Neural mechanism by which transcranial direct current stimulation reduces cigarette cravings: study protocol for a randomized controlled crossover trial
Bin Shi1, Li-zhuang Yang2, Ying Liu M.D. 1, Xiaochu Zhang Ph.D. 3
1 The First Affiliated Hospital of University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui Province, China
2 Medical Physics Center, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui Province, China
3 School of Life Sciences, University of Science and Technology of China, Key Laboratory of Brain Function and Brain Diseases, Chinese Academy of Sciences, Hefei, Anhui Province, China
|Date of Web Publication||8-Mar-2018|
School of Life Sciences, University of Science and Technology of China, Key Laboratory of Brain Function and Brain Diseases, Chinese Academy of Sciences, Hefei, Anhui Province
The First Affiliated Hospital of University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui Province
Source of Support: None, Conflict of Interest: None
Background and objectives: Controlling the urge to smoke that stems from a cue-induced craving is the key to successfully breaking the habit. Transcranial direct current stimulation (tDCS) has been shown to improve human control over cognition and behavior. Preliminary behavioral studies have shown that tDCS can reduce cigarette cravings. However, the underlying neural mechanism remains poorly understood. In this study, we used transcranial direct current to stimulate the dorsolateral prefrontal cortex in patients who were addicted to cigarettes. We analyzed the correlation between changes in brain function indicators (e.g., local brain activation and long-distance connectivity) caused by tDCS and the change in cigarette cravings, with the purpose of identifying the neural mechanism by which tDCS to the prefrontal lobe reduces cigarette cravings.
Design: A prospective, single-center, randomized, controlled crossover trial.
Methods: Forty-two patients addicted to cigarettes who received treatment in the Affiliated Hospital of Anhui Medical University, China received one session each of real and sham tDCS. The time interval between real and sham stimulations was 1 week. The order of stimulation was determined using a random number table. For real tDCS, stimulation intensity was 1 mA, and stimulation time was 30 minutes. For sham tDCS, stimulation intensity was increased to 1 mA within 30 seconds, and then decreased to 0 mA within the next 30 seconds. Stimulation was not performed within the subsequent 29 minutes. At the end of each stimulation session, functional magnetic resonance imaging was performed to record brain activity in patients during a smoking-cue task. Participants reported how much they craved cigarettes using a Visual Analog Scale before and after watching smoking scenes.
Outcome measures and results: The primary outcome measure was the degree to which cigarette cravings increased after watching smoking scenes following each stimulation session. The secondary outcome measures were local brain activation and long-distance connectivity between activated brain regions after watching smoking scenes, as well as the incidence of reverse reactions following each stimulation session. After the data collection was complete, data from 32 of the 42 initial patients were included in the final analysis. The results revealed that the increase in cue-induced cigarette cravings was significantly reduced (t = 2.319, df = 31, P = 0.027) after real tDCS compared to sham tDCS. Significant effects were observed in the left superior frontal gyrus and left middle frontal gyrus. Psychophysiological interaction revealed that the connectivity between the dorsolateral prefrontal cortex and the right parahippocampal gyrus was correlated with the amount of increase in cue-induced cigarette cravings (r = 0.522, P = 0.002).
Discussion: Based on fMRI findings, the present study was performed to identify the neural mechanism through which tDCS reduces cue-induced cigarette craving. Preliminary results suggest that electrical stimulation to the dorsolateral prefrontal cortex reduces craving by modulating the long-distance coupling associated with the dorsolateral prefrontal cortex.
Ethics and dissemination: This study was approved by the Biomedical Ethics Committee, Anhui Medical University, China (approval number: 20140241). The study protocol was performed in strict accordance with the Declaration of Helsinki formulated by the World Medical Association. Written informed consent of the study protocol and procedure was obtained from each patient. Patient recruitment and data collection began in March 2014. Outcome measures were analyzed in February 2015. The trial ended in March 2015. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.
Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-IPR-16007980).
Keywords: smoking; nicotine; craving; cognition; prefrontal lobe; attention; neuroimaging; functional magnetic resonance imaging
|How to cite this article:|
Shi B, Yang Lz, Liu Y, Zhang X. Neural mechanism by which transcranial direct current stimulation reduces cigarette cravings: study protocol for a randomized controlled crossover trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:17-21
|How to cite this URL:|
Shi B, Yang Lz, Liu Y, Zhang X. Neural mechanism by which transcranial direct current stimulation reduces cigarette cravings: study protocol for a randomized controlled crossover trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 Mar 22];3:17-21. Available from: http://www.actnjournal.com/text.asp?2018/3/1/17/226188
Bin Shi#, Li-zhuang Yang#
#These two authors contributed equally to this manuscript.
| Introduction|| |
Nicotine is an important component of tobacco, and long-term smoking makes smokers addicted to and dependent on nicotine (Engelmann et al., 2012; Majeed et al., 2016; Laude et al., 2017; Peng et al., 2017; Petrakis et al., 2017; Yang et al., 2017). Therefore, controlling an urge to smoke that stems from a cue-induced craving is the key to successfully breaking the habit (Erblich et al., 2015; Wray et al., 2015; Zanchi et al., 2015; Veilleux et al., 2016). Transcranial direct current stimulation (tDCS) is an extracranial brain-stimulation method that is used to modulate cortical excitability using a constant, low-intensity (1–2 mA) current (Fregni et al., 2008; Lefaucheur et al., 2009). tDCS has three stimulation types: anodic, cathodic, and false (sham). Anodic stimulation reportedly enhances the excitability of neurons at the stimulation site, while cathodic stimulation decreases neuronal excitability, and sham stimulation is generally used as a control (Utz et al., 2010). tDCS has been shown to improve human cognitive and behavioral control. Preliminary behavioral studies have shown that tDCS can reduce cigarette cravings (Fregni et al., 2006; Nitsche and Paulus, 2011; Nardone et al., 2012). However, the underlying neural mechanism remains poorly understood.
Features of existing studies
A functional magnetic resonance imaging (fMRI) study regarding nicotine addiction found a distributed system of relevant brain regions, including the amygdala, anterior cingulate gyrus, orbital gyrus, and dorsolateral prefrontal lobe (DLPFC) (Wilson et al., 2004). However, no consensus has been reached regarding the brain regions that play the most important roles in reducing cue-induced cigarette cravings.
Main objective of this study
Based on fMRI findings, this study was performed to investigate the neural mechanism through which tDCS reduces cue-induced cigarette craving.
| Methods/Design|| |
Affiliated Hospital of Anhui Medical University, China
Male participants who received treatment at the Affiliated Hospital of Anhui Medical University for nicotine addiction from March 2014 to February 2015 were recruited through recruitment advertisements on the hospital website. Forty-two male patients (aged 18–60 years) met the inclusion criteria (see below) and provided informed consent before participation in the study.
Patients presenting with all of the following criteria were considered for inclusion:
- Smoke > 10 cigarettes per day for 2 consecutive years
- Normal or corrected to normal vision
- No nervous system disease or mental or physical disorder
- No other treatments
- No MRI-incompatible implants
After initially being included, patients were withdrawn from the study in the following situations:
- The sponsor requested withdrawal for safety reasons.
- The patient was unable to complete the test task.
This was a prospective, single-center, randomized, controlled crossover trial. Patients received two types of tDCS delivered to the DLPFC. Each type was administered in a single 30-minute session. In real tDCS sessions, current density was increased to 1 mA within 30 seconds, stabilized at 1 mA for 29 minutes, and then reduced to 0 mA in the final 30 seconds. In the sham tDCS sessions, current intensity was increased to 1 mA within 30 seconds, reduced to 0 mA in the next 30 seconds, and continued at 0 mA (i.e., no stimulation) for the subsequent 29 minutes. We measured (1) the degree to which cue-induced cigarette cravings increased after each stimulation session and (2) local brain activation and connectivity between activated brain regions after stimulation sessions. We also monitored patient condition for adverse reactions. A flow chart for the study is shown in [Figure 1].
|Figure 1: Flow chart for the trial.|
Note: Black triangles represent times when cue-induced cigarette cravings were reported. tDCS: Transcranial direct current stimulation.
Click here to view
We used a randomized crossover grouping. A random number table was generated by SPSS 13.0 software (SPSS, Chicago, IL, USA). The order of stimulation (i.e., real →sham followed by sham→real, or the reverse) was determined according to the random number table. The two stimulation sessions were separated by one week. The details are shown in [Figure 1]. Blind grouping was not used.
We used neuroConn's DC-Simulator (neuroConn GmbH, Ilmenau, Germany) for administering tDCS. The anode of the tDCS device was a conductive-rubber electrode (5 cm × 7 cm) and the cathode was used as a reference electrode (10 cm × 10 cm). Both the anode and cathode were placed in saline-soaked sponges for stimulation delivery. According to the International 10–20 System of Electrodes, we placed the anode and cathode at the F4 and F3 positions, respectively. A plastic cap was used to fix the electrodes to the skull. The start and end of the current delivery were performed using a progressive approaching which current was increased to 1 mA within the first 30 seconds of stimulation and reduced to 0 mA during the last 30 seconds of stimulation. The tDCS procedure is shown in [Figure 2].
|Figure 2: A schematic of the transcranial direct current-stimulation (tDCS) procedure.|
Click here to view
Smoking cue task
We measured brain activity while patients performed a smoking-cue task. The task lasted 8 minutes and consisted of 150 trials. In each trial, participants viewed a randomly presented picture for 0.9 second that included varying numbers of lines (2–5) at the center. Then a fixation appeared with a jittered duration within a range of 1.1–5.1 seconds. Patients were asked to report the number of lines on the picture using two MRI-compatible keypads in their hands. Half the pictures (75) were images related to smoking, while the other half were not. We used the difference in brain activity between smoking/non-smoking trials as an indicator for smoking cue-induced brain activity.
fMRI scanning parameters
fMRI was performed using an 3.0 T Achieva MRI system (Philips Healthcare, Best, The Netherlands). T2*-weighted gradient echo sequences were used to acquire functional images. The scanning parameters were: scan layers = 32, layer thickness = 4 mm, repetition time = 2 seconds, echo time = 30 milliseconds, angle of deflection = 90°, matrix = 64 × 64, field of view = 240 mm × 240 mm. After acquiring functional images, 3D images with an accuracy of 1 mm were acquired for spatial registration. Images were processed using AFNI. The functional 3D volume images were corrected for slice-acquisition time differences, registered to the last volume, and spatially normalized to Talairach space. Then, they were spatially smoothed (full width at half maximum = 6 mm) and each voxel time series was temporally normalized by scaling each trial by its mean so that all trials had a mean signal of 100. In the first level GLM, head movements in six directions were entered as covariates. The contrast between smoking pictures and neutral pictures (smoking − neutral) in the cue-reactivity task was the interest. The smoking − neutral contrast was used to define the main nodes of the cue-reactivity system. To correct for multiple comparisons, a cluster-wise threshold was determined using the Monte Carlo simulation.
Primary outcome measure
The primary outcome measure was the degree to which cigarette cravings increased after being cued. It was calculated according to the following formula: the craving increase = 100 × (craving after smoking cue − craving before smoking cue)/craving before smoking cue × 100%.
Secondary outcome measures
Local brain activation induced by the smoking cue: Smoking cue-induced local brain activation was calculated as the contrast between smoking scene-induced brain activation and non-smoking scene-induced brain activation. These values were tested for correlations with the level of cue-induced cigarette-craving increase.
Smoking cue-induced brain connectivity: The DLPFC was used as a seed brain region for a psychophysiological interaction analysis. Smoking scene-induced and non-smoking scene-induced brain connectivity was analyzed. We analyzed the relationship between smoking cue-induced brain connectivity and the level of cue-induced cigarette-craving increase
Incidence of adverse reactions: The incidence of adverse reactions was the number of patients having adverse reactions divided by the total number of patients.
Adverse reactions, including sleepiness, drowsiness, itchy, tingling or burning sensations of the scalp, and inattention were recorded. The possible causes of adverse reactions were analyzed. Data on patient's adverse events and side effects were tabulated. The causes and explanations were recorded. Proper treatments were immediately used to treat the adverse events occurring during the trial. These adverse events and side effects as well as their causes and explanations were reported to the researchers in charge, the ethics committee of the clinical research institute, state and provincial food and drug administration, the sponsor, and clinical research associate within 24 hours.
This study was approved by the Biomedical Ethics Committee, Anhui Medical University, China, and a protocol agreement was signed. Researchers were familiar with clinical trial imaging method and the flow chart of the trial.
During the trial
During patient recruitment, regular audits were necessary to ensure included patients were eligible, the trial was performed in strict accordance with the study protocol, and related data were complete.
At the end of all trial procedures, a final visit was required to ensure relevant records were complete and accurate.
All data were statistically analyzed using SPSS19.0 software (IBM, Armonk, NY, USA) and followed the intention-to-treat principle. Normally distributed measurement data are expressed as the mean ± standard deviation. Non-normally distributed measurement data are expressed as lower quartile (q1), median, and upper quartile (q3). Numerical data are expressed as percentage. Paired sample t test was used for comprising the difference in the amount of increase in cue-induced cigarette cravings between real tDCS and sham tDCS. Pearson's chi-square test was used for comparing the incidence of adverse reactions between real tDCS and sham tDCS. Brain function activation was analyzed using AFNI method. The current effect of each voxel in the brain was analyzed using analysis of variance. The brain connectivity between activated brain regions was analyzed using psychophysiological interaction. The connectivity between activated brain regions was correlated with the amount of increase in cigarette cravings using Pearson correlation method, with inspection level both sides of α = 0.05.
In accordance with a previous study (Jansen et al., 2013), the average effect amount of cigarette craving evoked by a single tDCS was 0.476 (CI: 0.316–0.636). Taking effect amount 0.476 as a standard, α = 0.05 (one-sided), power = 85%, paired sample t test was used, and the effective sample size n = 33 was calculated. Assuming a patient loss rate of 20%, we included 42 patients in each group.
Processing method for missing data
If a patient's records were lost, the patient was excluded from this study. Corresponding numbers of new cases were supplemented.
Baseline data collection
[Table 1] shows patient's baseline information.
Researchers completed the case report form for each case. After the completed case report form was reviewed by an inspector, data input and management were performed. After data transfer, contents recorded in the case report form were not modified.
Quality control of the clinical trial
During the clinical trial, sponsor inspectors conducted regular periodic visits to the research center to ensure strict adherence to all aspects of the research program. In addition, the original data were checked to ensure that the contents of the case report forms were correct and complete.
Ethical considerations and informed consent
This clinical trial followed the relevant laws and regulations of the Declaration of Helsinki. This manuscript was prepared and modified according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 1 [Additional file 1]). The researchers took the responsibility of providing the independent ethics committee with the clinical trial protocol and informed consent forms and providing patients with related informational materials. The trial was not initiated until approval from the ethics committee was received. This study was approved by the Biomedical Ethics Committee, Anhui Medical University, China (approval No. 20140241).
| Results|| |
Forty-two participants were initially supposed to be included in the study, however, only 40 were actually included. Among them, eight dropped out or were rejected because of poor fMRI image quality. Thus, 32 participants were included in the analyses.
Change in cue-induced cigarette cravings
Cue-induced cigarette cravings (0.2 ± 2) after real tDCS were significantly less than those after sham tDCS (8.3 ± 3.6, t = 2.319, df = 31, P = 0.027).
Smoking cue-induced local brain activation
Whole-brain family-wise error rate correction of the fMRI data revealed significant activation in the left superior frontal gyrus (t = 3.812, df = 31, P = 0.0006) and left middle frontal gyrus (t = 2.721, df = 31, P = 0.011) when viewing the smoking cues. The Voxel-wise threshold of P < 0.005 combined with a minimum volume of 1,203 mm3 was needed to get a family-wise error corrected P < 0.05.
Smoking cue-induced brain connectivity
A psychophysiological interaction analysis indicated that the functional brain connectivity between the left DLPFC and the rest of the brain significantly changed after real tDCS (t = 3.859, df = 31, P = 0.0005). Additionally, the connectivity between the DLPFC and right parahippocampal gyrus was positively correlated with the increase in cue-induced cigarette craving (r = 0.522, P = 0.002).
| Discussion|| |
Significance of this study
This study is the first to report that tDCS delivered to the DLPFC can reduce how much nicotine addicts crave cigarettes. More importantly, our fMRI findings confirm that local DLPFC function can be altered by tDCS, suggesting that the change in cigarette cravings depends on the long-distance connectivity between the DLPFC and the hippocampus. This indicates that the change in cigarette craving might be related to the retrieval of addiction-related memory, and that the key to treating addiction is to disrupt the extraction of these memories by altering the functional connectivity with the prefrontal lobe.
Limitations of this study
This study only investigated the immediate behavioral changes after a single tDCS session, and did not track the long-term effects. A randomized parallel-controlled trial will be performed to investigate the long-term effect of multiple tDCS sessions and the underlying neural mechanism.
Evidence for future contributions to research in the field
This study showed that tDCS of the DLPFC can reduce cigarette craving and that the neural mechanism might involve local changes in the functional connectivity between the DLPFC and the hippocampus. 
Additional file 1: SPIRIT checklist.
XZ, YL, LZY, and BS designed this study protocol. YL and BS were responsible for patient recruitment. BS and LZY collected and analyzed the data. LZY, BS, YL and XZ contributed to writing of the manuscript. All authors approved the final version of this manuscript for publication.
Conflicts of interest
The authors declare that they have no confilcts of interests.
This study was supported by a grant from 100 Talents Program of Chinese Academy of Sciences, No. BJ2070000047; the National Natural Science Foundation of China, No. 31230032, 31171083, 31471071, 31500917; the Natural Science Foundation of Anhui Province of China, No. 1208085MH179; a grant from the Key Research and Development Program of Anhui Province of China, No. 1704f0804003. The funding bodies played no role in the study design, in the patient recruitment, in the data collection and analysis, in the writing of the manuscript, and in the decision to submit the manuscript for publication.
This study protocol was approved by the Biomedical Ethics Committee, Anhui Medical University, China (approval number: 20140241). The study protocol was performed in strict accordance with the Declaration of Helsinki formulated by the World Medical Association.
Declaration of patient consent
The authors certify that they have obtained patient consent forms. In the form, patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Data sharing statement
Datasets analyzed during the current study are available from the corresponding author on reasonable request.
Checked twice by iThenticate.
Externally peer reviewed.
Funding: This study was supported by a grant from 100 Talents Program of Chinese Academy of Sciences, No. BJ2070000047; the National Natural Science Foundation of China, No. 31230032, 31171083, 31471071, and 31500917; the Natural Science Foundation of Anhui Province of China, No. 1208085MH179; a grant from the Key Research and Development Program of Anhui Province of China, No. 1704f0804003.
| References|| |
Engelmann JM, Versace F, Robinson JD, Minnix JA, Lam CY, Cui Y, Brown VL, Cinciripini PM. Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies (2012) Neuroimage 60:252-262.
Erblich J, Michalowski A (2015) Impulsivity moderates the relationship between previous quit failure and cue-induced craving. Addict Behav 51:7-11.
Fregni F, Boggio PS, Santos MC, Lima M, Vieira AL, Rigonatti SP, Silva MT, Barbosa ER, Nitsche MA, Pascual-Leone A (2006) Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease. Mov Disord 21:1693-1702.
Fregni F, Orsati F, Pedrosa W, Fecteau S, Tome FA, Nitsche MA, Mecca T, Macedo EC, Pascual-Leone A, Boggio PS (2008) Transcranial direct current stimulation of the prefrontal cortex modulates the desire for specific foods. Appetite 51:34-41.
Jansen JM, Daams JG, Koeter MW, Veltman DJ, van den Brink W, Goudriaan AE (2013) Effects of non-invasive neurostimulation on craving: a meta-analysis. Neurosci Biobehav Rev 37:2472-2480.
Laude JR, Bailey SR, Crew E, Varady A, Lembke A, McFall D, Jeon A, Killen D, Killen JD, David SP (2017) Extended treatment for cigarette smoking cessation: a randomized control trial. Addiction doi: 10.1111/add.13806.
Lefaucheur JP (2009) Methods of therapeutic cortical stimulation. Clin Neurophysiol 39:1-14.
Majeed BA, Stanton CA, Dube SR, Sterling KL, Burns JD, Eriksen MP (2016) Electronic cigarette use among current smokers: a pilot qualitative study. Health Behav Policy Rev 3:590-596.
Nardone R, Bergmann J, Christova M, Caleri F, Tezzon F, Ladurner G, Trinka E, Golaszewski S (2012) Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review. Int J Alzheimers Dis 2012:687909.
Nitsche MA, Paulus W (2011) Transcranial direct current stimulation-update 2011. Restor Neurol Neurosci 29:463-492.
Peng AR, Morales M, Wileyto EP, Hawk LW Jr, Cinciripini P, George TP, Benowitz NL, Nollen NL, Lerman C, Tyndale RF, Schnoll R (2017) Measures and predictors of varenicline adherence in the treatment of nicotine dependence. Addict Behav doi: 10.1016/j.addbeh.2017.07.006.
Petrakis IL, Ralevski E, Gueorguieva R, O'Malley SS, Arias A, Sevarino KA, Jane JS, O'Brien E, Krystal JH (2017) Mecamylamine treatment for alcohol dependence: a randomized controlled trial. Addiction doi: 10.1111/add.13943.
Utz KS, Dimova V, Oppenländer K, Kerkhoff G (2010) Electrified minds: transcranial direct current stimulation (tDCS) and galvanic vestibular stimulation (GVS) as methods of non-invasive brain stimulation in neuropsychology-a review of current data and future implications. Neuropsychologia 48:2789-2810.
Veilleux JC, Skinner KD, Pollert GA (2016) Quit interest influences smoking cue-reactivity. Addict Behav 63:137-140.
Wilson SJ, Sayette MA, Fiez JA (2004) Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci 7:211-214.
Wray JM, Gray KM, McClure EA, Carpenter MJ, Tiffany ST, Saladin ME (2015) Gender differences in responses to cues presented in the natural environment of cigarette smokers. Nicotine Tob Res 17:438-442.
Yang LZ, Shi B, Li H, Zhang W, Liu Y, Wang H, Zhou Y, Wang Y, Lv W, Ji X, Hudak J, Zhou Y, Fallgatter AJ, Zhang X (2017) Electrical stimulation reduces smokers' craving by modulating the coupling between dorsal lateral prefrontal cortex and parahippocampal gyrus. Soc Cogn Affect Neurosci doi: 10.1093/scan/nsx055.
Zanchi D, Brody AL, Montandon ML, Kopel R, Emmert K, Preti MG, Van De Ville D, Haller S (2015) Cigarette smoking leads to persistent and dose-dependent alterations of brain activity and connectivity in anterior insula and anterior cingulate. Addict Biol 20:1033-1041.
[Figure 1], [Figure 2]