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Neurophysiologie Clinique/Clinical Neurophysiology (2014) 44, 312

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ORIGINAL ARTICLE/ARTICLE ORIGINAL

Body schema building during childhood and


adolescence: A neurosensory approach
Construction du schma corporel au cours de lenfance et de
ladolescence : une approche neurosensorielle

C. Assaiante , F. Barlaam , F. Cignetti , M. Vaugoyeau

Laboratoire de Neurosciences Cognitives (UMR 7291), CNRS & Aix-Marseille Universit, Centre St-Charles,
Case B, 3, place Victor-Hugo, 13331 Marseille cedex 03, France

Received 14 October 2013; accepted 14 October 2013


Available online 30 October 2013

KEYWORDS Summary In order to perceive and act in its environment, the individuals body and its inter-
Body schema; actions with the sensory and social environment are represented in the brain. This internal
Internal representation of the moving body segments is labeled the body schema. Throughout life, body
representations; schema develops based on the sensory information used by the moving body and by its inter-
Anticipation; actions with the environment including other people. Internal representations including body
Multisensory schema and representations of the outside world develop with learning and actions throughout
integration; ontogenesis and are constantly updated based on different sensory inputs. The aim of this review
Childhood and is to present some concepts and experimental data about body schema, internal representa-
adolescence tions and updating process during childhood and adolescence, as obtained using a neurosensory
approach. From our developmental studies, it was possible to explore the slow maturation of
the sensorimotor representations by examining the anticipatory control. By manipulating pro-
prioceptive and visual information, which are at the heart of the construction of body schema,
we wished to highlight notable differences between adolescents and young adults on both a
postural and perceptual level, which conrms the late maturation of multisensory integration
for central motor control.
2013 Elsevier Masson SAS. All rights reserved.

Rsum Pour percevoir et agir dans son environnement, les caractristiques du corps de
MOTS CLS lindividu ainsi que ses interactions avec son milieu sont reprsents dans le cerveau. Cette
Schma corporel ; reprsentation interne du corps en action est appele le schma corporel. Au cours des diff-
Reprsentations rentes tapes de la vie, le schma corporel se construit sur la base des informations sensorielles
internes ; utilises par le corps en interaction dans son milieu aussi bien physique que social. Les reprsen-
Anticipation ; tations internes qui incluent la fois le schma corporel et les reprsentations du monde
extrieur, se dveloppent avec lapprentissage et lacquisition de nouvelles habilets motrices

Corresponding author.
E-mail address: christine.assaiante@univ-amu.fr (C. Assaiante).

0987-7053/$ see front matter 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.neucli.2013.10.125
4 C. Assaiante et al.

au cours de lontogense et sont constamment ractualises partir des diffrentes infor-


Intgration mations sensorielles. Le but de cette revue est de prsenter quelques concepts et rsultats
multisensorielle ; exprimentaux sur le schma corporel, les reprsentations internes et les processus de ractual-
Enfance et isation tudis au cours de lenfance et de ladolescence, selon une approche neurosensorielle.
adolescence partir de nos travaux dveloppementaux, il a t possible dexplorer la lente maturation des
reprsentations sensorimotrices ncessaires au dveloppement de la fonction danticipation.
En manipulant les informations proprioceptives et visuelles, qui sont au cur de la construction
du schma corporel, nous avons souhait mettre en avant les diffrences persistantes entre les
adolescents et les jeunes adultes aussi bien au niveau postural que perceptif qui conrment
ainsi la maturation tardive de lintgration multisensorielle au service du contrle moteur.
2013 Elsevier Masson SAS. Tous droits rservs.

Introduction Body schema from a neurosensory approach

In everyday activities, we rely on signals coming from From a neurosensory approach, the body schema is
our moving body to be able to respond to the space supramodal, relying on proprioceptive, tactile and visual
around us and react rapidly to changing circumstances. information [55]. These afferents produce primary,
The perception-action coupling theory assumes that central modality-specic, internal representations that are after-
mechanisms provide a functional link between the sen- wards fused into a unique and coherent representation
sory representations activated during the perception of an [41,53]. However, all of the above sensory modalities do not
action and the motor representations used during the plan- contribute evenly to body schema. Proprioception is likely
ning of the action [71]. From birth, one essential aspect the most important modality to body schema building,
of motricity is to achieve a fundamental adaptive func- given that it provides direct information on the position and
tion: communication. In order to perceive and act in its the dynamics of body segments [38,57,75]. As soon as 1982,
environment, the individuals body and its interactions with Paillard [66] introduced a functional distinction between
the sensory and social environment are represented in the body image, which is based on the identied body,
brain. This internal representation of the moving body seg- and body schema, which is based more on the situated
ments is labelled the body schema [26,45,55]. Body schema body. According to Paillard, proprioceptive information
is based on an internal representation of body geometry, is necessary for updating body schema, whereas extero-
its dynamics and its orientation relative to verticality, to ceptive information, mainly visual, underpins body image.
the segments in relation to each other or to the environ- Proprioceptive information is therefore predominant for
ment [45]. Although the main function of the body schema body schema, whereas visual information is predominant
is to contribute to action execution, it is also involved in for representations of the environment.
action understanding and social interactions [16,60,72,73]. Interestingly, patients suffering either peripheral neu-
These functions arise from the fact that body schema relates ropathy or Duchenne muscular dystrophy whose propriocep-
to action/perception coupling but also to environmental tive function is altered or nonexistent are characterized by
communication, so that this concept became even central alterations in body schema. As a consequence, they have
to contemporary social cognitive theories as the embodied difculties in ne motor control that requires accurately
mind theory and the theory of mind [51,73]. This cogni- estimating spatial relationships between body segments
tive aspect of the body schema is not new since Piaget [11,49]. Moreover, a direct relationship was also reported
[68] already proposed that perception of the external world between proprioception and the morphokinetic component
was based on internal representations of actions. Recent of writing [1,76], which further supports the major contri-
studies have strengthened this view, bringing evidence that bution of proprioception to spatial coding of movement, and
internal representations of action are altered in individuals thus to body schema.
with impaired social interaction in verbal and non-verbal
communication, as those with autism spectrum disorders
[43,46,56,80]. Internal representations
Throughout life, body schema develops based on the
sensory information used by the moving body and by its Computational theories of motor control have proposed
interactions with the environment including other people that the brain uses multiple internal models or internal
[24,92]. Moreover, internal representations including body representations to ensure accurate control of movements
schema and representations of the outside world develop [93]. Whenever a motor command is issued, the appropri-
with learning and actions throughout ontogenesis and are ate forward model predictor generates an estimation of
constantly updated by different sensory inputs [6]. There- the consequences of the action [96], which is integrated
fore, understanding how the body schema is built during in the planning of the action to maintain postural con-
childhood and adolescence is clearly critical, to develop a trol [30,95]. The theory of internal models stipulates that
clearer understanding of both typical and atypical cognitive specied neuronal networks link the motor commands to
motor development. the sensory signals from the moving body (forward model),
Body schema building during childhood and adolescence: A neurosensory approach 5

and the desired movements are linked to the appropri- of postural forearm stabilisation after the age of 16 years.
ate motor commands (inverse model) [25,96,98]. In this Moreover, it appears that adolescent performances do not
way, the motor prediction is optimal and reproducible for differ greatly from those of children aged 7 to 8-years-
a movement that is planned and controlled in an anticipa- old, and that they are still far from equalling those of
tory fashion. This means that the forward model possesses adults. Thus, despite the early emergence of anticipatory
a sufcient quantity of information before the movement is adjustments from the age of 3 years, feedforward control
executed to accurately predict the sensory consequences of continues to mature in late childhood and adolescence,
the motor command [31,95]. In the case of motor imagery, probably due to the slow construction of internal models
when the movement is not actually executed, the forward of action [39,79]. This development is more advanced in
model provides accurate information on the chronology of girls, suggesting that puberty has a greater inuence. The
the movement based on the motor commands predicted by updating of internal models of action and body schema as
the inverse model [67,94]. well as the development of the associated brain regions such
Postural body schema [23] may therefore enable pos- as the parietal cortex underlie the nal maturation of the
tural control to be organised in a proactive manner. This anticipatory function.
control would be achieved based on internal representa- Accordingly, the body schema matures as we grow [6,79],
tions at the interface of perception and action, such as likely making updating of internal models of action more dif-
body geometry, ground reaction force, and body orienta- cult in children than in adults. Over recent years, motor
tion in relation to the gravitational vertical. These internal imagery studies have also provided evidence of the slow
representations are constructed based on sensory informa- renement of the internal forward models of action dur-
tion that forms several reference points. Microgravity is a ing development [29]. In fact, mentally simulating actions
tool of choice to investigate the body schema in adults pertains to a category of processes similar to those that are
by transiently disturbing sensory informations and particu- involved in programming and preparing real actions; that
larly proprioceptive messages, which are determinant in the is, it reects internal forward models of volitional move-
body schema. During parabolic ights, it has been reported ments [48]. Using chronometry paradigms, studies showed
that orientation and voluntary stabilisation of the head in temporal similarities between imagined and executed move-
space during rhythmic lateral movements of the trunk per- ments (e.g., moving a puppet to a location, drawing) in
formed in microgravity and without vision could rely on body children aged 7 to 10 years, supporting the proposal that
schema, since the residual head movements could in this children already possess sophisticated internal models of
case anticipate those of the trunk [3]. A recent study inves- action [61,84]. Signicant correlations between the fea-
tigating motor imagery in microgravity [17] revealed that tures of executed hand movement and those of imagined
internal models of action do not adapt to sudden new envi- hand movements were also revealed in adolescents [18,19].
ronmental changes. In microgravity, the storage of afferent Importantly, an increase in the strength of association
information is insufcient to enable the recalibration of the between actual and imagined movements was also reported
forward model. This study shows that the modication of the from adolescence to adulthood, suggesting that internal
sensorial afferents disturbs the updating of internal models. models of action keep undergoing renement until adult-
This sheds new light on rehabilitation prospects for patients hood [18,19].
with sensorial decits.

Updating process of internal representation as


Ontogenesis of body schema and assessed from sit-to-stand in children
representation of action
Internal models need to be continually updated based on the
The building of body schema has been classically approached actions and experiences acquired by the subject in the envi-
from a psychological perspective, by examining the posi- ronment [95,97]. As body kinetics constantly change during
tion and conguration of the body as a volumetric object childhood, the representations and predictions of actions
in space. A more recent approach, including computa- made by the internal models also need to be updated. To
tional and cognitive neuroscience, gets information on examine the development of this updating process, a recent
body schema from anticipatory functioning during volun- experiment from our group consisted in modifying the sup-
tary motor action. The rst approach examines body schema port on which sit-to-stand (STS) actions were performed
using tests in which the infant/child has to point parts of (Fig. 1A). The underlying hypothesis was that motor and
his own body or of the body of other individuals [92]. A postural strategies would integrate these new constraints
main nding is that body schema is not innate but rather in order to produce the most efcient movement while
develops progressively until the age of 8. Perceptions and maintaining balance. As predicted, adults immediately inte-
beliefs concerning another body become mature later, from grated the new constraints of the support, which involved
8 to 10 years old [68,92]. The second approach focuses on a new body conguration, particularly the angle of the
the ability to anticipate postural perturbations during vol- ankle, exion-extension of the trunk at the different plan-
untary actions. Studies have evidenced that the anticipatory ning stages, postural control and performance of the task
function, which relies on internal models of action and body [7].
schema, is not fully mature at 8 years of age [78,79]. Indeed In children, although adaptations were made, they were
a recent study involving the bimanual load-lifting task [8] incomplete (Fig. 1C and D). Indeed, our results show that in
reported that the maximal elbow rotation is enhanced in contrast to the adults, the children did not decrease their
adolescents compared to adults, suggesting an improvement trunk exion when the support surface was tilted forwards
6 C. Assaiante et al.

Figure 1 A. Experimental set-up with the horizontal platform, the platform tilted 10 to the right and the platform tilted 10
forward during the sit-to-stand task. B. Medians and interquartiles of STS durations in children and adults with eyes opened (EO) or
closed (EC). C. Medians and interquartiles of trunk exion and trunk extension amplitudes in adults and children with eyes opened
(EO) or closed (EC) during the sit-to-stand task. D. Stick diagrams of the individual values of trunk orientation for the adults and
children with eyes open in the three support conditions.

during STS [21]. However, a signicant reduction in trunk Proprioception: relevant sensory information
extension was observed in both children and adults. The chil- for the development of body schema
dren only partially took into account the support constraints
when planning the STS movement, which was not sufcient
to improve their trunk vertical orientation in the upright Proprioception results from the integration of different
position. According to the ascending system described by information from joint and muscle receptors situated all
Mergner and Rosemeier [59] in their theoretical postural over body, thus contributing to the awareness of body parts,
model, the relationship between the body and the support their movement and their position. Motion sense and posi-
surface constitutes an essential reference frame for the tion sense, which dene kinaesthesia, are both involved in
CNS, based on proprioceptive and vestibular information, for postural control. Motion sense relates to the ability to detect
the internal representation of postural orientation [52] and the direction, amplitude and speed of a movement, whereas
movement [81]. In children, it is likely that this reference position sense relates to the ability to compare a nal posi-
frame is still too affected by constant morphological changes tion with an initial position, i.e. to determine if a movement
for its use to be as efcient as in adults. Similar results has been performed [37,57]. Among the receptors involved
describing partial adaptations of the internal model and an in proprioception, muscle spindle primary endings (mainly
efcient use of anticipation and posture-movement coor- involved in the detection of muscle contractions) contribute
dination have been widely reported in the developmental greatly to the sense of both limb position and movement
literature. Various studies have also emphasised that coor- [69]. It seems, however, that the central processes linked to
dination between posture and movement is slow to mature, the integration of proprioceptive information for the control
and continues to develop into the latter stages of child- of movements and positions are also different [70].
hood [5,8,39,40,44,79]. Thus, despite a partial adaptation, Muscle spindle primary endings are particularly sensi-
it appears that the updating of internal model of action is a tive to vibratory stimulations. During the transcutaneous
process that matures slowly throughout childhood. application of a vibration to the tendons or muscles at a
Body schema building during childhood and adolescence: A neurosensory approach 7

specic frequency, action potentials are emitted at a simi- of the trunk oscillations, the control of balance was ensured
lar frequency in the muscle receptors. The nerve message in adolescents, for whom no falls were recorded. The
generated is then transmitted to the central nervous sys- trunk constitutes a reference point for postural control,
tem (CNS), which interprets it as a muscle contraction. Two as much for the orientation element as for balance [58].
outcomes are then possible according to whether or not bal- Indeed, stability of the trunk and pelvis constitutes the
ance is engaged. When the participants task is to maintain main reference point prior to the acquisition of the major-
balance, the erroneous interpretation of a muscle contrac- ity of posturokinetic activities during infancy [4]. In these
tion by the CNS causes compensatory postural responses in conditions, it is particularly interesting to note that it is
the entire postural chain [74]. Tendon vibrations applied to precisely the trunk that was disturbed in the adolescents
the ankle muscles induce inclinations towards the vibrated in our study, emphasising a transient loss of reference
muscle. For example, a bilateral vibration of the Achilles point, which was probably linked to a disturbance of body
tendons, simulating a contraction of the soleus muscles and schema.
therefore a forward body tilt, brings about a backward pos-
tural correction, which results in the body being brought Illusory motion is age-sensitive
back to a balanced position by shortening the virtually
lengthened muscle [27,50,74]. However, illusory sensations
In the same developmental study [20], all the subjects
of displacement of the body or of the vibrated body part
perceived illusory motion of their feet at least once. To
have also been reported in experimental conditions where
perform the perceptual task, the participants sat with the
balance is not engaged [15,38]. Thus, muscle-tendon vibra-
eyes closed and with the vibrators placed on bilateral tib-
tion results in a kinaesthetic illusion of muscle contraction in
ialis anterior tendons. During the trial, the participants
the absence of any real movement. These studies have con-
were asked to move the right index nger on a support as
cluded that the illusions and postural responses induced by
soon as they felt an illusory foot movement, by matching
muscle-tendon vibrations are behavioural specically tested
direction and amplitude to that of the illusory movement.
[91].
After the trial, the participants had also to report on a
sheet of paper, on which was represented a range of motion
The stimulation of dynamic proprioception scale of the ankle, the maximum range of motion reached
disturbs postural control more strongly in by the ankle during the illusion, in order to also evalu-
ate the amplitude of the illusion. The amplitude of the
adolescents
illusory movement in real time was greater in adolescents
than in adults and, above all, more frequent (see top and
During adolescence, it has been reported that propriocep- down parts, Fig. 2). These results provide an initial trail
tive contributions, when they are available, are neglected for exploring the effect of age on the perception of illusory
in postural control [4,54,91]. However, it emerges from motion.
a recent study [20] that the stimulation of propriocep- If we consider that the perception of illusory motion
tive information by tendon vibrations induces a greater is a preferred means for exploring body schema and its
postural control disturbance in adolescents (aged 14 to modications during the different periods of life, it is com-
17 years) than in adults. Indeed, adolescents have a back- pletely logical to report that illusory motion is age-sensitive.
ward postural reaction, which is not only quicker, but Goble et al. [33] showed that peak proprioceptive abil-
also more pronounced throughout the vibration and even ity in the control of movements guided by proprioception
when the vibration stops. These results, which appear to is only reached at the end of adolescence. Thus, ado-
contradict the literature, can be explained by the fact lescents would nd difcult to control their movements
that the slow oscillations protocol proposed by Viel et al. just by proprioception. For the same reasons, it could be
[91], focused above all on activating the static propri- that they also nd difcult to perceive the nal illusory
oceptive information involved in the control of postural position reached by their feet, with a tendency to overes-
orientation, whereas in this study, it was mainly dynamic timate the maximal inclination reached compared to that
proprioceptive information that was stimulated and would reported by adults. These results could be linked to the fact
been more involved in the control of postural stability that the structures involved in the central integration of
[2]. dynamic proprioceptive information are not yet mature in
Indeed, the largest oscillations reported in the adoles- adolescence, which is a period of cortical maturation, par-
cents, particularly in the trunk, reveal a worse control of ticularly in the frontal and parietal regions, which are also
postural stability than in adults, regardless of the visual involved in motor function and the development of body
condition. Nevertheless, the presence of visual afferents sig- schema.
nicantly reduced oscillations in adolescents, without even
affecting the postural performances of adults. This pos-
tural instability in adolescents, which conrms the role of Perception of human movement and
dynamic proprioceptive information in the control of stabil- perception-action coupling
ity, could be interpreted as a transient decit in the central
integration of proprioceptive information. However, it is The perception of biological movements (BM) is an innate
important to note that variations in stability were especially ability that has been demonstrated in newborns [82].
pronounced in the trunk in adolescents, whereas the con- However, the perception and visual recognition of human
trol of the centre of pressure was similar to that of adults. movements (HM) develops throughout life and requires
This result suggests that in any case, despite the amplitude sensorimotor representations to enable the accurate
8 C. Assaiante et al.

Figure 2 Results from the illusory movement perception task in adolescents and adults. The upper part reports the occurrence
of illusory movements, while the lower part reports the maximum range of motion reached by the ankle during the illusion.

identication of the perceived actions. Four- to ve-month- Recognition of human movement performed
old infants with a very few motor experience can recognize with or without gravity: a developmental
both HM [10,12,28] and biological motions [71,82]. Percep-
approach
tion of HM is a robust and efcient ability of our visual system
but it has been shown that this ability is disrupted when
the HM is presented upside-down [86]. On the basis of the Based on the hypothesis that perception-action coupling
latter results, Troje and Westhoff [88] demonstrated that changes throughout ontogenesis, we recently investigated
this disruption was not caused by the loss of the human during childhood and adolescence the ability to recognize
shape but rather by the inversed orientation of the grav- human movement using a paradigm where the participants
ity vector. One study carried out by Jacobs et al. [47] tested had to discern between human movements performed with
the ability of subjects to efciently categorise possible and or without gravity [20]. Children aged 5 to 8 years, adoles-
impossible HMs. These authors discovered that the subjects cents aged 14 to 17 years and adults aged 20 to 40 years
performances were better with HM respecting the laws of participated to the study. The task was a two-alternative
body biomechanics, highlighting the close link between the forced-choice task where participants were sitting in front
visual and motor systems. In the same vein, Casile and of a computer. Specically, they had to rst look on a com-
Giese [14] tested the hypothesis of perception-action cou- puter monitor three-second silent point-light displays of a
pling by asking subjects to identify HM before and after human model performing movements (e.g. standing-up from
motor learning. The subjects carried out some of the walk- a chair, crouching, moving the arms, touching the oor
ing variations before and after learning, with their eyes from a sited position) with or without gravity, and second
closed. The results show that the subjects were better at answer as fast as possible the question whether the move-
recognising a HM when they had acquired the motor learn- ments were performed on Earth (with gravity) or in
ing required to perform it. Thus, other than an evident Space (without gravity) by pressing a button on a keyboard
motor function, body schema, through its close links with (Fig. 3A). Point-light displays were used to prevent informa-
perception-action coupling and communication with the tion not related to movement per se (e.g. facial expression,
environment, fully contributes to the cognitive processes environmental information) from inuencing perception of
enabling the actions of others and social interactions to be human movement.
interpreted [16,72]. This coupling of perception and action Similarities and differences between children, adoles-
has been widely investigated through the mirror-neuron sys- cents and adults emerged from this study. Except some
tem (MNS). Lastly, the MNS, which seems to be functional in youngest participants, all our subjects successfully cat-
six-month-old infants [65], also develops throughout child- egorised human movements performed with or without
hood and adulthood as the result of sensorimotor experience gravity. The robustness of this perceptual ability in chil-
[90]. dren is probably linked to the fact that an early sensitivity
Body schema building during childhood and adolescence: A neurosensory approach 9

Figure 3 A. Paradigm of visual recognition of human movements performed with or without gravity. After having provided an
answer to the question Is the movement performed on Earth or in Space? B. Percentage of correct answers. C. Effect of gravity
in correct answers. D. Corresponding reaction time. Data are presented as median and interquartile range in children, adolescents
and adults.

in infants to biological aspects of movement using point- structural role, ensuring functional stability, in a period
light displays was reported in the literature [10,12,28,82]. characterised by a changing body and brain [20].
Moreover, despite the absence of gravity, the presented
movements conserved all the rules of human biomechanics
and were not in any case perceived as impossible move- The body in the developing brain
ments, which could have affected the performances of our
subjects [47]. Nevertheless, percentage of correct answers Many regions in the brain are suspected of supporting the
revealed a clear developmental effect with lower perform- internal models of action, including the prefrontal cor-
ances (Fig. 3B) and higher reaction time (Fig. 3D) in children tex, the primary and premotor cortices, the supplementary
with respect to both adolescents and adults. Lastly, from 7 to motor area, the parietal cortex, the basal ganglia and
8 years of age, children, as adolescents and adults reported the cerebellum [43,61,62,98]. These regions mature dur-
similar performances whatever the human movements per- ing childhood through early adulthood, involving signicant
formed with or without gravity. By contrast, a signicant grey and white matter changes [9,36]. Moreover, stud-
difference between normo- and microgravity was reported ies on kinesthetic illusions in adults, which used tendon
in the youngest subjects (Fig. 3C). vibration paradigms, provided important insights on brain
No signicant difference was found between the per- network underlying body schema [34,35,42,63,64,70,77].
formances of adolescents and adults in either the normo- or Results revealed a complex network that includes:
the microgravity condition. This robustness of the percep-
tion of human movement during adolescence does not seem brain areas commonly involved in motor planning and
to be impaired by the changes in body schema that occur execution (e.g., motor and premotor cortices, primary
during adolescence. It emerges from our study that adoles- somatosensory cortex, supplementary motor area, cere-
cents, like adults, have similar sensorimotor performances bellum);
with regard to the items presented. Finally, the robustness higher-level regions responsible for executive functioning
of vision that appeared in adolescents in terms of the privi- and cognitive representations, including prefrontal and
leged contribution to postural control highlights its major parietal areas.
10 C. Assaiante et al.

During adolescence, height and weight increases tran- manuscript. This work was supported by grants from the
siently alter the representation of the body and, con- French National Center of Scientic Research (CNRS), the
sequently, motor control [19,91]. In addition, the brain French National Center of Space Study (CNES) and the Cotrel
undergoes one of the nal major periods of maturation, Foundation.
which has a crucial impact on the organisation of cortical
neuronal networks [13,89]. Moreover, a number of studies
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Disclosure of interest ical motion perception. Curr Biol 2006;16(1):6974.
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Acknowledgments neuroimaging study. PLoS One 2011;6(1):e15749.
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The authors are grateful to the children and adolescents environmental constraints do not update internal models of
for their precious collaboration and to Dr. Jasmine Menant action as assessed from motor imagery in adults. Neuroscience
for her helpful comments and for critically reviewing the 2012;222:6974.
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