Transcranial Magnetic Stimulation for the Treatment of Gambling Disorder: A Systematic Review

J. Integr. Neurosci. 2023; 22(6): 164 https://doi.org/10.31083/j.jin2206164 Copyright: © 2023 The Author(s). Published by IMR Press. This is an open access article under the CC BY 4.0 license. Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Systematic Review Transcranial Magnetic Stimulation for the Treatment of Gambling Disorder: A Systematic Review Carmen Concerto1,*,†, Maria Salvina Signorelli1,†, Cecilia Chiarenza1, Alessia Ciancio1, Antonio Di Francesco1, Ludovico Mineo1, Alessandro Rodolico1, Giulia Torrisi1, Pasquale Caponnetto2,3, Manuela Pennisi4, Giuseppe Lanza5,6, Antonino Petralia1 1Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, 95123 Catania, Italy 2Department of Educational Sciences, Section of Psychology, University of Catania, 95121 Catania, Italy 3Center of Excellence for the Acceleration of Harm Reduction (COEHAR), University of Catania, 95121 Catania, Italy 4Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy 5Department of Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy 6Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, 94018 Troina, Italy *Correspondence: [email protected] (Carmen Concerto) †These authors contributed equally. Academic Editor: YoshihiroNoda Submitted: 28 June 2023 Revised: 27 August 2023 Accepted: 30 August 2023 Published: 21 November 2023 Abstract Background: Gambling Disorder (GD) is a behavioral addiction listed within the diagnostic category of substance-related and addictive disorders. Recently, transcranial magnetic stimulation (TMS), which non-invasively stimulates the brain and has neuromodulatory properties, has emerged as an innovative treatment tool for GD, thus offering a new option for the management of this complex disorder. The present review explored the efficacy of TMS as a possible non-pharmacological treatment for GD. Methods: An exhaustive search was performed across the MEDLINE, Web of Science, and EMBASE databases using a specific search string related to GD and TMS. A total of 20 papers were selected for full-text examination, out of which eight fulfilled the inclusion criteria and were therefore systematically analyzed in the present review. Results: This review included eight studies: three randomized-controlled trials (RCTs), three non-controlled studies, one case series, and one case report. Two cross-over RCTs described a decrease in craving after high-frequency (excitatory), repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (PFC), respectively; another study applying low-frequency (inhibitory) rTMS on the right DLPFC did not find any positive effect on craving. Among uncontrolled studies, one demonstrated the beneficial effect of high-frequency rTMS over the left DLPFC, while another showed the efficacy of a continuous theta burst stimulation protocol directed over the pre-supplementary motor area, bilaterally. Conclusion: The included studies showed the promising effect of excitatory stimulation over the left PFC. However, further investigation is needed, particularly in terms of standardizing stimulation protocols and psychometric assessments. Keywords: gambling disorder 1; craving 2; repetitive transcranial magnetic stimulation 3; theta burst stimulation 4 1. Introduction Gambling disorder (GD) is a well-recognized psychiatric condition prevalent worldwide, with a prevalence in the general population of approximately 0.1–5.8% [1]. It is listed in the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) under the classification of “Substance-Related and Addictive Disorders” [2], thus marking a shift from the earlier categorization as an “Impulse-Control Disorder” (DSM-IV). This reclassification underscores the recognition of behavioral addictions, alongside substance use disorders, highlighting their shared characteristics, including loss of control, craving, and significant impairment or distress [3]. GD is featured by a recurrent and persistent maladaptive gambling behavior which significantly affects personal, familial, or vocational pursuits. Core symptoms include persistent thoughts about gambling, a compulsion to gamble with escalating sums of money to achieve the excitement desired, recurrent unsuccessful endeavors to manage or cease gambling, restlessness or irritability when trying to stop gambling, and gambling as a mean of evading challenges or alleviating feelings of guilt, helplessness, depression, or anxiety [4]. Theories and ongoing investigations propose that addictive behaviors exhibit shared neurobiological modifications in certain brain areas. It is suggested that impaired activity of the dopaminergic system is associated with the experience of craving within the reward system [5]. Craving refers to a strong and insistent desire to encounter behaviors and is recognized as a significant pathomechanism in the development of the addiction disorder [6,7]. Indeed, addiction is characterized by a state of compromised decisionmaking and diminished responsiveness to innate rewards, which can be attributed to the modified operation of the prefrontal cortex (PFC) and basal ganglia. Additionally, there is an observed escalation in stress-conditioned reactions influenced by the limbic system [8]. Dopamine functions play a crucial role in different stages of drug addiction, also holding therapeutic potentials. The dopamine transporter (DAT) is responsible for controlling dopamine’s activity at the synaptic level. Accordingly, in the study by Pettorruso et al. [9] in 2019, the authors found a decreased availability of striatal DAT in individuals with GD compared with healthy controls. They also discovered that the availability of striatal DAT exhibited an opposite relationship with the number of days devoted to gambling and the process of reward-based decision-making among individuals with GD. In this context, the discovery of decreased DAT availability in GD provides further confirmation of the significant involvement of dopamine dysregulation in this condition. Similarly, human imaging research has revealed a decline in dopamine receptors and reduced release of endogenous dopamine in the ventral striatum of individuals addicted to cocaine, heroin, and alcohol. Collectively, this evidence provides insights on the “dopamine-impoverished” state in the addicted human brain [10]. Regarding therapeutic options, although GD is considered an addictive disorder, there is currently no designated pharmacotherapy officially recommended for addressing GD. Opioid antagonists such as naltrexone and nalmefene have been suggested as potential substances for the treatment of GD. Other interventions that have shown potential benefits and have been examined as promising options include agents affecting the glutamatergic system, glutamatergic agents, and a combination of pharmacological and psychological interventions. Studies on the effectiveness of serotonergic antidepressants, opioid antagonists, and mood stabilizers showed inconclusive results; regarding psychotherapies Cognitive Behavioral therapy (CBT), family therapy and motivational interviewing are considered the most effective therapeutic strategies for treating GD [11,12]. Although further research is needed in this area, combining pharmacotherapy with psychotherapy may potentially result in improved positive outcomes rates compared with pharmacology-based treatments only [13]. Non-invasive brain stimulation techniques (NIBS) have been recently explored as potential diagnostic probe and treatment options for behavioral addictions and other psychiatric or neuropsychiatric disorders [14–18]. These techniques have been developed to study brain functions, to diagnose neurological and psychiatric disorders, and to provide treatments for various psychiatric and neurological conditions [15,16,19–21]. Among the commonly employed stimulation techniques for addiction treatment, theta burst stimulation (TBS) and repetitive transcranial magnetic stimulation (rTMS) have emerged as the most frequently adopted methods [22]. Transcranial magnetic stimulation (TMS) has demonstrated therapeutic promise in addressing substance and behavioral addictions by targeting specific regions of the brain, either focal or wide bilateral areas. Mostly based on the frequency of stimulation (with high frequencies being excitatory and low frequencies being inhibitory), TMS can improve the reduced functionality of the prefrontal areas using excitatory protocols or it can decrease the abnormally increased functionality of the limbic system through inhibitory protocols. The application of this technique might potentially help in regulating activity in certain brain areas that have been implicated in the development of the disorders [23]. The persistent decrease in the physiological activity of the dopamine system suggests that increasing its activity to reestablish pre-drug levels might result in substantial clinical benefits, including reducing cravings, relapse, and drug-seeking/taking behaviors [24]. Moreover, previous research indicates that the mesolimbic dopamine system is “hypofunctional” in the addicted brain [25], thus suggesting that diminished dopamine functionality results in reduced engagement with stimuli unrelated to drugs and an increased susceptibility to the drug that is most frequently consumed. Consequently, it has been hypothesized that restoring dopamine function might offer therapeutic advantages in treating addiction. The PFC has a crucial role in controlling the release of dopamine in subcortical regions. Functional brain imaging, such as positron emission tomography (PET), can be applied to evaluate alterations in cerebral blood flow and glucose metabolism induced by TMS [23]. As such, TMS can be employed to enhance the endogenous activity of dopamine-containing neurons. Of note, Strafella et al. [26] in their study discovered that rTMS targeted to the left mid-dorsolateral prefrontal cortex was able to induce the release of dopamine in the striatal region of the human brain, thus opening a window into a potential wide range of clinical applications. From this pioneering discovery, novel targets for rTMS are under evaluation to increase its effectiveness in treating addiction, and research is ongoing to find the optimal protocol to boost dopaminergic transmission in the addicted brain. TMS can thus be considered a useful tool to test the dopamine hypothesis of drug addiction and instrumental in the search for addiction therapeutics [27]. However, although recent studies have shown evidence supporting the effectiveness of TMS in addiction, it has not yet been established as a standard treatment. Among the available publications, in 2020 Zucchella et al. [28] systematically reviewed studies applying rTMS or transcranial direct current stimulation (tDCS) in GD and problem gambling, identified using the PubMed, Web of Science, and Science Direct databases, from database inception to December 19, 2019. Eleven studies were analyzed, of which six were controlled and five were uncontrolled; however, the clinical and methodological heterogeneity of the included studies prevented the authors from drawing any conclusion on the efficacy of NIBS interventions for GD. Therefore, the current study aimed to provide an updated and comprehensive systematic review based on multiple 2 databases and not limited to clinical trials, focusing on the assessment of the efficacy of TMS protocols, specifically rTMS and TBS, for the treatment of GD. 2. Materials and Methods 2.1 Protocol A systematic search was carried out following the Preferred Reporting Items for Systematic Reviews and MetaAnalysis (PRISMA) Statement [29]. The protocol was registered prior to the start of the search process. We registered our protocol on INPLASY with the following registration number: INPLASY 202310054. PRISMA checklist is shown in Supplementary Material. 2.2 Information Sources and Search Strategy On May 16, 2023, we carried out a comprehensive search across the MEDLINE (via PubMed), EMBASE, and Web of Science databases. In our original protocol, we intended to incorporate PsycInfo as one of our primary databases for the literature search. However, due to the subsequent constraints on resources, we had to prioritize our database selection. To carry out our comprehensive research on the various databases, we employed the following search string: (“gambling disorder” OR “problem gambling” OR “pathological gambling” OR “compulsive gambling” OR “gambling addiction” OR “gambling addictions” OR “problematic gambling” OR “pathological gamblers” OR “problem gamblers” OR “pathological gamblers” OR “gamblers anonymous” OR “gambling addicts” OR gambling) AND (“transcranial magnetic stimulation” OR TMS OR rTMS OR “repetitive TMS” OR “theta burst stimulation” OR “theta burst” OR TBS OR cTBS OR iTBS). The string was modified, when necessary, to accommodate the specific formatting and search parameters of each individual database. Both the process of selecting studies and extracting data were conducted by two pairs of authors (AC/CCh and ADF/GT) in a blinded manner. All discrepancies were resolved by a third expert author (CCo). 2.3 Inclusion and Exclusion Criteria 2.3.1 Design Both randomized controlled trials (RCTs) and nonrandomized controlled trials written in English were initially sought based on our protocol. Upon further screening and for a more comprehensive search, we also included case series and case studies, whereas conference abstracts, letters, commentaries, books, and chapters were excluded. 2.3.2 Population In the initial protocol, we aimed to focus on adult patients diagnosed solely with GD or clinically significant gambling. However, during the review process, we recognized the relevance of studies that included participants also with some coexisting psychiatric conditions, given the frequent comorbidity observed in this patient population. Therefore, as a deviation from the original protocol for the sake of completeness, we also included studies that involved adult patients with GD or clinically significant gambling, regardless of the presence of other psychiatric disorders, setting, or ongoing therapy. Pediatric or adolescent populations remained excluded, thus ensuring our focus on adult-based interventions and outcomes only. 2.3.3 Intervention Studies that used rTMS and TBS were included. There was no restriction on the number of sessions; therefore, every study evaluating both single sessions and multiple sessions was included. 2.3.4 Comparator No restriction on the comparator was applied. Therefore, all types of comparators were included, such as shamstimulation, treatment as usual, waiting list, or no treatment. 2.3.5 Outcomes The primary outcome was the efficacy of TMS in reducing gambling symptoms, which were evaluated by using self-rated and clinician-rated psychometric scales. As secondary outcomes, we assessed changes in anxiety and depressive symptoms, sleep quality, and safety outcomes, including both serious and non-serious adverse events. 2.4 Data Extraction and Analysis Information was collected using a data extraction form located on Airtable, encompassing the following details: author, publication year, country, study design, patient characteristics, stimulation protocol (including the total number of sessions and session frequency), stimulation frequency and intensity, stimulation area, comparator, primary outcomes, and follow-up information. Data extraction was performed independently by two pairs of authors (AC/CCh and ADF/GT) and conflicts were resolved with the involvement of a third, experienced author (CCo). 2.5 Quality Assessment for Included Studies The evaluation of risk bias was carried out utilizing the Cochrane risk-of-bias tool 2 for RCTs, while for noncontrolled studies, the National Institutes of Health Quality Assessment Tool was employed [30]. The assessment of bias was carried out independently by two authors (ADF and AR), and any discrepancies were resolved through the intervention of a third experienced author (CCo). 3. Results The search yielded an initial total of 207 results. After removing duplicates, 100 studies were screened based on their title and abstract, leading to the inclusion of 20 papers for thorough examination of their full texts. After the full-text examination, 12 studies were excluded, whereas 3 Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart outlining the study selection process. eight studies fulfilled the inclusion criteria and were consequently included in the systematic review. Fig. 1shows the PRISMA flowchart illustrating the search, scrzeening, and selection process. 3.1 Study Characteristics Three of the included studies were RCT [31–33], three were open label [34–36], one was a case series [37], and one was a case study [38]. The earliest publication date was 2013 and the most recent was 2022. In our systematic review, we analyzed and synthesized studies published from 2013 to 2022. Specifically, two articles were published in 2013–2016 [33,36] one in 2017 [31], one in 2018 [32], two in 2019 [9,37], one in 2020 [34], and one in 2022 [35]. The therapeutic protocols identified were highfrequency (HF)-rTMS and cTBS. The areas of stimulation were the dorsolateral prefrontal cortex (DLPFC), the medial prefrontal cortex (mPFC), and the pre-supplementary motor area (pre-SMA). Treatment duration ranged from one day (one single session) to several weeks. Two studies used 4 Table 1. Description of the included studies. Author (year) Country Study Design Setting Population Intervention Stimulation protocol Comparator GamblingRelated outcomes Other outcomes Timeframe for follow-up Results Cardullo et al. [37] 2019 Italy Case series Not specified N = 7 (7 males) rTMS Sessions: twice a day for the first 5 days, then two sessions daily once a week over 8 weeks. NA - GamblingSymptom Assessment Scale (G-SAS) - Cocaine Craving Questionnaire (CCQ) - Baseline - G-SAS: Improvement at each time point Mean Age (Standard deviation - SD): 42.14 years (5.74) High frequency Stimulation parameters: 100% of motor threshold, 15 Hz, 60 impulses per stimulation train. - 19-item Pittsburgh Sleep Quality Index (PSQI) - 5 days - CCQ: Improvement at each time point Diagnosis: South Oaks Gambling Screen (SOGS) score ≥5 Area: left DLPFC Inter-train interval: 15 s; 40 total trains for a session duration of 13 min. - Beck Depression Inventory-II (BDI-II) - 30 days - PSQI: Improvement at each time point - Self-rating Anxiety Scale (SAS) - 60 days - SAS: Improvement at each time point - Symptoms checklist90 (SCL-90) - GSI: Improvement at each time point - Global Severity Index (GSI) - BDI-II: improvement at each time point 5 Table 1. Continued. Author (year) Country Study Design Setting Population Intervention Stimulation protocol Comparator GamblingRelated outcomes Other outcomes Timeframe for follow-up Results Gay et al. [31] 2017 France RCT Not specified N = 22 (14 males - 8 female) rTMS Sessions: single session TMS-Sham - Yale-Brown ObsessiveCompulsive Scale adapted for Pathological Gambling (PGYBOCS) None - Baseline - Cue-induced craving (VAS): Improvement Mean Age (SD): 51.0 years (13.7) High frequency Stimulation parameters: 110 of RMT; 10 Hz; 94 trains of 3.2-s duration at 10-s intervals, for a total of 3008 pulses per session and total treatment duration of 20 min 30 ss - 100-mm visual analogue scale - 7 days - PG-YBOCS: No improvement Diagnosis: DSMIV Criteria Area: left DLPFC - (VAS) for cueinduced craving - Numeric scale for desire to gamble: No improvement - Numeric scale for desire - Numeric scale for control to gamble: No improvement - Numeric scale for control 6 Table 1. Continued. Author (year) Country Study Design Setting Population Intervention Stimulation protocol Comparator GamblingRelated outcomes Other outcomes Timeframe for follow-up Results Pettorruso et al. [9] 2019 Italy Case study Out-patients N = 1 (male) rTMS Session: 20 sessions (twice a day, 5 days/week), then a weekly maintenance protocol (two applications/week) for 12 weeks. None - G-SAS (Gambling Symptom Assessment Scale) - BDI (Beck Depression Inventory) - T0: baseline - No episodes of gambling relapse over six months Age 40 years High frequency Duration of each individual session: NR. - PG-YBOCS (Pathological Gambling Adaptation of the Yale-Brown ObsessiveCompulsive Scale) - ISI (Insomnia Severity Index) - T1: 1 week - Patient-reported significant decrease in gambling craving Diagnosis: patient with 12-year history of GD, according to DSM-5 Area: left DLPFC Stimulation parameters: 100% of the RMT; 15 Hz; 60 pulses per train, inter train pause of 15 s, 40 stimulation trains, 2400 pulses/session. - YMRS (Young Mania Rating Scale) - T2: 2 weeks - Reduced in DAT presence in striatal regions - DAT-SPECT (Only at T0 and T2) - T3: 1 months - T4: 2 months - T5: 3 months - T6: 6 months 7 Table 1. Continued. Author (year) Country Study Design Setting Population Intervention Stimulation protocol Comparator GamblingRelated outcomes Other outcomes Timeframe for follow-up Results Pettorruso et al. [34] 2020 Italy Open label study Out-patients N = 8 (1 female) rTMS Sessions: 20 sessions (twice a day, 5 days/week) + 24 session (two daily, once a week) in 12 weeks. Each session lasting 13 min None - Gambling Symptom Assessment Scale (G-SAS) - Beck Depression Inventory - T0: baseline - G-SAS: Improvement at each time points; Mean Age (SD): 40.6 (11.2) High frequency Stimulation parameters: 100% of the RMT; 15 Hz; 60 pulses per train, inter-train interval of 15 s, 40 trains/session, 2400 pulses/session) - Pathological Gambling Adaptation of the Yale-Brown ObsessiveCompulsive Scale - Zung Self-Rating Anxiety Scale - T1: after 2 weeks of intensive treatment phase - Days of gambling (Timeline Follow Back): Improvement at each time points Diagnosis: DSM5 Criteria for GD Area: left DLPFC - Gambling behaviors Timeline Follow Back - T2: after 4 weeks of rTMS maintenance treatment - PG-YBOCS: No improvement - T3: after 8 weeks of rTMS maintenance treatment - BDI: No improvement - T4: after 12 weeks of rTMS maintenance treatment - SAS: No improvement 8 Table 1. Continued. Author (year) Country Study Design Setting Population Intervention Stimulation protocol Comparator GamblingRelated outcomes Other outcomes Timeframe for follow-up Results Sauvaget et al. [32] 2018 France RCT Out-patients N = 30 rTMS Sessions: single session TMS-Sham - Visual Analog Scale (VAS) for craving - Heart rate (bpm) - At baseline - VAS - cue induced craving: No differences between active and sham rTMS Mean Age (age interval): Active arm: 33 (28–42) Low frequency Stimulation parameters: 120% of the RMT, 1 Hz with one train producing 360 pulses in a single 6min session. - Gambling Craving Scale (GACS) (only 3 first questions) - Systolic blood pressure - Before the rTMS session - GACS (gamblingrelated craving) - 3 items used to measure the desire to gamble: No differences between active and sham rTMS Sham arm: 39 (34.5–56) Area: right DLPFC - Diastolic blood pressure - Immediately after the rTMS session - Heart rate: No differences between active and sham rTMS Diagnosis: 5 or more of the DSMIV diagnostic criteria for GD - Every 5 min until the craving intensity returned to the baseline level. - Systolic blood pressure: No differences between active and sham rTMS - Diastolic blood pressure: No differences between active and sham rTMS 9 tiple sessions of HF-rTMS was based on the inconclusive results of previous studies employing single-session HFrTMS targeting the same area. The authors proposed that multiple sessions would play a more crucial role in maintenance treatment and be able to sustain positive outcomes on general symptoms. 4.2 Studies Delivering LF-rTMS to the Right DLPFC Only one study conducted by Sauvaget et al. [32] assessed the efficacy of LF-rTMS over the right DLPFC in reducing cue-induced craving. The authors addressed cueinduced craving in their study using LF-rTMS in a single session over the right DLPFC. They ascribed their lack of success to a robust placebo effect and the specific parameters chosen for rTMS. This was grounded in earlier evidence that highlighted a connection between craving and heightened activity in the right DLPFC [60]. The authors induced craving by presenting visual cues and then asked the patients to complete a VAS assessment immediately after. Since visual-induced craving may contribute to this overactivation in pathological gamblers [61,62], the authors indicated that the rTMS occurred during the peak level of craving, and it was anticipated that subsequent measurements would decrease at a later point in time. 4.3 Studies Delivering LF-rTMS to the Left DLPFC Among the eight studies included, Rosenberg et al. [36] applied deep H-coil LF-rTMS over the left DLPFC. The rationale was substantiated by prior research that indicated heightened activation of the PFC in individuals when exposed to gambling-related stimuli in cue-exposure paradigms, as demonstrated by van Holst et al. in 2010 [63], and the possibility to reach dopaminergic subcortical areas with the use of an H-shaped coil [64]. The Deep H coil TMS was administered targeting the left DLPFC. Despite the patients reporting immediate improvement, this protocol showed ineffectiveness. Based on the initial effect, it was assumed that there might have been a transient positive, sham-like, effect, as it was unlikely a real effect of rTMS. 4.4 Studies Delivering cTBS to the Right DLPFC or Pre-SMA Zack et al. [33] assessed the efficacy of a single cTBS session directed over the right DLPFC. Regarding TBS, specifically continuous stimulation protocols have demonstrated a positive effect on impulsivity, decisionmaking, and delayed discounting by targeting the right DLPFC, which is a brain area known for its inhibitory control [43]. Zack and colleagues [33] administered a cTBS session over the right DLPFC compared with a sham stimulation. They did not observe any difference in the “desire to gamble”, as measured by a post-session VAS. Considering previous research by Ngetich et al. [65], who found that cTBS over the right DLPFC had mixed effects (resulting in impaired goal-directed behavior on one hand and reduced impulsivity on the other), the lack of significant findings in the desire to gamble could be explained by the interference caused by impaired goal-directed behavior on decision-making. Nevertheless, the study yielded significant findings in terms of secondary outcomes: these included a notable reduction in subjective psychostimulantlike arousal effects, in the Stroop interference test, and in diastolic blood pressure compared with the sham group. The authors attributed these outcomes to the enhancement of gamma-aminobutyric acid (GABA) levels, the involvement of which was demonstrated in studies involving cTBS over the primary motor cortex [66]. The mechanism behind this phenomenon suggests that cTBS may increase the inhibitory activities of interneurons, resulting in higher concentrations of GABA. Zack and colleagues explained the reduction in psychostimulant-like and arousing effects of the task, as well as the increase in the Stroop interference test, by proposing that stimulation of the prefrontal GABA neurons may impair the ability to shift attention away from a target stimulus [67]. Concerning cTBS, it has shown the ability to modulate cognitive control and motor inhibition in healthy participants by targeting the pre-SMA [68]. This modulation can be achieved either through the hyperactivation of pathways to the subthalamic nuclei or through its direct connections with the striatum. Building upon these promising findings, Salerno et al. [35] designed their study using cTBS as a “proof-of-concept” trial. Although cTBS over the pre-SMA was not originally part of the protocol, previous evidence highlighted it as a crucial region to target for ongoing response inhibition and conflict resolution, eventually resulting in a decrease in risky decisions and an enhancement in inhibitory control [69]. The study showed a progressive reduction in severity, measured by PG-YBOCS over the follow-up period, and an improvement in the CGI scores. Additionally, the study confirmed that cTBS was a safe treatment option, without any reported side effects. 4.5 Current Evidence and Study Limitations The articles included in our systematic review have various limitations. Most of the included studies did not employ validated questionnaires to evaluate the sensation of craving, but different VASs, thus making it difficult to compare all these results. Additionally, not all articles mentioned the term ‘craving’, but rather defined symptoms such as ‘urge to gamble’ or ‘desire to gamble’. Craving, alongside the compromised capacity to manage impulses, stems from gradual alterations in synapses and circuits, brought about by prolonged exposure to addictive substances [24]. Interestingly, all these neural alterations may be targeted by TMS, although, to date, it remains challenging to implement. It would be advantageous to establish a common “craving network” that is consistent among individuals, regardless of whether they have substance use-related disor16 ders. This would enable the identification and tracking of a neural pattern associated with craving or the drive for motivated behaviors [70]. Furthermore, the included studies had short follow-up periods, often limited to the time of the procedure, which resulted in an inadequate evaluation of the long-term effects. Our systematic review also had some intrinsic limitations. The inclusion of diverse clinical populations, as well as the inclusion of case reports and case series, the high risk of bias in multiple domains of the included studies, and the concurrent use of other treatments introduce limitations and cofounding factors regarding treatment efficacy. In particular, the placebo effect may have influenced many of the results obtained, and randomized sham control trials are therefore needed in future. 5. Conclusions The studies included in this systematic review focused on the modulation of different brain regions, particularly with respect to the right and left DLPFC. Although the evidence regarding inhibitory protocols over the left DLPFC did not support its efficacy, activating approaches over the left DLPFC may be considered useful to treat different clinical aspects of GD. Continuous TBS shows encouraging results, although two different areas, with different rationales and outcomes, were selected. Future research should place greater emphasis on characterizing study samples based on specific symptoms and further longitudinal RCTs should be carried out to monitor the long-term effects and safety of NIBS in GD and other addiction disorders. Availability of Data and Materials The datasets analyzed during the current study are available from the corresponding author on reasonable request. Author Contributions CCo, MSS, AP designed the research study. CChi, AC, ADF, GT performed the research. LM, AR, PC, MP, GL, provided help and advice on the research methodology. AD and AR analyzed the data. CCo, CChi, AC, ADF, GT, and GL wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work. Ethics Approval and Consent to Participate Not applicable. Acknowledgment Not applicable. Funding This research received no external funding. Conflict of Interest The authors declare no conflict of interest. Carmen Concerto is serving as one of the Guest editors of this journal. Giuseppe Lanza is as serving as one of the Editorial Board member of this journal. We declare that Carmen Concerto and Giuseppe Lanza had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gernot Riedel. Supplementary Material Supplementary material associated with this article can be found, in the online version, at https://doi.org/10. 31083/j.jin2206164. References [1] Bijker R, Booth N, Merkouris SS, Dowling NA, Rodda SN. Global prevalence of help-seeking for problem gambling: A systematic review and meta-analysis. Addiction. 2022; 117: 2972– 2985. [2] Association AP. Diagnostic and Statistical Manual of Mental Disorders. 5th edn. 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