The aim of the trial is to investigate the feasibility and efficacy of a new intensive
cognitive rehabilitation protocol in a sample of Italian patients aged 7-25 years
with congenital cerebellar diseases. For what concerns the efficacy, the aim is to
measure outcomes improvement in social prediction abilities. The hypothesis is that
the VR-Spirit rehabilitation protocol should:
1. Enhance social prediction ability resulting in better understanding of other people’s
intentions and behaviours
2. Facilitate general-domain implicit learning ability
3. Indirectly improve cognitive performance in specific domains (attention and executive
functions, memory, visuospatial abilities, sensorimotor integration)
4. Produce an amelioration of patients’ quality of life.
The study applies a single-centre, randomized active controlled trial design. Patients
are allocated to one of two groups undergoing two different rehabilitation programs
through a stratified permuted block randomization procedure (42). Age and cognitive
level (more recent available full-scale intelligent quotient, FSIQ) are chosen as
stratification factors. In particular, we consider two levels for age, corresponding
to 7.0-12.9 and ≥ 13.0 years, and three stages for cognitive level consistent with,
respectively, absence of intellectual disability (FSIQ > 80), from borderline intellectual
functioning to mild intellectual disability (80 ≥ FSIQ ≥ 61) and from mild to moderate
intellectual disability (60 ≥ FSIQ ≥ 45) (43). Doing so, 6 blocks are generated and
within each block an estimated number of 8 patients should be enrolled to achieve
and overcome the established sample size. First, participants are allocated to a block
depending on the two stratification variables. Second, patients are assigned to one
of the two interventions according to specific permuted sequence. Details of the permuted
blocks are reported in Table 1.
Table 1. Stratified permuted blocks randomization of the study.
Group 1 (S) receives the social prediction VR training for two weeks (four daily sessions
in a week). In each 1-hour session, 80 trials of the experimental program and one
of four motor games, selected among the applications available in the GRAIL, are administered;
for each weekly session, a different game is administered in random order. Group 2
(C) receives a control VR training of the same duration (two weeks, four 1-hour sessions
per week) as the experimental training; the control training involves, for each session,
a navigational game and the daily repetition of all the four games from the GRAIL
suite that are also presented, one per day, in the experimental session; the social
prediction experimental program is not presented in the control training.
Before the training (T0), a battery of neurocognitive tests from the Developmental
NEuroPSYchological Assessment 2nd edition (NEPSY-II; (44,45)) spanning different domains,
and specifically social perception abilities, are administered to all participants.
Both groups also receive a 10-minute training of how to move within the GRAIL environment
using a custom-made navigational application. Then, a pre-training evaluation through
a VR game session, based on the same paradigm of the VR experimental training but
in a different scenario, and a computer-based Action prediction task (46) are administered. Moreover, at T0, both patients and parents compile questionnaires
on quality of life (TACQOL, TNO Quality of life / LUMC, 2001; (47)) and parents also
complete the Child Behaviour Check List (CBCL;(48,49)).
In order to verify and compare the effects of the experimental and control training
sessions, at the end of the two-week training (T1) all participants are re-evaluated
with the same neurocognitive tests, the VR evaluation scenario and the Action prediction
With the aim to investigate the far transferability of the effects, a follow-up evaluation
is provided after two months (T2) with the same protocol used at T0 except the GRAIL
evaluation scenario. Details of the study design are set out in Figure 1 according
to the “Standard Protocol Items: Recommendations for Interventional Trials” (SPIRIT)
statement (50,51) (see also Additional file 1).
[Insert Figure 1 About here]
Legend: VR: Virtual Reality; NEPSY-II: Developmental NEuroPSYchological Assessment
2nd edition; WISC-IV: Wechsler Intelligence Scale for children 4th edition; CBCL: Child Behavior Check List; TACQOL: (TA) Children's Quality Of Life
Setting of the study
The rehabilitation trainings are administered in the GRAIL Lab at the Scientific Institute
(IRCCS) E. Medea (Bosisio Parini, Italy). The GRAIL system is an integrated platform
equipped with a treadmill on a motion frame, a Vicon motion-capture system (Oxford
Metrics, Oxford, UK) and a 180° cylindrical projection screen. The D-flow software
controls the relationship between the patient, the scenery and the interactive feedbacks
and stimulations. This software runs on Microsoft Windows and it was used to develop
the interactive virtual reality applications with a block diagram approach. For the
creation of the GRAIL scenes, objects and scenario were modelled separately by means
of Google SketchUp while the avatars were created by using MakeHuman and then modified
in Blender. The modelling process was first dedicated to the creation of three-dimensional
geometries and then to the application of selected materials and textures. Files generated
in SketchUp and Blender were exported in the COLLADA interchange format and then imported
into Autodesk 3ds Max software. The latter allowed to convert models in Wavefront
OBJ format and to assemble all the models created within the scenery. The whole scene
was exported in Ogre format to be used within the D-flow software: the final scene
contained the environment and the individual objects.
Two different scenes were developed specifically for this study: the “sweet stands”
environment for the pre- and post-training evaluations and the “playground” scenario
for the social prediction training. Both scenes are designed with a linear 9-meter
long path that branches into three 3-meter long streets. At the end of each branch,
one of three objects are located in a semicircle at the same distance from the starting
point: the “playground” setting includes a swing, a circular carousel and a rocking
carousel, while the “sweet stands” setting includes an ice cream, a donut and a lollipop
stand. Furthermore, four different avatars, two males and two females, were designed:
they are adolescents, clearly identifiable by body and clothing features (i.e., hair and t-shirt colours). An example of the two scenarios and of the avatars,
respectively, for the evaluation and for the training sessions, is reported in Figure
Figure 2: (A) The VR environment designed for the evaluation sessions. (B) The GRAIL
platform and the VR application running a training session; one of the avatars is
visible to the subject. (C) The four avatars used during the training session.
[Insert Figure 2 About here]
Before the beginning of the session, the patient wears two reflective markers on the
posterior superior iliac spines, that allow to trace patient’s movements and control
the virtual environment: to go faster, the patient has to move forward, to slow down
he/she has to move backward, while to turn right or left he/she has to shift the pelvis
right or left. Then, the patient come up the GRAIL system, the trainer calibrates
his/her starting position and the session can start. The patient has to reach one
of the objects in maximum 15 seconds and his/her maximum speed is 2 m/s. The avatar,
one per trial and visibly positioned next to the patient, moves towards an object,
reaching it in ten seconds. The path is not rectilinear: it is a 9-meter straight-line
trajectory and, then, it splits into three ways. After this division the speed of
the avatars equals the maximum available for the patients, so that they cannot be
surpassed anymore. When the participant reaches an object, the object is activated
providing a visual reinforcement, otherwise the event is interrupted five seconds
after the avatar has reached the object and patients are invited to try again. Furthermore,
when the participant anticipates the avatar in reaching the correct object he/she
also receives an auditory reinforcement (clapping sound), which signals the scoring
of a point in the game in addition to visual reinforcement (activation of the object).
The object reached by the avatar is always visible to the participant, for both successful
and unsuccessful trials, in order to provide information on the avatar’s preferences
that can be used in the next trial.
For each trial, the D-flow software automatically saves one raw with the following
measures in a .txt file:
duration of the trial, mean speed of the subject, speed of the subject at specific points of the path (e.g. at 0.5, 1, 9 meters from
the starting point), specific avatar, object selected by the avatar, object selected by the subjectvictory/no victoryincremental score.
At the end of the 80 trials, the D-flow automatically saves the total score of the
session in a different .txt file.
Participants are children, adolescents and young adults aged 7-25 years with congenital
cerebellar malformations and with a FSIQ greater than 45. Cerebellar malformations
refer to anatomical abnormalities affecting the vermis and/or the hemispheres not
due to acquired lesions and not associated with progressive pathologies. Though, it
is noteworthy that these patients could exhibit malformations in other cortical structures.
As an example, patients with Joubert syndrome often present with malformations of
pontine and medullary areas (52). Participants are recruited at the Child Neuropsychiatry
and Neurorehabilitation Unit of the Scientific Institute, IRCCS E. Medea. The following
exclusion criteria are adopted:
1. Severe sensorial, motor and/or behavioural problems that could interfere with the
use of GRAIL technology;
2. Being simultaneously involved in a different cognitive rehabilitation treatment,
to avoid excessive demands to children and possible interference on training adherence
3. Having been involved in a different cognitive rehabilitation treatment in the last
six months before training, to avoid confounding follow-up effects.
Parents of the eligible patients are contacted telephonically by the attending physician
and are informed about aims and methods of the protocol. Whether they agree with the
study, the intervention assignment is carried out by a research assistant (i.e., psychologist) while a member of the administrative staff newly contacts the parents
to organize the recovery. Before starting the baseline evaluation, a research assistant
provides a description of material and procedures to parents and patients and asks
them to sign an informed consent.
A neuropsychological assessment is administered at each stage of the study using the
Italian version of the NEPSY-II battery. The NEPSY-II is designed to evaluate six
different cognitive domains in children and adolescents aged 3-16 years. In our study,
we administer tests that assess visual attention and executive functions, visuo-spatial
memory and functions, sensorimotor integration and social perception skills. The Visual
attention test assesses speed and accuracy of patients in focusing and maintaining
attention on visual targets among a series of distracting stimuli. To assess executive
functions, we adopt the Inhibition test, in which participants are asked to denominate
different figures respecting diverse rules, thus inhibiting automatic responses. In
the Memory for drawing test, children are exposed for ten seconds to a table representing
drawings in diverse spatial position and then they are asked to choose the correct
stimuli in a series of cards and place them in a panel in the same position they have
seen before. The recall is asked immediately later the exposition and after 20 minutes.
The Picture and the Geometric puzzles use, respectively, concrete and abstract examples
to evaluate visual-perceptual and visual-spatial representation abilities. For sensorimotor
integration, we administer the Finger tapping test, which measures the ability to
repeat fast finger movements and maintain a motor program. To assess social perception
skills, we administer the Theory of mind and the Affect recognition tests. The first
is composed of two parts resulting in one score. In the verbal part, verbal or pictorial
descriptions of social situations are presented in order to evaluate the ability to
understand mental constructs, such as beliefs and intentions, and how other people
could have thoughts, emotions and perspectives, which might be different from ours.
Conversely, the contextual part assesses the ability to infer others’ emotion and
mental state by social context. The Affect recognition test provides a measure of
the ability to recognize affective states from emotional facial expressions using
pictures of children. Moreover, the baseline assessment includes a full cognitive
evaluation with the Wechsler Intelligence Scale for children 4th edition (WISC-IV)
to estimate IQ scores (53). Finally, we adopt a validated computer-based Action Prediction
task as an experimental outcome measure for prediction and implicit-learning abilities.
This experimental paradigm consists of a probabilistic learning task (familiarization
phase) followed by an action prediction task (testing phase). During familiarization,
participants are exposed to videos showing a child actor performing two different
grasping-actions associated with specific contextual cues and they are asked to recognize
actor’s intention. Notably, in this phase the association between contextual cues
and actions was implicitly biased with pre-established probability of co-occurrence.
During testing, the second half of the same videos is occluded and patients are asked
to predict the final outcome of the action. Since movement kinematics are ambiguous,
responses should be biased toward the contextual priors acquired during the familiarization
At the baseline (T0) and follow-up evaluations (T2) the TACQOL is administered to
parents and children. This questionnaire has been primarily designed for research
and evaluates quality of life in diverse domain: body, movements, autonomy, cognitive
abilities, sociality, positive and negative emotionality. At the same time points,
parents are asked to compile the CBCL, the most adopted questionnaire about the behaviour
of children and adolescents. This questionnaire provides scores for eight empirically-based
syndrome scales, namely aggressive behaviour, anxious/depressive symptoms, attention
problems, rule-breaking behaviour, somatic complaints, social problems, thought problems
and withdrawn. These scales are further aggregated in three main dimensions: internalizing,
externalizing and total problems.
Evaluation sessions and experimental training paradigm
Before the first evaluation session, both the experimental and the control groups
perform a short and effective navigational training with the aim to learn to navigate
within the GRAIL VR environments. Evaluation sessions and the experimental training
exploit the same logic in two different VR environments: participants compete with
four avatars to activate chosen objects before them. Considering twenty trials per
avatar, eighty trials are administered in each session. Within a session, events take
place in a pseudorandom way in respect to the pre-established probabilities. Specifically,
in each trial, one of four avatar moves from the starting point to one of the objects
with pre-established probabilities as shown in Table 2, which change in each training
and evaluation session:
Table 2. Example of Event probability in a training session with the playground setting.
With the aim to balance the association between avatars and objects, four diverse
sessions (A, B, C, D) were obtained, such that avatars’ probability of moving toward
a specific object is equally distributed across the four session. The four sessions
are randomly administered during the first week and repeated in the same order in
the second week. In a similar vein, two different evaluation sessions were generated,
changing the avatar-object associations and event sequence, and are presented, respectively,
at T0 and T1 in random order. In this way, we avoid repetition of the same events
in the two evaluation sessions in order to minimize learning effects. The order of
the two sessions is counterbalanced between patients of the same group (e.g., for
patient 1 session A at T0 and session B at T1, for patient 2 session B at T0 and session
A at T1 etc.).
At the beginning, a GRAIL therapist gives the instructions of the game to the participants,
asking them to move toward the object chosen by the avatar and activate it before
him/her to score a point. Specific features of the applications force the patients
to move according to the anticipation of the avatars’ preference rather than following
his/her movements. Indeed, the path is linear at the beginning so that participants
are not exposed to motion cues concerning avatars’ directions until the crossroad.
Moreover, they can surpass the avatar only before the fork in the path because the
speed of the avatar is exactly the maximum speed available for the players. This way,
patients are prompted to implicitly learn the probabilistic associations between the
avatar and the most chosen object, thus allowing this paradigm to evaluate and improve
the ability to form predictive models of other’s behaviour.
Every day, the experimental group is administered with one of the four diverse sessions
of the Spirit Training so that avatars’ preferences change day by day both in the
first and in the second week. Moreover, after the participants have completed the
eighty social prediction trials, they play also one of four selected games from the
GRAIL kit (see below for the description of the games).
Active control training
The control group is exposed for the same amount of time (1-hour session per day,
four sessions per week for two weeks) to sessions requiring the participants play
a navigational game, in which they have to conduct a ball out of three mazes, and
all four selected GRAIL games. The four selected games are “skiing”, “balloons shooting”,
“world soccer” and “traffic jam”. These games have been chosen because they do not
present social agents and do not require any form of prediction ability. In the “skiing”
game, participants have to do a slalom between snowmen, scoring a point when they
pass each snowman on the right side. In the “balloon shooting” game, participants
have to hit balloons appearing in a natural environment simply by pointing at them.
In the “world soccer” game, children kick a virtual ball toward a goal: they score
points when they hit targets put inside the goal. In the “traffic jam” game, participants
are in the middle of a crossroad and they have to raise the left or right foot according
to the cars’ movements.
A physical therapist specifically patented for using GRAIL technology administers
the two trainings.
Number of dropouts: number of children who renounce to complete the two-weeks trainingNumber of sessions completed per child: total number of sessions done in front of
the total number proposed of eight sessions.
To assess training feasibility:
Acceptability questionnaire: an ad hoc questionnaire completed by participants and
another one by their parents after training conclusion (T1) to assess subjective evaluation of training accessibility and efficacy. It is to note that the same questionnaires
are fulfilled by patients of the active control group and their parents.
To assess training acceptability:
Social prediction ability: performance during the pre (T0) and post-training (T1)
evaluation in the “sweet stands” scenario. On-line monitoring of participants performance during the VR social prediction training
(e.g. scores in each session, duration per trial, mean speed).Accuracy and reaction time in the testing phase of a validated pc-based Action prediction
task administered at every time point (T0, T1, T2).
Social cognition: Theory of mind Part A and B and Emotion recognition of NEPSY-II
testing battery. Implicit learning: accuracy and reaction time in the familiarization phase of an Action
prediction task.Executive functions (inhibition and flexibility): Inhibition test of NEPSY-II.Visual attention: Visual attention test of NEPSY-II.Visuospatial and visual-perceptual abilities: Geometric Puzzle and Picture Puzzle
tests of NEPSY-II.Memory: Memory for drawings test of NEPSY-II.Sensorimotor functions: Fingers-tapping of NEPSY-II.Behavioural problems: CBCL 6-18, Parent version.Overall functioning and quality of life assessed using the TACQOL questionnaire, presented
in two forms: the self-compiled and the parent-compiled one.
Secondary outcome measures:
Demographic, clinical and neuropsychological variables of the two groups of patients
are inspected through descriptive statistics. T-test and χ2 are used to assess differences between the experimental and control training groups
at baseline for continuous and categorical variables, respectively. For each outcome
measure, we calculate the change between T0 and T1 (training effect delta) and between
T0 and T2 (follow-up effect). Delta is calculated as the arithmetic difference between
the second/third time points and the first time point. The delta values of the two
groups for the primary outcome measure are compared using independent sample t-tests
(two-tailed). Multivariate analysis of variance will be used to explore differential
effects of the trainings in the secondary outcome measures.
Estimation of sample size
A final sample of 21 patients per group has been set for such a study in order to
detect a between-group difference (independent sample t-test, two tailed) between
the effects of the experimental vs. control training (T1-T0) of moderate effect size
(Cohen’s d = 0.8) with a power of 0.80 and alfa level set at 0.05. The software G
Power 3 was used for this estimation.