No effect of repetitive tDCS on daily smoking behaviour in light smokers: A placebo controlled EMA study.

INTRODUCTION: The effectiveness of repetitive transcranial Direct Current Stimulation (tDCS) on reducing smoking behaviour has been studied with mixed results. Smoking behaviour is influenced by affect and context, therefore we choose to use mobile ecological momentary assessments (EMA) to measure changes in smoking behaviour after tDCS.
METHODS: In a randomized, placebo-controlled, between subject study, we applied tDCS bilaterally with the anodal electrode targeting the right DLPFC (https://clinicaltrials.gov/ct2/show/NCT03027687). Smokers were allocated to six sessions of either active tDCS (n = 35) or sham tDCS (n = 36) and received two sessions on three different days in one week. They were asked to keep track of their daily cigarette consumption, craving and affect in an application on their mobile phones for three months starting one week before the first tDCS session.
RESULTS: Number of smoked cigarettes a day progressively decreased up to one week after the last tDCS session in both conditions. Active treatment had no additional effect on cigarette consumption, craving and affect.
CONCLUSIONS: In this exploratory study, repetitive bilateral tDCS over the DLPFC had no effect on daily smoking behaviour. Future research needs to investigate how motivation to quit smoking and the number of tDCS sessions affect the efficacy of repetitive tDCS.

RCT Entities:   Population Interventions Outcomes

Introduction

Smoking is associated with serious health risks and causes approximately 8 million deaths worldwide each year [1]. Although the health risks of smoking are generally well known, 1.1 billion people of the global population are still smokers [1]. The maintenance of tobacco addiction may be explained by an interplay of increased reward processing for smoking cues and decreased self-control over addictive behaviours [2, 3]. One brain area that plays a crucial role in this interaction is the dorsolateral prefrontal cortex (DLPFC) by its involvement in top down-control over reward processing [4]. Non-invasive neurostimulation (NIBS) is designed to directly modulate brain activity in specific brain areas. It is therefore suggested that NIBS over the DLPFC could enhance cognitive control of executive functioning, hereby reducing craving and substance use [5].

Transcranical Direct Current Stimulation (tDCS) is a well-tolerable NIBS that has no known serious adverse effects [6]. tDCS modulates membrane potentials in the brain by means of small electrical currents [7]. The electrical current flow from the anodal electrode to the cathodal electrode produces an electrical field that modulates the excitability of underlying brain areas [8]. This modulation of excitation levels is able to induce changes in behaviour, mood and cognition [9]. Also, cognitive control processes related to substance use disorder can be affected by tDCS [10]. Importantly, several studies on addictive behaviours have shown that tDCS could reduce craving. This effect has been found for a variety of substances, such as tobacco [11, 12], marijuana [13], cocaine [14], heroin [15], and alcohol [16]. For tobacco addiction specifically it was found that tDCS could not only reduce craving, but also cigarette consumption [17-21].

In a double-blind, sham-controlled, crossover study, Fecteau and colleagues [17] found that five tDCS sessions on consecutive days could decrease cigarette consumption for up to 4 days in participants who wanted to quit smoking. In another study where smokers were not planning to quit smoking in the next three months, results showed that cigarette consumption temporarily decreased after one session of tDCS [18]. Recently, it was found that five sessions of tDCS could decrease cigarette consumption for up to 4 weeks [19]. Here, motivation to quit modulated the effect of active tDCS on cigarette consumption. The results of these studies suggest that a variety of tDCS protocols could cause a decrease in cigarette consumption and craving. In addition, it was found that multiple sessions of tDCS may even provide a promising substitute to bupropion treatment in tobacco addiction [20]. Findings from a recent meta-analysis indicate that anodal tDCS over the right DLPFC with cathodal tDCS over the DLPFC had the most positive effects on smoking behaviour [21].

However, the exact parameters of the effectiveness of this specific tDCS protocol remain unknown. For example, it is unclear how many sessions are needed for tDCS to be effective in tobacco addiction and for how long the effects last beyond one-month follow-up. Recently, it was shown that 20 sessions of anodal tDCS over the left DLPFC may reduce cigarette consumption beyond one-month follow-up [20]. The current study will explore whether the protocol with anodal tDCS over the right DLPFC can also have extended effects on smoking behaviour with fewer sessions. Ad libitum smokers were included to pilot whether tDCS affects the natural course of smoking behaviour, without smokers being motivated to quit.

For the current study we choose to measure smoking behaviour by means of Ecological Momentary Assessment (EMA). Effects of tDCS on addictive behaviour have often been measured with retrospective self-reports in the lab. Since craving and substance use are both episodic phenomena that are associated with affect and context [22-24], measuring these variables in daily life may lead to more reliable answers. Furthermore, retrospective measurements may be influenced by recall biases [25, 26]. EMA therefore establishes more ecologically valid results as compared to retrospective self-reports by collecting data in real-time repeatedly.

In sum, the aim of the current study is to explore the duration of the effect of repetitive tDCS on cigarette consumption by means of EMA in a sample of ad libitum smokers. Following the design of Falcone and colleagues [18], participants were included if they had no plans to actively try to quit smoking in the next three months. In line with previous studies, we expected that active tDCS can reduce the number of daily smoked cigarettes and we hypothesized that this decrease can last for up to 3 months after the last session. We also expected reduced craving after active tDCS [27] during and after the intervention week, and at three months follow-up.

Materials and methods

Participants

Seventy-three participants signed the informed consent form and completed the first tDCS session. Inclusion criteria were: 1) Between the age of 18 and 65 years; 2) Currently smoking 10 cigarettes or more a day; 3) The ability to speak, read, and write in Dutch. Exclusion criteria were: 1) Current substance use disorder of a substance other than nicotine or caffeine; 2) History of neurological or psychiatric disorders; 3) Any contraindication for electrical brain stimulation procedures (i.e. electronic implants or metal implants); 4) Pregnancy or breast-feeding; 5) Intentions to actively try to quit smoking in the next three months. Participants were recruited via advertisement at Erasmus University Rotterdam from October 2016 until March 2018 and received either course credit or a financial compensation of 20 euro. Two participants dropped out during the intervention week, because of personal circumstances (n = 1) and because of schedule issues (n = 1). Also due to schedule issues, three participants received tDCS on only two instead of three days. Leaving these participants out of analyses had no effect on the results, therefore they were included in the final analyses. Nine participants could not be reached after three months and were therefore lost to follow-up, leaving a total of 62 participants for follow-up analyses (Fig 1).

Fig 1

Flow diagram.

The study was approved by the Medical Ethics Committee of the Erasmus Medical Center, Rotterdam, the Netherlands. All procedures were carried out after participants were fully informed and had signed a written informed consent form. This report is part of the pre-registered study with identifier NCT03027687 at ClinicalTrials.gov. The complete study protocol can be found at http://dx.doi.org/10.17504/protocols.io.bcgdits6.

Experimental design

The current study had a double-blind, randomized, sham-controlled design in which subjects received a total of six tDCS sessions (active or sham) on three days in one week with at least one day in between (Fig 2). Participants were first randomly assigned to either sham or active tDCS. Then, before the tDCS sessions and at three months follow-up, participants completed the Fagerström Test of Nicotine Dependence (FTND; [28]). Breath carbon monoxide concentrations were also measured using a Micro+ Smokerlyzer (Bedfont Scientific Ltd., Rochester, UK) to objectively define smoking. In addition, participants completed two behavioural tasks in the Erasmus Behavioural Lab (EBL) before the first session, one day after the last tDCS session and at three months follow-up. With these tasks we measured changes in cognitive control and feedback processing by means of EEG. The results of the tasks will be discussed elsewhere, in order to remain focus on the scope of this paper (e.g. changes in smoking behaviour after tDCS).

Fig 2

Experimental procedure.

To measure changes in smoking behaviour, participants were asked to keep track of their cigarette consumption, craving and affect in an application on their mobile phones (EMA). Questions in the application were presented at four random times a day for three weeks in total (random assessments; RA’s), starting the week before the first tDCS session (T1). After three months, participants were asked to fill out the same four-time daily random assessments for one more week (T2). In addition, participants were asked to start a session every time they smoked a cigarette (user-initiated smoking assessment; SA) for three months in total. An ‘end of the day’ assessment (EA) was also implemented for three months, which asked participants to fill out the total number of smoked cigarettes of that day.

Participants are asked to fill out the following EMA assessments: Random assessments (RA’s), end of the day assessments (EA’s), user-initiated smoking assessment (SA’s). TDCS sessions last 13 minutes each with 20 minutes in between.

Transcranial Direct Current Stimulation (tDCS)

Participants in the active tDCS group received tDCS by an electric DC-plus stimulator (NeuroConn, Ilmenau, Germany) via a pair of carbonated silicone electrodes with a thick layer of high-conductive EEG gel underneath them (35 cm2). During each session, tDCS was applied two times for 13 minutes with a 20-minute break in between, and a current intensity of 2.0 mA with a 30 sec ramp at the beginning and end of the session [14]. The anodal electrode was placed over F4 area (10–20 international system) to stimulate the right DLPFC, the cathodal electrode was placed over the F3 (left DLPFC). Beneficial effects were found on smoking behaviour with this ‘right anodal/left cathodal’ positioning [17].

The control group received sham tDCS by the DC-plus stimulator. For sham, the electrodes were positioned at the same locations as active tDCS, but in this case the stimulator was gradually turned off after 30 s. Since the itching sensation of tDCS is often only experienced initially during stimulation, subjects remained blinded of the stimulation condition they received [e.g. 8, 29]. The experimenter was also blinded from the tDCS condition. That is, the codes that can automatically activate sham or active tDCS, were randomly assigned to participant numbers by an independent researcher. Then, the experimenter assigned the participant numbers.

Ecological momentary assessment

Procedure

The LifeData platform () was used to develop the application for this study and to securely collect data. Participants were instructed by email to download the LifeData application on their smartphone one week before the first tDCS session. The start-up session of the application provided general information about how to use the app. After participants had finished the start-up session, they received random prompts four times a day between 10 am and 10 pm for 21 consecutive days to complete a RA. After three months, the application automatically started prompting participants again for four times a day for seven consecutive days. All RA’s that were not completed within 90 minutes after the notification disappeared and were marked as missed.

In addition, participants were asked to initiate an assessment whenever they started smoking a cigarette (SA). The application further alerted participants at the end of the day (22 pm) to fill out the total number of cigarettes they had smoked during the day (end-of-day assessment; EA). EA’s were prompted for 90 consecutive days, starting from the day the application was downloaded.

Measures

Cigarette consumption. During RA’s, participants were asked how many cigarettes they had smoked since the last assessment and how many minutes had passed since they had smoked their last cigarette. Participants were also instructed to start a SA whenever they smoked a cigarette. During EA’s participants filled out the total amount of cigarettes they had smoked during the day.

Craving. During RA’s, participants were asked to indicate the urge to smoke a cigarette at that moment on a Likert scale ranging from 0 (no urge) to 100 (very strong urge).

Mood. General mood was measured during RA’s by a prompt stating: “What is your general mood at the moment?” with response possibilities ranging from very negative (0) to very positive (5). In addition, participants were asked to evaluate the following specific affects for themselves on a 5-point Likert scale: Happiness, enthusiasm, relaxedness, irritability, sadness, stress, and how bored they felt.

Data analyses

In order to fit the nested data structure of Time within individuals (Level 1), and Group (tDCS vs. Sham) at Level 2, the primary analysis was conducted using multilevel regression modeling, also known as hierarchical linear modeling (see [30] for further details), in HLM 7.01. By using the maximum likelihood estimation method in multilevel modelling of the EMA data, all data points of individuals with missing data could be analyzed [31]. Missing data is almost inevitable in EMA studies, since most participants miss at least some prompts due to daily activities.

For the analyses, first a baseline model was fitted to every outcome variable (cigarette consumption and craving), including random intercepts across participants. With this model, it was assessed whether multilevel analysis was required. By significant variance at Level 2, the other models were fitted. It was confirmed that multilevel analyses could be applied in the current study, because fitting the baseline models to the data showed there was a significant amount of variance of the regression coefficients on the subject level (Level 2). The second model included the Level 1 predictor Time as fixed effect and was then extended by adding random slopes for Time. The final model included cross-level interactions between Time at Level 1 and the predictor variable Group (Active or Sham tDCS) at Level 2. The assumptions of normality and linearity were assessed by inspecting the residuals of each best fitted model. Unless otherwise reported, the assumptions were met. Further analyses examined smoking behaviour as a function of craving, and positive and negative affect on the momentary level (Level 1).

Since age and craving significantly differed for the sham and active tDCS group, multilevel analyses with cigarette consumption as outcome variable were also carried out with age and craving as covariates. Both covariates did not influence the results of tDCS on cigarette consumption. Explorative analyses were performed with the following covariates: Gender, overall FTND scores at baseline, and number of years the participant had been smoking. These variables had no influence on the effect of tDCS on cigarette consumption and craving. Finally, Spearman correlation coefficients were calculated for all three carbon monoxide scores on the one hand and mean number of cigarettes indicated by EA’s in the week before each carbon monoxide concentration was measured on the other hand.

Results

Descriptive statistics

The final sample consisted of 71 participants (36 females, 35 males) between the age of 19 and 53 years (M = 22.3, SD = 4.7) who smoked an average of 11.3 cigarettes a day (SD = 4.2) and had a mean FTND score of 3.4 (SD = 1.9). Of these 71 participants, 35 received active tDCS and 36 received sham treatment. Because of the double-blind method the groups were not matched at baseline. As a result, the average age of the sham group (M = 23.4) was slightly higher compared to the active tDCS group (M = 21.1), t(69) = 2.119, p = .038. In addition, the active tDCS group experienced more craving at baseline (p = .001). For follow-up analyses, 62 participants were included (n = 30 Sham tDCS, n = 32 Active tDCS).

Ecological momentary assessment: Compliance

RA’s were initially prompted four times a day for 21 days, which means that the total number of possible prompts for 71 participants was 5964. The total number of completed RA’s during the first 21 days was 2650. Therefore, the compliance rate for completed random assessments was 44.4%. Ninety days after the start-up session, RA’s were prompted for one more week. During this follow-up week the compliance rate was 46.6%.

In addition, EA’s were presented on each day for 90 days. During the first 21 days, participants completed a total of 810 out of 1491 EA’s (54.3% compliance rate). During the follow-up week, 62 participants completed 242 out of 434 possible EA’s, making the compliance rate 55.8%.

Additional exploratory analyses showed that 54 participants filled out at least one third of all EA’s, and 38 participants filled out at least 50% of all EA’s. Further analyses with these two groups showed no difference in results on the primary outcomes as compared to analyses with the entire sample. In addition, compliance on EA’s did not correlate with the outcome measures for both groups.

Primary outcome: Number of smoked cigarettes

The primary outcome measure was mean number of smoked cigarettes a day. Multilevel analysis with mean number of smoked cigarettes as dependent variable and time in days as predictor, showed that the mean number of smoked cigarettes slightly decreased over two weeks’ time from the first tDCS intervention up to one week after the last tDCS session (b = -.07, t(471) = -2.086, p = .038). This decrease over time was observed for both active tDCS and sham tDCS (Fig 2) and did not correlate with EMA compliance. Importantly, no differences were found between the groups in the amount of change over time on number of smoked cigarettes (p = .745). Also at follow-up, the sham tDCS and active tDCS group did not differ in number of smoked cigarettes (p = .859).

Correlational analyses: CO scores

Additional analyses showed that number of smoked cigarettes in the week before the first tDCS session correlated with the breath concentration of carbon monoxide (CO; in parts per million) on the day of the first tDCS session (r = .416, p < .001). CO scores on the day of the last tDCS session also correlated with the mean number of cigarettes smoked during the intervention week (r = .303, p = .041). Finally, it was found that mean number of smoked cigarettes in the week before the follow-up session correlated with CO scores at follow-up (r = .486, p < .001).

Secondary outcomes: Craving and affect

Participants in the active tDCS group experienced significantly more craving (p < .001) the week before the first tDCS session (M = 56.1, SD = 20.7) as compared to the sham tDCS group (M = 48.7, SD = 19.6). Multilevel analysis with craving for cigarettes as dependent variable and time in days as predictor, showed a main effect of group in the two weeks after the first tDCS session (b = 11.75, t(69) = 3.87, p = .003), meaning that the baseline difference in craving was maintained throughout T1. There was no main effect of time (p = .184) and no interaction effect of time and groups (p = .970) on craving at T1 (Fig 3). No differences between groups were found for overall mood at T1 (p = .599). For T2 at 3 months follow-up, no main effect of time and condition, or interaction effect was found for craving and overall mood.

Fig 3

Number of smoked cigarettes on each day starting from one week before the 1st tDCS session.

Analyses at T1 showed that total number of smoked cigarettes was associated with craving on the same day (b = .035, p < .001). In addition, smoking behaviour was related to positive affect. Specifically, it was found that happiness was positively related to total number of smoked cigarettes on the same day (b = .726, p < .001).

tDCS side effects

Side effects were recorded after each tDCS session. Participants were asked to indicate the amount of itching, burning, and tingling sensations on a 5-point Likert scale, ranging from none (1) to extreme (5) sensations. In addition, we asked participants about difficulties with concentrating and whether they experienced acute mood changes during tDCS. Questions about sleepiness, neckpain and pain in the head were also rated on a 5-point Likert scale. Results showed that overall, the active tDCS group experienced significantly more itching sensations (F = 11.379, p = .001) as compared to the sham group. No other differences between the groups were observed regarding the side-effects.

Discussion

The current study was the first to use mobile Ecological Momentary Assessments (EMA) to investigate non-invasive neurostimulation as a tool to reduce smoking behaviour. The aim of this exploratory study was to test with EMA whether tDCS over the right DLPFC could modulate cigarette consumption and craving in ad libitum tobacco smokers. Results showed that over the course of the intervention week, the number of smoked cigarettes decreased during the application of sham or active tDCS. This finding is consistent with observations from a previous study with multiple tDCS sessions in tobacco smokers [17] and may result from the participants’ awareness of their smoking behaviour.

Most importantly, however, no differences were found between the sham and active tDCS group in cigarette consumption and craving. This finding is not in line with a series of previous studies that have demonstrated that tDCS is effective in reducing cigarette smoking [17-20] and cigarette craving [11, 12]. A possible explanation for this unexpected finding is that in the current study craving and cigarette consumption were assessed by means of EMA. With this experience sampling method, we were able to measure cigarette consumption and craving in real time. The outcomes are therefore measured in a more ecologically valid manner as compared to retrospective self-reports. This is of importance, since smoking behaviour is associated with mood and context [23, 24]. Individuals may for instance smoke more during the weekend or on stressful days [31]. This pattern of change over time is clearly illustrated in Figs 3 and 4. Moreover, with the use of momentary assessments retrospective recall biases can be avoided.

Fig 4

Mean craving on each day starting from one week before the 1st tDCS session.

Another explanation for the lack of effect of tDCS on craving levels and cigarette consumption can be found in the study’s sample that consisted of mostly light smokers who, in addition, had no desire to quit smoking. It can be suggested that motivation of smokers to quit plays an important role in the efficacy of tDCS. The current study included ad libitum smokers (i.e., individuals who have no intention to quit smoking at the moment of the intervention), whereas a recent study that was published after we started our data collection showed that the effect of tDCS on smoking behaviour was modulated by motivation to quit [19]. It was also found that repetitive tDCS decreased cigarette consumption in participants who wanted to quit smoking [17]. These findings, in combination with the results of the present study, seem to suggest that tDCS is at least effective if there is a clear motivation to quit smoking. Future studies should explore the direct relationship between motivation to quit smoking and the efficacy of tDCS on smoking behaviour.

Finally, in contrast with previous studies that applied multiple sessions of tDCS, we applied 6 tDCS sessions on three different days in one week, instead of 5 or more session on at least five different days [e.g. 17, 20]. A reduction in cigarette consumption could nevertheless be expected on the days that tDCS was applied. That is, since Falcone and colleagues [18] found an immediate temporary effect of one tDCS session on smoking in ad libitum smokers. In this study, however, tDCS was applied online during cue exposure which may have influenced the effects [18].

Besides the important improvement of using real-time assessment in the natural environment of smokers, several critical remarks can be made and therefore caution should be taken when interpreting the findings. First, while participants were randomly allocated to either the active or sham condition, groups significantly differed on baseline craving levels. That is, participants in the active condition showed higher craving levels before the intervention compared to the control group which could have affected the results of this study.

A second limitation that should be mentioned is the relatively low compliance rate, ranging from 44% to 56%, on EMA assessments. A recent meta-analysis has shown that the average compliance rate in substance dependent samples is 69.8% [32]. Even though multilevel modelling in HLM 7.01 reliably corrects for random missing data, we performed additional analyses where participants with low compliance rates were excluded to investigate whether compliance rate might have influenced the outcomes. The results of these analyses indicated no change in outcome if compliance rates are higher. Reliability of the data is further supported by the finding that carbon monoxide concentrations correlated with number of smoked cigarettes as indicated in EMA end of the day assessments. Moreover, the EMA data showed that ad libitum smoking was related to craving and positive affect. Specifically, the number of smoked cigarettes increased with both craving and positive affect on the same day. These findings are in accordance with the results from an earlier EMA study with a higher compliance rate [22]. Finally, participants in the active tDCS group indicated they experienced more itching sensations during neurostimulation than the sham tDCS group. This finding is in line with observations from previous studies where participants reported tingling and itching sensations after stimulation [e.g. 17]. However, blinding can still be reliable despite of differences in comfortability between the two conditions [33]. In addition, blinding with sham tDCS is considered reliable [29].

This was the first exploratory investigation using EMA to study the effects of tDCS on smoking behaviour. With the use of EMA, further insights were provided on the course of smoking behaviour over time. In sum, we did not find evidence that tDCS over the DLPFC decreases cigarette consumption and cigarette craving in light smokers that have no desire to quit at the moment of intervention. These findings raise intriguing questions regarding the nature and extent of the effects of tDCS on smoking behaviour. In a previous study it was found that motivation to quit smoking modulated the efficacy of tDCS on smoking behaviour [19], and therefore it may be necessary for smokers to actually quit smoking or at least be motivated to quit smoking at the moment of intervention. Future studies should explore this hypothesis by investigating the effects of repetitive tDCS in a larger sample of heavier smokers who are motivated to quit.

CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(DOC)

Click here for additional data file.

Demographics.

(SAV)

Click here for additional data file.

HLM Level 1 data at T1.

(SAV)

Click here for additional data file.

HLM Level 1 data at T2.

(SAV)

Click here for additional data file.

HLM Level 2 data for S2 File and S3 File.

(SAV)

Click here for additional data file.

4 Sep 2019

PONE-D-19-19431

Effects of repetitive tDCS on ad libitum smoking behaviour: An EMA study

PLOS ONE

Dear Ms. Verveer,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Yours sincerely,

Berthold Langguth

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The study presented to with a well rounded design, with a lot of sense of detail concerning means of control and potential critical aspects.

However, the following questions and recommendations arised:

Abstract:

- As lack of acute motivation to quit smoking is an important distinguishing aspect to related studies, it would be beneficial if it could be mentioned not only in the conclusions, but also in the introduction section of he abstract

Introduction:

- Please give further explanation on the underlying assumptions concerning the DLPFC and its role on reward processing and self-control as well as more detailed background information concerning hypothesized effects of tDCS on these mechanisms.

Methods:

- You state in line 119 that behavioural tasks where completed by the participants prior and after the tDCS sessions where conducted. While you report that the results and nature of these tasks are irrelevant for this paper, could you still please give more details?

- There are a few small punctuation errors (for example in line 167, 184, 220)

In line 168 probably “to be bored” is ment, rather then “boringness”.

- Was there a reason that lead to the decision to make intention to quit smoking an exclusion criteria? Please give more information on this topic.

Results:

- It could contribute to the information value, if the visual depiction and diagrams of the results would go along with a short inscription.

- Was there any noticeable relevance of the Fagerström test scores?

Discussion:

- Again, the lack of motivation could be, as you stated, an important modulating factor on the efficiancy of any quit smoking treatment approach. It should therfore be further elobarated on why the choice to exclude it was intentional and was of further benefit, compared to other study designs.

- In consideration of this, the assumptions you made in line 292- 297 seem risky.

Reviewer #2: This manuscript examines the effects of repetitive tDCS over DLPFC on smoking behavior using EMA(ecological momentary assessments). The idea was to measure smoking behavior in a "more ecologically valid manner as compared to retrospective self-reports". The main finding of this research is that both sham and tDCS groups show decreased cigarette consumption as well as craving, but no difference was found between the two groups.

General remark. As the authors mentioned, they hypothesized that tDCS over of the DLPFC would reduce cigarette smoking and craving as many others have reported, however, their results were negative. Although the authors argued that negative results can be valuable, but sole negative results are difficult to explain. There are many possible reasons for negative results.

1. The subjects were relatively light smokers.

2. It is hard to explain why right anodal/left cathodal DLPFC stimulation should have any effects.

As I understand, anodal stimulation increases brain activity whereas cathodal stimulation decrease brain activity. Unless left DLPFC and right DLPFC have totally opposite functions, why should we activate one side and inactivate the other side?

3. The baseline craving scores for the two groups were significantly different(p = 0.001). That makes it difficult to examine any effects of tDCS on craving.

4.Using EMA to measure cigarette consumption and craving is the novel part of this manuscript, however, the authors mentioned in the discussion that the controversial results might due to using EMA. As showed in the manuscript, EMA did not provide more information, especially how mood and context would influence the effects of tDCS. Low compliance rate is another problem.

5. The fact that cigarette consumption in Sham group decreased need to be explained.

6. There are no figure legends.

Reviewer #3: This is a study that seeks to determine the effect of tDCS on smoking behavior. Overall, the topic is important; however, a number of issues may limit the value of the article, I hope below comments improve the quality of the paper.

Title

According to the CONSORT statement, authors should indentify in the title that this is a controlled trial. Abbreviated words also should be removed from the title.

Abstract

1. Introduction is too long. Here the authors should use effectiveness instead of efficacy.

The sentence “To determine the duration of treatment effects, daily smoking behavior was studied for three months.” should be moved to method section.

2. The definition of all outcomes and statistical methods should be provided.

3. In contrast to introduction with unnecessary sentences, the results section is very brief with no effect sizes, confidence intervals and P values!

3. The conclusion should be according to presented results.

Introduction

1 Line 27, please provide the latest evidences

2. Lines 33-34, Please provide references for this sentence.

3. Line 44, marihuana or marijuana?

4. Line 46-52. There are still other related studies which should be cited such as:

https://www.sciencedirect.com/science/article/pii/S0924933819300793

5. Lines 56-63. Current study is also with limited sample size and follow up for three months is not long follow up, therefore it is not clear that what will be added this study to current knowledge.

6. I am not agreeing with authors that previous studies used retrospective measurements! with some degree of recall bias. Especially EMA is a subjective measurement with high probably of information bias.

Methods

1. No information provided about randomization type and method, concealment method, sample size calculation. Please consider CONSORT with caution.

2. The information about blinding and statistical methods is also insufficient. I am not believed that this study is double blind.

3. More details are required about assessments (i.e RA, SA and EA).

4. Line 121, why the results of behavioral tasks are beyond the scope of this paper?! Authors should provide all outcomes, declared in clinicaltrials.gov registration.

5. I am not sure that the method used for measurement of craving and mood are correct and based on DSM5.

6. Simple statistical methods such as independent t-test for changes over different intervals, repeated measured ANOVA and GEE are more appropriate especially for general readers. The methods for comparing baseline data should also be provided.

Results

1. It is unusual that with including participants who smoked more than 10 cigarettes per day, the mean daily cigarettes smoked become 11.29 with a SD equal to 4.2. Please provide the range of cigarettes smoked per day.

2. Line 194-198, with a true randomization there is no need for matching. Is this a randomized control trial?? The differences in age and craving of participants are attributed to inappropriate or lack of randomization although small differences between baseline variables may be present due to random error. Again please consider CONSORT and compare all studied variables at the baseline and different intervals.

3. The compliance rates for RA and EA are very low and this is a big limitation. Surprisingly authors did not compare these rates between intervention and control groups. Non respondents should be compare according to the other outcomes.

4. There are many fluctuations in number of smoked cigarettes in both groups (Fig 3). When one group show increased number of cigarettes other groups show decreased smoked cigarettes! This may be attributed to incorrect randomization, low compliance rate and information bias.

5. The results of statistical test should be provided in tables with all details.

6. Although the P-values are significant, the correlation coefficients between smoked cigarettes and CO are below 0.5 and contrary to the authors' claim it shows a low correlation.

Discussion

1. Lines 270-271, I am not agree that the data collected by EMA is more valid than previous studies. This study has many methodological errors.

2. Lines 282-283, Low compliance rate is an important issue. By excluding participants with low compliance, the sample size will be decrease (Although the total sample size was also low) and lack of significant difference between groups can be attributed to type two error.

3. Discussion should be revised after new and complete analysis of data and with addressing many limitations of study.

References

Should be updated.

Figures

Have low resolution and should be revised according to the new results.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

- - - - -

For journal use only: PONEDEC3

Submitted filename: Thank you5.docx

Click here for additional data file.

29 Oct 2019

The first two reviewers were quite positive and stated that we used an adequate methodology. The third reviewer was more critical but we believe that several responses of particularly this reviewer seem to indicate that there was some misconception about important aspects of the method and result section which we would like to address here. Considering all responses, the following seem crucial for the rejection of the current paper and were revised in the following manner:

1. Participants were light smokers:

This is correct, we were not only interested in heavy smokers, but all (including light) smokers. We have addressed this more clearly in the resubmitted paper.

2. Motivation to quit has not been taken into account:

We did not take motivation into account since it only became apparent that motivation may influence the effects of tDCS after we had started the data collection. That is, the data collection started end of 2016 and the paper which indicates that motivation to quit may be an important modulation factor appeared in 2018. We therefore mention in our discussion that this might be a valid explanation for our null-findings.

3. The sham and active tDCS group differed in craving at baseline:

This is an unfortunate result of our double-blind randomization procedure. To our surprise, the reviewer in question (3) mentions that “he/she is not believed that the study is double-blind”. In appeal to this response, we would like to refer to lines 141-143 where it’s stated that the tDCS system enabled the researcher to fill out a code which starts the procedure (either sham or active tDCS). The codes were assigned to participant numbers by an independent researcher. The procedure was therefore most certainly double-blind. We therefore believe that this baseline difference is the unfortunate result of chance.

4. Compliance rate of EMA responses was low:

This is correct and we agree. However, as mentioned by our review paper on this topic (Jones and colleagues; line 287 – 289) little is known about how to increase compliance rates. To correct for the low compliance rate, we performed exploratory analysis only including participants with a high compliance rate. This did not result in different outcomes. Other indicators of the reliability of our EMA data are also mentioned (line 290-298).

Point-by-Point responses to the third reviewer:

Title and Abstract

The title and point 1-4 for the abstract have been adjusted in revisions.

Introduction

Point 1-3: Indicated that small adjustments had to be made in certain sentences.

Point 4: The reviewer referred that the following paper should have been cited: https://www.sciencedirect.com/science/article/pii/S0924933819300793. However, this article was published in August 2019, whereas we submitted the manuscript in July. We have included the reference in the revised version of our manuscript.

Point 5: The reviewer mentioned that the study has a limited sample size and that 3 months is not a long follow-up. Still, the sample size is larger compared to previous studies with a between subject design that investigated the effects of tDCS on smoking behavior.

As far as we know, the largest sample for active tDCS in smokers was 19 participants (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791546/pdf/fphar-09-00014.pdf) before we submitted the manuscript in Juli 2019, whereas we’ve included 35 participants for active stimulation. In addition, 3 months follow-up was the longest follow-up that had been performed in smokers so far.

Point 6: The reviewer claimed that previous studies did not use retrospective self-reports. However, in comparison with ecological momentary assessments by which smoking behavior multiple is measured multiple times a day in different contexts, questionnaires at the end of the day or week (in the lab) are retrospective and could therefore affect recall. That is, since for example craving is a momentary phenomenon, and this sensation can be difficult to recall after a while. Participants also indicated that they became aware of how often they smoked by filling in the app, and that this was often more than they thought in retrospect.

Method:

Points 1 and 2: We would like to refer to line 104-106 and line 143-145, and the response above stating that our study design was randomized and double-blind.

Point 3: Details about assessments are provided under “Procedure” and “Measures”.

Point 4: Behavioral tasks are beyond the scope of the paper because these also include EEG measures. It would make the article unnecessarily long and incomprehensive, and therefore we decided to publish the outcomes of the tasks in a separate article.

Point 5: The reviewer mentions that simpler statistical methods could have been used. This is not the case since our data has a multilevel design with Time within participants at level 1 and Group at level 2, and should therefore be analyzed as such. We have addressed this more clearly in our revision (lines 176-182).

Results:

Point1: Participants were indeed lighter smokers. We have addressed this in the discussion (Line 300).

Point2 and 3: Randomization and compliance are addressed above.

Point 4: The reviewer mentions that many fluctuations in number of smoked cigarettes can be attributed to flaws in the research design. However, it’s more likely that smoking and craving (at least in light smokers) fluctuates over time according to mood and context. At the same time, this result therefore indicates the importance of using EMA measures.

All other points are related to above mentioned points or were small points that have been taken into account in the revision.

Submitted filename: Appeal request incl modifications PONE-D-19-19431.docx

Click here for additional data file.

31 Jan 2020

PONE-D-19-19431R1

No effect of repetitive tDCS on daily smoking behaviour as measured by EMA: A placebo-controlled study

PLOS ONE

Dear Ms. Verveer,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

As you can see, one reviewer still has Major concerns about your work. Please provide a revision, if you feel that you are able to address all concerns of the reviewer.

==============================

We would appreciate receiving your revised manuscript by Mar 16 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Berthold Langguth

Academic Editor

PLOS ONE

and

Tifei Yuan

Academic Editor

PLOS ONE

1) When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2) Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Overall, this is not a well controlled study. The results are not sufficient to support the conclusion that rtDCS has no effects on daily smoking behavior. There are many possible reasons that the results are negative. For instance, the baseline of craving from two groups are significantly different; all subjects were light smokers so that there was the floor effect; main effects may be lost because of the low compliance rate, and so on.

Reviewer #4: In this study, the authors investigated the effectiveness of repetitive transcranial direct current stimulation to reduce smoking behaviour. The study was previously registered by clinicaltrials and has a sufficiently large sample (atDCS=35, stDCS=36) to answer the scientific questions raised. Participants received 6 prefrontal tDCS (anode F4, cathode F3, 2mA, 13 minutes) sessions on a total of three days. Outcome measures of smoking behaviour were collected using a mobile app with a frequency of responses (21 days, 4 times per day).

All in all, this is an interesting study that is well designed and sufficiently powered for a pilot study. There are still some minor issues:

- It makes sense to use age and craving as co-variables in the statistical model, but I don't understand why the gender was not included?

- Fig3/4: The SD for active and sham tDCS should be stored in the figure, e.g. less contrasting background.

P.S.: Another plus is the disclosure of the data in the supporting information (SPSS files).

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #4: Yes: Daniel Keeser

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

13 Feb 2020

Response reviewer #2: Overall, this is not a well controlled study (1). The results are not sufficient to support the conclusion that rtDCS has no effects on daily smoking behavior (2). There are many possible reasons that the results are negative. For instance, the baseline of craving from two groups are significantly different (3); all subjects were light smokers so that there was the floor effect (4); main effects may be lost because of the low compliance rate (5), and so on:

1. The statement that the current study is not well-controlled seems very unfair and is unsubstantiated. The study had a double-blind, randomized, sham-controlled design (line 104-106) as explained in the following paragraph (line 139-145):

“The control group received sham tDCS by the DC-plus stimulator. For sham, the electrodes were positioned at the same locations as active tDCS, but in this case the stimulator was gradually turned off after 30 s. Since the itching sensation of tDCS is often only experienced initially during stimulation, subjects remained blinded of the stimulation condition they received [e.g. 8, 29]. The experimenter was also blinded from the tDCS condition. That is, the codes that can automatically activate sham or active tDCS, were randomly assigned to participant numbers by an independent researcher. Then, the experimenter randomly assigned the participant numbers.”

This is the standard protocol for tDCS studies with a between subject design (see for example refs 14 and 19). We even preregistered the study; we have done everything in compliance to current standards.

2. We have revised the title of the manuscript accordingly. We are careful not to explicitly state this conclusion and clearly describe in the discussion that the findings of the current study should be interpreted with caution because of several limitations (starting from line 300). The conclusion of the discussion points out that we refer only to the results provided in the current study, stating:

“In sum, in the current study we did not find evidence that tDCS over the DLPFC decreases cigarette consumption and cigarette craving in ad libitum smokers that

have no desire to quit at the moment of intervention.”

3. It is indeed the case that there are baseline differences in craving. This is however the result of randomization, as can happen in clinical trials. It does not assume a flaw in the design. We agree that it should be taken considered when interpreting the results. Therefore, we have taken craving at baseline into account as covariate and this did not change the results (line 191-193). In addition, the difference in craving remained over time (line 246-248). It would have been more problematic if we had found an effect of tDCS on craving, since that could have been attributed to a regression to the mean, but this was not the case.

4. We don’t agree that including light smokers is related to problems with the design of the study. We understand that our results in light smokers cannot by extrapolated to heavy smokers. In the discussion we mention that the smokers were light smokers and how this may have affected the results (line 288-299). We disagree that there was a floor effect, since cigarette consumption for both groups decreased over time (line 224-228).

5. The EMA compliance rate was already discussed as a limitation, and further elaborated on in the discussion. We now slightly revised this to make it hopefully more clear (line 313 – 324):

“A second limitation that should be mentioned is the relatively low compliance rate of between 44.4% and 55.8% on EMA assessments. A recent meta-analysis has shown that the average compliance rate in substance dependent samples is 69.8% [31]. Even though multilevel modelling in HLM 7.01 reliably corrects for random missing data, we performed additional analyses where participants with low compliance rates were excluded to investigate whether compliance rate might have influenced the outcomes. The results of these analyses indicated no change in outcome if compliance rates are higher. Reliability of the data is further supported by the finding that carbon monoxide concentrations correlated with number of smoked cigarettes as indicated in EMA end of the day assessments. Moreover, the EMA data showed that ad libitum smoking was related to craving and positive affect. Specifically, the number of smoked cigarettes increased with both craving and positive affect on the same day. These findings are in accordance with the results from an earlier EMA study with a higher compliance rate [22].”

Response reviewer #4: In this study, the authors investigated the effectiveness of repetitive transcranial direct current stimulation to reduce smoking behaviour. The study was previously registered by clinicaltrials and has a sufficiently large sample (atDCS=35, stDCS=36) to answer the scientific questions raised. Participants received 6 prefrontal tDCS (anode F4, cathode F3, 2mA, 13 minutes) sessions on a total of three days. Outcome measures of smoking behaviour were collected using a mobile app with a frequency of responses (21 days, 4 times per day).

All in all, this is an interesting study that is well designed and sufficiently powered for a pilot study. There are still some minor issues:

- It makes sense to use age and craving as co-variables in the statistical model, but I don't understand why the gender was not included? (6)

- Fig3/4: The SD for active and sham tDCS should be stored in the figure, e.g. less contrasting background (7)

P.S.: Another plus is the disclosure of the data in the supporting information (SPSS files):

6. Gender was also included as covariate (line 193 – 195). In addition, the study included a similar amount of male and female participants and there were no differences of gender between groups (active and sham tDCS).

7. We have revised the figures accordingly.

The main point we would like to make is that we don’t agree with reviewer #2 that there are flaws in the research design and/or methodology. The results may be disappointing - it did not show the hypothesized effects of tDCS - yet they are what they are. We hope that given the recent developments in improving science by facilitating the publication of null results when a study is well-designed (as reviewer # 4 also acknowledges) and the policy of PLOS ONE, the study will be published despite the fact that we were not able to find effects of tDCS in this population. We have addressed possible limitations clearly and critically in the discussion and therefore request that our resubmitted manuscript can be considered for publication in PLOS ONE.

3 Apr 2020

PONE-D-19-19431R2

No effect of repetitive tDCS on daily smoking behaviour in light smokers: A placebo controlled EMA study

PLOS ONE

Dear Ms. Verveer,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Please consider the Points raised by Reviewer 5 (statistical reviewer).

==============================

We would appreciate receiving your revised manuscript by May 18 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Berthold Langguth

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

Reviewer #4: The authors have answered all my open questions. The revised manuscript has improved significantly. I have no further questions. However, I would like to emphasize the importance of non-result studies for the field. These are important and should be published. Daniel Keeser

Reviewer #5: The authors were able to address the previous comments raised satisfactorily. The study can be highlighted as a "pilot study" in the manuscript. If I am not mistaken, there is no sample size/power statement presented in the manuscript. On what basis was 73 participants included ? At this late stage, I am not asking authors to propose and justify this, but some comments in this regard (claiming this as a pilot study) would be helpful.

I have some additional minor comments. Although the statistical methods presented have been broadly classified as "multilevel methods" (see Page 10; Data Analyses section), more details are expected for the reader to understand better. Specificaly, are they fitting a linear (or non-linear) mixed effects model (pretty typical in repeated measures scenario)? The repeated measures in those models are usually factored in by introduction of random effects. It is unclear what they are doing; some more details would have assisted in a smoother reading.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #4: Yes: Daniel Keeser

Reviewer #5: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

1 May 2020

Response to reviewer #4:

We would like to thank Daniel Keezer for his valuable comments, and we agree that the results of the current study are highly important in the field of neurostimulation in addiction and should be published.

Response to reviewer #5:

Dear reviewer, thank you for raising these important questions.

1. Regarding the sample size: we have conducted a power analysis before the start of the study, which we indicated in our medical ethical submission. The following power statement was made:

“The number of participants was based on a previous study in which the effect of repetitive tDCS on cigarette consumption was examined in 12 participants using a within-subject design (Fecteau et al., 2014). Our sample size was estimated based on a moderate effect size of tDCS on cigarette consumption on the last day of their study, which was four days post treatment (d = -.58). Based on a two-tailed p-value of .05 and a power of .80, we need approximately 80 participants to find significant between-subject differences, if present.”

We agree that this sample estimation is subjective to bias, as their study design was different from ours and the outcomes were previously not measured by EMA. We therefore adapted the manuscript by mentioning the exploratory nature of the current study.

2. We have added information to the manuscript regarding multilevel modeling (lines 181-196) and referred to Hox (2010) for further information.

6 May 2020

No effect of repetitive tDCS on daily smoking behaviour in light smokers: A placebo controlled EMA study

PONE-D-19-19431R3

Dear Dr. Verveer,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Berthold Langguth

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #5: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #5: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #5: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #5: No

11 May 2020

PONE-D-19-19431R3

No effect of repetitive tDCS on daily smoking behaviour in light smokers: A placebo controlled EMA study

Dear Dr. Verveer:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Berthold Langguth

Academic Editor

PLOS ONE