Noninvasive brain stimulation of addiction: one target for all?

Abstract Noninvasive brain stimulation includes repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), and emerges as a prospective approach for addiction treatment in clinical practices. The dorsolateral prefrontal cortex (DLPFC) is regarded as the most effective stimulation target, giving its important position in controlling cue-elicited drug craving and initiating drug abuse. In this paper, through literature searches (e.g. Pubmed, Google Scholar), 34 studies (2003–2021) were identified examining the effect of rTMS, tDCS on cravings, and consumption of substance use disorders, including tobacco, alcohol, opioids, and stimulants. We summarize the main methods, designs, and effects of rTMS or tDCS that are delivered to the DLPFC on different types of addiction. We conclude that targeting DLPFC might be effective for all types of drug addiction.


Introduction
Addiction impacts public health significantly, with a high relapse rate in the current set of management.In past decades, noninvasive brain stimulation (NIBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), is demonstrating their efficiency and advantages as alternative approaches in addiction treatment.The basic principle of brain stimulation-based therapy is to restore the physiological synaptic strength and to rehabilitate the neural circuits impaired in disease.
Currently, there are multiple protocols for clinical studies using rTMS to treat substance use disorders.The lack of protocol consistency in such rTMS studies is common, as there is no systematic approach to elucidate which parameters can best achieve specific goals.Nonetheless, there is general consensus among researchers regarding the cerebral cortex to be stimulated: targeting the modulatory midbrain cortical system, most studies have targeted the DLPFC, and only a few have stimulated the medial prefrontal cortex (mPFC) (Hanlon et al., 2017).Furthermore, most studies tend to stimulate only one side of the brain, usually the left side, although some studies comparing stimulation of the DLPFC on the left and right side of the brain have not shown significant brain lateralization effects (Liu et al., 2017).Addiction leads to systemic changes in the mesolimbic dopamine system and connected brain regions, including nucleus accumbens, amygdala, the ventral tegmental area, prefrontal cortex, and hippocampus (Hou et al., 2014).Within all these areas, the dorsolateral prefrontal cortex (DLPFC) direct or indirect projects to and controls the functioning of rest regions, and is controlling cue-elicited drug cravings.In terms of manipulation, targeting DLPFC has operational convenience due to the shallow location compared to other regions (Luigjes et al., 2019).Indeed, NIBS-mediated functional modulations on the DLPFC affect the release of neurotransmitters, such as the dopamine efflux in different brain regions (Spagnolo and Goldman, 2017), or altered response inhibition in addicts (Goldstein and Volkow, 2011).DLPFC itself is involved in emotion regulation, cognitive control, and decision-making, all of which were implicated in addiction (Volkow and Baler, 2014).All these pieces of evidence emphasized the potential importance of DLPFC in multiple aspects in addiction rehabilitation.
Here we summarize the effects of noninvasive stimulation targeting DLPFC in the context of addiction medicine.For the literature search, "transcranial magnetic stimulation" and "addiction" or "transcranial direct stimulation" and "addiction" was input on PubMed or Google scholar from 2003 to 2021.

The Basic Principles and Applications in Addiction of tDCS and rTMS
Both tDCS and TMS could modulate cerebral cortex function in two directions: excitation and inhibition (Jansen et al., 2013).Through saline-soaked electrode pads, tDCS sends a constant direct current to the cortex.Some parts of the current spread along the scalp and the others penetrate the skull into the brain, which causes intracranial depolarization/hyperpolarization in a safe, efficient, and painless way.Previous research has demonstrated that this type of current effectively regulates the excitability of the cortical circuit (Nitsche and Paulus, 2001).The anode stimulation increases resting potential depolarization and may increase the frequency of spontaneous discharge of neurons, which leads to increased neuronal excitability, while the cathode stimulation induces the resting potential hyperpolarization and reduces the excitability of neurons.
The principle of TMS is to place a coil over the skull, and pass through alternating short current pulses, which generate alternating magnetic fields that induce electrical pulses in the brain (George and Aston-Jones, 2010).The induced current within the cortex is therefore determined by the frequency, strength, direction, and area of the current passing through the coil.Generally speaking, low-frequency (LF ≤ 1 Hz) TMS decreases neuronal activity and cortical excitability, and high-frequency (HF ≥ 5 Hz) TMS evokes a contrary outcome (Hallett, 2007).
An increasing number of tDCS and TMS studies have been performed for treating addictive disorders.Despite the design differences (e.g.duration of sessions, interval time, number, and sample size), most of the studies have adopted targeted stimulation to the DLPFC for the purpose of reducing cue-evoked craving (Spagnolo and Goldman, 2017).

The pros and cons of the tDCS and TMS
Generally speaking, tDCS has several advantages compared with TMS, for example, tDCS is compact, portable, lower cost, and has small electrodes, which makes it more suitable for household and medical investigation.However, tDCS has several shortcomings, first, tDCS has a temporary skin reaction to the electrode, which might cause pain; second, the spatial accuracy of tDCS is worse than TMS (Gandiga et al., 2006); and third, tDCS is usually made by two electrodes on the scalp, and current formed between the reference electrode and the target electrode will interfere with the cortical excitability (Nitsche et al., 2007).
TMS is a safe means of physical therapy.Compared with drug therapy, it has a quick effect, a few side effects, and is not easy to become addicted.TMS is low cost for long-term treatment.Compared with other physical therapy, especially electroconvulsive therapy, it is safe, painless, and does not affect cognitive function.The main side effects of TMS are head discomfort, such as dizziness and headache.There are a few cases of epilepsy.The most common discomfort during treatment is local to the scalp.Most of these cases are mild and temporary.They usually fade after a week.

tDCS of the DLPFC as a treatment for addiction
Preventing relapse is one major task in addiction management.Although the influence factors and the neurobiological mechanism are not fully clear, a great amount of evidence indicates that addiction relapse is largely affected by craving.The application of tDCS on the DLPFC to modulate craving brings up abundant results: in a randomized, double-blind, sham-controlled study, tDCS stimulation on both the left and the right DLPFC results in remarkably reduced cue-provoked craving (Fregni et al., 2008), and a cumulative effect of tDCS significantly attenuating smoking cue-induced craving has also been confirmed in another study (Boggio et al., 2009).Moreover, the smokers exhibited significantly decreased nicotine cravings and more active rejections to cigarette offers after tDCS stimulation on the right DLPFC than those with sham treatment (Fecteau et al., 2014).One study found that tDCS reduces the negative effect rather than cigarette craving and attention performances in overnight abstinent smokers, possibly due to the experiment design and withdrawal length differences (Xu et al., 2013).Another study reported that active prefrontal tDCS significantly decreased the rest craving state in the abstinent methamphetamine users, but increased craving if the stimulation is administrated during cue exposure (Shahbabaie et al., 2014).Participants who received active stimulation of tDCS showed reduced alcohol consumption, decreased craving, and improved cognitive performances (da Silva et al., 2013).In a study on alcohol addiction, 13 alcohol addicts were selected for double-blind real and sham tDCS stimulation with electrodes placed in the DLPFC (anode-left/cathode-right and anode-right/cathode-left), and alcohol-related videos were presented to the participants to induce alcohol cravings, and craving was measured by the Visual Analogue Scale before and after the simulation.The results showed that the real stimulation on the left side of the anode/right side of the cathode and the real stimulation on the right side of the anode/left side of the cathode significantly reduced craving compared to sham stimulation (Boggio et al., 2008).Alcohol craving was markedly decreased after tDCS to the left DLPFC, but was not influenced by tDCS to the right frontal gyrus, a region related to response inhibition, measured by the implicit association test (den Uyl et al., 2015).Klauss et al. conducted a study using 2 mA of stimulation in cocaine dependence with positive results (Klauss et al., 2018).The mechanism underlying the modulation is yet unclear, with few electrophysiological studies suggesting that tDCS modulate the activity or connectivity between the DLPFC and other prefrontal areas (Conti et al., 2014;da Silva et al., 2013;Nakamura-Palacios et al., 2012;Shahbabaie et al., 2018).A recent study investigated the combined effects of tDCS acting on the DLPFC and computerized cognitive addiction treatment (CCAT) on cue-induced craving and cognitive functioning in female patients living with methamphetamine use disorder.The investigators recruited 75 patients and randomly assigned them into three groups: a CCAT + tDCS group, a CCAT + sham tDCS group, and a control group.The first two groups underwent 20 sessions of cognitive training combined with 1.5 mA active/sham tDCS (20 min per session, five sessions per week) on the DLPFC and the control group underwent usual care.Cue-induced craving and cognitive function were tested at baseline, at week 2, and at the end of week 4.The results showed that CCAT + tDCS group significantly reduced cue-induced craving after 4 weeks of intervention.At the end of week 4, craving scores were significantly lower in the real CCAT + tDCS + group than in the CCAT + sham CCAT group and the control group.Compared to baseline, a significant improvement in the accuracy of the two back task was observed only in the CCAT + tDCS group at the end of week 4. Surprisingly, participants who received CCAT + active or sham tDCS did change their discounting, while participants in the control group showed more impulsivity over time.The study found a potential benefit of tDCS over DLPFC combined with CCAT to improve treatment outcomes in methamphetamine use disorder patients (Xu et al., 2021).In addition, a double-blind sham control study showed that tDCS on DLPFC had some effect on patients with cocaine use disorder over an extended treatment period (Gaudreault et al., 2021).
With dense connectivity to DLPFC, the fronto-parietotemporal junction region demonstrated its usefulness in regulating smoking-related behavior and cue-induced heroin craving (Meng et al., 2014;Wang et al., 2016).(Table 1) rTMS of the DLPFC as a treatment for addiction rTMS has been approved by FDA for depression treatment, and is being clinically tested for an arsenal of psychiatric disorders, such as anxiety, schizophrenia, and obsessive-compulsive disorder.Two pioneering experiments uncovering the relationship between rTMS and subjective craving or consumption were first performed on smokers: HF rTMS of the left DLPFC significantly reduced cigarette smoking and significantly decreased nicotine craving (Eichhammer et al., 2003).Such an effect has been further confirmed by several other studies: for example, smokers exposed to smoking-related pictures followed a HF rTMS of the DLPFC remarkably reduced nicotine consumption or nicotinic craving (Amiaz et al., 2009).Recent studies have further shown that HF rTMS of the left DLPFC remarkably reduces heroin/cocaine/methamphetamine cue-induced craving in long-term addicts (Liang et al., 2018;Liu et al., 2017;Liu et al., 2019;Shen et al., 2016;Su et al., 2017;Terraneo et al., 2016).However, other research has failed to observe any effects of rTMS of DLPFC on alcohol craving or intake in alcohol-dependent participants (Del Felice et al., 2016;H öppner et al., 2011).
Most clinical rTMS studies related to substance use disorders use HF rTMS.HF rTMS is designed to increase the activity of frontal neural circuits, and the withdrawal phase of substance use disorders is marked by hypoactivity of frontal neural circuits, which is accociated with a weakening of executive control networks and a reduction in dopaminergic transmission.In clinical studies, HF rTMS acting on DLPFC has a cue-induced craving-reducing effect.Most studies adopt long-term stimulation (e.g.20 stimulation sessions, once a day), and some studies use single sessions.Single sessions often produce inconsistent results.One study reported a significant reduction in craving in methamphetamine dependent individuals after a single session of stimulation using 10 Hz for both left and right DLPFC, while there was no change in the control condition (Liu et al., 2017).Simultaneously, a small sample of cocainedependent individuals undergoing a single session of the right DLPFC stimulation showed a decrease in craving, whereas stimulation of the left DLPFC showed no change (Camprodon et al., 2007).Another sham-controlled study found that a single session of 10 Hz rTMS acting on the left DLPFC significantly reduced craving in patients  with methamphetamine substance use disorder (Su et al., 2017).HF rTMS applied to multiple sessions may have better and more reliable treatment outcomes for substance use disorders than single sessions.A metaanalysis examining single and multiple sessions of neuromodulation across all substance use disorder domains found that multiple sessions of neuromodulation were more effective in reducing craving compared to single sessions (Song et al., 2019).In fact, it has been shown that after the first treatment, there was no change in craving, while after five HF rTMS sessions there was a significant reduction in craving, whereas the sham group did not show the same effect (Su et al., 2017).In addition to reducing craving, studies have shown that longterm HF rTMS can improve several aspects of withdrawal symptoms, anxiety and depression scores, sleep quality, and cognition in patients with methamphetamine or heroin substance use disorder (Liang et al., 2018;Lin et al., 2019;Su et al., 2017).HF rTMS acting on the left DLPFC also reduced cue-evoked craving in patients with long-term heroin use disorder in a randomized, pseudo-stimulation-controlled crossover study in which researchers assessed participants' cue-evoked craving at baseline, after the first day of treatment, and at the end of the fifth day of treatment.After the first treatment and after the fifth day of treatment, heroin use disorder patients showed a significant decrease in craving in both the first and fifth day of treatment (Shen et al., 2016).Thus, long-term rTMS may have an improving effect on many aspects for patients who live with substance use disorder, possibly due to altered frontal cortex plasticity.The iTBS is becoming increasingly popular in rTMS treatment, especially for treatment of major depression, due to its shorter stimulation time and higher efficiency compared to the traditional HF 10-Hz protocol (Blumberger et al., 2018).There have been no studies setting up the sham group iTBS to treat substance use disorders.A recent preliminary study using iTBS or 15-Hz intervention in patients with cocaine use disorder for 4 weeks and a twice-daily iTBS stimulation protocol in the first week found no significant differences in the treatment effects of the two treatment protocols on cocaine craving and usage amount.However, due to the lack of a sham group in this study, although there was a significant decrease in craving and usage amount in both treatment groups at 25 days posttreatment, the effect of time or a placebo effect could not be excluded (Sanna et al., 2019).This suggests that iTBS is as effective as 15 Hz in reducing cocaine craving and intake.Thus, the advantage of iTBS over 15 Hz is that the stimulation time is shorter and less intense, which makes iTBS more acceptable and tolerable for the patient, and more cost-effective for the clinician (Oberman et al., 2011).Another study found that a protocol of three daily iTBS interventions for 2 weeks significantly reduced cocaine intake as well as nicotine, alcohol, and tetrahydrocannabinol (Steele et al., 2019).Therefore, these studies provide preliminary evidence that iTBS is an effective and feasible treatment for patients with frequent cocaine use disorder.
The effects of low-frequency rTMS of the left DLPFC have not been adequately studied and are controversial.A single-blind, sham controlled crossover study, which recruited nontreatment-seeking methamphetamine users, found that 1 Hz rTMS intervention with left DLPFC increased cue-induced craving in the experimental group, but not in healthy controls, compared to the sham group (Li et al., 2013).In contrast, in a parallel, active control stimulation study with five 1-Hz rTMS stimulations on either the left or right DLPFC, cue-induced craving was significantly lower in patients with methamphetamine use disorder after both the first and the last stimulations compared to baseline at the time of treatment (Liu et al., 2017).The reason for the different results in these two studies may be that the participants in the former study were patients who were still using methamphetamine, and the participants in the latter were in rehab and had stopped using drugs in the past 2 months.Moreover, animal studies have shown that the accumulation of AMPA receptors is different at different stages of substance use disorders (Scheyer et al., 2016).In a recent double-blind, sham study, which recruited patients with methamphetamine use disorder, it was found that the 1 Hz rTMS intervention left DLPFC not only reduced cue-induced craving in the experimental group compared to the sham group, but also improved inhibitory control and reduced impulsivity in the experimental group (Yuan et al., 2020), and it is worth noting that the participants in this study were also in a drug rehabilitation facility.Similar to iTBS, cTBS (In the continuous theta burst stimulation paradigm (cTBS), a 40 s train of uninterrupted TBS is given (600 pulses)) is a shorter stimulation time protocol and has a stronger inhibitory effect on the cerebral cortex than 1 Hz (Huang et al., 2005).A preliminary sham-controlled study found that functional magnetic resonance imaging (fMRI) results showed a reduction activity in the insula, middle temporal gyrus, thalamus, and caudate nucleus regions after cTBS stimulation of mPFC in patients with chronic cocaine use disorder compared to the sham group, but the study showed no significant reduction in craving (Hanlon et al., 2015).In a larger, sham-controlled follow-up study, cTBS add-on the left mPFC-reduced activity in the striatum, ACC, and the parietal cortex, these regions associated with salience processing (ACC), attention/executive control (parietal cortex), and craving (striatum) in long-term cocaine dependents (Seeley et al., 2007).However, compared to the sham group, cTBS, while altering changes in brain activity, did not significantly alter cravings in patients with cocaine use disorder (Hanlon et al., 2017).In a follow-up study, a recent study added a cue response task before and after receiving a real or sham-stimulus to assess the state-dependent effects of rTMS.During the stimulation, participants were asked to think and describe the time of their last cocaine use, rather than simply resting.Compared to neutral cues, drugrelated cues significantly increased functional connectivity in the mPFC, striatum, and areas associated with   salience for cocaine users at baseline levels.Compared with the sham group, participants in the experimental group receiving cTBS had diminished frontal connectivity for drug-neutral cues, although there was no significant interaction with any regions of interest in the task, suggesting a general effect of cTBS on all brain regions (Kearney-Ramos et al., 2018).More recently, studies have also found that both HF and low-frequency rTMS over the left DLPFC are effective in reducing craving in people with heroin and methamphetamine use disorders, and the efficacy can be maintained for more than 60 days (Liu et al., 2020a;Liu et al., 2020b).Besides many investigations of rTMS made on the left DLPFC, a small amount of rTMS have been conducted involving the right hemisphere; for example, one study observed that only the right DLPFC stimulation reduced the cocaine craving (Camprodon et al., 2007), and the craving score reduced significantly in patients receiving stimulation to either the right or the left side rTMS (Liu et al., 2017;Mishra, Praharaj et al., 2015).DLPFC connected brain regions could act as potential targets for TMS.A 10-Hz rTMS of the superior frontal gyrus, a brain region correlated with craving, induced elevated craving to a smoking cue but a reduced craving to a neutral cue (Rose et al., 2011).Although a great number of studies confirm that the craving is reduced in the addicts receiving rTMS compared with the sham controls, future studies are required to elucidate whether rTMS has a stable and persistent effect on improved craving (Table 2).

Conclusion and Future Perspectives
In terms of addiction treatment, tDCS and rTMS are the two most commonly used noninvasive physical therapy methods.Both methods have the advantages of noninvasive and painless, and both can be combined with electroencephalogram (EEG), functional near-infrared spectroscopy, and other technical means for efficacy evaluation, and are therefore popular among researchers and physicians.These are widely used in psychology and clinical applications.However, there are also many differences between them.In comparison, tDCS is inexpensive and usually chooses DLPFC for anode or cathode electrical stimulation, for example, in one study, when electrodes were placed on the DLPFC (left side of the anode/right side of the cathode and the right side of the anode/left side of the cathode), alcohol addicts in the real stimulation group had significantly lower craving compared with the sham stimulation (Boggio et al., 2008).In studies related to addiction, researchers have located the DLPFC, which is located in the prefrontal cortex and is related to many functions.Previous studies have not clarified the direct link between this location and its effectiveness in improving addiction.Further research is needed to determine the validity of this location.While TMS is expensive and has different treatment targets depending on the purpose of treatment, researchers usually choose HF rTMS over the left DLPFC for addiction rehabilitation treatment.In summary, in the studies related to addiction, researchers have largely localized this to the DLPFC, which is located in the prefrontal lobe and is associated with numerous functions.Previous studies indicate that HF rTMS of the left DLPFC and lowfrequency rTMS over the right DLPFC may reduce cueinduced craving for methamphetamine (Liu et al., 2020b;Zhang et al., 2019).Different studies have confirmed the stimulation of this site benefits a decrease in craving, can overcome emotional problems, and promotes cognitive and executive functions due to substance addiction.For instance, recent studies expanded TMS targets for depression treatment to the ventrolateral prefrontal cortex, the ventromedial prefrontal cortex, frontopolar cortex, and dorsomedial prefrontal cortex (Downar and Daskalakis, 2013).These stimulation sites are potentially effective for treating addiction as well.
The following problems should be taken into consideration in future studies: (i) on which brain regions does NIBS achieve the optimal anti-craving effect?(ii) Although NIBS on DLPFC causes clinical effects, the underlying mechanisms are largely unknown, e.g.whether the effects are obtained by strengthening the left hemisphere or reducing the right hemisphere, or are they a summation of both?(iii) It would be interesting to combine NIBS on DLPFC with behavioral therapy in future management.

Table 1 :
Studies about tDCS of the DLPFC for addictive disorders.

Table 2 :
Studies about rTMS of the DLPFC for addictive disorders.