Research in Developmental Disabilities 53–54 (2016) 73–85

Contents lists available at ScienceDirect

Research in Developmental Disabilities

Cognitive training modifies frequency EEG bands and

neuropsychological measures in Rett syndrome
Rosa Angela Fabio a,*, Lucia Billeci b, Giulia Crifaci b, Emilia Troise a,
Gaetano Tortorella c, Giovanni Pioggia d
a
Department of Cognitive Science, University of Messina, Messina, Italy
b
Department of Clinical Physiology, CNR Pisa, Pisa, Italy
c
Department of Pediatric Science, University of Messina, Messina, Italy
d
ISASI (Istituto di Scienze Applicate e Sistemi Intelligenti), CNR, Messina, Italy

A R T I C L E I N F O A B S T R A C T

Article history: Rett syndrome (RS) is a childhood neurodevelopmental disorder characterized by a

Received 13 April 2015 primary disturbance in neuronal development. Neurological abnormalities in RS are
Received in revised form 9 January 2016 reflected in several behavioral and cognitive impairments such as stereotypies, loss of
Accepted 11 January 2016
speech and hand skills, gait apraxia, irregular breathing with hyperventilation while
Available online
awake, and frequent seizures. Cognitive training can enhance both neuropsychological
and neurophysiological parameters. The aim of this study was to investigate whether
Keywords:
behaviors and brain activity were modified by training in RS. The modifications were
Rett syndrome
Cognitive training assessed in two phases: (a) after a short-term training (STT) session, i.e., after 30 min of
Electroencephalographic pattern training and (b) after long-term training (LTT), i.e., after 5 days of training.
Eye-tracking Thirty-four girls with RS were divided into two groups: a training group (21 girls) who
Neuroplasticity underwent the LTT and a control group (13 girls) that did not undergo LTT. The gaze and
quantitative EEG (QEEG) data were recorded during the administration of the tasks. A
gold-standard eye-tracker and a wearable EEG equipment were used. Results suggest that
the participants in the STT task showed a habituation effect, decreased beta activity and
increased right asymmetry. The participants in the LTT task looked faster and longer at the
target, and show increased beta activity and decreased theta activity, while a leftward
asymmetry was re-established. The overall result of this study indicates a positive effect of
long-term cognitive training on brain and behavioral parameters in subject with RS.
ß 2016 Elsevier Ltd. All rights reserved.

1. Introduction

Rett syndrome (RS) is a childhood developmental disorder whose prevalence is estimated to be 1:8000 in females
(Moretti & Zoghbi, 2006). Females are primarily affected, although a few cases of males have been reported in the literature
(Leonard et al., 2001; Cohen et al., 2002). Its etiology involves the genetic mutation of gene MECP2 on the X-chromosome
(Amir et al., 1999; Guy, Hendrich, Holmes, Martin, & Bird, 2001). RS was originally classified in the category of Pervasive
Developmental Disorders according to the DSM-IV-TR (American Psychiatric Association, 2000) and has now been removed
from the DSM-V because of its genetic etiology (APA, 2013).

* Corresponding author. Tel.: +39 90 344831.

E-mail address: rafabio@unime.it (R.A. Fabio).

http://dx.doi.org/10.1016/j.ridd.2016.01.009
0891-4222/ß 2016 Elsevier Ltd. All rights reserved.
74 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85

Its clinical features suggest that this disorder is the result of a primary disturbance of neuronal development (Johnston,
Hohmann, & Blue, 1995), perhaps resulting in maturational arrest in selected brain regions (Armstrong, Dunn, Antalffy, &
Trivedi, 1995). For example, the basis of this maturational arrest could be defective neurotransmitter systems that fail to
provide normal trophic factors (Armstrong, Dunn, Antalffy, & Trivedi, 1995; Johnston et al., 1995).
Quantitative Electroencephalography (QEEG) is currently attracting great interest due to its characterization of brain
functioning, and it is increasingly used in studies on neurodevelopmental disorders (Billeci et al., 2013; Blue Cross Blue
Shield Association, 2014). It has been found to be a relevant aid in diagnosis, evaluating heterogeneity of behavioral
disorders, treatment responses, and outcomes, among other issues.
Few studies have applied QEEG for the characterization of neurophysiological functioning in RS. In the study of
Gorbachevskaya, Bashina, Gratchev & Iznak, (2001) QEEG revealed that RS girls were characterized by higher levels of theta
activity and reduced levels of alpha and beta activity. Grachev (2001) showed that increased frontal theta activity in RT girls
was significantly positively related with earlier onset of disease, reflecting more severe damage of the frontal lobes.
Gorbachevskaya et al. (2006) successively confirmed the presence of significantly higher levels of theta activity and
decreased alpha activity in RS patients with MECP2 mutations, and showed that this pattern was particularly evident when
mutations were at the 3rd disease stage. Gorbachevskaya, Bashina, Gratchev, and Iznak (2001) also showed a modification of
EEG parameters after Cerebrolysin treatment, in particular a decrease in theta activity over all cortical regions, an increase in
beta activity, and some restoration of the occipital alpha rhythm.
Neurological abnormalities in RS are reflected in several behavioral and cognitive impairments. Cross-disciplinary studies
have been performed with the aim of defining the RS phenotype and behavioral condition (Mount, Hastings, Reilly, Cass, &
Charman, 2001, 2002; Berger-Sweeney, 2011; Gadalla, Bailey, & Cobb, 2011; Matsuishi, Yamashita, Takahashi, & Nagamitsu,
2011). Recently, technology has improved the possibility of assessing behavior and cognitive processes in girls with RS.
Baptista, Mercadante, Macedo, and Schwartzman (2006) were among the first to use eye-tracking technology during various
cognitive tasks in which the subject was asked to choose the target stimulus between a target and a distractor. Girls with RS
reported high rates of correct answers, thus suggesting that intentional gaze in girls with RS is measurable and can be used as
a way to explore their cognitive performances. Other recent studies have focused on the relationship between cognitive and
neurophysiological factors, showing that the age of onset of epilepsy and seizure frequency were strongly correlated with
neuropsychological outcomes and that the age of onset of epilepsy was inversely correlated with the ability to recognize
stimuli (Vignoli et al., 2010). Girls with RS were also found to have longer event-related potential latencies and smaller
event-related potential amplitudes than controls, suggesting slowed information processing and reduced brain activation
with advancing years (Stauder, Smeets, van Mil, & Curfs, 2006).
Although the overview of cognitive deficit in RS is not yet exhaustive or clear, girls with RS show intention and preference
regarding social and cognitive stimuli, and also seem to have the potential for learning in an intentional way (Fabio,
Giannatiempo, Antonietti, & Budden, 2009a; Fabio, Antonietti, Marchetti, & Castelli, 2009b; Fabio, Giannatiempo, Oliva, &
Murdaca, 2011). Cognitive rehabilitation in RS in the form of behavioral training based on operant conditioning principles
(Lovaas & Leaf, 1981; Smith, Klevstrand, & Lovaas, 1995), as well as in the form of intervention in the communication
(Sigafoos, Laurie, & Pennell, 1995; Watson, Umansky, Marcy, & Repacholi, 1996), have been implemented. Other
interventions have been focused on the role of the environment and of the caregiver (Burford & Trevarthen, 1997; Evans &
Meyer, 1999, 2001; Koppenhaver et al., 2001; Tortora, 2001; Ryan et al., 2004; Skoto, Koppenhaver, & Erickson, 2004) and on
the use of special programs and devices (Hetzroni, Rubin, & Konkol, 2002; Lotan, Isakov, & Merrick, 2004), including non-
verbal training aimed at teaching basic and complex emotion recognition (Antonietti, Castelli, Fabio, & Marchetti 2008) in
order to understand other people’s behavior on the basis of mental state reasoning (Antonietti, Castelli, Fabio, & Marchetti,
2002).
The underlying process of rehabilitation is linked to modifiability. Cognitive modifiability through the impact of external
conditions show previously non-existent capacities (Feuerstein, Rand, & Rynders, 1988). In a recent study Fabio, Castelli,
Antonietti, and Marchetti (2013) applied cognitive training in a single case of RS. The girl achieved adequate reading-writing
abilities, proving the validity of cognitive intervention.
Cognitive training or rehabilitation can enhance both neuropsychological and neurophysiological parameters.
Extensive research has been dedicated to understanding the neurophysiological mechanisms of cortical plasticity
(Buonomano & Merzenich, 1998; Jagadeesh et al., 2006). Several authors have shown the ability of long-term training or
behavioral intervention to alter cortical connectivity in neuropsychiatric and neuropsychological disorders using EEG. For
example Spironelli, Penolazzi, Vio, and Angrilli (2010) suggested that 6 months of phonological training might reorganize
cortical areas in dyslexic children. In another study the effect of a 3-month cognitive behavioral therapy program,
performed with children with clinical levels of externalizing behavior, was analyzed on EEGs recorded during a go/no-go
task requiring inhibitory control (Woltering, Granic, Lamm, & Lewis, 2011). More recently, Faja et al. (2012) investigated
the effect on EEG activity of expertise training with faces in adults with ASD who showed initial impairment in face
recognition.
A few studies have also demonstrated that learning or repetitive activity leaves local traces that can be detected
immediately after the performance, using EEG. For example, after 24 h of continuous performance, theta activity increases in
parieto-occipital areas after a driving video game (Hung et al., 2013), and over language-related areas after listening to
audio-books (Landsness et al., 2011). Similar traces in the spontaneous EEG could also be detected after tasks of shorter
duration. Landsness et al. (2011) showed significant changes in alpha power in resting-state EEG after a 40-min motor task
 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85 75

where subjects implicitly learned to adapt their movements to a rotated display. Moisello et al. (2013) found increased alpha
power in the occipito-parietal region after a visual task.
The general aim of the present work is to investigate – through gaze and QEEG analysis – whether cognitive training can
modify behavior and brain activity in RS. Specifically, we aimed to assess if there were modifications in gaze/QEEG measures:
a) after a short-term training session (STT), i.e., after 30 min of training and b) after long-term training (LTT), i.e., after 5 days
of training.

2. Methods

2.1. Participants

Thirty-four girls with RS, ranging from ages 5 to 36 years (mean = 13.9  8.7 years) were classified between clinical stage III
and IV (Tables 1 and 2). The sample was divided into two groups: training and control. The training group comprised 21 girls who
underwent long-term cognitive training plus the treatment as usual. The control group was composed of 13 girls who were not
subjected to such cognitive training and continued the treatment as usual. The analyses of MCP2 mutation were conducted in the
laboratories of the Istituto Auxiologico Italiano in Milan; MCP2 specific mutations of RS are presented in Table 1. All participants
were diagnosed with Rett syndrome following the guidelines established by the Criteria Work Group and mutation analysis of the
methyl-CpG binding protein 2 gene (1988). A total of 17 girls presented an epilepsy pattern. Mean age at epilepsy onset was
5.1 years (range = 1–14 years); seizures were focal in seven patients, tonic in five, generalized tonic-clonic in three, myoclonic in
one, and atonic in one. Seizures were controlled in four cases and occurred sporadically in five patients. In the other cases, epilepsy
was drug-resistant, and seizure frequency was described as monthly in two, weekly in six, and daily in one patient. Eleven girls
were on AED monotherapy and six on polytherapy.
The families of the girls were recruited by the Italian Rett Syndrome Association. Twenty-six girls were recruited in
Tuscany during a summer campus organized by the Association, seven girls were recruited in Campania, while the last girl
was recruited the Hospital of the University Hospital Messina.
Almost all of the girls came from the north, center and south of Italy. They were severely mentally retarded and were
unable to use verbal speech. All showed little or no purposeful hand use and pervasive hand stereotypies were striking. At
many different levels and if properly supported, they could have ambulated.
Subjects were randomly assigned to control (13) and experimental (21) groups. The random assignment of intervention
was made according to the Melia criteria (Melia, 2015), after subjects have been assessed for eligibility and recruited, but
before the intervention begins. Moreover, to exclude their potentially confounding influences upon the dependent variables,
a specialized psychologist carried out a general assessment on the Vineland Adaptive Behavior Scale (VABS) (Sparrow, Balla,
& Cicchetti, 1984), on the standardized test Rett Assessment Rating Scale (RARS) (Fabio, Martinazzoli, & Antonietti, 2005) and
on the Modified Raven’s Colored Progressive Matrices (Raven, 1940). Tables 1 and 2 summarize means and standard
deviation related to each scale and subscales. No statistical differences were found between the two groups at baseline.

2.2. Material

2.2.1. Functional/cognitive description of the sample

Functional scales. The Vineland Adaptive Behavior Scales are designed to support the diagnosis of intellectual and
developmental disabilities. The Scales are organized into four domains: Communication (Receptive, Expressive, Written);
Daily Living (Personal, Domestic, Community); Socialization (Interpersonal Relationships, Play and Leisure Time, Coping
Skills); and Motor Skills (Gross, Fine).
The Rett Assessment Rating Scale (RARS) is a standardized scale used to evaluate subjects with Rett syndrome (Fabio et al.,
2005). The structure of RARS is similar to that of the Childhood Autism Rating Scale (CARS), Gilliam Autism Rating Scale
(GARS), and Asperger Syndrome Diagnostic Scale (ASDS), well-known instruments devised to assess the presence/absence of
symptoms characterizing the pervasive developmental disorders included in the same nosographic category as RS. The RARS
is organized into seven domains: cognitive, sensorial, motory, emotional, of autonomy, of the typical characteristics of the
disease and of behavior. The cognitive area consists of evaluations of attention, spatial orientation, temporal orientation,
memory, eye contact, replying by smiling, shared attention, verbal communication and non-verbal communication; the
sensorial area consists of eyesight and hearing; the motor area consists of position and movement of the body, movement of
hands, scoliosis, problems in the feet; the emotional area refers to understanding emotions and the expression of emotions;
the autonomy area refers to excretive control, feeding, ability to wash and dress; the typical characteristics of the disease
area refer to mood changes, convulsions, breathing problems, hyperactivity, anxiety, aggressiveness, bruxism, rolling of the
eyes, epilepsy, aerophagia, muscular tension, feeding habits; the overall impression area refers to the general evaluation of
the symptoms of Rett syndrome (from no symptoms (1) to all the symptoms (4)).
The items in RARS were constructed following the diagnostic criteria for RS proposed by the DSM-IV-TR (American
Psychiatric Association, 2000) and recent research and clinical experience. A total of 31 items was generated as
representative of the profile of RS. Each item concerns a specific phenotype characteristic and describes four increasing levels
of severity. Each item is provided with a brief glossary explaining its meaning in a few words. Each item is rated on a 4-point
scale, where 1 = within normal limits, 2 = infrequent or low abnormality, 3 = frequent or medium-high abnormality, and
 76
Table 1
Characteristics of the RS participants.

Experimental RS Participants
group
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Age (Years) 7 21 9 16 6 11 5 22 9 36 5 5 7 5 11 12 16 30 15 8

VABS subscales

Communication 26 15 21 19 18 21 17 17 18 18 13 15 19 10 20 23 23 28 23 19 23
Daily ability 29 22 16 28 14 25 22 18 17 24 15 18 11 15 19 21 30 31 17 21 20
Socialization 41 19 21 31 21 29 21 17 30 34 15 42 35 23 43 49 30 29 24 20 24
Motor ability 29 15 12 14 18 35 14 16 6 6 7 13 8 8 10 23 7 28 29 20 15

RARS total score 56 63.5 59 76.5 69 72 48.5 / 71 66.5 / 66.5 66 60 80.5 52.5 69 49 / / /

RARS subscales
Cognitive 13 14.5 14 19 20.5 15 8.5 / 19 22.5 / 17 12.5 14.5 18 11 15 10.5 / / /
Sensory 4 3 3 6 4.5 2 2 / 2 5 / 4 4 2.5 2.5 2 5 2.5 / / /
Emotional 8 7.5 7 6.5 5.5 12 6 / 7 8.5 / 9 10 6 10.5 8 8.5 5 / / /
Autonomies 9 11 11 12 12 11 8 / 7 4 / 10 7 10 10.5 10 9 7.5 / / /
Behavior 8 10 7.5 10 11.5 12 7.5 / 9 8.5 / 10 10.5 9 12 8.5 9.5 8 / / /
Motor 7 9.5 6.5 11 8.5 7 7 / 11 10 / 8 8 8.5 10.5 5.5 11 7 / / /

Typical 4 5 7.5 9 4 10 7.5 / 12 6 / 5.5 11 7 12.5 5 8.5 6 / / /

properties

Overall 3 3 2.5 3 2.5 3 2 / 4 2 / 3 3 2.5 4 2.5 2.5 2.5 / / /

impression

Type Of c.1164–1189 R306C Mecp2 T158M C.1063 Mecp2 T158M 1079–1081 Mecp2 R270X Mecp2 T158M Mecp2 P 152 R Mecp2 T158M T158M Mecp2 Mecp2 Mecp2
Mutation Del 26 del. ACG

Control group RS Participants

1 2 3 4 5 6 7 8 9 10 11 12 13
Age (Years) 17 34 10 22 7 11 11 27 13 22 5 9 13

VABS subscales

Communication 20 12 16 12 19 10 20 17 21 12 23 19 23
Daily ability 12 11 17 22 11 15 19 13 21 21 17 21 20
Socialization 25 29 30 31 35 23 43 22 34 24 24 20 24
Motor ability 28 28 23 11 8 8 10 22 29 15 20 15

RARS Total score 49 49 71 66.5 61 60 80.5 66 56 66.5 45 67 88

R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85

RARS subscales
Cognitive 11.5 6.5 23 21.5 12.5 14.5 18 12.5 18 15.5 / / /
Sensory 1.5 2.5 2 6 4 2.5 2.5 4 9 4 / / /
Emotional 7 5 7 8.5 10 6 10.5 10 5 8.5 / / /
Autonomies 5.5 11.5 7 4 7 10 10.5 7 9 11 / / /
Behavior 8 8 9 8.5 10.5 9 12 10.5 8 10 / / /
Motor 7 7 7 10 8 8.5 10.5 8 7 9.5 / / /

Typical 6 6 12 6 11 7 12.5 11 12 5 / / /
properties

Overall 2.5 1 4 2 3 2.5 4 3 3 3 / / /

impression

Type of mutation T158M T158M Mecp2 R270X T158M Mecp2 P 152 R T158M c.1164–1189 Del 26 R306C Mecp2 Mecp2 Mecp2
 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85 77

Table 2
Means (and standard deviations) of the characteristics of the RS participants.

Experimental group Control group

Age (Years) 12.8 (8.66) 13.46 (8.51)

VABS subscales
Communication 19.15 (4.21) 17.23 (4.45)
Daily ability 20.62 (5.56) 16.98 (4.11)
Socialization 28.48 (9.40) 28.00 (6.49)
Motor ability 15.86 (8.58) 18.08 (7.91)
RARS total score 63.44 (7.82) 61.20 (11.74)
RARS subscales
Cognitive 15.67 (2.78) 19.67 (2.88)
Sensory 3.50 (1.38) 4.83 (2.38)
Emotional 7.80 (2.03) 7.14 (2.11)
Autonomies 9.36 (2.23) 7.86 (2.23)
Behavior 9.78 (1.48) 9.14 (1.46)
Motor 8.70 (1.85) 7.71 (1.11)
Typical properties 7.18 (2.82) 8.44 (2.96)
Overall impression 3.00 (0.66) 2.88 (0.99)

Raven total score 4.7 (1.82) 5.1 (1.74)

4 = strong abnormality. Intermediate ratings are possible; for example, an answer between 2 and 3 points is rated as 2.5. For
each item, the evaluator circles the number corresponding to the best description of the patient. After a patient has been
rated on all 31 items, a Total score is computed by summing the individual ratings. This Total score allows the evaluator to
identify the level of severity of RS, conceptualized as a continuum ranging from mild symptoms to heavy deficits. The RARS
was established by a standardization procedure, involving a sample of 220 patients with RS, proving that the instrument is
statistically valid and reliable. More precisely, normal distribution analyses of the scores were computed, and the mean
scores of the scale were similar to the median and the mode. Skewness and kurtosis values, calculated for the distribution of
the Total score, were 0.110 and 0.352, respectively. The distribution was found to be normal. Cronbach’s alpha was used to
determine the internal consistency for the whole scale and subscales. Total alpha was 0.912, and the internal consistency of
the subscales was high (from 0.811 to 0.934).

2.2.1.1. Cognitive measures. Raven’s Colored Progressive Matrices (Raven, 1940) are used for children aged 5 through
11 years of age and mentally and physically impaired individuals. In this study Modified Raven’s Colored Progressive
Matrices were used (Antonietti, Castelli, Fabio, Marchetti, 2003). Series A was administered to the girls and each table was
larger (42 cm  29.7 cm) than the standard CPM. Two items to be chosen were placed separately in front of the girl. Each
target was presented together with a single distractor of the standard series. Both items (target and distractor) were shown
three times and the spatial position of target and distractor was randomized. When the girl gave two consecutive and correct
answers the examiner presented the following table; when the girl replied erroneously three times, the test was interrupted.

2.2.2. Cognitive training assessment

2.2.2.1. Eye-tracking. Tobii 456 (Tobii Technology, Sweden) was used to record the subject’s visual scanning response to
visual computer screen stimulation. The device was integrated in a microcomputer with a 15-inch LCD monitor. The girl was
positioned at a distance of about 30 cm from the screen and the direction of the gaze was determined according to the Pupil
Center/Corneal Reflection Method of low-intensity infrared light. The software Passive Gaze Tracing (LC Technologies, Inc.,
Sao Paulo, Brazil) was used to generate gaze data during visual scanning.

2.2.2.2. Stimuli. The stimuli used for the eye-tracking paradigm and the training consisted of a discrimination task. The girl
had to choose between two different stimuli of the same semantic category (two animals, two fruits, two vehicles, two toys,
two objects, two emotions); the images (10  10 cm), were placed 10 cm from each other, 5 targets were presented together
with 5 distractors (targets: chick, kiwi, happy face, shoes, drum; distractors: dog, apple, sad face, bus, rackets). The examiner
asked each girl to look at the target on the screen, saying for example: ‘‘Where is the chick? Please look at the chick!’’.

2.2.2.3. EEG registration. Enobio wireless device (STARLAB, Barcelona, Spain) was used to record EEG activity. It uses a
BluetoothTM gateway and offers a high degree of unobtrusiveness (easy to use, wearable, only 65-g weight). The system
continuously recorded EEG signals over 19 channels positioned according to the 10/20 standard scheme and two references
placed on the mastoid. Signals were acquired using dry electrodes with a sample frequency of 500 Hz.
78 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85

2.3. Procedures

All the activities were performed in a setting suitable for cognitive activity with patients: all distracting stimuli were
removed so the girls were focused only on the task.
On the first day both the girls of the training and the control groups underwent the same procedure (stages A–B–A). The
procedure started with a pre-training assessment (phase A). In this stage a baseline EEG recording was performed at rest
with eyes open, without the presentation of any stimulus (10 min). Then each girl sat in front of the eye-tracker and
performed a test consisting of the discrimination task (5 min). Each item was shown five times and the spatial position of
target and distractor was randomized.
During the STT (phase B), girls learned to discriminate the images presented in the test phase, and the presentation of the
stimuli on the screen was randomized. The examiner directed the eyes of a girl toward the target and she named it (‘‘this is
the kiwi’’). The examiner directed the eyes of the girls toward the target in three ways: (a) just naming it (for example ‘‘this is
the kiwi’’), if the girl didn’t look, (b) saying its name and showing the target with a finger or making a sound near the correct
stimulus, and if again the girl didn’t look, saying its name, making a sound and keeping her head still so that she could
concentrate her gaze.
As in phase A the target was associated with the distractor of the same semantic category but during the training the
examiner provided aid and reinforcement when the girl gave a correct answer. Reinforcers were only given following a
correct answer. If the girl gave the correct answer the examiner gave her a verbal reinforcement (‘‘Great!’’, ‘‘Very good!’’). If
the girl gave an incorrect answer or did not answer at all, the examiner provided no feedback. Another reinforcement was a
multimedia cartoon shown to the girls when they looked at the correct stimulus. When the girls focused on the target
correctly five times, the examiner showed another stimulus.
Immediately after the training the same procedure as phase A was repeated (second phase A). The test with the eye-
tracker and the EEG recordings were repeated to evaluate changes induced by training.
From the second day, only the training group repeated the training for five consecutive days for about 30 min each day
(LTT). As the girl learned to discriminate the first level, a distractor of increasing difficulty was presented (Fig. 1). The first day
the target was presented with a neutral distractor, the second day it was shown with an image of a landscape with low
perceptual salience while on the third day it was associated with a distractor of the same semantic category.
[(Fig._1)TD$IG]

Fig. 1. Examples of stimuli with distractors of increasing difficulty presented to the girls in the training.
 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85 79

On the fifth day all the girls, both of the training and the control group, repeated the same procedure as that of the first day
(stages A–B–A).
The research design of the study was a group by doubly repeated measures ABA–B–ABA where the intermediate phase B
was administered only to the training group. Phase A consisted of an assessment, while phase B involved cognitive training.

2.4. Data analysis

2.4.1. Eye-tracking
Within each stimulus, a squared area of interest (AOI) around the target was defined. The size of the AOI covered a visual
field of about 19 degrees.
For each AOI, relative to each stimulus, the following parameters were computed: Fixation Length (FL), which is the
amount of time (seconds) spent by the girl when looking at the target; Fixation Count (FC), which is the number of times the
girl looks at the target, and the Time to First Fixation (TFF), which is the time spent by the girl before looking at the target for
the first time. Fixations were extracted using a threshold of 100 ms.

2.4.2. QEEG
The pre-processing of the EEG was performed in Matlab using EEGLAB (Delorme & Makeig, 2004). First the baseline was
removed from each channel. Then EEG signals were high passed at 0.5 Hz to get rid of noise from breathing and low passed at
a cutoff frequency of 50 Hz to get rid of the high frequency noise. A 50 Hz Notch filter was also applied to remove power line
interference. Signals were also visually inspected to manually remove residual artifacts. Data were then segmented into 4-s
artifact-free epochs. Quantitative analysis was performed by algorithms developed for this purpose in Matlab code. The
Power Spectral Density (PSD) was evaluated by transforming the signal from the time domain to the frequency domain using
the Welch method (Welch, 1967). PSDs were computed for each epoch and were averaged. First the absolute total power of
the signal and the absolute power of each band were computed for each electrode. The bands considered were: delta (1–
4 Hz), theta (4–7 Hz), alpha (8–13 Hz) and beta (14–29 Hz). Since absolute power values of the spectrum are highly variable
among subjects (Duffy & Als, 2012), relative powers were considered as they show less interindividual variability and are less
affected by recording condition variability among subjects and by artifacts.
Relative powers are expressed as a percentage, and were obtained by dividing the absolute power of a specific band by the
total absolute power of the spectrum. Brain Symmetry Index (BSI) (John et al., 1977; van Putten et al., 2004) was also
computed as a measure of asymmetry in spectral power between the two cerebral hemispheres. It is computed as the
difference on the EEG absolute power between homologous contralateral electrodes and is calculated as:

ðLHRHÞ
BSI ¼
ðLH þ RHÞ

where LH is the absolute power at one electrode in the left hemisphere and RH at its homologous electrode in the right
hemisphere. It is normalized between 0 (perfect symmetry) and 1 (maximal asymmetry). The BSI is calculated within each
EEG band considering the total power in left and right hemispheres (sum of all the electrodes).

2.5. Statistical analysis

Statistical analysis was performed using SPSS 20.0 for Mac. The descriptive statistics for each of the dependent variables
were examined. With reference to eye tracker parameters, FL and TFF were considered, while with reference to
neurophysiological parameters relative power at each electrode and asymmetry index, both computed in each frequency
band, were evaluated.
To address the issue of the effectiveness of STT for the eye tracking measures, we first conducted a 2 (group: LTT vs.
control)  2 (time point: pre- vs. post-STT) multivariate analyses of variance, a separate analysis for each measure, in which
time point was a repeated-measures factor. For the LTT group, pre- and post-STT measures were averaged across days 1 and
5. The dependent measures for these analyses were FL and TFF. (FC was not analyzed in this way because it was strongly
correlated with FL, r = 0.91, p < 0.001).
The issue of the effectiveness of STT for the QEEG measures was addressed in much the same way, except that for the PSD
measures, the initial analysis was a 2 (group)  2 (time point)  19 (channel) multivariate analysis, with time point and
channel as two repeated-measures factors, and for the asymmetry measures, the initial analysis was a 2 (group)  2 (time
point)  5 (band) multivariate analysis, with time point and band as the two repeated-measures factors. Again, for the LTT
group, measures were averaged across days 1 and 5.
The effectiveness of LTT was initially evaluated in much the same way as for the STT evaluations, with multivariate
analyses as above, except that the time point measures in these analyses involved only the pre-STT measures on days 1 and
5. For both STT and LTT analyses, and for both eye tracking and QEEG measures, initial multivariate analyses were followed
up with repeated-measures t-tests. Where there was no group effect and no interactions involving group, these follow-up
tests combined data across groups; where there was a group effect or an interaction involving group, they were done
separately by group.
80 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85

Bonferroni’s correction for multiple comparisons was applied (p < 0.05; p < 0.01; p < 0.001).
The alpha-level was set to 0.05 for all statistical tests. In case of significant effects, the level of significance and the effect
size are reported. The effect sizes were computed and categorized according to Cohen (1988a,b). The Greenhouse-Geisser
adjustment for non-sphericity was applied to probability values for repeated measures.

3. Results

The first aim of the study was to assess if there were modifications in eye-tacking/QEEG measure after the STT.
As regarards eye-tracking measures, multivariate analysis showed that there was no significant effect of the group or of
time of training.
As expected in both the training and control groups, TFF and FL on the target stimulus tended to remain stable,
respectively F(1, 31) = 0.93, p = 0.57 and F(1, 31) = 1.23, p = 0.33. The repeated-measures t-test showed that there were no
differences from the pre-training to the post-training test session in the the STT (Fig. 2; Table 3).
As regards QEEG measures, in the STT there was a significant effect of the time of training (F(1,85) = 6.93, p = 0.01;
d = 0.88) and of the interaction time of training  channel (F(4,18) = 4.23, p = 0.002, d = 0.76) for relative power in the alpha
band. In the beta band there was also a significant interaction of time of training  channel (F(18,58) = 2.42, p = 0.001;
d = 0.98). In delta there was a significant effect of time of training (F(1,18) = 8.85, p = 0.008; d = 0.68) and of the interaction
time of training  channel (F(6,116) = 1.85, p = 0.004; d = 0.78). In theta there was a significant effect of the time of training
(F(1,17) = 8.40, p = 0.01; d = 0.77) and of the interaction time of training  channel (F(5,85) = 3.54, p = 0.006; d = 0.75). There
was no significant effect of group for any of the bands.
Combining the two groups, the repeated-measures t-test showed that alpha significantly decreased in the left frontal
area, specifically at F3 (p = 0.007; d = 0.69) and Fz (p < 0.001; d = 0.98) and in the left parietal area, specifically at P7
(p < 0.001; d = 0.88), P3 (p = 0.001; d = 0.76) and Pz (p < 0.001; d = 0.88). Beta significantly decreased in the left frontal area,
specifically at F3 (p = 0.02; d = 0.65) and Fz (p < 0.001; d = 0.98) and in the left parietal area, specifically at P7 (p = 0.005;
d = 0.78) and P3 (p = 0.04; d = 0.58). Delta activity increased in frontal left area, specifically at Fp1 (p = 0.002; d = 0.77), F7
(p < 0.001; d = 0.63), F3 (p = 0.004; d = 0.65), Fz (p < 0.001; d = 0.77) and in parietal areas, specifically at P7 (p = 0.005;
d = 0.83), P3 (p = 0.04; d = 0.58), P4 (p = 0.01; d = 0.76), Pz (p < 0.002; d = 0.78) and P8 (p = 0.04; d = 0.56). Theta significantly
decreased in the left frontal area, specifically at Fp1 (p < 0.001; d = 0.98), F7 (p < 0.001; d = 0.97), F3 (p = 0.02) and Fz
(p < 0.001), and in the parietal area, specifically at P3 (p = 0.04), Pz (p < 0.001) and P4 (p = 0.02; d = 0.57). In addition, theta
decreased in the central left (C3, p = 0.01; d = 0.77) and occipital left (O1, p = 0.01; d = 0.76) regions.
For asymmetry in STT there was a significant effect of time of training  band (F(3,54) = 4.26, p = 0.01; d = 0.88). There was
no significant effect of the group for any of the bands.
Combining the two groups, the repeated-measures t-test showed that asymmetry significantly decreased in alpha
(p = 0.005; d = 0.84) and in beta (p = 0.02; d = 0.55) in STT. In both bands asymmetry changed from a positive value (left
asymmetry) in the pre-training phase to a negative value (right asymmetry) in the post-training phase.
The second aim of the study was to evaluate if there were modifications in eye-tacking/QEEG measure after the LTT.
As regards eye-tracking, there were significant effect of the group (TFF: F(1, 31) = 7.21, p < 0.01; d = 0.88 and FL: F(1,
31) = 5,81, p < 0.01; d = 0.88), and a significant effect of interaction group  time of training for both TFF and FL measures
(TFF: F(1, 61) = 3.74, p < 0.01; d = 0.88 and F(1, 61) = 2,78, p < 0.01, d = 0.88). As we did find a significant effect of group on
measures the repeated-measures t-test was performed separtaly for the two groups. The control group did not show a
significant difference in FL and TFF from pre-training to post-training. In the training group the FL for the target stimulus
[(Fig._2)TD$IG]

Fig. 2. Means and standard deviations of the length of fixations of each target before and after the long term empowerment (LTT).
 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85 81

Table 3
Means (and standard deviations) of the parameters of eye tracking on the correct stimulus before and after the short term training (STT) and before and after
the long term training (LTT).

STTa LTTb

Pretest Posttest Pretest Posttest

Length of fixation (in s)

Animals 0.5 (0.01) 0.50 (0.08) 0.5 (0.11) 2.98 (0.22)
Fruits 0.4 (0.12) 0.20 (0.33) 0.4 (0.60) 3.15 (0.31)
Transport 0.5 (0.60) 0.30 (0.22) 0.5 (0.21) 1.99 (0.22)
Toys 0.6 (0.12) 0.40 (0.24) 0.6 (0.33) 2.00 (0.28)
Objects 0.4 (0.32) 0.30 (0.23) 0.4 (0.11) 2.30 (1.32)
Emotions 0.6 (0.32) 0.50 (0.22) 0.6 (0.11) 2.00 (0.21)
Average 0.5 (0.13) 0.36 (0.12) 0.50(0.32) 2.40 (1.01)

Time before the first fixation (in s)

Animals 2.00 (0.01) 3.00 (0.08) 3.00 (0.01) 0.30 (0.1)
Fruits 3.10 (0.12) 2.15 (0.33) 2.10 (0.33) 0.15 (0.24)
Transport 2.50 (0.60) 2.00 (0.22) 2.40 (0.22) 1.00 (0.24)
Toys 1.80 (0.12) 2.30 (0.24) 1.70 (0.24) 0.10 (0.24)
Objects 2.40 (0.32) 2.00 (0.23) 2.40 (0.32) 1.00 (0.24)
Emotions 1.00 (0.32) 3.20 (0.22) 1.00 (0.32) 0.20 (0.24)
Average 2.13 (0.13) 2.28 (0.42) 2.13 (0.33) 0.45 (0.24)
a
In STT the means were calculated by summing the values of the day1 and day5 and dividing the total score by 2.
b
In LTT the means were calculated on the measures of the pretest of the day1 and day5.

increased from the pre-training to the post-training test sessions in the LTT (FL: p < 0.001, d = 1.82, see Fig. 4) while TFF
decreased (TFF: p < 0.001, d = 0.90, see Figs. 3 and 4).
Fig. 4 shows an example of the increased attention (length of fixation) on the target stimulus after the LTT.
Considering the QEEG modifications with LTT, there was a significant interaction time of training  channel  group for
the beta band (F(5, 72) = 4.19, p = 0.01; d = 0.82) and in the theta band (F(4,50) = 2.48, p = 0.03; d = 0.78). No other statistically
significant interaction were found for the QEEG measures.
The repeated-measures analysis showed that in the training group beta was significantly increased in the frontal right,
specifically at F4 (p = 0.02) and F8 (p = 0.03), parietal left, specifically at P7 (p = 0.03; d = 0.62) and P3 (p = 0.001; d = 0.78) and
occipital right (O2, p = 0.001; d = 0.78).
Theta was significantly decreased in the training group in the frontal left, specifically at F3 (p = 0.04; d = 0.77) and F7
(p = 0.008; d = 0.81) and the parietal region, specifically at P7 (p = 0.01; d = 0.80) and Pz (p = 0.002; d = 0.78). In the controls
group there were not statistically significant differences between pre-traing and post-training measures.
In Fig. 5 the effect of LTT on EEG relative powers is summarized.

4. Discussion

The results of this study show that long-term cognitive training can have a positive effect on behavior and
neurophysiological parameters in girls with Rett syndrome, and measurements following training on discrimination tasks
[(Fig._3)TD$IG]

Fig. 3. Means and standard deviations of the time before the first fixation of each target before and after the long term empowerment (LTT).
[(Fig._4)TD$IG]
82 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85

Fig. 4. Heat maps of fixations of one girl for one of the stimuli of the discrimination task. The image shows that while in the first day of the study, before the
training, the girl looked both at the target (drum) and at the distractor (rackets) (a), the fifth day, at the end of the long-term cognitive empowerment, the
girl looked mostly at the target (b).

increase in patients with RS. Indeed, this study showed that after STT, they decrease or remain stable in patients with RS. This
confirms the result of the studies of Vignoli et al. (2010) and Fabio et al. (2014). More precisely, in STT after a repetitive
presentation of the stimuli, girls appeared to be bored and presented an effect of habituation. Habituation, defined as the
simplest form of learning, is the decrement of a behavior in response to repeated presentations of a (typically innocuous)
stimulus (Stopfer, Chen, Tai, Huang, & Carew, 1996). In STT girls were exposed for 30 min to repetitive presentation of the
same type of discrimination task, and as in the habituation paradigm, measurements related to attention decrease. Sokolov
(1963) argued that when the habituation function appears, the rate of the change of related parameters reflects (among other
factors) the speed or efficiency of information storage. In this study, the rate of FC, FL and TFF may reflect short-term storage.
Bornstein, Pêcheux, and Lécuyer (1988) and Colombo and Mitchell (1990) also studied different measures of attention,
including fixation duration and the rate of decline in fixation duration during habituation. Their studies showed an increase
in different measures of cognitive development as the habituation paradigm took place. In our study, we observed that after
STT the length and the number of fixations on the target decreased. Indeed, after the LTT the girls became attentive to the task
and vigilant, were quicker to look at the target stimulus and looked at it longer. Neuropsychological indices showed a
decrease in the parameter TFF and increase in the parameters FL and FC.
In this study, concurrently with neuropsychological changes, neurophysiological changes appear in both LTT and STT.
Beta activity was found to decrease after STT and increased after LTT, especially in frontal and temporal regions. It is known
from the literature that beta frequency is directly correlated with sustained attention (Kamiński, Brzezicka, Gola, & Wróbel,
2012). We can hypothesize that the decrease in beta activity after STT could be a marker of diminished sustained attention

[(Fig._5)TD$IG]

Fig. 5. Means and standard deviations of the comparison of relative powers in Rett girls after versus before long term empowerment (LTT). It is evident the
increase of beta activity in the frontal, parietal and occipital regions and the decrease of theta in frontal and parietal regions.
 R.A. Fabio et al. / Research in Developmental Disabilities 53–54 (2016) 73–85 83

due to habituation. The increased beta activity after LTT might be an indication of the positive effect of training on the girls’
attention to the stimuli.
Along with the increase in beta the LTT induced a decrease in theta activity in frontal and parietal areas. The decrease in
theta was already present after STT. As outlined in the Introduction, Rett subjects are characterized by an excess of theta
activity (Gorbachevskaya et al., 2001) and the decreased index of rhythmic theta-activity is significantly correlated with
improved attention and behavioral and social activity.
Our findings agree with the study by Gorbachevskaya et al. (2001), in which the authors showed that 20 days of
Cerebrolysin (CL) treatment induced changes in EEG parameters, including decreased theta activity in all brain regions but
particularly in the frontal and central regions, and increased beta activity in the parietal region. Concurrently with
neurophysiological changes, CL treatment also had an effect on clinical outcomes, which were based on both clinicians’ and
parents’ qualitative assessments. Improvement in the clinical state included increase in behavioral activity, increased
attention level, improved gross motor function, and non-verbal social communication.
After STT we also observed an increase in delta activity and a decrease in alpha activity. As suggested [1_TD$IF]by delta activity
increases with the performance of a mental task and can be linked to attention to internal processing during the performance
of the task. Also, alpha desynchronization is an effect of mental tasks (Chen, Bin, Daly, & Gao, 2013). Moreover, changes in
delta and alpha bands are dependent on the level of task complexity (Harmony et al., 1996; Dujardin, Bourriez, & Guieu,
1995). This could be the reason why these differences are no longer evident after LTT, when the girls are trained to perform
the task, which becomes simpler for them.
Finally, the increased right asymmetry in beta and alpha bands after STT could be due to a reaction of anxiety induced by
the task. Conversely, the increase in the left hemisphere of beta activity after LTT can be associated with a fully attentive and
less anxious state, which was achieved by the girls after a week of training. This hypothesis is supported by a large number of
EEG studies, reviewed in earlier papers by Davidson (Davidson, 1992, 1995, 1998), which established that the left frontal area
is associated with more positive affect and memories, whereas the right hemisphere is more involved in negative emotions
such as anxiety.

5. Conclusion

The general aim of this study was to investigate whether training could modify behavior and brain activity in RS. The
results of the study show that it is possible: not only do behavior measurements change, as with the eye-tracking
parameters, but neurophysiological parameters, measured using QEEG analysis, change as well.
In our study, after 5 days of long-term training the girls became attentive to the task and vigilant, and they looked at the
target stimuli faster and for a longer time. Neuropsychological indices show a decrease in the TFF parameter and an increase
in the parameters FL and FC. In this study, neurophysiological and neuropsychological parameters increase and decrease
together in the same way in both long-term and short-term training.
The results of the current study suggest that cognitive training is a promising way to intervene and improve behaviors and
brain activation in patients with RS and suggest the application of this kind of tratment in clinical practise.
In the future, randomized control trials should incorporate pre and post-training neurophysiological and behavioral
assessment protocols and compare the effects of different types of cognitive training on patients’ behavior and brain activity.

Acknowledgments

We would like to thank the Italian Airett association and all the girls and their families for their willingness to participate
in this research.

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