An Interventional Study to Improve Social Attention in Autistic Spectrum Disorder (ASD): A Brain Computer Interface (BCI) Approach
Phase: NA
Conditions: Autism Spectrum Disorder
Sponsor: University of Coimbra

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 1 
 
 
 
 
AN INTERVENTIONAL STUDY TO IMPROVE SOCIAL 
ATTENTION IN AUTISM SPECTRUM DISORDER (ASD): A 
BRAIN COMPUTER INTERFACE (BCI) APPROACH 
 
PROTOCOL VERSION NUMBER 
24.06.2015  
Sponsor: 
 
University of Coimbra (FMUC) 
 
 
Sponsor ref: 
 16482 (UC number) 
 
 
Funder: 
 
EU-FP7 
 
 
Funder ref: 
 
602186 
 
 
Ethics Committee/Board ref: 
 
Comissão de Ética - FMUC 
 
 
Trial registration no:                       NCT02445625 
 
 
 
 
This protocol has 
been authorised by: 
 
 
 
Name 
Role 
Signature 
Date 
Miguel Castelo-Branco 
PI for University of Coimbra 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 2 
 
General Information This protocol describes the ‘An interventional study to improve social 
attention in autism spectrum disorder (ASD): a Brain-Computer Interface (BCI) approach’ study, 
and provides information about procedures for entering participants. The protocol should not be 
used as a guide, or as an aide-memoire for the care of other participants. Every care has been taken 
in drafting this protocol; however, corrections or amendments may be necessary. These will be 
circulated to the local study team and the most current approved version will be available on the 
BRAINTRAIN extranet. 
 
Compliance This study will adhere to the ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (CPMP/ICH/135/95). It will be conducted in compliance with the protocol and other 
regulatory requirements as appropriate.  
The conducting of clinical trials on medicines for human use is governed by Law n.º 46/2004 of 
19 August that implements Directive 2001/20/EC of the European Parliament and of the Council of 4 
April in Portuguese legislation. In addition to the above legislation there are a series of guidelines 
covering various matters related to clinical trials which can be found in volume X of Eudralex (see 
link in PNEC portal below). To that end, and as part of the harmonised European system, the 
conducting of clinical trials in Portuguese research centres requires authorisation from INFARMED, 
I.P. (Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.) and a favourable, prior opinion 
from the CEIC (Clinical Research Ethics Committee). 
We will register our trial to http://www.pnec.pt/portal/page/portal/PORTAL_PNEC. PNEC 
portal is a forum that allows all players to work together to transform research in Portugal, through 
a strategic approach that identifies national clinical research opportunities and barriers.  All of the 
procedures described in this project have already been approved by the Ethics Committee of the 
Faculty of Medicine of the University of Coimbra. 
The ‘An interventional study to improve social attention in autism spectrum disorder (ASD): 
a Brain-Computer Interface (BCI) approach’ study is funded by the European Commission 7th 
Framework Programme for Research, Technological Development and Demonstration, and is a 
component of Work Package 4. 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 3 
Sponsor contact details: 
 
Title and name 
Sónia Pires 
Role & responsibilities in relation to trial 
Administrative 
Address 
ICNAS - Instituto de Ciências Nucleares Aplicadas 
à Saúde, University of Coimbra, Azinhaga Santa 
Comba, Celas 
Postcode 
3000- 548 Coimbra 
Tel: 
+ 351 239 488510 
Fax: 
+ 351 239 480117 
E-mail: 
icnas-lmn@uc.pt 
 
Contact details –Lead Researcher& Co-Investigators  
 
LEAD RESEARCHER 
 
Title and name 
Miguel Castelo-Branco, MD, PhD 
Role & responsibilities in relation to trial 
Principal Investigator 
Address 
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 
Postcode 
3000- 548 Coimbra 
Tel 
+ 351 239 480261 
Fax 
+ 351 239 480117 
E-mail 
mcbranco@fmed.uc.pt 
 
 
CO-INVESTIGATOR/RESEARCHERS 
 
Title and Name 
Guiomar Oliveira, MD, PhD 
Role & responsibilities in relation to trial 
Consultant of Pediatrics; Auxiliar Professor of 
Pediatrics – Faculty of Medicine, University of 
Coimbra; 
Head 
of 
Unidade 
de 
Neurodesenvolvimento e Autismo (UNDA) and 
Director of Centro de Investigação e Formação 
Clínica from Centro Hospitalar e Universitário de 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 4 
Coimbra – Hospital Pediátrico (CHUC-HP) 
Address 
UNDA-CDC-HP/CHUC Rua Doutor Afonso Romão 
Postcode 
3030 Coimbra 
Tel 
+351 239488700 ext. 11703 
E-mail 
guiomar@chc.min-saude.pt 
 
Contact Details – Study Team:  
 
Post-doctoral researcher 
 
PhD student 
Bruno Direito, PhD 
Carlos Amaral, MSc  
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 
+ 351 239 480261 
+ 351 239 480261 
+ 351 239 480117 
+ 351 239 480117 
migueldireito@gmail.com 
carlos.amaral@student.fisica.uc.pt 
 
Researcher 
 
Researcher 
João Andrade, MSc 
João Lima, MSc 
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 
+ 351 239 480261 
+ 351 239 480261 
+ 351 239 480117 
+ 351 239 480117 
joao.andrade@uc.pt 
joao.lima@uc.pt 
 
Post-doctoral researcher 
 
PhD student 
José Cecílio, PhD 
Marco Simões, MSc 
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 5 
+ 351 239 480261 
+ 351 239 480261 
+ 351 239 480117 
+ 351 239 480117 
josemcecilio@gmail.com 
msimoes@dei.uc.pt 
 
PhD student 
 
Susana Mouga, MSc 
 
IBILI, Faculty of Medicine, University of Coimbra 
(FMUC), Azinhaga Santa Comba, Celas 
 
3000- 548 Coimbra 
 
+ 351 239 480261 
 
+ 351 239 480117 
 
susana.mouga@fmed.uc.pt 
 
 
Clinical queries: 
 
 
Serious Adverse Events: 
 
 
 
 
 
 
 
 
 
 
 
Clinical queries 
Miguel Castelo-Branco (MD PhD) and Guiomar Oliveira (MD PhD). 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 6 
Table of Contents 
 
1 
Amendment History ...................................................................................................................... 11 
2 
Synopsis......................................................................................................................................... 12 
3 
Study summary & schema ............................................................................................................ 13 
3.1 
Study schema ........................................................................................................................ 13 
3.2 
Participant flow diagram ....................................................................................................... 13 
3.3 
Study summary ..................................................................................................................... 13 
4 
Introduction .................................................................................................................................. 13 
4.1 
Background ........................................................................................................................... 13 
4.2 
Rationale for current study ................................................................................................... 15 
5 
Study objective(s) .......................................................................................................................... 16 
5.1 
Primary objective(s) .............................................................................................................. 16 
5.2 
Secondary objectives ............................................................................................................ 16 
6 
Study design .................................................................................................................................. 16 
7 
Participant selection ..................................................................................................................... 16 
7.1 
Inclusion criteria .................................................................................................................... 17 
7.2 
Exclusion criteria ................................................................................................................... 17 
8 
Recruitment .................................................................................................................................. 17 
8.1 
Number of participants ......................................................................................................... 17 
8.2 
Recruitment process ............................................................................................................. 17 
8.3 
Informed consent .................................................................................................................. 17 
8.4 
Screening logs ....................................................................................................................... 17 
9 
Withdrawal & loss to follow-up .................................................................................................... 18 
10 
Intervention .............................................................................................................................. 18 
10.1 
EEG ........................................................................................................................................ 18 
10.2 
Possible undesirable effects ................................................................................................. 18 
10.3 
Intervention arms ................................................................................................................. 19 
10.4 
Brain area/s of interest ......................................................................................................... 19 
10.5 
Adherence ............................................................................................................................. 19 
11 
Outcome measures ................................................................................................................... 19 
11.1 
Primary outcome measure ................................................................................................... 19 
11.2 
Secondary outcome measures .............................................................................................. 19 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 7 
12 
Study procedures ...................................................................................................................... 22 
12.1 
Data collection ...................................................................................................................... 22 
12.2 
Screening ............................................................................................................................... 23 
12.3 
Pre-test .................................................................................................................................. 23 
12.4 
Post-test ................................................................................................................................ 23 
12.5 
Follow-up .............................................................................................................................. 23 
12.6 
Samples & storage ................................................................................................................ 23 
12.7 
Facilities & equipment .......................................................................................................... 23 
12.8 
Incidental findings ................................................................................................................. 24 
13 
Statistical considerations .......................................................................................................... 24 
13.1 
Randomisation ...................................................................................................................... 24 
13.2 
Sample size ............................................................................................................................ 24 
13.3 
Missing, unused & spurious data .......................................................................................... 24 
13.4 
Procedures for reporting deviation(s) from the original SAP ............................................... 24 
13.5 
Termination of the study ...................................................................................................... 24 
14 
Adverse Events .......................................................................................................................... 25 
14.1 
Definitions ............................................................................................................................. 25 
14.2 
Causality ................................................................................................................................ 25 
14.3 
Expectedness ........................................................................................................................ 26 
14.4 
Reporting procedures ........................................................................................................... 26 
14.4.1 
Events exempt from reporting (non-serious AEs) ......................................................... 26 
14.5 
Urgent Safety Measures (USMs) ........................................................................................... 27 
15 
Analysis ..................................................................................................................................... 27 
15.1 
Main analysis ......................................................................................................................... 27 
15.1.1 
Sub-group & interim analysis ........................................................................................ 28 
16 
Data storage & retention .......................................................................................................... 28 
17 
Study closure ............................................................................................................................. 28 
18 
Regulatory issues ...................................................................................................................... 28 
18.1 
Ethical and research governance approval ........................................................................... 28 
18.2 
Consent ................................................................................................................................. 28 
18.3 
Confidentiality ....................................................................................................................... 29 
18.4 
Indemnity .............................................................................................................................. 29 
18.5 
Trial sponsorship ................................................................................................................... 29 
18.6 
Funding ................................................................................................................................. 29 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 8 
18.7 
Audits & inspections ............................................................................................................. 29 
19 
Study/trial management ........................................................................................................... 29 
20 
Data monitoring & quality assurance ....................................................................................... 29 
20.1 
T/SSC (Trial/Study Steering Committee) ............................................................................... 30 
20.2 
IDMC (Independent Data Monitoring Committee) ............................................................... 30 
21 
Publication policy ...................................................................................................................... 30 
22 
Milestones ................................................................................................................................. 30 
23 
References ................................................................................................................................ 31 
24 
Appendices ................................................................................................................................ 33 
 
 
 
 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 9 
Glossary of abbreviations 
AE 
Adverse Event 
ASD 
Autism Spectrum Disorder 
ATEC 
Autism Treatment Evaluation Checklist 
BCI 
Brain Computer Interface 
BDI 
Beck Depression Inventory 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
EEG 
Electroencephalography 
EU 
European Union 
FEEST 
Facial Expressions of Emotion – Stimuli and Tests  
FP-7 
7th Framework Programme for Research, Technological Development & 
Demonstration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
ICH 
International Conference on Harmonization 
ISRCTN 
International Standard Randomised Controlled Trial Number 
PIS 
Patient Information Sheet 
POMS 
Profile of Mood States questionnaire 
RCT 
Randomised Controlled Trial 
SAE 
Serious Adverse Event 
SEWTU 
South East Wales Trials Unit 
SOP 
Standard Operating Procedure 
STAIC 
State/Trait Anxiety Inventory for Children 
TCQ 
Thought Control Questionnaire 
TCAQ 
Thought Control Ability Questionnaire 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 10 
USM 
Urgent Safety Measure 
VABS 
Vineland Adaptive Behaviour Scales  
WAIS-III 
Wechsler Adult Intelligence Scale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 11 
1 
Amendment History 
Amendment 
No. 
Protocol 
version 
no. 
Date 
issued 
Author(s)  
of changes 
Details of changes made 
 
V 1.0 
 
 
 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 12 
 
2 
Synopsis 
Short title 
BCI (Brain Computer Interface) Intervention in Autism (BCIAUT) 
Acronym 
BCIAUT 
Internal ref. no. 
IBILI - VB - 2015 – 01 
Study design 
SINGLE ARM WITHIN – SUBJECT “BEFORE-AFTER” DESIGN. 
Trial/study participants 
ASD (experimental) 
Planned sample size 
15 (plus 3 in case of drop outs) 
Follow-up duration 
6 months after last intervention session 
Planned 
trial/study 
period 
4 months 
Primary objective 
Increase the number/rate of responses to initiation/response to joint attention 
cues in a serious game 
Secondary objectives 
Improve general social cognition functions 
Primary endpoint 
Number/rate of responses to initiation/response to joint attention cues 
Secondary endpoints 
ATEC, Vineland Scores 
Interventions 
BCI to train joint attention mechanisms 
 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 13 
3 
Study summary & schema 
3.1 
Study schema 
 
3.2 
Participant flow diagram 
 
 
3.3 
Study summary 
Clinical research has demonstrated that ASD children have deficits in the interpretation of 
others’ intentions from gaze-direction or other social attention cues (Baron-Cohen, Baldwin, & 
Crowson, 1997; Baron-Cohen, 1989).  
The purpose of the study is to investigate whether a brain computer interface (BCI) using 
electroencephalographic (EEG)  signals can be used to train social cognition skills (in particular 
interpretation of gaze direction pointing to objects of interest) in ASD patients and whether this 
improves clinical symptoms.  
The intervention comprises seven BCI sessions spread over four months. The first four 
sessions are planned to occur weekly, and the rest monthly. In each session, the subject is asked to 
identify objects of interest based on the gaze direction of an avatar. The subject response is 
interpreted from the EEG signal (using the P300 component, as established in our previous work). 
 
4 
Introduction 
4.1 
Background 
Autism Spectrum Disorder and Joint Attention 
Autism spectrum disorder (ASD) is a severe, early-onset and life-long neurodevelopmental 
disorder with a high worldwide prevalence and a distribution of four males (M) to one female (F) 
(Baron-Cohen et al., 2009; Fombonne, 2003; Oliveira et al., 2007). ASD is characterized by deficits in 
social interaction and communication as well as by a repetitive pattern of behaviour and interests 
(American Psychiatric Association, 2013). 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 14 
 Joint attention is an early-developing social communication skill defined by the coordination 
of attention of two individuals towards a third object or event (Bakeman & Adamson, 1984). This 
skill is critical in the development of language and communication abilities later in life, and people 
with ASD show severe deficits in joint attention abilities.  
Clinical research studies proved that ASD children show a deficit in interpreting others 
intentions from gaze-direction (Baron-Cohen et al., 1997; Baron-Cohen, 1989). ASD subjects also 
demonstrated a lack of attentional modulation in a fMRI study especially evident for social stimuli 
(Bird, Catmur, Silani, Frith, & Frith, 2006). Other studies suggest that ASD patients may have deficits 
in the cognitive processing of social stimuli: impairments in exogenous orienting of attention to 
social cues but not to objects (Leekam & Moore, 2001) and reduced saliency of social 
stimuli/preference for non-social stimuli (Dawson et al., 2004; Klin, 2002; Swettenham et al., 1998). 
Altogether, this inability means they are unable to predict or understand other people’s actions 
suggesting dysfunctional social behaviours. 
Gaming and Intervention Strategies 
ASD subjects often experience discomfort with unpredictable social environments (Charlop-
Christy, Le, & Freeman, 2000). The use of computerized intervention enables the development of 
skills in a highly standardized, predictable, consistent and controlled environment. Simultaneously, it 
allows individuals to work at their own pace and ability level (Golan & Baron-Cohen, 2006). This is a 
crucial point for this population. For many years the use of technology in ASD intervention relied 
primarily on the use of videotapes for instructional video modelling (Bellini & Akullian, 2007), but 
now the potential of technology extends far beyond simple video modelling to areas such as 
interactive computer programs and virtual reality.  
Individuals with ASD often have relatively strong visual processing skills and a preference 
towards electronic media, thus it is likely that the dissemination of intervention via computer 
technology would be particularly appropriate and motivating for these individuals (Shane & Albert, 
2008). An interesting and updated review about the use of innovative computer technology for the 
development of social skills to individuals (Wainer & Ingersoll, 2011) reveals the promising potential 
of this kind of approach, in particular if realistic scenes are used. The studies mentioned in this 
review reported significant improvements in the social skills addressed, but, altogether, some 
studies did not verify the transfer of these skills to more realistic and meaningful contexts. In the 
field of joint attention, some other studies have explored methods for systematically teaching joint 
attention to children with autism (Jones, Carr, & Feeley, 2006; Koegel, Vernon, & Koegel, 2009; 
Whalen, Schreibman, & Ingersoll, 2006).  
These studies included embedding motivating social interactions into the intervention which 
effectively improved childrens’ social areas. However, the infrequent implementation of the 
protocols compromised the carryover after the end of the interventions. 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 15 
Brain-Computer Interfaces, Electroencephalography and the P300 signal 
The EEG P300 oddball signal is a well-known neural signature of attention processes for 
detection of rare items in a series of distinct stimuli types. It has been classically reported as an 
enhanced positive-going component with a latency of about 300 milliseconds and a normal scalp 
distribution over the midline electrodes (for a review see Duncan et al., 2009; Patel & Azzam, 2005; 
Polich, 2007). P300 based oddball paradigms are often used in BCI which are systems that allow 
individuals to communicate without having to use verbal or motor means of communication 
(Blankertz et al., 2010; Farwell & Donchin, 1988; Kleih et al., 2011; Mak et al., 2011; Wolpaw & 
Wolpaw, 2012). P300 can be identified even at single-trial level (high signal-to-noise ratio) allowing 
good communication speeds for BCIs. 
 
4.2 
Rationale for current study 
The main hypothesis is that training of initiation and response to joint attention cues using 
gaming/BCI interfaces can be used to improve joint attention social cognition skills in ASD 
participants. 
The BCI setup will be used to train initiation and repeated responses to a joint attention 
object. An independent game platform will be used to test whether enhanced rates of joint 
attention (initiation and responses) were achieved. 
This study aims to demonstrate that improvements in identification of social cues (and 
improvement of overall social behaviour) in subjects with ASD can be achieved using social games 
together with a BCI setup. The primary goal is to ensure increased rate of responses to joint 
attention cues. 
To evaluate the improvements, we will use a new task/realistic game that will challenge the 
detection of initiation of joint attention cues (from avatars – gaze or pointing). The number of 
correct responses (to particular objects and not to non-object parts of the scene, will be recorded).  
We will also record incorrect responses to non-pointing body gestures. Participants will be 
challenged with about 20 events per minute (one every three seconds), of variable degree of 
difficulty. Given that the experiment lasts 10 minutes, and some events are control measures, we 
will have a total of 150 test events and 50 control events. We expect that ASD subjects will be able 
to correctly report a mean of 75 of the target events, based on tailored task difficulty. 
Considering the longitudinal design proposed, with alpha 0.05, power of 80%, and 
standardized effect of 0.8 (improvement of 8 points for an estimated SD of 10 points) we would 
need 15 subjects. We will consider three additional subjects to account for drop-offs. The sample 
size calculations were performed based on a matched 2 sided paired t-test. To determine these 
values we used the G*Power tool (Faul, Erdfelder, Lang, & Buchner, 2007). The sample size 
calculations were performed under the assumption that the distribution of the mean differences is 
normal. Without the normality assumption, we would also need 15 subjects, considering a non-
parametric Wilcoxon test. 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 16 
The structure proposed for this study is the following: (1) initial eligibility screening, (2) pre-
intervention, (3) intervention process, (4) post-intervention, and (5) follow-up. 
5 
Study objective(s) 
5.1 
Primary objective(s) 
Improvement of social attention skills (training joint attention mechanisms) by increasing the 
rate of responses to joint attention cues. We expect that ASD subjects will be able to increase the 
number of target events correctly reported, based on a tailored task difficulty. 
 
5.2 
Secondary objectives 
Improvements in general aspects of social cognition (as measured by neuropsychological 
tests) derived from a generalization of the skills learned.  
 
6 
Study design 
 
Allocation: not applicable 
Endpoint Classification: Efficacy Study 
Intervention Model: Single arm 
Primary Purpose: Basic Science and clinical feasibility study 
Participants: 15 ASD subjects (plus 3 in case of drop outs) 
 
7 
Participant selection  
The eligible patients for the study should be high functioning ASD adolescents and adults. 
These participants should also meet all the following inclusion criteria and none of the exclusion 
criteria. All queries about patient eligibility should be directed to Susana Mouga before registration. 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 17 
7.1 
Inclusion criteria 
● Positive diagnostic results for ASD in: 
○ Autism Diagnostic Interview-Revised; 
○ Autism Diagnostic Observation Schedule;  
○ The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
criteria. 
 
7.2 
Exclusion criteria 
● Global Intelligence Quotient  < 80 
● Associated medical condition such as epilepsy, neurocutaneous or other genetic syndromes, 
or other usual comorbidity in ASD samples 
 
8 
Recruitment  
8.1 
Number of participants  
A total of 15 (plus 3 in case of drop outs) participants will be recruited. We expect to 
recruit one subject each three weeks. The study is expected to start on the second semester of 2015 
and last up to 82 weeks (including follow-up). 
 
8.2 
Recruitment process 
Participants will be recruited from the National Clinical Program for ASD at University of 
Coimbra. The Lead Researcher is responsible for contacting the participants. 
 
8.3 
Informed consent 
Informed Consent can be found attached in the appendices. This Informed Consent must be 
signed by each participant/legal representative before the beginning of the study. 
 
8.4 
Screening logs 
The data related to screening logs (paper format) will be kept in a secured room only 
accessible by BRAINTRAIN researchers. Additionally, data required to support analysis of the study 
will be entered and stored in an MS SQL Server database hosted on servers at Cardiff University. The 
hosting server is on a locked, secure machine room at Cardiff University. 
The database will be backed up daily and access to the database will be via secure logon 
(username and password) and restricted to named study personnel only, as detailed in the study’s 
PRA log. Each study will only see data and actions relating to their own study. 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 18 
 
9 
Withdrawal & loss to follow-up 
Participants have the right to withdraw consent for participation in any aspect of the BCI 
intervention at any time. The participant’s care will not be affected at any time by declining to 
participate or withdrawing from the study.  
If a participant initially consents but subsequently withdraws from the study, clear distinction 
must be made as to what aspect of the study the participant is withdrawing from. These aspects 
could be:   
 
Withdrawal from study intervention  
 
Withdrawal from study follow-up  
 
Withdrawal from entire study and does not want data to be used. 
A patient may withdraw or be withdrawn from the intervention for the following reasons: 
 
Withdrawal of consent for intervention by the participant 
 
Any alteration in the participants condition or circumstances which justifies the 
discontinuation of the intervention in the Investigators’ opinion  
In all instances participants who consent and subsequently withdraw should complete a 
withdrawal form or the withdrawal form should be completed on the participant’s behalf by the 
researcher/clinician based on information provided by the participant.  
 
10 
Intervention 
10.1 EEG 
During the EEG acquisition, researchers will stay in the same room as participants. 
Researchers will be able to see and monitor participant’s behaviour and their performance. The 
acquisition can be stopped at any time, should participants’ request this or researchers become 
concerned about participant’s health. 
10.2 Possible undesirable effects 
Serious adverse effects are highly unlikely. 
 
The acquisition is not painful but requires participants to remain as motionless as 
possible for up to 50 minutes. 
 
Virtual Reality setup may induce momentary dizziness. 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 19 
 
10.3 Intervention arms 
Experimental: BCI intervention 
This group will undergo seven sessions of BCI intervention. Each subject will also undergo 
neuropsychological evaluations and “Joint-attention task” before the first BCI session (week 0) and 
after the last BCI session (week 16). The first four sessions are weekly while the other three are 
monthly. The intervention will take a total of four months. 
10.4 Brain area/s of interest 
Brain areas of interest include the parietal lobe of the brain because P300 has been classically 
reported as an enhanced positive-going component with a centro-parietal scalp distribution that is 
maximal over midline scalp sites. This way EEG electrodes of BCI will be strategically placed in the 
central, parietal and occipital electrodes positions (following the international 10-20 system), 
specially over the midline positions. 
10.5 Adherence 
Adherence is defined as attending all seven BCI sessions. 
After the enrolment, the participant will be given a schedule with the sessions plan. 
Additionally, the participant or caregiver will be reminded of each session by telephone-call one 
week earlier and by message the day before. 
On the basis of following the study protocol, follow-up plan should depend on specific 
situation of participants such as avoiding the holiday or the inconvenient day. When the intervention 
is over, researchers should remind patients of the next appointment time. For eventual absent 
participants, researchers should do telephone interviews in time, ask the reason and try to 
reschedule. 
 
11 
Outcome measures 
11.1 Primary outcome measure 
The results [Number of items of social attention that a patient can accurately identify in the 
avatar’s action, e.g. looking at, pointing at] in a separate “Joint-attention task” will be the primary 
outcome measure. The experimental group will be evaluated in the pre and post evaluation time 
with this test. 
 
11.2 Secondary outcome measures 
Secondary outcomes comprise the core measures detailed in Table 1 below. 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 20 
- The results in Autism Treatment Evaluation Checklist (ATEC) [Sociability and Cognitive 
Awareness Subtests] will be one of the secondary outcome measures. The group will be evaluated in 
the pre and post evaluation time with this test. 
- The results in Vineland Adaptive Behavior Scale (VABS) [Socialization and Daily Living Skills 
Domains] will be one of the secondary outcome measures. The group will be evaluated in the pre 
and post evaluation time with this test. 
Table 1. Other BRAINTRAIN core outcomes 
Measure 
Outcomes 
Description 
Timepoint 
Demographic 
questionnaire 
Age, gender, 
education, 
SES 
  
Baseline 
Thought 
control 
questionnaire 
(TCQ)(Wells 
& 
Davies, 
1994) 
Thought 
control 
(distraction, 
punishment, 
worry; re-
appraisal; 
social 
control) 
30-item measure to 
assess effectiveness of 
strategies used for the 
control of 
unpleasant/unwanted 
thoughts 
Baseline 
Thought 
control ability 
questionnaire 
(TCAQ)(Lucia
no 
et 
al., 
2005) 
Thought 
control 
25-item measure of 
individual differences in 
perceived ability to 
control unwanted & 
intrusive thoughts 
Baseline 
Wechsler 
Adult 
Intelligence 
Scale (WAIS-
III)(Wechsler
, 1997) 
IQ 
Global intelligence/IQ 
measure 
Baseline 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 21 
Profile 
of 
Mood States 
(POMS)(Heuc
hert 
and 
McNair, 
2012) 
Anger; 
confusion; 
depression; 
fatigue; 
tension and 
vigour 
  
Pre-post 
assessment 
(each session) 
Hospital 
Anxiety 
& 
Depression 
Scale 
(HADS)(Zigm
ond 
and 
Snaith, 1983) 
Anxiety; 
depression 
24-item scale (7 
depression & 7 anxiety 
items) 
Pre-post 
assessment 
(across 
intervention) 
Beck 
Depression 
Inventory 
(BDI-II)(Beck 
et al., 1996) 
Depression 
21-item measure of 
clinical depression 
Pre-post 
assessment 
(across 
intervention) 
Autism 
Treatment 
Evaluation 
Checklist 
(ATEC) 
(Rimland and 
Edelson, 
1999) 
Autism 
Traits 
77-items: 
speech/language/commu
nication (14 items); 
sociability (20 items); 
sensory/cognitive 
awareness (18 items); 
health/physical/behaviour 
(25 items) 
Pre-post 
assessment 
(across 
intervention) 
Vineland 
Adaptive 
Behaviour 
Scales 
(VABS) 
(Sparrow 
et 
Adaptive 
Behaviour 
297 items measure of 
adaptive behaviour 
Three main domains: 
Communication (COM), 
Daily Living Skills (DLS) 
and Socialization (SOC) 
Pre-post 
assessment 
(across 
intervention) 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 22 
al., 1984) 
and total score, the 
Adaptive Behaviour 
Composite (ABC) 
Debriefing 
interview 
questionnaire 
  
Covers: strategies; 
general experience of the 
process; adverse effects; 
awareness of group 
allocation 
Post-
assessment 
(ideally each 
session) 
  
12 
Study procedures 
12.1 Data collection 
Each BCI session consists of selecting targets of social cues through an oddball paradigm 
designed in a virtual reality scenario. The BCI virtual reality scenario will be presented via Oculus Rift 
DK2. The EEG acquisition will be made via EEG electrodes placed on participant’s head using an EEG 
cap. The task was initially thought to be based on mentally counting how many times a virtual 
human character directs its attention (gaze) to a specific object in the scene. Based on a pilot study 
the task is to mentally count the blinks of the object to which the virtual human character directed 
its attention (gaze) at the beginning of each run. The computer reads/stores the EEG signal and 
detects if the subject was counting the correct object via detection of P300 elicited by the target 
object blink. Each session is composed by the following steps: 
● Subject and BCI setup preparation (10 minutes) 
○ 
Explain the task to participant; 
○ 
Place the cap with electrodes on participant’s head; 
○ 
Check EEG signal quality. 
● Data Acquisition (up to 40 minutes) 
○ 
BCI Training phase - ~ 20 minutes; 
○ 
BCI Testing – 5 minutes (single trial classification) to 20 minutes (ten trials 
classification). The number of trials needed to validate depends on a predefined accuracy 
(equal for every subject).  Subjects may need different number of trials to achieve this 
accuracy, thus the higher the number of trials, the longer the experiment is. The task 
consists in the presentation of 50 target events 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 23 
The sessions will be controlled by the EEG technician responsible for the BCI interventions of 
the BrainTrain research team at UCo. 
All data collected from training and testing phases will be stored in digital format inside the 
stimulation machine. Upon concluded the session, data will be copied into a hard-drive for posterior 
analysis. 
Stored data will be processed and analysed by the BrainTrain research team at UCo. 
Personal identification of each participant will be hidden. Unique ID will be used to identify 
each participant’s data for the whole course of the clinical trial and future references. 
 
12.2 Screening 
Not applicable. 
 
12.3 Pre-test 
The experimental group will undergo an initial diagnostic and neuropsychological evaluation, 
followed by a customized “Joint-attention” assessment test and Autism Treatment Evaluation 
Checklist (ATEC) [Sociability and Cognitive Awareness Subtests], Vineland Adaptive Behaviour Scale 
(VABS) [Socialization and Daily Living Skills Domains].  
 
12.4 Post-test 
Once concluded the intervention, the group performs the a posteriori evaluation, to assess 
the hypothesized improvements on the measures, as compared to pre-test assessment. 
 
12.5 Follow-up 
We will perform a final follow-up 6 months after the intervention. Not applicable otherwise. 
 
12.6 Samples & storage 
Not applicable. 
 
12.7 Facilities & equipment 
BCI sessions will be carried out in spacious and quiet room with minimal electrical 
interference. The room must have at least one table and one chair. 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 24 
The BCI acquisition module consists of a cap with eight active electrodes that will be placed in 
the head of participant. The electrodes are connected to g.tec amplifier that sends the data 
wirelessly for the computer. 
The computer contains the data processing module (Matlab) and the virtual-reality module 
(Vizard). 
The BCI loop is closed with the Oculus Rift DK2 (Oculos VR, Inc), placed on participant’s head.  
 
12.8 Incidental findings 
Not applicable. 
 
13 
Statistical considerations 
13.1 Randomisation 
Not Applicable 
 
13.2 Sample size 
Considering the longitudinal design proposed, with alpha 0.05, power of 80%, and standardized effect of 0.8 
(improvement of 8 points for and estimated SD of 10 points) we would need 15 subjects (plus 3 in case of drop 
outs). We will add three additional subjects to account for drop-offs. The sample size calculations were 
performed based on a matched 2 sided paired t-test. To determine these values we used the G*Power tool 
(Faul et al., 2007). The sample size calculations were performed under the assumption that the distribution of 
the mean differences is normal. Similarly, without the normality assumption, we would also need 15 subjects, 
considering a non-parametric Wilcoxon test. 
 
13.3 Missing, unused & spurious data 
Detail provided in the Statistical Analysis Plan (SAP). 
 
13.4 Procedures for reporting deviation(s) from the original SAP 
These will be submitted as substantial amendments where applicable and recorded in 
subsequent versions of the protocol and SAP. 
 
13.5 Termination of the study 
Reasons for early termination of the study include unexpected, unacceptable side effects.  
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 25 
14 
Adverse Events 
14.1 Definitions 
Adverse Event (AE): Any untoward medical occurrence in a participant which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable 
and unintended sign (including abnormal laboratory finding), symptom, or disease.  
 
Serious Adverse Event (SAE): Any adverse event that:  
• Results in death  
• Is life-threatening*  
• Required hospitalisation or prolongation of existing hospitalisation**  
• Results in persistent or significant disability or incapacity  
• Consists of a congenital anomaly or birth defect  
• Other medically important condition ***  
* Note: The term “life-threatening” in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
** Note: Hospitalisation is defined as an inpatient admission, regardless of the length of stay, 
even if the hospitalisation is a precautionary measure, for continued observation. Pre-planned 
hospitalisation e.g. for pre-existing conditions which have not worsened or elective procedures does 
not constitute an adverse event.  
*** Note: other events that may not result in death are not life-threatening, or do not require 
hospitalisation may be considered as a serious adverse event when, based upon appropriate medical 
judgement, the event may jeopardise the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  
 
14.2 Causality 
The assignment of causality should be made by the Investigator responsible for the care of the 
participant.  
Table 2. Causality 
Relationship 
Description 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 26 
Unrelated 
There is no evidence of any causal relationship with the study or 
intervention.  
Unlikely 
There is little evidence to suggest there is a casual relationship (e.g. 
the event did not occur within a reasonable time after intervention) 
with the study or intervention. There is another reasonable 
explanation for the event (e.g. the participant’s clinical condition, 
other treatment). 
Possible 
There is some evidence to suggest a causal relationship with the study 
or intervention (e.g. because the event occurs within a reasonable 
time after intervention). However, the influence of other factors may 
have contributed to the event (e.g. the participant’s clinical condition, 
other treatments). 
Probable 
There is evidence to suggest a causal relationship and the influence of 
other factors is unlikely. 
Definite 
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out. 
Not 
assessable 
There is insufficient or incomplete evidence to make a judgement of 
the causal relationship. 
 
14.3 Expectedness 
The assessment of whether or not an SAE is an expected consequence of receiving the 
intervention will be provided by the Lead Researcher.  
Depending on the nature of the event, the reporting procedures outlined in this protocol 
should be followed. Any queries concerning adverse event reporting should be directed to Miguel 
Castelo-Branco - Principal investigator. 
 
14.4 Reporting procedures 
14.4.1 Events exempt from reporting (non-serious AEs) 
All such events, whether expected or not, should be recorded on the relevant case report 
form. 
An SAE form should be completed for all SAEs within 24 hours. Events exempt from SAE 
reporting are set out in Table 2 and information relating to them should instead be captured on the 
relevant CRF. 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 27 
Table 3. Adverse Events exempt from reporting 
Adverse Event 
Information 
Nausea 
Immersive Virtual Reality setup may induce momentary nausea 
to the participants. 
Discomfort 
EEG cap and electrodes, as well as Virtual Reality setup may 
cause discomfort to the participants 
 
Additional information should be sent within 5 days if the event has not resolved at the time 
of reporting. All events should be followed up through to resolution.  
In the case of serious, unexpected and related adverse events, the procedures will be taken as 
referred in the Informed Consent Form. This document can be found attached in the appendices. 
 
14.5 Urgent Safety Measures (USMs) 
An urgent safety measure is an immediate change in a trial procedure or temporary halt to a 
trial procedure, put in place prior to approval in order to protect participants from any immediate 
hazard to health and safety following new safety information (SAE or other information received 
from an external source). The Principal Investigator may carry out USMs to protect participants from 
immediate harm. 
 
15 
    Analysis 
15.1 Main analysis 
A priori, we will analyse the data normality. Considering a normal distribution of the mean 
differences, the main analysis will consist on a t-test on the means - difference between two 
dependent means (matched pairs). 
 The null hypothesis of this test is that the means µx, µy of pre- and post- intervention, 
respectively, are identical.  
The null hypothesis that µx = µy can be reformulated in terms of the difference di = xi - yi. The 
null hypothesis is then given by µd = 0. The alternative hypothesis states that µd has a value different 
from zero:  
H0 : µd = 0  
H1 : µd  ≠ 0  
However, without the normality assumption, we will consider a non-parametric Wilcoxon test. 
Further details will be found in the SAP 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 28 
 
15.1.1 Sub-group & interim analysis 
Not applicable. 
 
16 
Data storage & retention 
Data collected on paper will be kept in a secured room only accessible by BRAINTRAIN 
researchers, for a minimum period of 5 years after publication. 
Data required to support analysis of the study will be entered and stored in an MS SQL Server 
database hosted on servers in a secure machine room at Cardiff University. This room is locked and 
entry is via a swipe card system. 
The database will be backed up daily and access to the database will be via secure logon 
(username and password) and restricted to named study personnel only, as detailed in the study’s 
PRA log. 
 
17 
Study closure 
The trial will end up to 82 weeks after its start. 
 
18 
Regulatory issues 
18.1 Ethical and research governance approval 
The study will be conducted in accordance with the recommendations for physicians involved 
in research on human participants adopted by the 18th World Medical Assembly, Helsinki 1964 and 
later revisions. 
Ethical approval for this study was given by the Ethical Committee of the Faculty of Medicine 
of University of Coimbra. Research governance approval (granted by CEIC/Infarmed) will be sought 
after document approval. 
 
18.2 Consent 
Consent will only be considered informed following provision of adequate participant 
information (see attached information sheet/s and consent form). Participants will be informed that 
they are free to withdraw at any time and that this will not impact on current or future care. 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 29 
18.3 Confidentiality 
Data Confidentiality is assured as stated in the Informed Consent form, according with the 
Portuguese data protection regulations as per the EU directive. This document can be found 
attached in the appendices. 
 
18.4 Indemnity 
Although not expected due to the participation, if the subject suffers any injury as a result of 
any study procedures, performed according to the protocol, the subject will be reimbursed for 
medical expenses necessary to treat them. All procedures are reviewed by staff and all incidents 
reported to the persons and / or entities. 
 
18.5 Trial sponsorship 
Faculty of Medicine of University of Coimbra. 
 
18.6 Funding 
The ‘An interventional study to improve social attention in autism spectrum disorder (ASD): 
a brain computer interface (BCI) approach’ study is funded by the European Commission 7th 
Framework Programme for Research, Technological Development and Demonstration. 
 
18.7 Audits & inspections 
The study may be participant to inspection and audit by CEIC/Infarmed. 
 
19 
Study/trial management 
LBIM (Laboratory of Biostatistics and Medical Informatics of the Faculty of Medicine of 
University of Coimbra) will manage the study. 
We will keep, weekly project team meetings, monthly study management group meetings. 
These meetings will be attended by researchers directly involved in running the study. 
 
20 
Data monitoring & quality assurance 
LBIM (Laboratory of Biostatistics and Medical Informatics of the Faculty of Medicine of 
Coimbra) will manage the quality of the study. 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 30 
20.1 T/SSC (Trial/Study Steering Committee) 
The TSC/SSC will be established centrally for the BRAINTRAIN consortium and include external 
clinical and methodological experts, at least one service user and an independent statistician. 
Members will be required to sign up to the remit and conditions as set out in the TSC Charter. 
20.2 IDMC (Independent Data Monitoring Committee) 
The nature of this study makes it unlikely that a separate Data Monitoring Committee (DMC) 
will be required; however, this will be discussed with the TSC at their first meeting and a DMC will be 
set up if deemed necessary. Members will be required to sign up to the remit and conditions as set 
out in the DMC Charter. 
 
21 
Publication policy 
The Publication Policy is detailed in <<document title>> and can be found on the BRAINTRAIN 
extranet <<file location>>. 
 
 
22 
Milestones 
Table 4. Milestones 
 
 
 
 
TASK 
START 
DURATION Months 
  
  
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 
Recruiting 
1 
5 
 
 
Intervention 
2 
15 
 
 
Follow-up 
8 
15 
 
 
 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 31 
23 
References 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th 
ed.). Arlington, VA: American Psychiatric Association. 
Bakeman, R., & Adamson, L. B. (1984). Coordinating attention to people and objects in mother-infant 
and peer-infant interaction. Child Development, 55(4), 1278–89. 
Baron-Cohen, S. (1989). Perceptual role taking and protodeclarative pointing in autism. British 
Journal of Developmental Psychology. 
Baron-Cohen, S., Baldwin, D. A., & Crowson, M. (1997). Do children with autism use the speaker’s 
direction of gaze strategy to crack the code of language? Child Development, 68(1), 48–57. 
Baron-Cohen, S., Scott, F. J., Allison, C., Williams, J., Bolton, P., Matthews, F. E., & Brayne, C. (2009). 
Prevalence of autism-spectrum conditions: UK school-based population study. The British 
Journal of Psychiatry : The Journal of Mental Science, 194(6), 500–9. 
doi:10.1192/bjp.bp.108.059345 
Bellini, S., & Akullian, J. (2007). A Meta-Analysis of Video Modeling and Video Self-Modeling 
Interventions for Children and Adolescents with Autism Spectrum Disorders. Exceptional 
Children, 73(3), 264–287. doi:10.1177/001440290707300301 
Bird, G., Catmur, C., Silani, G., Frith, C., & Frith, U. (2006). Attention does not modulate neural 
responses to social stimuli in autism spectrum disorders. NeuroImage, 31(4), 1614–24. 
doi:10.1016/j.neuroimage.2006.02.037 
Blankertz, B., Tangermann, M., Vidaurre, C., Fazli, S., Sannelli, C., Haufe, S., … Müller, K.-R. (2010). 
The Berlin Brain-Computer Interface: Non-Medical Uses of BCI Technology. Frontiers in 
Neuroscience, 4(December), 198. doi:10.3389/fnins.2010.00198 
Charlop-Christy, M. H., Le, L., & Freeman, K. A. (2000). A Comparison of Video Modeling with In Vivo 
Modeling for Teaching Children with Autism. Journal of Autism & Developmental Disorders, 
30(6), 537. Retrieved from 
http://search.ebscohost.com/login.aspx?direct=true&db=a9h&AN=11305563&site=ehost-
live&scope=site 
Dawson, G., Toth, K., Abbott, R., Osterling, J., Munson, J., Estes, A., & Liaw, J. (2004). Early social 
attention impairments in autism: social orienting, joint attention, and attention to distress. 
Developmental Psychology, 40(2), 271–83. doi:10.1037/0012-1649.40.2.271 
Duncan, C. C., Barry, R. J., Connolly, J. F., Fischer, C., Michie, P. T., Näätänen, R., … Van Petten, C. 
(2009). Event-related potentials in clinical research: guidelines for eliciting, recording, and 
quantifying mismatch negativity, P300, and N400. Clinical Neurophysiology : Official Journal of 
the International Federation of Clinical Neurophysiology, 120(11), 1883–908. 
doi:10.1016/j.clinph.2009.07.045 
Farwell, L. A. a, & Donchin, E. (1988). Talking off the top of your head: toward a mental prosthesis 
utilizing event-related brain potentials. Electroencephalography and Clinical Neurophysiology, 
70(6), 510–23. doi:10.1016/0013-4694(88)90149-6 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 32 
Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: a flexible statistical power 
analysis program for the social, behavioral, and biomedical sciences. Behavior Research 
Methods, 39(2), 175–191. doi:10.3758/BF03193146 
Fombonne, E. (2003). Epidemiological surveys of autism and other pervasive developmental 
disorders: an update. Journal of Autism and Developmental Disorders, 33(4), 365–82. 
Golan, O., & Baron-Cohen, S. (2006). Systemizing empathy: teaching adults with Asperger syndrome 
or high-functioning autism to recognize complex emotions using interactive multimedia. 
Development and Psychopathology, 18(2), 591–617. doi:10.1017/S0954579406060305 
Jones, E. A., Carr, E. G., & Feeley, K. M. (2006). Multiple Effects of Joint Attention Intervention for 
Children With Autism. Behavior Modification , 30 (6 ), 782–834. Retrieved from 
http://bmo.sagepub.com/content/30/6/782.abstract 
Kleih, S. C., Kaufmann, T., Zickler, C., Halder, S., Leotta, F., Cincotti, F., … Kübler, A. (2011). Out of the 
frying pan into the fire--the P300-based BCI faces real-world challenges. Progress in Brain 
Research, 194, 27–46. doi:10.1016/B978-0-444-53815-4.00019-4 
Klin, A. (2002). Visual Fixation Patterns During Viewing of Naturalistic Social Situations as Predictors 
of Social Competence in Individuals With Autism. Archives of General Psychiatry, 59(9), 809–
816. doi:10.1001/archpsyc.59.9.809 
Koegel, R., Vernon, T., & Koegel, L. (2009). Improving Social Initiations in Young Children with Autism 
Using Reinforcers with Embedded Social Interactions. Journal of Autism and Developmental 
Disorders, 39(9), 1240–1251. doi:10.1007/s10803-009-0732-5 
Leekam, S. R., & Moore, C. (2001). The development of attention and joint attention in children with 
autism. In J. A. B. P. R. Z. T. C. N. Yirmiya (Ed.), The Development of Autism: Perspectives from 
Theory and Research (1st ed., pp. 105–129). New Jersey: Lawrence Erlbaum. 
Mak, J. N., Arbel, Y., Minett, J. W., McCane, L. M., Yuksel, B., Ryan, D., … Erdogmus, D. (2011). 
Optimizing the P300-based brain-computer interface: current status, limitations and future 
directions. Journal of Neural Engineering, 8(2), 025003. doi:10.1088/1741-2560/8/2/025003 
Oliveira, G., Ataíde, A., Marques, C., Miguel, T. S., Coutinho, A. M., Mota-Vieira, L., … Vicente, A. M. 
(2007). Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical 
characterization, and medical conditions. Developmental Medicine and Child Neurology, 49(10), 
726–33. doi:10.1111/j.1469-8749.2007.00726.x 
Patel, S. H., & Azzam, P. N. (2005). Characterization of N200 and P300: selected studies of the Event-
Related Potential. International Journal of Medical Sciences, 2(4), 147–54. 
Polich, J. (2007). Updating P300: an integrative theory of P3a and P3b. Clinical Neurophysiology : 
Official Journal of the International Federation of Clinical Neurophysiology, 118(10), 2128–48. 
doi:10.1016/j.clinph.2007.04.019 
Shane, H., & Albert, P. (2008). Electronic Screen Media for Persons with Autism Spectrum Disorders: 
Results of a Survey. Journal of Autism and Developmental Disorders, 38(8), 1499–1508. 
doi:10.1007/s10803-007-0527-5 

 
 
 
BCI intervention in ASD 
V1.0, 24.06.15 
 
Page 33 
Swettenham, J., Baron-Cohen, S., Charman, T., Cox, A., Baird, G., Drew, A., … Wheelwright, S. (1998). 
The Frequency and Distribution of Spontaneous Attention Shifts between Social and Nonsocial 
Stimuli in Autistic, Typically Developing, and Nonautistic Developmentally Delayed Infants. 
Journal of Child Psychology and Psychiatry, 39(5), 747–753. doi:10.1111/1469-7610.00373 
Wainer, A. L., & Ingersoll, B. R. (2011). The use of innovative computer technology for teaching social 
communication to individuals with autism spectrum disorders. Research in Autism Spectrum 
Disorders, 5(1), 96–107. doi:10.1016/j.rasd.2010.08.002 
Whalen, C., Schreibman, L., & Ingersoll, B. (2006). The collateral effects of joint attention training on 
social initiations, positive affect, imitation, and spontaneous speech for young children with 
autism. Journal of Autism and Developmental Disorders, 36(5), 655–64. doi:10.1007/s10803-
006-0108-z 
Wolpaw, J., & Wolpaw, E. W. (2012). Brain–Computer Interfaces: Principles and Practice. Oxford 
University Press. doi:10.1093/acprof:oso/9780195388855.001.0001 
 
24 
Appendices 
 
Informed Consent Form 
 
Ethical Committee Approval