Home
JournalsCollections
For Authors For Reviewers For Editorial Board Members
Article Processing Charges Open Access
Ethics Advertising Policy
Editorial Policy Resource Center
Company Information Contact Us
Publications > Journals > Exploratory Research and Hypothesis in Medicine> Article Full Text
Original Article
OPEN ACCESS

Download PDF

Trans-cranial Magnetic Stimulation in Treatment of Alcohol Use Disorder: A Meta-analysis

  • Muhammad Irfan Kaleem1,*  and
  • Syed Mujtaba Azhar Bokhari2
Exploratory Research and Hypothesis in Medicine   2023;8(2):94-105

doi: 10.14218/ERHM.2022.00096

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Kaleem MI, Bokhari SMA. Trans-cranial Magnetic Stimulation in Treatment of Alcohol Use Disorder: A Meta-analysis. Explor Res Hypothesis Med. 2023;8(2):94-105. doi: 10.14218/ERHM.2022.00096.

Abstract

Background and objective

In the US, about 14.5 million people ages 12 and older suffered from alcohol use disorder (AUD) in 2019. AUD affects multiple systems and is a major cause of disability and morbidity, severely reducing quality of life. With currently available pharmacotherapy and psychotherapy (including behavioral therapy) relapse rates remain high due to poor patient acceptability as well as the added factor of craving and impulsivity in addiction disorders. This points to the development of therapies that also act on functional areas of brain responsible for craving and impulsivity. Transcranial magnetic stimulation (TMS) is one type of neuromodulation under study for the treatment of AUD. Here, we review the work done on TMS as a treatment for AUD.

Methods

We searched PubMed and Cochrane databases for relevant articles with the main search terms of “transcranial magnetic stimulation” and “alcoholism”.

Results

Most studies involve stimulation of right dorsolateral prefrontal cortex. Majority demonstrate a decrease in craving but only over time, not between groups. Overall, studies using TMS for the treatment of AUD show mixed results in changes in craving, impulsivity, and alcohol intake.

Conclusion

Mainly, the studies are limited by sample size and lack of uniformity in outcomes measured. Significance of TMS for treatment of AUD is still not clear. A standardized protocol of investigation is needed to allow for a meta-analysis to calculate the overall effect.

Keywords

Transcranial magnetic stimulation, Alcohol use disorder, Craving, Impulsivity

Introduction

Alcohol use disorder (AUD) is a medical condition characterized by an impaired ability to stop or control alcohol use leading to clinically significant impairment or distress.1 According to the 2019 National Survey on Drug Use and Health (NSDUH), 85.6 percent of people 18 years or older drank alcohol at some point in their life.2 the 2020 NSDUH reports about 14.5 million people ages 12 and older suffered from AUD in 2019, men forming greater proportion compared to women.3 Alcohol-related causes lead to approximately 140,000 deaths annually.4 Alcohol consumption adds to loss of quality of life of the patient as well as social and financial burden on the society.5,6 The consequences of alcohol dependence are multisystemic. There is also constant difficulty in achieving as well as maintaining abstinence,7,8 which have been challenging tasks for the treating physician as well as the patient. Furthermore, alcohol use disorder can co-present with neuropsychiatric disorders. A mechanism-based advancement in treatment to reduce dependence on pharmacotherapy or increase adherence to currently used medications for AUD is needed.9

There is abundance of literature on mechanism of alcohol dependence. Ceccanti et al. add evidence to Solomon’s opponent system that alcohol dependence occurs through sequential changes in the neurons.10–12 In earlier stages of alcohol dependence , positive reinforcement by dopamine opposes the stress system which would otherwise lead to negative behavioral symptoms. In later stages an imbalance occurs in dopaminergic and opposing system and dominance of latter system results in negative behavioral symptoms, leading to relapse. Furthermore, one of the mechanisms of craving, withdrawal and impulsivity is decreased dopamine activity in mesolimbic areas and Nucleus Accumbens (NAc) leading to hypo-frontality, measured through serum prolactin levels, which are indirect indicators of dopaminergic activity.10 Dopamine functionality in the brain is affected by various mechanisms which include alteration in levels of dopamine, dopamine receptors and dopamine transporter. All of these mechanisms point to decreased activity of dopamine in AUD.13

In a neural connectivity perspective, fronto-striatal pathways modulate limbic and executive control systems. The connections between medial prefrontal cortex (MPFC) and ventral striatum form the limbic circuit whereas projections between dorsolateral prefrontal cortex (DLPFC) and dorsal striatum make up executive control circuit. Mechanisms which make the alcohol use disorder patients prone to drug related cues could possibly be enhanced limbic circuit activity during an appropriate stimulus (drug cue) and reduced activity in executive control circuit to oppose the limbic drive for drug.14,15 These form a potential basis of neuromodulation, which could be direct (targeting MPFC) or indirect (targeting DLPFC).16 For DLPFC, dopamine release in nucleus accumbens (NAc) mediates its modulatory effects.17 Therefore idea of altering excitability of DLPFC noninvasively, by an electric or a magnetic field, emerged to reduce craving.18 Such modulation of neural circuits has already been significantly studied for major depressive disorder (MDD) and obsessive compulsive disorder (OCD).19

Current pharmacotherapy to treat alcoholism includes disulfiram, naltrexone and acamprosate.20 These drugs have been proven effective: Disulfiram works by causing nausea however fails to reduce craving. On the other hand naltrexone and acamprosate (effective for relapse prevention) may not cause nausea, but nonadherence to their oral formuations is a significant barrier to optimized care for many patients.21 Promising advancement in medical treatment with drugs such as topiramate, gabapentin and baclofen for AUD along with neuromodulation may play an important role in future.22 With current pharmacotherapy and psychotherapy, the abstinence rate by the end of 1st year of treatment is less than 40%.7,8,23 Keeping in view the adverse effects and high motivation needed to complete treatment, newer techniques have been sought to deal with AUD. Non-invasive neuromodulation has been one of the studied treatment modalities. Transcranial magnetic stimulation (TMS) and transcranial electric stimulation (TES) are two major types. TMS is a method of applying varying levels of magnetic field to the brain non-invasively (transcranial: through the scalp) to modulate neuronal excitability.24 We discuss TMS in treatment of AUD. TMS was initially used as an investigative technique, where the method of application is pulse application. With time, it found a therapeutic role as well.25,26 TMS is thought to work by long term potentiation (LTP) or long term depression (LTD) of neural activity depending on the frequency, type of stimulation and stimulated area.16

In this perspective, efforts have been directed at exploration of a non-invasive method of treatment for AUD to decrease the relapse rate as discussed above. For this purpose, TMS can be applied for the treatment of AUD which has previously been approved for depression and OCD. TMS is a safe procedure, with a common side effect being headache and a severe (but low risk) side effect being seizure.27,28 Apart from proven safety, the major advantages of TMS are that it is a non-invasive procedure compared to deep brain stimulation (DBS) and while it may produce twitching, the patient does not have to experience the annoying sensations when compared to TES.29 In near future it is already projected to become affordable like pharmacotherapy.30 However, disadvantages of TMS include that it cannot penetrate to deeper structures as DBS can and it is not as precise as DBS.31 Furthermore, the treatment duration is long, requiring 10 to 30 visits making it difficult for patients to follow. TMS is also being questioned, like other neuromodulation techniques, for its ability to affect patient autonomy and alter decision making capacity.32

Here, we review different original studies done to date to investigate the use of TMS in reducing subjective aspects of craving and/or impulsivity in AUD patients.

Methods

A thorough search on this topic was done in PubMed and Cochrane databases through March 2022. The search terms used were: “alcoholism”, “alcohol” AND “disorder”, “dependence ”, “addiction”, “alcohol use disorder” AND “stim*”, “magnetic”, “magnetic stimulation, transcranial”.

There was no restriction applied on age, gender, publication type or period of study. Studies identified through database searches were initially screened by their title. Articles with titles different from our interest were excluded, rest of the articles were reviewed by reading through abstracts and were finalized to be discussed in our review. Studies that targeted AUD (irrespective of presence of a comorbid disorder all types of studies whether randomized or open label, with or without any level of blinding, with or without control, and for any duration of follow up were considered for inclusion. However, studies that were only case studies did not describe the protocol for transcranial magnetic stimulation, or were only exploratory in purpose were excluded. A Flowchart demonstrating PRISMA exclusion strategy is shown in Figure 1.

Identification of studies via databases and registers.
Fig. 1  Identification of studies via databases and registers.

Results

Our review comprises of 19 studies. A good range of target sites have been stimulated. 9 studies stimulated Right Dorsolateral Prefrontal Cortex, 5 Medial Prefrontal Cortex, 2 Left Dorsolateral Prefrontal Cortex, 2 Bilateral DLPFC, 1 Right vs Left DLPFC and 1 study stimulated Insular Cortex. Maximum number of sessions performed was 20 excluding a case study of De Ridder (1Hz stimulation of dorsal Anterior Cingulate Cortex, not included in the table because it involves only one subject) where it was 21. Most studies used a frequency of 10 Hz for stimulation. 13 studies used a figure of 8 coil, 5 studies used an H coil, and one study used a double cone coil.

Types of assessments used include craving scales as Alcohol Craving Questionnaire (ACQ), craving Visual Analog Scale (VAS), Obsessive Compulsive Drinking Scale (OCDS), Penn Alcohol Craving Scale (PACS), and Alcohol Usage Questionnaire (AUQ). Impulsivity scales include Go-no-go task, Delay Discounting Time (DDT), Stop Signal Task (SST). Alcohol intake and consumption scales include Days of Maximum Alcohol Intake (DMAI), percentage Heavy Drinking Days (pHDD) and daily consumption. Some studies also measured relapse rate.

It is interesting to note the differences on a subgroup level of assessment methods. Two studies, from the same group utilized ACQ, which measures the level of alcohol craving, and did not show any significant difference between the active and sham groups. 7 studies utilized OCDS to measure obsessive compulsivity and craving towards alcohol. Overall, there was no significant between the groups in 4 studies while 3 demonstrated a significant effect, real group scores better than sham group scores. In VAS and AUQ measurements only one out of 4 respective studies showed a significant difference in scores between real and sham groups. However, there have been improvements within the groups. Other factors such as years of education have a positive correlation while the age of onset of alcohol use has a negative correlation with outcome scores. The results are summarized in Table 1.10,13,33–49

Table 1

Characteristics and outcomes of studies included in this meta-analysis

StudyStudy designInclusion criteriaFrequency of stimulation, Coil shapeTarget location# of TMS sessions1) Severity of alcohol abuse (years of drinking or by scale); 2) Alcohol use status on starting TMS; 3) Co morbid psychiatric disordersNumber of participantsOutcome
Mishra 201033Randomized single blind sham controlled, 1 month follow-upAge:18–60 years, CIWA-Ar score 10 or less10 Hz; Figure-of-8 coil; 110% MTRight DLPFC101)15.3 years in active 13.5 years in shamSham 15 + Active 30 = 45Significant effect of treatment over time for ACQ-NOW(p < 0.0005).
Hoppner 201134Randomized sham controlled, 10 days follow-upMean age(years): Real: 43.1; Sham: 48; Females only20 Hz; 90% MTLeft DLPFC101) 8 years in real; 6.7 years in sham; 2) 14 days after detoxificationSham 9 + Active 10 = 19OCDS: No significant difference in craving between real and sham groups.
Herremans 201235Randomized single blind sham controlled, between subjects, 3 days follow upAge: 18–65 years20 Hz; Figure of 8 coil; 110 % of MTRight DLPFC12) Detoxified (Substitution phase completed in mean duration of 12 days)Sham 16 + Active 15 = 31OCDS: Significant main effect of time (p = 0.02). However, no significant main effect for group. In delayed effects of one stimulation session, no main effects for test moment (Saturday, Sunday, Monday) or for Group.
Herremans 201336Randomized single blind sham controlled, crossover designAge: 18–65 years20 Hz; Figure of 8 coil; 110% MTRight DLPFC12) Detoxified (Diazepam substitution completed in mean duration = 14 days and then benzodiazepine-free period 7 days)29 patients, crossover designOCDS: A significant main effect for time (p = 0.03).
Mishra 201537Single-blind, active- comparator. 10 days follow upAge: 18–60 years, Male CIWA = Ar score 10 or less10 Hz; Figure of 8 coil; 110% MTRight vs Left DLPFC101) 16.9 years in Right, 17.7 years in Left; 2) 3 days of detoxification10 Right + 10 Left = 20ACQ-NOW: No main effect of group (right & left DLPFC) but significant main effect of time (p < 0.0001). The interaction effect between group and time was not significant. GCI:No main effect of group (right & left DLPFC) but significant main effect of time (p < 0.0001). The interaction effect between group and time was not significant.
Girardi 201538Open label add-on compared to standard treatment, 6 months follow upAge: 16–65 years >5-year duration of illness20 Hz; H1 coil; Deep TMS; 120% MTBilateral DLPFC201) 9.6 years in add-on 12.6 years in standard; 2) Detoxified for 1 month; 3) Dysthymic disorderAdd-on dTMS 10 + standard treatment 10 = 20Add-on deep TMS to standard leads to significant reduction in craving, OCDS. Reduction of OCDS from baseline was significantly larger in the experimental than in the control group at all time-points(p < 0.01).
Ceccanti 201510Randomized double blind placebo controlled, 6 months follow upMean age(yeats): Real: 43; Sham: 47; Males only20 Hz; H coil; Deep TMS; 120% MTMedial PFC101) 26 years in real, 25 years in sham; 2) 10 days of residential withdrawal for benzodiazepines flush out. TMS only therapy provided.Sham 9 + Real 9 = 18Daily alcohol consumption(drinks/day): Real vs sham not significantly different. DMAI: Real vs sham not significantly different. VAS: Real vs sham not significantly different.
Herremans 2015392-part study: Experimental part: single blind sham controlled between subjects; Treatment part: open labelAge: 18–65 years20 Hz; figure-of 8 coil; 110% MTRight DLPFC15 (in 4 days)1) Mean 12 years, # of days patients drank more than 5units/day: 19.6; 2) No alcohol for at least 7 days, 2 weeks washout period for those on anti-craving medicationsExperimental part:13 Sham + 13 Active = 26 in 1 rTMS session; reatment part: All 23 subjects in Accelerated HF-rTMS treatment partExperimental part: TLS (ten-point Likert scales): Active v sham (1 rTMS session) No significant effect on TLS-scores for the active stimulation and the sham stimulation. No significant difference in TLS between both (active vs sham) stimulation groups. Accelerated HF-rTMS treatment part: Significant decrease for both the OCDS (p = 0.02) and the AUQ (p = 0.02) after HF-rTMS treatment. A significant effect between all TLS of the first scan compared with all TLS of the last scan (all p < 0.05). However, all other TLS comparisons were not significant.
Herremans 201640Open label; 4 weeks follow upAge: 18–65 years20 Hz; Figure of 8 coil; 110% MTRight DLPFC15 (in 4 days)1) 14.5 years in relapsers, 9.8 years abstainers# of days patients drank more than 5units/day: Relapsers; 17.7. Abstainers: 20 2) At least 1 week diazepam free before stimulation19Relapse rate of 68% (13/19) at 1 month with no significant difference in characteristics of relapsers and abstainers.
Del Felice 201641Add-on rTMS with disulfiram, Single blind, randomized sham controlled1 month Follow upAge: 18–65 years10 Hz; Figure of 8 coil; 100% MTLeft DLPFC42) Abstained for more than 6 days before the beginning of the rTMS sessionsSham 10 + Active 10 = 20Alcohol intake: No significant modifications over time or group Craving (VAS): No significant modifications over time or group. Attentional bias (Mean Numeric Stroop scores): Improved from 0.311 to 0.901 at 1 month (p = 0.004). Go/No-Go task: Improved from 0.450 to 0.966 at 1 month (p = 0.0.015)
Addolorato 201713Double blind, randomized sham controlled trialAge: 39–64 years Alcohol withdrawal CIWA-AW score 10 or less.H coil, 10Hz (deep rTMS); 100% MTBilateralDLPFC121) 17 years; ADS:13.8 ± 7.5Sham 6 + active 5 = 11OCDS: Craving did not significantly change in the real and sham group. Alcohol intake (Abstinence days, number of drinking days number of drinks per drinking days and total drinks): Significantly reduced alcohol intake(p = 0.008) in real group only, with time.
Hanlon 201742Single blind sham controlled crossover studyMean age in years: 27cTBS; 5Hz; Figure of 8 coil; 110% MTLeft Frontal pole(MPFC)11) Duration of use:13.2 ± 12; AUDIT:14.2; TLFB:11.7; 2) Allowed to drink but undetectable blood alcohol levels in the lab.24Self-reported craving (VAS): Significant main effect of time (F(2,132) = 3.62), but no interaction nor effect of condition (real versus sham).
McNeill 201843Counterbalanced, within-participants, controlled stimulationAge: 18 - 27 yearscTBS, 50 Hz; Figure of 8 coil; 80% MTRight DLPFC11) AUDIT: 11.75 ± 4.4; TLFB:39.6 units; 2) Actively consuming20Alcohol consumption: Participants consumed significantly more beer following active stimulation compared with control stimulation (p < 0.001).
Kearney-Ramos 201844Single blind, active-sham controlledAge: 21–54 years5Hz; cTBS; Figure of 8 coil; 110% MTLeft Ventral MPFC11) Years of alcohol use: 10 ± 5.1, AUDIT:14.2 ± 4.8; 2) Time since last alcohol use:2.8 ± 2.6 daysSham 12 + active 12 = 24Self-reported alcohol craving: No significant main or interaction effects of time (pre/post) or treatment (real/sham) on self-reported alcohol craving (p ≥ .05).
Schluter 201945Single blind Randomized Controlled TrialAge: 20- 65 years; Less than 4 months after detoxification10 Hz; Figure of 8 coil; 110% MTRight DLPFC101) 11 years in active, 10 years in sham; 3) Active group taking antidepressants significantlySham 40 + active 40 = 80DDT: No significant main effects of session, or treatment group; GNGT:No significant main effects of session or treatment group. SST: No significant main effects of session, or treatment group.
Jansen 201946Single blind, sham controlledMean age in years: AUD: 42; HC: 4410 Hz; Figure of 8 coil; 110% MTRight DLPFC11) Mean AUDIT of all participants: 22.11; 2) Sober for at least 3 weeksSham 18 + active 20 = 38 (AUD; n = 39) and healthy controls (HC; n = 36)AUQ: No differential effect on change in craving over time (pre and post) for AUD patients and/or HC.
Irene 202047Double-blind, randomized, sham-controlled, clinical trial. 12 weeks follow up25–64 years, postmenopausal or negative UPT females10 Hz; H8 coil; 120%; MTInsular cortex, bilaterally, excluding prefrontal areas151) ADS: 19.3 in rTMS group, 16.7 in sham group, Peth 0.9–1.1, TLFB 39–48%. 3) Mild cognitive impairment (MMSE not less than 24)Sham 22 + active 23 = 45AUQ: Significant main effect of time during treatment, for both (p < 0.001). PACS: Significant main effect of time during treatment (p = 0.01). However, no between group effect.
Maayan Harel 202148Randomized double blind, sham controlled, 12 weeks Follow upMean age in years: Active: 43.7; Sham: 42.510 Hz; H7 coil; Deep TMS; 100% of MTMPFC and ACC20AUDIT active 24.5 (7.2); 26.1 (6.3); ADS 16.5 (7.5); 17.8 (6.2); TLFB, HDD, % 36.8% (32%); 37.6% (27%); 2) Abstinent from alcohol for at least 5 days (but no more than 1 month)Sham 24 + active 27 = 51pHDD: Significantly lower in the active group than the sham group (p = 0.037). PACS: During follow up craving levels increased in the sham group but less so in the active group.
Maarten Belgers 202249Single blind randomized sham controlled12 months Follow upAge: 20 to 65yearsFigure of 8 coil; 10 Hz; 110% MTRight DLPFC101) Years of problematic use add on tms 16.4 (6.5) years; 14.3 (7.4) years; 2) Detoxification less than 6 weeks; 3) Some patients with PTSDSham 16 + active 14 = 30VAS, OCDS-5, and AUQ: In the follow-up period, from after rTMS, increased craving over time for all participants but less increased craving over time in the rTMS group versus sham (p < 0.05 for main effect of time and group and interaction effect of group by time). Alcohol use (alcohol use per day and the total amount of alcohol): Decreased alcohol use in the rtms group vs sham p = 0.001. Percentage abstinence: The percentage abstinence at the endpoint did not differ between groups.

ACC, Anterior cingulate cortex; ACQ-NOW, Alcohol craving questionnaire; ADS, Alcohol dependence scale; AUD Alcohol use disorder; AUDIT, Alcohol use disorders identification test; AUQ, Alcohol usage questionnaire; CIWA-AR, Clinical Institute withdrawal assessment alcohol scale revised; cTBS, continuous theta burst stimulation; DDT, Delay discounted task; DLPFC, Dorsolateral prefrontal cortex; DMAI, Days of maximum alcohol intake; dTMS, deep TMS; GCI, General craving index; GNGT, Go-no-go task; HC, Healthy controls; HDD, Heavy drinking days; HFrTMS, High frequency repetitive TMS; MMSE, mini mental state examination; MPFC, Medial prefrontal cortex; MT, Motor threshold; OCDS, Obsessive compulsive drinking scale; PACS, Penn alcohol craving scale; pHDD, percentage heavy drinking days; PTSD, Post traumatic stress disorder; SST, Stop signal task; TLFB, Timeline followback; UPT, Urine pregnancy test; VAS, Visual analog scale.

Discussion

The aim of this review is to highlight the studies done on TMS therapy for AUD, their promising features and limitations. Non-invasive neuromodulation therapies, such as transcranial magnetic stimulation and transcranial electrical stimulation, are rapidly gaining interest in the treatment of addiction and psychiatric disorders. Treating these disorders will ameliorate the multisystemic deteriorating effects on the patient and society. TMS was approved by FDA as a treatment modality for major depressive disorder in 200850 and obsessive compulsive disorder in 2018.51 The effect of TMS on craving in AUD has been studied in some combination of open label, single blind and sham controlled, but very few randomized sham-controlled double-blind trials. Most of the studies have measured outcomes/endpoint from 1 to 6 months. There are very few studies which follow patients beyond the 6-month period.38,49 The outcomes measured include craving, impulsivity, alcohol consumption and blood alcohol levels. There is consistency in measuring craving in most of the studies. However other outcomes such as impulsivity or consumption are not measured as consistently. Mishra et al. initially demonstrated decrease in craving using rTMS.33 His study was based on randomized single blind sham-controlled design with one month follow-up. This was followed in 2015 by Girardi et al. who performed an open label study to prove significant effect of add on TMS therapy compared to standard treatment.38 Studies gained pace afterwards, most finding decrease in craving or alcohol intake with time, but not significantly different from non-treatment (control) group.10,47

AUD often coexists with other psychiatric diagnoses. This has two-pronged significance. With TMS treatment, the coexisting psychiatric condition may improve together with craving in AUD,52 or the medication used for the psychiatric condition may confound the results of TMS. Similarly consumption of other substances of abuse and severity of abuse of each of these, including alcohol, can determine effect of treatment.45 The severity of AUD can affect the outcomes after TMS therapy. Chronic alcohol use causes cortical atrophy which implies that intensity of stimulation that reaches the cortex and sub-cortex of these subjects will also vary by the severity of disease.53,54 Thus, patients must be classified accordingly to determine their respective dosage regimens.

There is a need to find out possible duration for which maintenance treatment can be administered like depression where authors have recommended it for up-to several years.55,56 It is also important to know whether this will have any possible side effects for example headache, seizures in the long term and also whether altering one reward function affects other daily activities possibly resulting in a general lack of motivation.

Most of the studies have been conducted only on a relatively smaller sample size. To measure the effect of TMS, which is statistically significant in treatment of AUD, multi-centric larger sample studies should be under taken.38 The context in which a study is conducted can also impact the results. This includes measuring craving in a subject’s natural environment compared to a testing environment where a subject is given a cue and impulsivity is measured. However in trying to measure effect of TMS in a patient’s natural environment rather than in a clinical setting, accurate cues and controls are difficult to set up.35

Depth of stimulation is also important as the distance from scalp to cortex is variable in the population.42 The depth of stimulation is determined by the coil shape (e.g. flat vs bent, figure of 8 vs H- coil design) which is further compounded by the shrinkage of cortex in alcoholics and aged groups.31,57 The shape of TMS coil also determines regional precision and cortical surface area affected.54 Modelling techniques have revealed that H-coil designs affected greater cortical area and depth compared to figure of 8 coil and circular coil designs. Other than affecting the depth of stimulation, age is also a clinical factor in predicting the efficacy of TMS.58 TMS therapy benefit appears later in the older patients than in the younger patients and this has implications for setting treatment guidelines and insurance based health systems.59 However, the age factor may be confounded by the years of alcohol abuse which in itself is an independent prognostic factor.

Majority of studies have investigated Right DLPFC. Others have worked on MPFC, Left DLPFC, dorsal Anterior Cingulate Cortex and insula. When comparing effect of rTMS on right with rTMS on left DLPFC,37 craving was reduced in both right and left stimulation groups but without any significant difference between the side stimulated. rTMS over left side had a positive correlation between severity of alcohol dependence and reduction in craving scores. Right sided rTMS was more effective in mild to moderate cases, authors thus postulating that right sided rTMS affected indirectly through transcallosal suppression of left DLPFC. VMPFC has also shown promising results with respect to cue reactivity however not as successful with reduction in craving. It provides an insight into other possible target areas for stimulation.44 One study is based on the role of insula in craving.47,60 Although it shows no significant effect, but wider connections of insula to several other areas have been proved.

The behavioral state of subjects when they are undergoing TMS is also very important. Emphasis has been placed on this by Mahoney et al.,54 who build on the work of Ramos et al.61 The operating state of a synapse during TMS application determines the degree to which it can be modulated.61–63 This operating state further depends on prior activation of the circuit, therefore leading to the concept of behavioral priming for stimulation.

Future direction

TMS is gaining popularity as a therapy for addiction including alcohol addiction, psychiatric and cognitive disorders. In the case of TMS for AUD, it is most important for the scientific community to develop a consensus on how the outcomes will be measured and also to collaborate towards a larger, multicenter study. Furthermore, many studies have missed out on the value of control and all future studies should include a control group. Any protocol that may be formed for multicenter studies must include daily alcohol consumption as an outcome measure as it is the final goal of any type of therapy combatting AUD. Moreover, a standardized cue exposure for behavioral priming during TMS therapy session for AUD should also be developed and documented as a variable in future studies. This is significant because cue exposure is a requirement during TMS for OCD and has been studied in a similar context for PTSD and smoking, enhancing efficacy of TMS in these subjects.54,64,65 Recently Maayn Harel et al. have inducted this concept into their study by allowing the subjects to hold and smell alcohol before undergoing TMS procedure.48

Conclusion

Pharmacotherapy for the treatment of AUD works in the short term and requires strict patient compliance. This management strategy may be further strengthened by adding on TMS, to reduce craving and relapse. Although multiple studies have been conducted on TMS to prove it an effective treatment modality as in the case of depression and OCD, the results of these studies are mixed and still not directing to a definite conclusion. Future studies should be multicentric and based on a standardized protocol.

Abbreviations

ACQ: 

alcohol craving questionnaire

AUD: 

alcohol use disorder

AUQ: 

alcohol usage questionnaire

DBS: 

deep brain stimulation

DLPFC: 

dorsolateral prefrontal cortex

MPFC: 

medial prefrontal cortex

OCDS: 

obsessive compulsive drinking scale

PACS: 

penn alcohol craving scale

TMS: 

transcranial magnetic stimulation

VAS: 

craving visual analog scale

Declarations

Acknowledgement

The authors do not have any acknowledgements to make.

Funding

The authors did not receive any funding or support from any organization for the submitted work.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose. The authors have no conflict of interest related to this publication.

Authors’ contributions

The authors contributed equally to this work.

References

  1. Kranzler HR, Soyka M. Diagnosis and Pharmacotherapy of Alcohol Use Disorder: A Review. JAMA 2018;320(8):815-824 View Article PubMed/NCBI
  2. Substance Abuse and Mental Health Services Administration. View Article PubMed/NCBI
  3. Substance Abuse and Mental Health Services Administration. View Article PubMed/NCBI
  4. Esser MB, Leung G, Sherk A, Bohm MK, Liu Y, Lu H, et al. Estimated Deaths Attributable to Excessive Alcohol Use Among US Adults Aged 20 to 64 Years, 2015 to 2019. JAMA Netw Open 2022;5(11):e2239485 View Article PubMed/NCBI
  5. Daeppen JB, Faouzi M, Sanchez N, Rahhali N, Bineau S, Bertholet N. Quality of life depends on the drinking pattern in alcohol-dependent patients. Alcohol Alcohol 2014;49(4):457-465 View Article PubMed/NCBI
  6. GBD 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2018;392(10152):1015-1035 View Article PubMed/NCBI
  7. Quelch D, Pucci M, Marsh A, Coleman J, Bradberry S. Elective alcohol detoxification - a resource and efficacy evaluation. Future Health J 2019;6(2):137-142 View Article PubMed/NCBI
  8. Miller WR, Walters ST, Bennett ME. How effective is alcoholism treatment in the United States?. J Stud Alcohol 2001;62(2):211-20 View Article PubMed/NCBI
  9. Donoghue K, Hermann L, Brobbin E, Drummond C. The rates and measurement of adherence to acamprosate in randomised controlled clinical trials: A systematic review. PLoS One 2022;17(2):e0263350 View Article PubMed/NCBI
  10. Ceccanti M, Inghilleri M, Attilia ML, Raccah R, Fiore M, Zangen A, Ceccanti M. Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation: A pilot study. Can J Physiol Pharmacol 2015;93(4):283-90 View Article PubMed/NCBI
  11. Solomon RL, Corbit JD. An opponent-process theory of motivation. I. Temporal dynamics of affect. Psychol Rev 1974;81(2):119-145 View Article PubMed/NCBI
  12. Comer CS, Harrison PK, Harrison DW. The dynamic opponent relativity model: an integration and extension of capacity theory and existing theoretical perspectives on the neuropsychology of arousal and emotion. Springerplus 2015;4:345 View Article PubMed/NCBI
  13. Addolorato G, Antonelli M, Cocciolillo F, Vassallo GA, Tarli C, Sestito L, et al. Deep Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex in Alcohol Use Disorder Patients: Effects on Dopamine Transporter Availability and Alcohol Intake. Eur Neuropsychopharmacol 2017;27(5):450-461 View Article PubMed/NCBI
  14. Ersche KD, Barnes A, Jones PS, Morein-Zamir S, Robbins TW, Bullmore ET. Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain 2011;134(Pt7):2013-2024 View Article PubMed/NCBI
  15. Goldstein RZ, Leskovjan AC, Hoff AL, Hitzemann R, Bashan F, et al. Severity of neuropsychological impairment in cocaine and alcohol addiction: association with metabolism in the prefrontal cortex. Neuropsychologia 2004;42(11):1447-1458 View Article PubMed/NCBI
  16. Hanlon CA, Dowdle LT, Austelle CW, DeVries W, Mithoefer O, Badran BW, et al. What goes up, can come down: Novel brain stimulation paradigms may attenuate craving and craving-related neural circuitry in substance dependent individuals. Brain Res 2015;1628(Pt A):199-209 View Article PubMed/NCBI
  17. Wing VC, Barr MS, Wass CE, Lipsman N, Lozano AM, Daskalakis ZJ, et al. Brain stimulation methods to treat tobacco addiction. Brain Stimul 2013;6(3):221-30 View Article PubMed/NCBI
  18. Klomjai W, Katz R, Lackmy-Vallée A. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS). Ann Phys Rehabil Med 2015;58(4):208-213 View Article PubMed/NCBI
  19. Carmi L, Tendler A, Bystritsky A, Hollander E, Blumberger DM, Daskalakis J, et al. Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial. Am J Psychiatry 2019;176(11):931-938 View Article PubMed/NCBI
  20. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 2014;311(18):1889-900 View Article PubMed/NCBI
  21. Carpenter JE, LaPrad D, Dayo Y, DeGrote S, Williamson K. An Overview of Pharmacotherapy Options for Alcohol Use Disorder. Fed Pract 2018;35(10):48-58 View Article PubMed/NCBI
  22. Addolorato G, Leggio L, Hopf FW, Diana M, Bonci A. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation. Neuropsychopharmacology 2012;37(1):163-77 View Article PubMed/NCBI
  23. Louis ED, Mayer SA. Merritt's Neurology. Lippincott Williams & Wilkins; 2021 View Article PubMed/NCBI
  24. Liu W, Li H, Lu Y, Yuan J, Yang R, Zhang L, et al. Repetitive Transcranial Magnetic Stimulation (rTMS) with Traditional Chinese Medicine for Depression: Study Protocol for A Pragmatic Randomized Controlled Trial. Explor Res Hypothesis Med 2022;7(4):267-272 View Article PubMed/NCBI
  25. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet 1985;1(8437):1106-1107 View Article PubMed/NCBI
  26. Chervyakov AV, Chernyavsky AY, Sinitsyn DO, Piradov MA. Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation. Front Hum Neurosci 2015;9:303 View Article PubMed/NCBI
  27. Loo CK, McFarquhar TF, Mitchell PB. A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. Int J Neuropsychopharmacol 2008;11(1):131-147 View Article PubMed/NCBI
  28. Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmöller J, et al. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol 2021;132(1):269-306 View Article PubMed/NCBI
  29. Zeng FG, Tran P, Richardson M, Sun S, Xu Y. Human Sensation of Transcranial Electric Stimulation. Scientific Reports 2019;9(1):15247-15247 View Article PubMed/NCBI
  30. Voigt J, Carpenter L, Leuchter A. Cost effectiveness analysis comparing repetitive transcranial magnetic stimulation to antidepressant medications after a first treatment failure for major depressive disorder in newly diagnosed patients – A lifetime analysis. PLOS ONE 2017;12(10):e0186950-e0186950 View Article PubMed/NCBI
  31. Zangen A, Roth Y, Voller B, Hallett M. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-Coil. Clin Neurophysiology 2005;116(4):775-779 View Article PubMed/NCBI
  32. Schutter DJLG, van den Hoven M. Ethical considerations regarding the use of transcranial magnetic stimulation in the treatment of depression. Tijdschrift voor psychiatrie 2015;57(1):42-46 View Article PubMed/NCBI
  33. Mishra BR, Nizamie SH, Das B, Praharaj SK. Efficacy of repetitive transcranial magnetic stimulation in alcohol dependence: a sham-controlled study. Addiction 2010;105(1):49-55 View Article PubMed/NCBI
  34. Höppner J, Broese T, Wendler L, Berger C, Thome J. Repetitive transcranial magnetic stimulation (rTMS) for treatment of alcohol dependence. World J Biol Psychiatry 2011;12(Suppl 1):57-62 View Article PubMed/NCBI
  35. Herremans SC, Baeken C, Vanderbruggen N, Vanderhasselt MA, Zeeuws D, Santermans L, et al. No influence of one right-sided prefrontal HF-rTMS session on alcohol craving in recently detoxified alcohol-dependent patients: Results of a naturalistic study. Drug Alcohol Depend 2012;120(1-3):209-213 View Article PubMed/NCBI
  36. Herremans SC, Vanderhasselt MA, De Raedt R, Baeken C. Reduced Intra-individual Reaction Time Variability During a Go–NoGo Task in Detoxified Alcohol-Dependent Patients After One Right-Sided Dorsolateral Prefrontal HF-rTMS Session. Alcohol Alcohol 2013;48(5):552-557 View Article PubMed/NCBI
  37. Mishra BR, Praharaj SK, Katshu MZUH, Sarkar S, Nizamie SH. Comparison of Anticraving Efficacy of Right and Left Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence: A Randomized Double-Blind Study. J Neuropsychiatry Clin Neurosci 2015;27(1):e54-e59 View Article PubMed/NCBI
  38. Girardi P, Rapinesi C, Chiarotti F, Kotzalidis GD, Piacentino D, Serata D, et al. Add-on deep transcranial magnetic stimulation (dTMS) in patients with dysthymic disorder comorbid with alcohol use disorder: A comparison with standard treatment. World J Biol Psychiatry 2015;16(1):66-73 View Article PubMed/NCBI
  39. Herremans SC, Van Schuerbeek P, De Raedt R, Matthys F, Buyl R, De Mey J, et al. The Impact of Accelerated Right Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) on Cue-Reactivity: An fMRI Study on Craving in Recently Detoxified Alcohol-Dependent Patients. PLOS ONE 2015;10(8):e0136182-e0136182 View Article PubMed/NCBI
  40. Herremans SC, De Raedt R, Van Schuerbeek P, Marinazzo D, Matthys F, De Mey J, et al. Accelerated HF-rTMS Protocol has a Rate-Dependent Effect on dACC Activation in Alcohol-Dependent Patients: An Open-Label Feasibility Study. Alcoholism: Clin Exp Res 2016;40(1):196-205 View Article PubMed/NCBI
  41. Del Felice A, Bellamoli E, Formaggio E, Manganotti P, Masiero S, Cuoghi G, et al. Neurophysiological, psychological and behavioural correlates of rTMS treatment in alcohol dependence. Drug Alcohol Depend 2016;158:147-153 View Article PubMed/NCBI
  42. Hanlon CA, Dowdle LT, Correia B, Mithoefer O, Kearney-Ramos T, Lench D, et al. Left frontal pole theta burst stimulation decreases orbitofrontal and insula activity in cocaine users and alcohol users. Drug Alcohol Depend 2017;178:310-317 View Article PubMed/NCBI
  43. McNeill A, Monk RL, Qureshi AW, Makris S, Heim D. Continuous Theta Burst Transcranial Magnetic Stimulation of the Right Dorsolateral Prefrontal Cortex Impairs Inhibitory Control and Increases Alcohol Consumption. Cogn Affect Behav Neurosci 2018;18(6):1198-1206 View Article PubMed/NCBI
  44. Kearney-Ramos TE, Dowdle LT, Lench DH, Mithoefer OJ, Devries WH, George MS, et al. Transdiagnostic Effects of Ventromedial Prefrontal Cortex Transcranial Magnetic Stimulation on Cue Reactivity. Biol Psychiatry Cogn Neurosci Neuroimaging 2018;3(7):599-609 View Article PubMed/NCBI
  45. Schluter RS, van Holst RJ, Goudriaan AE. Effects of Ten Sessions of High Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) Add-on Treatment on Impulsivity in Alcohol Use Disorder. Front Neurosci 2019;13:1257 View Article PubMed/NCBI
  46. Jansen JM, van den Heuvel OA, van der Werf YD, de Wit SJ, Veltman DJ, van den Brink W, et al. The Effect of High-Frequency Repetitive Transcranial Magnetic Stimulation on Emotion Processing, Reappraisal, and Craving in Alcohol Use Disorder Patients and Healthy Controls: A Functional Magnetic Resonance Imaging Study. Front Psychiatry 2019;10:272 View Article PubMed/NCBI
  47. Perini I, Kämpe R, Arlestig T, Karlsson H, Löfberg A, Pietrzak M, et al. Repetitive transcranial magnetic stimulation targeting the insular cortex for reduction of heavy drinking in treatment-seeking alcohol-dependent subjects: a randomized controlled trial. Neuropsychopharmacology 2020;45(5):842-850 View Article PubMed/NCBI
  48. Harel M, Perini I, Kämpe R, Alyagon U, Shalev H, Besser I, et al. Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence: A Randomized, Double-Blind, Sham-Controlled Proof-of-Concept Trial Targeting the Medial Prefrontal and Anterior Cingulate Cortices. Biol Psychiatry 2022;91(12):1061-1069 View Article PubMed/NCBI
  49. Belgers M, Van Eijndhoven P, Markus W, Schene A, Schellekens A. rTMS Reduces Craving and Alcohol Use in Patients with Alcohol Use Disorder: Results of a Randomized, Sham-Controlled Clinical Trial. J Clin Med 2022;11(4):951-951 View Article PubMed/NCBI
  50. Yan J. FDA Approves New Option to Treat Major Depression. Psychiatric News 2008;43(22):2-17 View Article PubMed/NCBI
  51. Cohen SL, Bikson M, Badran BW, George MS. A visual and narrative timeline of US FDA milestones for Transcranial Magnetic Stimulation (TMS) devices. Brain Stimul 2022;15(1):73-75 View Article PubMed/NCBI
  52. Rapinesi C, Kotzalidis GD, Ferracuti S, Girardi N, Zangen A, Sani G, et al. Add-on high frequency deep transcranial magnetic stimulation (dTMS) to bilateral prefrontal cortex in depressive episodes of patients with major depressive disorder, bipolar disorder I, and major depressive with alcohol use disorders. Neurosci Lett 2018;671:128-132 View Article PubMed/NCBI
  53. de la Monte SM, Kril JJ. Human alcohol-related neuropathology. Acta Neuropathologica 2014;127(1):71-90 View Article PubMed/NCBI
  54. Mahoney JJ, Hanlon CA, Marshalek PJ, Rezai AR, Krinke L. Transcranial magnetic stimulation, deep brain stimulation, and other forms of neuromodulation for substance use disorders: Review of modalities and implications for treatment. J Neurol Sci 2020;418:117149-117149 View Article PubMed/NCBI
  55. Rachid F. Maintenance repetitive transcranial magnetic stimulation (rTMS) for relapse prevention in with depression: A review. Psychiatry Res 2018;262:363-372 View Article PubMed/NCBI
  56. Senova S, Cotovio G, Pascual-Leone A, Oliveira-Maia AJ. Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systematic review and meta-analysis. Brain Stimul 2019;12(1):119-128 View Article PubMed/NCBI
  57. Maatoug R, Bihan K, Duriez P, Podevin P, Silveira-Reis-Brito L, Benyamina A, et al. Non-invasive and invasive brain stimulation in alcohol use disorders: A critical review of selected human evidence and methodological considerations to guide future research. Compr Psychiatry 2021;109:152257-152257 View Article PubMed/NCBI
  58. Grall-Bronnec M, Sauvaget A. The use of repetitive transcranial magnetic stimulation for modulating craving and addictive behaviours: A critical literature review of efficacy, technical and methodological considerations. Neurosci Biobehav Rev 2014;47:592-613 View Article PubMed/NCBI
  59. Cotovio G, Boes AD, Press DZ, Oliveira-Maia AJ, Pascual-Leone A. In Older Adults the Antidepressant Effect of Repetitive Transcranial Magnetic Stimulation Is Similar but Occurs Later Than in Younger Adults. Front Aging Neurosci 2022;14:919734 View Article PubMed/NCBI
  60. Garavan H. Insula and drug cravings. Brain Struct Funct 2010;214(5-6):593-601 View Article PubMed/NCBI
  61. Kearney-Ramos TE, Dowdle LT, Mithoefer OJ, Devries W, George MS, Hanlon CA. State-Dependent Effects of Ventromedial Prefrontal Cortex Continuous Thetaburst Stimulation on Cocaine Cue Reactivity in Chronic Cocaine Users. Front Psychiatry 2019;10:317 View Article PubMed/NCBI
  62. Hoogendam JM, Ramakers GMJ, Di Lazzaro V. Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul 2010;3(2):95-118 View Article PubMed/NCBI
  63. Karabanov A, Ziemann U, Hamada M, George MS, Quartarone A, Classen J, et al. Consensus Paper: Probing Homeostatic Plasticity of Human Cortex with Non-invasive Transcranial Brain Stimulation. Brain Stimul 2015;8(3):442-454 View Article PubMed/NCBI
  64. Isserles M, Shalev AY, Roth Y, Peri T, Kutz I, Zlotnick E, et al. Effectiveness of Deep Transcranial Magnetic Stimulation Combined with a Brief Exposure Procedure in Post-Traumatic Stress Disorder – A Pilot Study. Brain Stimul 2013;6(3):377-383 View Article PubMed/NCBI
  65. Dinur-Klein L, Dannon P, Hadar A, Rosenberg O, Roth Y, Kotler M, et al. Smoking Cessation Induced by Deep Repetitive Transcranial Magnetic Stimulation of the Prefrontal and Insular Cortices: A Prospective, Randomized Controlled Trial. Biol Psychiatry 2014;76(9):742-749 View Article PubMed/NCBI

Copyright © 2023 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2640718
  • Visits today : 2724