot generated a velocity-dependent clockwise force
field [12], [13], [15], [22] to which subjects were required
to adapt. Perturbing force was perpendicular to the instan-
taneous movement direction and had a magnitude proportional
to the handle speed. This force disturbed the
movement executed by the subject by deviating hand’s trajec-
tory from the nominal straight path. During each epoch, force
was unexpectedly turned off in 1/5 of the movements (catch
trials, 4 per epoch) to monitor the progress of adaptation. In par-
ticular, if adaptation is occurring and the subject is learning the
appropriate internal model to predict and cancel the perturba-
tions induced by the robot, two effects should be noticed: 1) a
gradual reduction of the execution errors in the force trials and
2) a gradual increase of erroneous movements in directions op-
posite to the perturbations in catch trials, when the force is un-
expectedly removed (see also [12], [13], [15], [16], [22]). To
increase the difficulty of the exercise, the robot generated also a
spring-like resistive force which opposed hand’s movement.
In particular, the force was proportional to
the distance between the current position of the end-effector and
the starting position and was directed along the line which con-
nected the starting point and the instantaneous position of the
handle.
RMT training sessions also consisted of a null field phase and
a force field phase. During the null field phase (2 epochs, 40
movements), subjects executed the reaching task (as in RT pro-
tocol), while the robot did not generate forces. At the end of this
phase, the “traditional” handle of the robot was replaced with
the “functional” handle [Fig. 1(c)] and the splint was worn by
the subject. During the force field phase (6 epochs, 120 move-
ments), subjects executed a set of 6 functional tasks (one per
epoch) involving reaching and manipulation of “real” objects,
built using LEGO bricks (LEGO Group, Billund, Denmark)
(e.g., small containers, pegs, beads, coin slots) or taken from
typical activities of daily living (e.g., bottles, jars, padlocks,
keys). The set of functional tasks was selected on the basis of
the specific deficit of each subject, as measured by clinical as-
sessment. The tasks included both grasp (e.g., grasp and release
of water bottles or cylindrical jars) and precision grips, mainly
key grip (e.g., locking of a padlock or insertion of a coin into a
slot) and pinch grip (e.g., putting a bead down a needle or insert
a rectangular peg into a squared hole). An example is shown in
353
Fig. 1(d). The objects to be reached and manipulated were fixed
on a LEGO supporting base and arranged on the table within
the elliptic workspace of the manipulandum. The positions of
the end-effector when each object had been reached were cali-
brated for each patient at the beginning of the first training day
and maintained for all sessions. These positions and the instan-
taneous position of the handle were represented on the screen by
circles, as in RT protocol. This allowed the operator to check the
correct execution of the task which was performed by the patient
by looking at the objects on the table. Subjects were invited to
perform the tasks at self-selected speed, trying to counteract the
pull of gravity by maintaining the ball bearing in the middle of
the handle rod and by avoiding to rest their elbow on the table.
During the training, the difficulty of the tasks was increased by
varying the size and the weight of the objects to be manipu-
lated. Each functional movement consisted in a transport phase
(during which the subject reached the object) and a manipula-
tion phase. During the transport phase the robot generated the
same forces and used in the RT protocol. Moreover the
same number of catch trials (4 per epoch) were inserted.
To analyze the effect of resistive force , all subjects were
also required to execute the reaching task (1 epoch, 20 move-
ments) while only was turned on. This test was performed
pre- and post-treatment.
D. Clinical Assessment
All subjects were evaluated pre- and post-treatment by means
of three clinical tests administered by a blinded examiner: Nine
Hole Peg test (9 HPT) [17], Action Research Arm Test (ARAT)
[29], and Tremor Severity Scale (TSS) [30].
The 9HPT evaluates hand dexterity. The test requires the sub-
ject to place nine pegs in nine holes. Subjects are scored on the
amount of time they take to place and remove all nine pegs.
The ARAT evaluates proximal and distal function of upper
limb and was used in this study to evaluate the transfer of the
training effects on functional tasks involving 3-D movements
not executed during the treatment. The ARAT consists of
19 items organized in four sections: Grasp, Grip, Pinch, and
Gross. Each item is given an ordinal score of 0, 1, 2, or 3, with
higher values indicating better performance. The maximum
ARAT score is 57. In the present study, total ARAT score and
sub-scores related to the four sections were considered. More-
over, a variable related to the execution time was analyzed.
When a subject was not able to perform some ARAT tasks
, execution time was used to calculate
execution frequency (60/time), that represents the number of
times an item was executed in a minute. A value of 0 was
assigned when subjects were unable to perform the task. Total
ARAT frequency was calculated as the mean frequency of all
items.
The TSS measures the severity of tremor in four domains:
1) rest tremor: tremor occurring at rest with the body part sup-
ported; 2) postural tremor: tremor occurring while maintaining a
position against gravity; 3) kinetic tremor: tremor during move-
ment; and 4) intention tremor: pronounced exacerbation of ki-
netic tremor towards the end of a goal directed movement. Each
domain is rated by a 10-point scale, with higher score indicating
more severe tremor.
354 IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 20, NO. 3, MAY 2012

E. Kinematic Analysis III. RESULTS

Handle coordinates were sampled at 100 Hz and low-pass fil- A. Null Field Trials
tered using a sixth-order Savitzky-Golay filter with a 200 ms The results related to the unperturbed reaching move-
window and a cutoff frequency of 9.4 Hz [12]. The same filter ments performed by the treated MS subjects are shown
was used to estimate the subsequent time derivatives of the tra- in Fig. 2. A significant effect of session was found for
jectory. Kinematic data were segmented into separated move- reaching duration , jerk index
ments and, for functional tasks, each movement was divided and mean lateral devia-
into a reaching phase and a manipulation phase. Then, the fol- tion , which gradually decreased
lowing parameters were extracted. during the training [Fig. 2(a)–(c)], while normalized path length
• Reaching duration: time between reaching onset and ter- remained almost unchanged [see
mination (first instants in which handle velocity exceeded Fig. 2(d)]. The effect of training protocol was not significant
and fell below a threshold of 20% of peak speed, respec- for all parameters. These results indicated that the unperturbed
tively [13]). reaching movements of MS subjects became gradually faster,
• Manipulation duration: time elapsed between reaching ter- smoother and more linear across sessions, similarly in both
mination and the end of whole task. This parameter was groups, as shown in the examples reported in Fig. 2(e)–(h).
calculated only for functional tasks.
• Jerk Index: logarithm of the jerk (norm of the third time B. Force Field Trials
derivative of the trajectory), averaged over the movement The subjects’ improvement in counteracting the robot-gen-
duration and normalized with respect to the amplitude and erated disturbing force is shown in Fig. 3. The amplitude
duration of the reaching movement [13]. Jerk Index eval- of the perturbing force field [Fig. 3(a)] showed a sig-
uates the smoothness of the trajectories. nificant effect of session .
• Mean and maximum lateral deviation: mean and maximum No difference was noticed between RT and RMT groups
distance of the actual trajectory from the nominal trajectory but the significant session
(straight line connecting the start and the end points). group interaction revealed that
• Normalized path length: length of the actual trajectory nor- amplitude increased mainly in RT group, while remained
malized with respect to the length of the nominal trajectory. almost stable in RMT group. Despite this difference, the
• Learning Index : calculated to assess the subjects’ rate of force field adaptation was similar in both groups. As
ability to adapt to the perturbing force field generated by shown in Fig. 3(b), the learning index increased over
the robot. In this study we used the definition of learning sessions , similarly in both groups
index proposed by Donchin et al. [15] and expressed by . The increase of was due to a
significant decrease of the lateral deviation in the force trials
[see Fig. 3(c)] and to a significant
(1) increase (in the opposite direction) of the execution error in
catch trials [see Fig. 3(d)]. Exam-
where and are the maximum lateral deviations ples of the trajectories executed during force field trials by two
in the field and catch trials, respectively. This index compares a representative MS subjects from RT and RMT group are shown
signed measure of execution error (here, maximum lateral devi- in Fig. 3(e)–(h), respectively. With respect to the first session
ation, positive in the direction of force ) in movements where [Fig. 3(e) and (g)], in the last training day [Fig. 3(f)–(h)] the
force is turned on (force trials) and where force is turned off deviation from the straight line decreased during force field
(catch trials). Values of equal to 1 indicate a perfect adapta- trials (continuous lines) and increased in the opposite direction
tion, in which errors in force trials tend to 0, while errors in catch during catch trials (dashed lines), thus indicating adaptation to
trials are large and in the opposite direction (negative values) the perturbing force.
with respect to force [15]. The results related to the trajectories executed pre and
post-treatment, when only force was turned on revealed
that, after the treatment, MS subjects improved their ability
F. Statistical Analysis in counteracting the resistive force which opposed the
movement. In particular the trajectories performed against
Kinematic parameters were analyzed with a two-way mixed resistance showed a significant decrease in duration
ANOVA, with session and group (RT versus , jerk index
RMT protocol) as fixed factors. Considering that clinical , and lateral deviation
data were not normally distributed (Shapiro-Wilks W test, , with respect to pre-
), nonparametric procedures were used. In partic- treatment evaluation. No statistically significant difference was
ular, comparisons between pre- and post-treatment data were noticed between the two groups. Moreover, similarly in both
evaluated using Wilcoxon matched pairs test (Wt), while dif- groups, movements executed against were characterized by
ferences between RT and RMT groups were tested by means higher duration and jerk
of Mann-Whitney U test (MWt). Level of significance was set index , with respect to
to 0.05. unperturbed reaching.
CARPINELLA et al.: ROBOT TRAINING OF UPPER LIMB IN MULTIPLE SCLEROSIS 355

Fig. 2. (a)–(d) Quantitative parameters (mean confidence interval) de- Fig. 3. (a)–(d) Quantitative parameters (mean confidence interval) de-
scribing null field trials. Significant differences with respect to session 1 are scribing force field trials. Significant differences with respect to session 1 are
reported for RT and RMT group . (e)–(h) Unperturbed reaching trajecto- reported for RT and RMT group . (e)–(h) Reaching trajectories executed
ries executed during the first and the last treatment sessions by two MS subjects during the first and the last treatment sessions by two MS subjects (V06 and F05)
(V09 and F03) treated with the RT and the RMT protocols, respectively. -axis treated with the RT and the RMT protocols, respectively. -axis represents the
represents the direction of movement. direction of movement. Continuous lines: force field trials; dashed lines: catch
trials.

The results related to the duration of the manipulation tasks

executed by the RMT group are reported in Fig. 4. The time symptoms. In particular, upper limb ataxia (as measured by
required for manipulative tasks involving grasp gradually de- items of the Ataxia scale
creased across sessions , while the [31]) was mild/moderate (Ataxia score: 1–3) in 18 subjects and
time of precision grip tasks (i.e., key or pinch grip) remained severe (5–6) in four subjects. Kinetic and intention tremor was
almost unchanged . mild/moderate (TSS score: 1–5) in 20 patients and severe (7–8)
in two patients.
C. Clinical Evaluations As concerns the effects of training on upper limb function
At the baseline evaluation (Pre) both groups showed (see Table II), both groups significantly improved ARAT total
similar clinical characteristics (Table II). The MS sub- score and Pinch sub-score, while only RMT group consistently
jects showed moderate to severe upper limb dysfunction increased Grasp and Grip sub-scores. Gross sub-score did not
(ARAT score: ). All subjects showed cerebellar change significantly in both groups because of a high ceiling
356 IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 20, NO. 3, MAY 2012
Fig. 4. Duration (mean confidence interval) of manipulation tasks, in-
volving grasp and precision grip, executed by MS subjects during the eight ses-
sions of the RMT protocol. ANOVA p-values related to the effect of session and
significant differences with respect to session are reported.
TABLE II
PRE- AND POST-TREATMENT CLINICAL SCORES FOR RT AND RMT GROUPS
effect. In particular, 16/22 patients (eight per group) showed a
baseline Gross score equal to the maximum (nine points) and
maintained the same score after the treatment. The remaining
subjects (three per group) significantly improved their Gross
sub-score . A direct comparison of the per-
centage change obtained by the two groups after the treatment
confirmed the above results. As shown in Fig. 5, RMT group
obtained a percentage improvement of Grasp sub-score signifi-
cantly higher than that attained by RT group. Analysis of the ex-
ecution frequency of ARAT tasks revealed that both groups sig-
nificantly increased this parameter after the treatment
. Again, the percentage change in execution frequency of
Grasp items was significantly higher in RMT group [RT: 14.3%
Fig. 5. Post treatment percentage change in ARAT total score and sub-scores.
- - . Column: mean; whisker: stan-
dard deviation. P-value from Mann Whitney U test comparing RT and RMT
groups are reported.
(15.8%); RMT: 38.4% (21.3%); ], while a sim-
ilar improvement in both groups was noticed for execution fre-
quency of Grip [RT: 18.1% (17.8%); RMT: 21.6% (19.8%);
] and Pinch items [RT: 17.2% (20.0%); RMT:
17.8% (34.0%); ].
As concerns manual dexterity, both groups significantly im-
proved the 9 HPT score after the treatment (Table II). The per-
centage change obtained after the training was similar in both
groups [RT: 14.1% (16.3%); RMT: 12.1% (19.3%);
]. Three subjects in the RT group and five subjects in the
RMT group attained an improvement greater than 20% (the
threshold for clinical significance [32]). No subjects showed a
significant worsening.
As shown in Table II, both groups significantly reduced in-
tention tremor. A significant reduction of postural tremor was
noticed in the RMT group.
IV. DISCUSSION
The main goal of the present study was to compare the effects
of two protocols for robot-based rehabilitation of upper limb in
MS: a protocol involving reaching tasks (RT) and a protocol
requiring objects’ reaching and manipulation (RMT).
The enrolled patients did not report any adverse event in
terms of muscle aches, fatigue or increased muscle stiffness.
The results related to the whole sample of treated MS subjects
(RT and RMT groups together) confirmed those found in
previous studies and added further evidence that robot-based
training significantly improved upper limb coordination, func-
tionality and dexterity in people with MS [12]–[14], thus
representing a valid complement to traditional rehabilitation
approaches. An important question that arises from these results
is whether the observed improvements are due to the forces
generated by the robot or are just the effect of repeated move-
ments. This pilot study did not analyze this aspect, but a recent
work of Vergaro et al. [13] found that, within each session,
motor improvements were significant only after robot-assisted
trials, whereas mere exercise alone did not show any effect.
This result suggests a specific within-session effect of the robot,
CARPINELLA et al.: ROBOT TRAINING OF UPPER LIMB IN MULTIPLE SCLEROSIS
but future studies comparing robot training with unassisted
exercise are warranted to explore long term effects.
Analysis of instrumental data confirmed that MS subjects
maintained the ability to adapt to novel dynamic environments
by learning to predict the perturbations induced by the robot. In
particular the appearance of erroneous movements in opposite
direction of force , when it was unexpectedly turned off (catch
trials), suggested that MS subjects reacted to the perturbation
by learning a suitable internal model of the disturbing field
rather than resisting the perturbation by increasing their arm
stiffness through muscles co-contraction, as found also in
healthy subjects [16]. The time course of learning index
indicated that the capability to adapt was preserved
not only within each session, as found by Casadio et al.
[22], but also across training days. Similar results were found
by Tomassini et al. [33] who analyzed the learning curves
of MS subjects during the execution of a simple tracking
task. Contrarily to the protocols described by Casadio et al.
[22] and Vergaro et al. [13], which forced the subjects to
maintain an approximately constant velocity, in the present
study MS patients executed the movements at self-selected
speed. In particular, MS subjects gradually increased their
reaching velocity across sessions, thus inducing a consequent
gradual augmentation of the perturbation generated by the
robot. Despite this factor, the parameters describing motor
learning improved along the treatment, thus suggesting that
MS subjects maintain the ability to adapt to the disturbing
force, not only when it remains nearly constant [13], [22]
but also when it increases across sessions. Analysis of the
learning curves obtained in the present study revealed that
MS subjects’ adaptation mainly improved in the first part of
the treatment, with an increase of of approximately 50%
during the first four training days, followed by a further but
lower increase of about 15% during the last four sessions.
This typical asymptotic behavior of motor learning has been
found also in several studies on healthy subjects and has been
demonstrated to be associated with different mechanisms of
neural plasticity indispensable for the acquisition of new skills
(e.g., [34]). This similarity with healthy subjects suggests, in
turn, that the mechanisms of force field adaptation and brain
plasticity are preserved, at least partly, in MS patients and that,
for this reason, these subjects may benefit of adaptive trainings
which have been shown to promote neural reorganization [35].
Interestingly, the rate of adaptation was similar in both groups,
thus indicating that subjects treated with the RMT protocol
adapted to the perturbing force field similarly to patients who
underwent RT training, even though the exercises proposed
in RMT protocol were more complex and the forces were
transmitted to the forearm of the patients and not directly
to the hand as in the RT protocol. The only difference
found in RMT group was the time course of the perturbing
force amplitude, whose increase across sessions was lower
with respect to RT group. This could be ascribed to the
difficulty of the proposed functional tasks which was gradually
augmented during the training, thus limiting the increase of
hand velocity and, consequently, of the disturbing force. Despite
357
this difference, direct comparisons between the two groups,
performed separately within each training day, revealed that,
during each session, both groups were exposed to forces
of similar amplitude, thus allowing the comparison of their
performances.
Analysis of trials executed when only was turned on, re-
vealed that movements against resistance were slower and less
smooth than unperturbed reaching. This suggested that adding
a spring-like resistive component to the task actually increased
the difficulty of the exercise. Moreover, after the treatment both
groups of MS subjects improved their ability in counteracting
the resistive force . This could be ascribed not only to an im-
provement in upper limb coordination, but also to an increase in
muscle strength. Future studies should include a direct measure
of muscle force to test this hypothesis.
Analysis of the reaching trajectories performed by the
subjects during null field trials clearly showed that kinematics
of unperturbed upper limb movements significantly improved
over sessions, independently from the training protocol. In
particular, arm movements became gradually faster, smoother
and more linear, similarly in both groups. According to Fitts’
law [36], an increase in movement speed should reduce
the accuracy of the trajectory. The fact that the movements
became smoother and more linear despite the increased velocity
suggested that the improvements in arm kinematics were
actually due to a beneficial effect of the therapy for both
groups. Clinical counterpart of this result was the similar
improvement attained by the two groups in Gross sub-score
of the ARAT, which evaluates the movement of proximal
arm only. Taken together, these results suggest that adding
a manipulation component to the reaching exercise did not
limit the improvements of proximal arm function in MS
subjects. An opposite result was found by Krebs et al. [20]
on chronic stroke patients. In particular, they found that subjects
who underwent a robot-assisted whole-arm training obtained
a significantly larger improvement in wrist/hand movement
but a consistently lower increase in proximal arm function,
with respect to stroke patients treated with a robot training
involving arm transport only. The authors speculated that
stroke subjects could have focused their attention on the
hardest component of the task, that was the manipulation of
the object, relying on the assistive force generated by the
robot for the transport of the arm to the target. This was
not the case of MS patients treated in the present study, as
they did not receive an assistive force which helped them to
extend the elbow, but, rather, resistive and perturbing forces
which disturbed their movement. This training paradigm, in
turn, required the subject to actively participate not only in
the manipulation phase of the task, but also in the reaching
phase, thus promoting the active use of whole arm.
Importantly, the applied clinical tests showed that both robot-
based protocols significantly reduced intention tremor and im-
proved upper limb functionality and dexterity. A hypothesis
about tremor reduction arises from the indication that cerebellar
symptoms typical of MS (including coordination deficit and
tremor), may partly depend on the alteration of the anticipatory
358 IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 20, NO. 3, MAY 2012
(feed-forward) component of motor control and, thus, on the
reduced, although present, capability to predict the motor com-
mands required to perform a complex task [37]. The fact that
force field adaptation exercises specifically train these feed-for-
ward control mechanisms could thus explain tremor reduction.
As concerns the improvements of upper limb function, the re-
sults related to the RT group confirmed those previously found
in [12]–[14] and suggested that the effect of robot-therapy may
partly transfer to tasks more related to ADL. This could be as-
cribed to two factors. Firstly, the reduction of tremor and the
improvement of coordination between shoulder and elbow may
have improved the control of proximal arm, thus allowing a
better orientation of the hand in space, that is a fundamental
prerequisite for a correct grip. Secondly, the beneficial effect of
the adaptive training on the feed-forward control mechanisms,
strongly involved in manipulative tasks [38], could explain the
improvement observed also in distal functions not directly in-
volved in the treatment.
Interestingly, the comparison between the two groups re-
vealed that MS subjects treated with the RMT protocol obtained
a significantly higher improvement in 3-D tasks involving grasp
but not precision grip (i.e., key and pinch grip). This finding
was confirmed by instrumental results, which revealed a signif-
icant decrease in the execution time of grasp tasks only. This
could be due to different factors. First of all, precision grip
is more complex than grasp, as it requires independent finger
movements that involve fine control of the directions and mag-
nitudes of fingertip forces [38]. This aspect has been confirmed
by fMRI studies which showed that precision grip engages
different and more complex neural circuits with respect to those
involved during grasp [39]. Moreover, it has been demonstrated
that MS subjects reported more difficulties in pinch than grasp
[40]. This could be ascribed not only to motor problems, but
also to altered and/or reduced tactile sensibility [41] which can
impair the feedback control of fingertip actions mainly during
manipulation of small and light objects. On the basis of these
considerations, it could be possible that more training sessions
are necessary to obtain a further improvement in precision grip.
A second hypothetical explanation could be ascribed to the
splint of the “functional” handle, which highly reduced forearm
prono-supination movements. Possibly, this characteristic may
have facilitated the subjects during the training by reducing
the degrees of freedom to be controlled and, consequently, by
simplifying the whole motor problem to be solved. This, in turn,
may have limited the transfer of the acquired skill to the more
complex 3-D tasks measured by ARAT. A third hypothesis can
also be formulated. In particular, in the investigated protocol
the haptic device generated forces only during the reaching
phase of the tasks while the patient-robot interaction was indeed
null during the manipulation phase. Moreover such forces were
applied to the forearm/wrist and not to the fingers. This leaves
open the possibility that assistive/resistive/perturbing forces
operating directly on the hand and/or fingers (as described
for example in [42], [43]) might be a significant factor for a
further improvement in manipulation tasks and, in particular,
in precision skills.
There are some limitations that need to be addressed re-
garding the present study. Considering that no correlation was
found between the baseline clinical characteristics and the level
of post-treatment improvement, studies on a greater number
of patients are warranted to identify the MS subjects who
would mostly benefit of robot therapy and to make the results
generalizable to the entire population with MS. A second
limitation concerns the design of the “functional” handle. In
particular, future studies should include the use of wearable
sensorized robotic handles which can generate forces operating
on the distal part of the upper limb (i.e., hand and fingers) and
which can provide an objective, quantitative measurement of
hand’s movement. The third limitation concerns the parameters
and related to the forces generated by the robot, that
were maintained fixed for all subjects and during all training
sessions. Given the high variability of the symptoms typical
of MS, these parameters should be tuned on the basis of the
individual capabilities and gradually adjusted to account for
the change of performance across the training sessions. Future
studies should include automatic procedures for the fine tuning
of the exercises.
In conclusion the present pilot study confirmed that adaptive
robot training may be a useful approach to improve upper limb
kinematics and functional ability in subjects with MS. Even
though caution must be taken given the small sample size, the
present results suggested that the inclusion of a manipulation
component to the typical reaching exercise can significantly im-
prove the execution of functional tasks involving grasp. Fur-
ther larger studies including follow-up evaluations are needed to
evaluate if longer treatments, which involve the use of a wear-
able robotic handle, could induced also significant amelioration
of precision grip and if the beneficial effects of robot therapy
are maintained long-term.
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Ilaria Carpinella was born in Vigevano, Italy, in
1977. She received the M.Sc. degree in biomedical
engineering from thr Polytechnic of Milan, Milan,
Italy, in 2002, with a thesis developed at the Univer-
sity of Glasgow, Glasgow, U.K.
Since 2003, she has been a Researcher with
the Biomedical Technology Department, Don C.
Gnocchi Foundation Research Hospital, Milan, and
from 2005 to 2007 she was a Professor of electric
and electronic measures at the University of Milan.
Her main research interests include rehabilitation
engineering and robotics, motor control, and movement analysis.
Davide Cattaneo was born in Milan, Italy, in 1970.
He received the M.Sc. degree in rehabilitation sci-
ence in 2007 and the Ph.D. degree in biomedical en-
gineering in 2010.
He is Research Coordinator at the Larice Lab, Don
C. Gnocchi Foundation Research Hospital, Milan. He
has published papers on the assessment and treatment
of functional disorders in subjects with neurological
diseases using traditional and innovative instruments.
He is a reviewer for several peer-reviewed interna-
tional journals and international research institutions.
Dr. Cattaneo is a member of the European Group for Rehabilitation in Mul-
tiple Sclerosis.
360 IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 20, NO. 3, MAY 2012

Rita Bertoni was born in Milan, Italy, in 1982. She Maurizio Ferrarin (M’97) received the M.Sc. and
graduated as a Sport Scientist from the Università Ph.D. degrees in biomedical engineering.
Cattolica del Sacro Cuore in 2005 and received the He is Research Coordinator with the Biomed-
B.S. degree in physical therapy, in 2008, from the ical Technology Department, Don C. Gnocchi
University of Milan with a thesis on the robotic re- Foundation Research Hospital, Milan, Italy. He
habilitation in people with multiple sclerosis. was Professor of rehabilitation engineering at the
Since 2010, she has worked as a Physical Thera- Polytechnic of Milan (1997–2003) and, since 2003,
pist and researcher at Don Carlo Gnocchi Foundation has been a Professor of electronic bioengineering
Onlus IRCCS, Milan. at the University of Milan. His research interests
include movement analysis, FES, motor control,
rehabilitation robotics. He authored 60 full papers in
peer-reviewed journals and two books.
He is member of IFESS and a Founding Member of the Italian Society of
Clinical Movement Analysis. He served in the board of directors of IFESS
(2003–2006) and SIAMOC (2009–present).

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