The Role of Neuromodulation for Cognitive Processing and Behavioural Inhibition in Gambling Disorder
Phase: NA
Conditions: Pathological Gambling
Sponsor: University of East London

UNIVERSITY OF EAST LONDON 
 
The role of neuromodulation for cognitive processing and 
behavioural inhibition in disordered gambling 
 
 
 
PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Elena Gomis Vicent, PhD student 
 
 
 
 
 
 
 
4th March, 2019  
 

 
University of East London 
Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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STUDY PROTOCOL 
1. PROCEDURE  
 
The research consists on studying the effects of tDCS in combination with cognitive behavioural 
therapy (CBT) in adults diagnosed with gambling disorder that attend the UK National Problem 
Gambling Clinic.  The design of the study consists on a double blind randomized control interventional 
trial with parallel assignment (two interventions – tDCS in combination with CBT that will be evaluated 
against CBT alone).   
Participants will be split in two groups depending on the treatment they receive. The treatment groups 
will be: tDCS real stimulation with CBT or tDCS sham with CBT. Real stimulation condition involves 
the application of tDCS stimulation for 20 minutes whereas sham condition is used as a control (similar 
to a placebo).  
The investigators aim to have a total of 32 participants diagnosed with gambling disorder based on the 
Problem Gambling Severity Index (PGSI). There will be 16 participants per condition, having two 
conditions (real stimulation and sham).   
Treatment 1. Participants will attend 8 weekly sessions where they receive tDCS real stimulation while 
complete CANTAB cognitive tasks to measure cognitive functions and following this, they will attend 
a CBT session.  
Treatment 2. Participants will attend 8 weekly sessions where they receive sham tDCS, while complete 
CANTAB cognitive tasks to measure cognitive functions and following this, they will attend a CBT 
session. 
 
Primary endpoint/outcomes 
 
1. Change in scores on the Yale-Brown Obsessive Compulsive Scale adapted for Pathological 
Gambling (PG-YBOCS). [Time Frame: Change from baseline PG-YBOCS scores at week 2, 
3, 4, 5, 6, 7 and 8]. 
 
2. Change in scores on the Visual Analogue Scale (VAS). [Time Frame: Change from baseline 
VAS scores at week 2, 3, 4, 5, 6, 7 and 8]. 
 
3. Change in scores on the Gambling Symptom Assessment Scale (G-SAS).  [Time Frame: 
Change from baseline G-SAS scores at week 8]. 
 
4. Change in scores on the Cambridge Gambling Task (CGT). [Time Frame: Change from 
baseline CGT scores at week 8]. 
 
Secondary endpoints/outcomes 
 
1. Change in scores on the Information Sampling Task (IST). [Time Frame: Change from baseline 
IST scores at week 2, 3, 4, 5, 6, 7 and 8]. 
 

 
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Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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2. Change in scores on the Stop Signal Task (SST). [Time Frame: Change from baseline IST 
scores at week 2, 3, 4, 5, 6, 7 and 8]. 
 
3. Changes in encephalography (EEG) neural oscillatory activity. [Time Frame: Correlation of 
tDCS and EEG activity in weeks 1, 2, 3, 4, 5, 6, 7 and 8]. 
 
Primary objective 
 
The main objective is to study whether 8 weekly sessions during 8 consecutive weeks of tDCS 
simulation will help to decrease cravings and addiction symptoms such as risk-taking behaviour and 
impulsivity in patients diagnosed with gambling disorder attending the UK National Problem Gambling 
Clinic, exploring whether tDCS combined with CBT will improve the treatment outcomes – reducing 
significantly more the symptomatology, compared to CBT treatment alone.  
 
 
Hypothesis 1: 
 
Null hypothesis (H0): The primary outcome measures results will be the same in the group of 
participants that receive tDCS real stimulation combined with CBT and the control group (sham tDCS 
+ CBT). 
 
Alternative hypothesis (HA): The primary outcome measures results will not be the same in the group 
of participants that receive tDCS real stimulation combined with CBT and the control group (sham 
stimulation + CBT). 
 
Hypothesis 2: 
 
H0: The primary outcome measures results obtained in the baseline will be the same to the outcome 
measures results at the end of the treatment.  
 
HA: The primary outcome measures results obtained in the baseline will not be the same to the outcome 
measures results at the end of the treatment. 
 
 
Secondary objectives 
 
To investigate if electrophysiological measures (EEG resting state) predict behavioural outcomes 
obtained from the cognitive task performance during tDCS experiments, as well as studying the task 
performance progression comparing every week´s results to the baseline.  
 
Hypothesis 1: 
 
H0: The secondary outcome measures results obtained from the EEG resting state will be the same in 
the group of participants that receive tDCS real stimulation combined with CBT and the control group 
(sham tDCS + CBT). 
 
HA: The secondary outcome measures results obtained from the EEG resting state will not be the same 
in the group of participants that receive tDCS real stimulation combined with CBT and the control 
group (sham tDCS + CBT). 

 
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Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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Hypothesis 2: 
 
H0: The secondary outcome measures results obtained in the baseline will be the same to the outcome 
measures results at the end of the treatment.  
 
HA: The secondary outcome measures results obtained in the baseline will not be the same to the 
outcome measures results at the end of the treatment. 
 
2. MATERIALS 
 
Participants 
 
The sample size will be 16 participants per group (2 groups) that attend 8 treatment sessions. 
Inclusion criteria 
Male or females between 18 and 65 years of age diagnosed with disordered gambling based on the 
Problem Gambling Severity Index (PGSI) who can speak and read English, capable of giving informed 
consent, and don't have any of the exclusion criteria. 
Minimum Age: 18 Years 
Sex: All 
Gender Based: No 
Accepts Healthy Volunteers: No 
 
Exclusion criteria 
a. History or evidence of chronic or residual neurological disease. 
b. A pacemaker or deep brain stimulation. 
c. Metal implants in head or neck area (e.g. postoperative clips after intracerebral aneurysm; arterial 
aneurysm in the vascular system, implantation of an artificial hearing aid). 
d. Intracerebral ischemia/history of bleeding. 
e. Prior evidence of epileptic seizures, history of epilepsy. 
f. History of head injury with loss of consciousness. 
g. Any serious medical conditions (disease of the internal organs). 
h. Pregnancy or breast-feeding. 
i. Negative screening from the clinic psychiatrist 
 
Software 
 
This research uses a CE marked medical device, transcranial direct current stimulation (tDCS) built in 
the international company Neuroelectrics (https://www.neuroelectrics.com/products/). Specifically, 
Starstim® is a wireless hybrid EEG/tCS neurostimulator system. It includes the comfortable neoprene 
head cap where the electrodes can be easily inserted. Starstim® complies with the European legislation 
for clinical research. 

 
University of East London 
Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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Cognitive and physiological measurement tools 
 
Primary outcomes:  
1. Yale-Brown Obsessive Compulsive Scale adapted for Pathological Gambling (PG-YBOCS): it 
is a 10-item questionnaire that measures the gambling severity. The scores range from 0 to 4. 
The questions 1 to 5 assess urges and thoughts associated with gambling disorder, and the rest 
of the questions assess the behavioural component of the disorder in the past week. The total 
score will be calculated as well as the separate scores. Gambling severity will be higher with 
higher scores (we will obtain measures of PG-YBOCS in all sessions 1,2,3,4,5,6,7 and 8). 
 
2. Visual Analogue Scale (VAS) for gambling cravings: it is a horizontal line which length is 100 
mm where the left side corresponds to the lower score and the right side to the highest score (it 
ranges from 0 to 10). The participant will draw a line starting from the lowest level to the level 
that better represents their gambling cravings at the current time. The score will be calculated 
by measuring this line (in millimetres). The gambling cravings will be higher with higher VAS 
scores (we will obtain measures of VAS in all sessions 1,2,3,4,5,6,7 and 8).  
 
3. Gambling Symptom Assessment Scale (G-SAS): it is a 12-item scale to measure gambling 
symptoms. Each of the 12 questions has a score ranging from 0 to 4 based on the last week, 
which makes it useful to measure changes during treatment. The total score ranges from 0 to 
48. The symptoms severity will be higher with higher G-SAS scores.  
 
4. Cambridge Gambling Task (CGT): it is a cognitive task that dissociates risk taking from 
impulsivity, because in the ascending bet condition the participant who wants to make a risky 
bet 
has 
to 
wait 
patiently 
for 
it 
to 
appear 
(10 
minutes). 
http://www.cambridgecognition.com/cantab/cognitive-tests/executive-function/cambridge-
gambling-task-cgt/ 
 
  
Secondary outcomes:   
 
1. Information Sampling Task (IST): it tests impulsivity and decision making. The participant is 
instructed that they are playing a game for points, which they can win by making a correct 
decision 
(up 
to 
15 
minutes). 
http://www.cambridgecognition.com/cantab/cognitive-
tests/information-sampling-task-ist/  
 
2. The Stop Signal Task (SST): it measures response inhibition or impulse control (up to 20 
minutes). 
http://www.cambridgecognition.com/cantab/cognitive-tests/executive-
function/stop-signal-task-sst/ 
 
3. Encephalography (EEG) activity:  EEG resting state oscillatory neural activity will be obtained 
before and after tDCS stimulation to study the correlation of tDCS effects and 
neurophysiological changes in the brain.   
 

 
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Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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Trial design 
 
 
Study Type: Interventional 
 
Primary Purpose: Treatment 
 
Framework: Superiority (Treatment will be superior to placebo (sham condition)). 
 
Interventional Study Model: Parallel Assignment. Investigation of the effects of transcranial direct 
current stimulation (tDCS) in combination with cognitive behavioural therapy (CBT) against the 
effects of CBT alone. 
 
Number of Arms: 2 
 
Masking: Double (Participant and Operator) Participants will be allocated either to a tDCS 
Stimulation condition or to a tDCS Sham condition. 
 
Allocation: Randomized 
 
 
Trial setting 
 
The trial will run at The UK National Problem Gambling Clinic (NPGC), in London. This is a single 
centre and it consists on an educational project and therefore a non-commercial trial. 
There are not specific requirements to run the trial or different types of site. All participants will be 
recruited at the NPGC through members of the staff when potential participants contact the clinic to 
receive treatment for gambling disorder. 
Patients that contact with the health care team at the NPGC will be offered the opportunity to participate 
voluntarily in the research. If they are interested they will need to confirm that they meet the inclusion 
criteria of the study which appears in the invitation letter and will be given the researcher contact details 
to obtain more information about the trial.    
 
Trial procedures  
 
The intensity for neuromodulation will remain constant across all groups at 1.8 milliamps (mA), which 
is a standard intensity for induced cognitive change in the tDCS literature. In the sham condition, 
participants will experience only 60 seconds of tDCS stimulation with 1.8 mA intensity (30 seconds 
ramp up and 30 seconds ramp down), which is enough to induce a tingling sensation that is associated 
with tDCS neuromodulation but at the same time this is not enough to alter neural activity and the left 
19 minutes of the tDCS intervention they will receive 0 mA intensity. Electroencephalography (EEG) 
resting state oscillatory activity will be recorded during 5 minutes before and 5 minutes after tDCS.  
 
Participants will be randomly allocated either to a real stimulation condition or to a control condition 
(sham). Each participant will attend to a 20 minutes transcranial direct current stimulation (tDCS) 
weekly session for 8 consecutive weeks (8 sessions). During the sessions they will complete cognitive 
tasks and questionnaires for a total time of 1 hour to assess individual characteristics (e.g. impulsivity, 
risk-taking behaviour) and where EEG resting state will be recorded to inform about the 
neurophysiology of tDCS effects in task performance.  
 
The participant will complete: 
 
- The consent form  
- A series of questionnaires to assess cravings, addiction severity and gambling symptoms. 
 

 
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Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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Consecutively, the researcher will set up of equipment and parameters (place the cap on the participant´s 
head); apply tDCS stimulation (20 minutes) while participant complete cognitive computer based tasks; 
remove the cap to conclude the session. 
 
 
In session 1 and session 8 participant will complete the next questionnaires and cognitive task 
before the tDCS/EEG protocol: 
 
1. Gambling Severity Symptom Assessment Scale (G-SAS). 
2. Cambridge Gambling Task (CGT). 
 
 
In sessions 1, 2, 3, 4, 5, 6, 7 and 8 participants will complete the next questionnaires and cognitive 
tasks (tests 1-3 before tDCS/EEG protocol and task 4 during tDCS stimulation). EEG resting state 
will be recorded before and after tDCS:  
 
1. Yale-Brown Obsessive Compulsive Scale adapted for Pathological Gambling (PG-
YBOCS) 
2. Visual Analogue Scale (VAS) for gambling cravings. 
3. Information Sampling Task (IST) 
4. Stop Signal Task (SST) 
5. EEG resting state recording  
 
Randomization method 
Simple randomization will be employed. This method is based on a single sequence of random assignments. 
Computer-generated random numbers will be used for simple randomization of subjects prior to the 
experiment start – assigning randomised numbers to the order in which participants sign up - to ensure 
equivalent numbers of participants per arm. This technique guarantees randomness of the assignment of a 
subject to a particular group. 
 
Masking 
Neuroelectrics tDCS software will be set up in double blind mode, which ensures that neither the 
investigator (who conducts the experimental session) nor the participant, will know the condition (real 
stimulation or sham) the participant has been allocated to. Participant allocation to each stimulation group 
will be randomized prior the study commences as stated above, and tDCS templates will be created for 
each participant, to ensure that they will remain during the 8 stimulation sessions in the same group.  
 
3. ETHICAL CONSIDERATIONS 
 
Ethical approval to conduct the study was obtained from the University Research Ethics Committee 
(UREC) at the University of East London and from the Health Research Authority (HRA) and will be 
conducted with Central and North West London (CNWL) NHS trust. Potential risks associated with 
tDCS are minor discomfort from wearing the tDCS electrode net and minor itchiness that immediately 
cease after stimulation, this is explained to the participants prior to starting. Participants will be 
reminded that they could stop the experiment at any time they wish, if they felt too much discomfort or 
distress.  
 

 
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Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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4.  DATA PROTECTION 
 
All data will be anonymised, treated confidentially and retained in accordance with the Data Protection 
Act, stored for a limited period of time on password protected hard drives. Each participant will be 
given a participant number that can be de-coded by the researcher. Hard copies of questionnaires and 
consent forms will be stored in a locked filing cabinet in a lockable room then destroyed in accordance 
with the university’s data protection policies. 
 
5. STATISTICAL ANALYSIS PLAN 
 
 
Data source 
Behavioural data sets will be obtained from computer-based cognitive tasks and questionnaires that 
participants complete during the stimulation sessions. The results obtained from completing these tasks 
and questionnaires generate measures for addiction-related symptoms such as cravings, impulsivity, 
risk-taking behaviour, delay aversion and control inhibition. Each participant will produce data at two 
time points for G-SAS and CGT measures and at eight time points for VAS, PG-BOCS and secondary 
measures. Electroencephalography (EEG) resting state neural oscillatory activity will be recorded for 5 
minutes prior and 5 minutes after the tDCS intervention.  
 
Analysis objectives  
The investigators will study whether the behavioural and cognitive data obtained from participants in 
different time points are significantly different between the two treatment groups. In addition, the 
investigators will investigate if electrophysiological measures (EEG resting state) predict behavioural 
outcomes obtained from the cognitive task performance during tDCS experiments, as well as studying 
the task performance progression comparing every week´s results to the baseline.   
 
Analysis sets/Subgroups  
The following data sets subgroups will be analysed: 
 
1. Experimental - Stimulation with CBT: Participants that attend to 8 weekly sessions of tDCS 
stimulation and that following the tDCS session, they attend to a cognitive behavioural therapy 
(CBT) session. 
 
2. Sham Comparator - Sham with CBT: Participants that attend to 8 weekly sessions of sham 
tDCS and that following the tDCS session, they attend to a CBT session. 
 
The aim is to study whether the combination of stimulation and therapy help to improve the treatment 
outcomes in comparison with CBT alone. 
 
 

 
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Effects of Transcranial Direct Current Stimulation (tDCS) in Gambling Disorder 
 
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Variables and covariates  
 
Primary Dependent Variables:  
1. Pathological Gambling adapted Yale-Brown Obsessive Compulsive Scale (PG-YBOCS) scores 
for gambling severity.   
2. Visual Analog Scale (VAS) scores for gambling cravings.  
3. Gambling Severity Symptoms Assessment (G-SAS) for gambling symptoms.  
4. Cambridge Gambling Task’s (CGT) scores for gambling behaviour.  
 
Secondary Dependent Variables: 
1. Stop signal task’s (SST) scores for inhibition control.  
2. Information Sampling Task’s (IST) scores for impulsivity.  
3. EEG resting state oscillatory neural activity.  
 
 
Independent Variables:  
1. tDCS condition (Stimulation or Sham) 
2. Time (sessions 1 to 8)  
 
Covariates: 
1. Age  
2. Gender   
 
Handling of missing values 
We expect to have very few cases of missing values due to the methodology used in the study. The 
variables will be measured with a computer software that doesn’t allow to continue with the test unless 
one of the options is selected. The only possible missing values would come by an error on the whole 
task, which will result in no data at all. In this case, we would withdraw this participant from the analysis 
of that specific task.  
 
The possible missing values that we would expect to deal with, will come from the covariates measures 
that are obtained from paper-based questionnaires. The researcher checks before the participant leaves 
the session that they have completed all the questions. However, if we have to deal with missing values, 
we will use common-point imputation that is commonly used for rating scales, which is the case in our 
questionnaires. With this technique we would use the most commonly chosen value for the rest of the 
questions and substitute it for the missing value 
 
Statistical Procedures 
The analysis performed will be as in Loo et al (2012): the two treatment groups will be analysed for 
differences in demographic and clinical variables at baseline using X2 -tests for categorical variables 

 
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and t-tests for continuous variables. To  test  the  effect  of  tDCS  on  test  performance, a  2  x  2  mixed  
between–within  ANOVA  will be  conducted. The  between-groups  factor  will be stimulation 
condition (real stimulation  vs  sham)  and  the  within-participants  factor  will be time (change from 
baseline).  Analyses  will test  for  main  effects  of  stimulation condition and  session  as  well  as  the  
stimulation-session interaction.  
Secondary measures involve cognitive tasks and EEG resting state neural oscillations recording. 
Differences between sessions scores will be analysed with mixed between-within repeated measures 
ANOVA. The  between-groups  factor  will be tDCS condition  (real tDCS  vs  sham tDCS)  and  the  
within-participants  factor  will be time  (change from baseline).  Analysis will test for main effects of 
group (tDCS condition) as well as for tDCS-time interaction to investigate the presumable accumulative 
effects of tDCS.  This analysis will serve to study if specific EEG resting state oscillatory activity 
correlates with the modulatory effect of tDCS on task performance and to explore the presumable 
accumulative effect of tDCS across time.