Prefrontal Modulation by Repetitive Bilateral Transcranial Direct Current Stimulation (tDCS) in Alcoholic Inpatients
Phase: NA
Conditions: Drug Addiction, Executive Dysfunction
Sponsor: Federal University of Espirito Santo

 
Title: Prefrontal Modulation by Repetitive Bilateral Transcranial 
Direct Current Stimulation (tDCS) in Alcoholic Inpatients 
 
Brief Title: Bilateral Prefrontal Modulation in Alcoholism 
(tDCS_ALCOHOL) 
 
Institution: Federal University of Espírito Santo 
 
Principal Investigator: Ester Miyuki Nakamura-Palacios, MD, 
PhD 
 
NCT 02091284 
 
Date: July 3, 2018 
 

Study Protocol  
Alcohol is a highly addictive substance and alcohol dependence is a chronically 
relapsing disorder. It induces tolerance such that increased doses of the alcohol are 
required to achieve the desired effects and is associated with adverse symptoms during 
its acute withdrawal. Progressing disease is accompanied with neglect of alternative 
interests, and social, family and occupational activities. Attempts to quit are often 
unsuccessful and the patient continues to use the substance despite knowledge of 
physical and/or psychological harm caused by alcohol (1). Alcohol dependence is thus a 
debilitating disorder that harms not only the individual, but inflicts significant costs to 
society, including loss of productivity, security challenges, crime and lawlessness, 
increasing health care costs and a myriad of negative social consequences (2).  
Craving is a common manifestation in all drug addictions. It is defined as the 
“pressing, urgent and irrepressible desire to give in to the substance” (3), resulting in an 
uncontrolled urge to consume a drug, with strong obsessions about and irresistible 
compulsions to use (4), even when the individual is well aware of the consequences that 
its use can bring to his life. Craving is now considered as part of the diagnosis criteria 
for Substance Use Disorders under the A4 criteria in the DSM-5 (1, 5, 6). One reason to 
add craving to the diagnostic criteria was that that it activates brain regions related to 
the reward system (7, 8). Indeed, craving can be caused by an alteration of the relevant 
brain circuitry, that may persist even when the individual is not currently using the 
substance, but is exposed to stimuli that are associated with it (1, 9, 10), constituting a 
recognized central driving force for successive relapses and perpetuation of drug use 
(11, 12).   
 
Psychosocial and pharmacological approaches, although essential, have shown 
limitations and modest efficacy in the treatment of alcohol dependence (13). Therefore, 
the development of more effective treatments or alternatives improving the efficacy of 
the current approaches is highly desired.  
Transcranial direct current stimulation (tDCS) is a non-invasive brain 
stimulation technique in which a weak current is applied to the brain for several minutes 
through electrodes, resulting in a polarity-dependent modulation of brain activity (14, 
15). Considering that a single bilateral tDCS, either left cathodal/right anodal or left 

anodal/right cathodal, over the dorsolateral prefrontal cortex (dlPFC) showed to reduce 
alcohol craving in AUD patients (16), but the repetitive unilateral anodal tDCS over the 
left dlPFC increased instance of relapses in AUD patients (17), in the following study in 
AUD outpatients, we applied five consecutive sessions of bilateral tDCS, having the 
cathodal electrode over the left and the anodal over the right dlPFC, and showed a 
reduced probability of relapse to the use of alcohol (18). Half (50%) of the AUD 
patients treated with tDCS, as compared to only 11.8% of subjects from the sham-tDCS 
group, were completely abstinent at the end of six months following the intervention. 
However, in this study craving during the period of brain stimulation was not 
significantly changed (18). 
 
The extension of tDCS sessions may clinically matters as 10 daily sessions have 
shown to result in more effective and long-lasting effects than 5 daily sessions (19, 20). 
Therefore, in the present study we aimed to investigate whether an intensified 
intervention with ten sessions of tDCS bilaterally applied over the dlPFC would reduce 
craving for alcohol use in AUD inpatients.  
 
Material and Methods  
We report this clinical trial according to CONSORT guidelines. This trial was 
registered under Clinical Trials.gov number NCT02091284. 
 Participants  
AUD patients of both genders were successively recruited between June of 2015 
and January of 2018 from three specialized clinics for drug dependence treatment, one 
public and two privates, from the State of Espírito Santo, Brazil. These specialized 
services applied standard protocols for the treatment of drug addiction, consisting of 
psychosocial approaches –conducted by a professional team of psychologists, nurses, 
social workers and physicians, and pharmacotherapy, including benzodiazepines, 
vitamin B, disulfiram and, when necessary, antidepressants, anxiolytics, 
antihypertensive, and gastric medications, and folic acid. Two dropouts occurred after 
randomization. One dropout had to be hospitalized due to clinical instability and another 
missed many stimulation sessions.   

The inclusion criteria for this study were: (1) male and female patients over the 
age of 18 years; (2) met criteria for alcohol dependence according to the Classification 
of Mental and Behavioral Disorders (ICD-10) and the Diagnostic and Statistical Manual 
of Mental Disorders, fifth edition (DSM-5), as determined by clinical evaluation; (3) in 
stable clinical condition with no need for emergency care; (4) able to read, write, and 
speak Portuguese; and (5) without severe withdrawal signs or symptoms at baseline.   
Exclusion criteria included: (1) a condition of intoxication or withdrawal due 
to a substance other than alcohol, (2) unstable mental or medical disorder or substance 
abuse or addiction other than alcohol dependence, except nicotine and/or caffeine or 
history of marijuana use during adolescence; (3) diagnosis of epilepsy, convulsions, or 
delirium tremens during the abstinence of alcohol; (4) a previous history of drug 
hypersensitivity or adverse reactions to diazepam or other benzodiazepines and 
haloperidol; (5) any contraindication for electrical brain stimulation procedures such 
as electronic or metal implants.  
Ethical approval was provided by the Brazilian Institutional Review Board of the 
Federal University of Espírito Santo (CAAE 19403713.6.0000.5060), Brazil, and it was 
registered in clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT02091284). The 
study was conducted in strict adherence to the Declaration of Helsinki and is in 
accordance with the ethical standards of the Committee on Human Experimentation of 
the Federal University of Espírito Santo, ES, Brazil, where this study was 
conducted.  Subjects were fully informed about the experimental protocol and 
voluntarily signed an informed consent form before the start of the study.   
Direct Current (DC) stimulation  
The intervention in this clinical trial was transcranial DC stimulation (tDCS). In 
each session, tDCS was applied via two carbonated silicone electrodes (35 cm2) with a 
thick layer of high-conductive EEG paste on the contact surface connected to a DC-
Stimulator (DC-Stimulator Plus, NeuroConn, Ilmenau, Germany) for 20 minutes with 
fade-in and fade-out periods of 30 seconds each. Intensity was set to 2 mA.   
The cathode was placed above F3 (according to the EEG international 10 –20 
system), corresponding to the left dlPFC, and the anode was positioned above the right 

dlPFC (F4). For the sham stimulation procedure, the stimulator automatically switched 
off after 30 seconds of either anodal or cathodal stimulation yielding sensations 
typically elicited by tDCS. Sham- or real tDCS was applied once a day, every other day, 
including weekends, until completion of 10 sessions (Fig. 1).  
Craving assessment: 5-items OCDS 
Craving was scored with a brief scale composed of 5 items (1, 2, 4, 5, and 13) 
from the Obsessive-Compulsive Drinking Scale (OCDS) (21-23), which assesses 
craving in a narrow sense according to De Wildt et al. (24).   
Questions of this brief scale allow quantification of thoughts and feelings 
(obsessions), and behavioral intentions (24), and are answered on a scale ranging from 0 
to 4, resulting in a total score between 0 and 20. They ask how much of a person’s time 
(total per day), when the drug is not used, is occupied by thoughts, ideas, desires, or 
impulses related to alcohol and its effects; how frequently these thoughts, ideas, desires, 
or impulses related to alcohol and its effects occur; how much distress or disturbance 
these ideas, thoughts, impulses or desire related to alcohol use cause when the person is 
under withdrawal; how much effort the person has to make to resist these thoughts, 
ideas, desires, or impulses, or how much energy he/she has to spend to think of 
something else when they enter the mind under withdrawal; and finally ask about the 
person’s drive to use alcohol. 
This scale was applied in the week before the beginning of the real or sham-
tDCS treatment (1st measurement), during the treatment over approximately 3-weeks 
(2nd, 3rd and 4th measurements) and in the week after the end of the brain stimulation 
protocol (5th measurement). 
3-months follow-up: Alcohol use relapses 
 
After their discharge from the hospital, patients from sham- and real tDCS 
groups were followed-up for three months, corresponding to a period of initial 
remission according to DSM-5, regarding alcohol use relapses. Alcohol use relapse here 
was considered as the first episode of return to the previous uncontrolled pattern of 
alcohol use (drinks per day) (18). Information of these relapses were gathered directly 

when patients regularly returned to the hospital for clinical follow-up after their 
discharge and/or by self-report or reports of family members by telephone calls. 
Procedures  
Those patients who were eligible for study participation according to the 
inclusion and exclusion criteria described above and agreed to participate in this study 
signed an informed consent form (Fig. 1). All data were originally acquired from 
participants participating in a randomized sham-controlled double-blind clinical trial to 
investigate the efficacy of tDCS treatment of alcohol dependence.  
After global physical and clinical examination, subjects were randomly assigned 
to one of the two intervention groups (sham- and real tDCS) in a 1:1 ratio using a 
computer-generated block randomization sequence that was kept with the unblinded 
study coordinator (not involved in recruitment) and only revealed to the co-investigator 
conducting treatments immediately before the first session.  
  
Craving (5-items OCDS) was measured before and after completion of the 
treatment and once per week during the three-weeks treatment, resulting in five 
measurements (Fig. 1). Alcohol use relapses after hospital discharge were verbally 
obtained from patients, families or caregivers. 
Participants and experimenters were blinded for brain stimulation assignments 
from the beginning of the study protocol up to the end of the 3-months follow-up after 
the end of sham-tDCS or real tDCS treatment, configuring a double-blind experimental 
design. 
 
 
 

Statistical Analysis  
 We powered the study for a small effect size given our hypothesis that tDCS 
would be associated with a relevant reduction in craving scores. Thus, assuming a small 
effect size of 0.3 specified for SPSS in G*Power 3.1 for a repeated measure (5 
measures) within-between interaction analysis of variance (ANOVA) as principal 
statistical test for the craving analysis with a power of 80%, a two-sided probability of a 
type I error of 5%, a minimum of 38 subjects would be necessary; however to account 
for waiving or dropouts expected to be very common in this condition, we increased the 
estimated sample to approximately 20%, resulting in 45 to 46 subjects (22 to 23 subjects 
in each group). 
Age, patterns of alcohol use and 5-items OCDS were normally distributed 
according to D'Agostino & Pearson normality test, thus they were analyzed by 
parametric tests.  
Besides the two-way ANOVA (sham-tDCS and tDCS groups as between-subjects 
factor) with repeated measures (five time-points as within-subjects factor) followed by 
Bonferroni’s multiple comparisons as post-hoc test, linear regression analyses were 
done over craving scores obtained over the respective five time-points for both groups 
and the slopes of the respective curves were compared using a modified version of the t 
test according to Zar (1984), which is equivalent to analysis of covariance. Additional 
comparisons between initial and final OCDS scores were done by paired t tests for each 
group, and differences between final and initial scores were compared between sham-
tDCS and tDCS groups with unpaired t tests. Effect sizes were calculated using Cohen’s 
d and corrected by Hedges’s gs for unpaired and Hedges’ gav for paired t-tests (Lakens, 
2013).  
Age and patterns of alcohol use were compared between groups by unpaired t-
test. For all other non-parametric data, Chi-square or Fisher tests were used to compare 
results between sham and real tDCS groups.  
A two-tailed p-value of 0.05 or less was considered to indicate statistical 
significance. SPSS Statistics Base 24.0 (SPSS Inc, USA) and GraphPad Prism 7.0 

(GraphPad Software Inc, USA) were employed for statistical analysis and graphic 
presentations. 
 
 
 

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