1. What Is Single-Pulse Transcranial Magnetic Stimulation?

Although a comprehensive review of the basic mechanisms of TMS is beyond the scope of this manuscript, prior behavioral, electrophysiological, and neuroimaging work in this area is well described and summarized in several review articles (see: Fitzgerald et al., 2006; Thickbroom, 2007; Hoogendam et al., 2010; Ziemann, 2011). In its most basic form, TMS is administered through a handheld circular coil that contains 100–200 windings of metal wire contained in a magnetically translucent casing (i.e., plastic). When electricity is passed through the wire, a magnetic field is created perpendicular to the plane of the wound coil. By applying pulses of electricity through the coil, the magnetic field will also have a pulsatile nature, and, consistent with Maxwell’s third law, will induce an electrical field perpendicular to the magnetic field.

When this field is induced in the vicinity of an electrically sensitive biologic system (such as muscle or neurons), an electrical current will be induced in the biologic medium. In practice, this is easily demonstrated by holding a TMS coil parallel to someone’s forearm. When pulses of electricity are allowed to run through the coil, a pulsatile magnetic field will be created, and in turn the muscles of the forearm that are in the spatial distribution of the induced electrical field will contract. The strength of the muscle contraction is proportional to the strength of the induced magnetic field, which is related to the current (Maxwell, 1861).

For transcranial magnetic stimulation, these same principles are applied to cortical neurons (rather than forearm muscles). In the first demonstration of TMS, Dr. Barker was able to show that when a circular TMS coil was positioned over the area of the left primary motor cortex somatotopically related to the right hand, he could induce a motor-evoked potential (MEP) in the right hand that was proportional to the strength of the TMS field. Since Dr. Barker’s discovery in 1984, there have been significant advancements in TMS coil designs, including figure-of-eight coils (which can induce a more focused field change) and H-coil designs (which allow a deeper penetration of the effects of TMS, enabling broader TMS target engagement).

2. The Spatial Topography of a Single Transcranial Magnetic Stimulation Pulse

One of the most common questions posed by clinical and preclinical researchers is the following: “How precise is a TMS pulse?” With a growing number of TMS coil designs, this is an increasingly complex question to answer. The focality of TMS is related to the shape of the coil. There is a substantial body of literature devoted to computational modeling of electric field distributions associated with different coil shapes. In one of the most comprehensive papers, Deng et al. (2013) investigated the focality and penetration depth of 50 existing TMS coils (Deng et al., 2013). Their computational models revealed that typical figure-of-eight coil affected approximately 10 cm² of cortical surface, circular coils affected approximately 50 cm², and H-coil designs affected approximately 100 cm². Most flat coil designs had penetration depths from 1 to 2 cm², whereas the H-coil designs had consistently higher depths of 2 to 3 cm. A single TMS pulse from a standard figure-of-eight coil stimulates a 12.5-cm² area, which is approximately 1/125 (0.8%) of the cortical surface area. By comparison, deep brain stimulation is an order of magnitude more precise, with volumes ranging from 1 to 20 cm (Wei and Grill, 2005), whereas electroconvulsive therapy and magnetic seizure therapy affect approximately 94% and 21% of the brain, respectively (Lee et al., 2016).

With TMS it is also possible to modulate monosynaptic (and possibly polysynaptic) targets of these cortical areas. The indirect effects of cortical TMS on monosynaptic afferent targets can be demonstrated through a behavioral assessment of the recruitment curve. When TMS is applied to the hand area of the primary motor cortex, there is a dose-dependent change in the amplitude of the MEP on the hand contralateral to the TMS coil. This pathway from the motor cortex to the hand requires at least two neurons—the upper motor neuron, which originates in the motor cortex and terminates in the spinal cord, and the lower motor neuron, which originates in the spinal cord and terminates in the muscles that will contract to produce the MEP. The majority of upper motor neurons, however, terminate on interneurons, which then facilitate lower motor neuron activity—suggesting that TMS can have polysynaptic effects. This ability to stimulate monosynaptic and possibly polysynaptic neurons is important for substance abuse treatment development research because many areas of interest for stimulation in substance use treatment are located in subcortical areas. Whereas these areas (i.e., striatum, amygdala) are not directly reachable with most TMS coils, neuroimaging data and electrophysiology data have demonstrated that they can be modulated via the cortical source of their afferent input.

3. Single-Pulse Transcranial Magnetic Stimulation as a Measurement Tool

Single and paired pulses of TMS are often used as a method to probe cortical excitatory and inhibitory tone (review Chen, 2000). The majority of our knowledge regarding the basic electrophysiological effects of TMS on the brain is from studies in the motor system. As mentioned above, a single pulse of TMS over the motor cortex results in a MEP in the limb contralateral to the stimulation site. A summary of the TMS probes commonly used and their sensitivity as markers of neurochemistry is displayed in Table 1. The most commonly reported dependent measure in TMS literature is the resting motor threshold (MT). This parameter is defined as the minimum TMS intensity required to generate a detectable MEP on 50% of the observations. Nearly all clinical treatment studies of rTMS use the MT as their dosing metric. In the FDA-approved protocol for TMS in depression, for example, patients are given 10 Hz stimulation over the dorsolateral prefrontal cortex at 120% of their resting MT. This enables rTMS to be titrated to each individual patient—an important step toward precision medicine. Although MT is consistent within an individual, there is a significant between-individual variability— nearly 70% of which is accounted for by variability in scalp-to-cortex distance (Herbsman et al., 2009).

Beyond calculating the resting MT, single pulses of TMS at variable intensities (80%–120% of MT) can also be used to calculate a recruitment curve. This is expressed as a dose-response relationship wherein the amplitude of the TMS intensity is plotted against the amplitude of the average evoked MEP at that intensity. The shape of the recruitment curve is influenced by the balance of local inhibition and facilitation. Paired pulses of TMS can be used to investigate intracortical inhibition (ICI) and intracortical facilitation (ICF). In these paired-pulse procedures, a subthreshold conditioning stimulus (typically 80% motor threshold) is followed by suprathreshold test stimulus (typically 120% motor threshold) (Ziemann et al., 1996; Kujirai et al., 2006). Short interstimulus intervals (1–4 milliseconds) lead to inhibition, whereas longer interstimulus intervals (8–15 milliseconds) lead to facilitation.

1. Cocaine

Single-pulse TMS protocols (such as paired pulse inhibition, facilitation, and cortical silent period) have been used to investigate disruptions in cortical excitability by multiple groups (Boutros et al., 2001, 2005; Sundaresan et al., 2007; Gjini et al., 2012; Bunse et al., 2014; Hanlon et al., 2015a). Our group, for example, demonstrated that the slope of the TMS dose-response curve was significantly steeper in current, chronic cocaine users than healthy controls. Additionally, the baseline motor threshold in cocaine users is higher than controls (Hanlon et al., 2015a). This difference means that it takes more energy to generate an initial MEP in cocaine users, but, once a threshold had been reached in cocaine users, the slope of the dose-response curve was very steep. These data suggest that the ratio of local excitatory to inhibitory processes in the motor cortex (e.g., likely glutamate or GABA mediated) is higher in cocaine users.

Several studies have demonstrated that abstinent cocaine users have lower motor cortex excitability than nondrug-using controls (Boutros et al., 2001, 2005; Sundaresan et al., 2007; Gjini et al., 2012). These lower MEPs in abstinent cocaine users are likely due to lower cortical (rather than peripheral nervous system) excitability (Ziemann et al., 1996; Di Lazzaro et al., 2008).

Furthermore, we have demonstrated that cocaine users had a lower ventral striatal blood-oxygen-level dependent (BOLD) response to single pulses of TMS stimulation to the medial prefrontal cortex (MPFC) than healthy controls (Hanlon et al., 2016). In this study, transcranial magnetic stimulation was applied to the left frontal pole (MPFC area of Brodmann area 10) and the left dorsolateral prefrontal cortex (DLPFC; lateral Brodmann 9) of 36 individuals—18 cocaine-dependent individuals with a history of failed quit attempts and 18 age-matched controls. Cocaine users had a lower ventral striatal BOLD response to MPFC stimulation. There was no between-group difference, however, in dorsal striatal response to DLPFC stimulation. Consistent with the competing neurobehavioral decision system (CNDS) theory, DLPFC stimulation led to a reciprocal decrease in MPFC activity (BA 10) in the controls. This reciprocal pattern did not exist, however, in the cocaine users.

2. Alcohol

In healthy controls, acute ethanol exposure leads to an increase in the duration of the cortical silent period (Ziemann et al., 1995; Conte et al., 2008). Despite this acute change, CSP is not altered in individuals who have consumed alcohol chronically (Conte et al., 2008; Nardone et al., 2010b; Naim-Feil et al., 2016), even during withdrawal states (Nardone et al., 2010b). Similarly, inhibition can be enhanced and facilitation reduced by acute alcohol consumption in healthy controls (Ziemann et al., 1995), but no difference in magnitude could be found among detoxified individuals with a history of chronic alcohol use (Nardone et al., 2010a,b; Naim-Feil et al., 2016), despite facilitation being increased in withdrawal states (Nardone et al., 2010b).

Some groups have used TMS to induce either LTD- or LTP-like plasticity. In healthy controls, acute alcohol exposure enhances LTD-like plasticity (Fuhl et al., 2015) but blocks LTP-like effects (Lucke et al., 2014; Loheswaran et al., 2016). In multiple studies, neither acute alcohol administration nor a history of chronic alcohol use had an effect on resting or active motor threshold (Ziemann et al., 1995; Conte et al., 2008; Nardone et al., 2010a,b; Kaarre et al., 2018), although one group did find a small difference between healthy controls and those with an alcohol use disorder when controlling for depression and intellectual function (Naim-Feil et al., 2016).

The primary findings, that of increased inhibition, reflect GABAergic properties. Similar intracortical inhibition can be seen after administration of a benzodiazepine such as lorazepam, a GABA-A agonist (Di Lazzaro et al., 2005a), and CSP elongation is observed following inhibition of GABA reuptake inhibition with tiagabine (Werhahn et al., 1999) or reduced GABA degradation with vigabatrin (Pierantozzi et al., 2004). Further work will be needed to explore the compensation methods that differentiate acute from chronic changes.

3. Nicotine

Chronic nicotine usage is related with a prolonged CSP duration, compared with healthy controls (Lang et al., 2008). Neither resting motor threshold (rMT) nor active motor threshold measured at the periphery appears to be sensitive to acute (Orth et al., 2005; Grundey et al., 2012a, 2013) or chronic (Orth et al., 2005; Lang et al., 2008; Grundey et al., 2012a; Strube et al., 2015) nicotine usage. rMT measured at the tongue, evaluating corticobulbar rather than corticospinal excitability, did find that chronic smokers had lower motor thresholds (Vicario et al., 2014). Evidence for changes in the recruitment curve is mixed, with chronic smokers showing greater MEPs at 150% of rMT (Grundey et al., 2013), but not 130% (Lang et al., 2008).

No effect of past nicotine usage was found for ICI (Lang et al., 2008; Grundey et al., 2013), although chronic smokers did show reduced ICF (Lang et al., 2008; Grundey et al., 2013). In deprived smokers, this loss of facilitation was restored to healthy control levels following the administration of nicotine (Grundey et al., 2013); however, acute nicotine did not alter ICF in healthy controls, but instead enhanced ICI (Grundey et al., 2013). Deprived chronic smokers showed enhanced short-interval afferent inhibition (SAI) at 20 milliseconds compared with controls, and this was not altered by a nicotine patch (Lang et al., 2008; Grundey et al., 2013). In contrast to this, SAI was enhanced in nonsmokers after a nicotine patch (Grundey et al., 2013).

Depending on the route of administration, nicotine was effective at blocking LTD-like plasticity in healthy controls (Thirugnanasambandam et al., 2011) as well as LTP-like effects (Grundey et al., 2012a). In deprived smokers, nicotine administration restored LTP-like plasticity with no effect on LTD-like plasticity (Grundey et al., 2012b). Further work is needed to determine what role these acute changes play in the addiction process and whether they can be used as an index of recovery or intervention effectiveness.

Together, these results highlight the complex interaction of the cholinergic system with both GABAergic and glutamatergic function. SAI is particularly relevant in studies of nicotine, as it is sensitive to cholinergic function and can be blocked by scopolamine, a muscarinic antagonist (Di Lazzaro et al., 2000b). This is a promising method for future work, as it appears to be sensitive to both acute and chronic nicotine effects.

1. Dopamine

The most cited studies in this domain have been done using positron emission tomography (PET) imaging, wherein the radioligand [¹¹C]raclopride, which is sensitive to D₂ dopamine receptors, is used to detect changes in levels of extracellular dopamine after rTMS. In a series of unique and important studies in this field, Strafella et al. have demonstrated the following: 1) 10 Hz rTMS to the left primary motor cortex (which increases cortical excitability) increases dopamine release in the left putamen (Strafella et al., 2003); 2) 10 Hz rTMS to the left DLPFC increases dopamine release in the caudate (Strafella et al., 2001); and 3) cTBS to the left DLPFC (which decreases cortical excitability) decreases dopamine release in the left and right caudate and disrupted performance on a card-sorting task (Ko et al., 2008). Notably, cTBS to the right DLPFC did not change dopamine release nor affect task performance, suggesting a hemispheric asymmetry in rTMS effects. Additionally, when using the radioligand [¹¹C]FLB457, which is a high-affinity D2 ligand sensitive to extrastriatal dopamine, 10 Hz rTMS to the left DLPFC increased dopamine release in the anterior cingulate and medial prefrontal cortex (Cho and Strafella, 2009). Again, 10 Hz TMS to the right DLPFC did not change dopamine release. This hemispheric asymmetry is consistent with clinical studies of rTMS for depression, which typically observe that whereas 10 Hz TMS to the left DLPFC (which increases cortical excitability) can be effective, 1 Hz TMS is typically used when targeting treatment to the right DLPFC (which decreases cortical excitability).

2. Glutamate and GABA

The rTMS-induced dopamine release is most likely due to direct effects of rTMS on glutamatergic pyramidal cells that originate at the site of stimulation and project to the striatum. One of the first studies to investigate the effects of single and multiple sessions of rTMS on neurochemistry was performed by Michael et al. in 2003 using proton magnetic resonance spectroscopy. A small group of healthy individuals was assigned to receive real (n = 7) or sham (n = 5) 20 Hz rTMS to the DLPFC. They demonstrated that both one and five sessions of rTMS increased glutamate/glutamine levels relative to sham rTMS. They also observed a rate-dependent effect of rTMS on glutamate/glutamine changes, wherein individuals with low baseline concentrations had highest levels of real TMS-associated increases in glutamate/glutamine (Michael et al., 2003). In addition to glutamate changes, several studies have also demonstrated that rTMS has direct effects on cortical GABA (Iwabuchi et al., 2017; Stagg et al., 2009; Vidal-Pineiro et al., 2015). Stagg et al. (2009), for example, demonstrated that the attenuating effects of cTBS on cortical excitability are related to an increase in GABA at the area of stimulation rather than a change in glutamate (Stagg et al., 2009). Iwabuchi et al. (2017) demonstrated that iTBS to the DLPFC (which typically increases cortical excitability) decreases the GABA/glutamate ratio in both the DLPFC and the insula (Iwabuchi et al., 2017).

3. Serotonin

Although the primary clinical indication for rTMS is major depressive disorder, a disease that is typically treated with selective serotonin reuptake inhibitors, very little is known about the effects of rTMS on serotonin. One of the few clinical studies done in this area used ¹²³I-5-I-R91150 single-photon emission-computed tomography to evaluate the effect of 10 sessions of 10 Hz left DLPFC rTMS on postsynaptic 5-HT(2A) receptor binding (Baeken and De Raedt, 2011). Relative to controls (n = 21), at baseline the depressed patients had lower 5-HT(2A) receptor binding in the DLPFC bilaterally and higher binding in the hippocampus. Following 10 sessions of 10 Hz rTMS to the left DLPFC, there was a positive correlation between the improvement in depressive symptoms (measured by the Hamilton depression rating scale) and the change in 5-HT(2A) receptor binding in the DLPFC. This relationship between baseline 5-HT(2A) receptor binding and clinical response to rTMS is aligned with evidence that 5-HT(2A) receptor binding is also related to treatment response with selective serotonin uptake inhibitors (Zanardi et al., 2001).

1.  Approved Pharmacotherapy

The pharmacotherapy of alcohol dependence is broken into therapies for acute alcohol withdrawal syndrome and therapies for relapse prevention and harm reduction. For acute alcohol withdrawal syndrome, benzodiazepines are safe, effective, and the preferred treatment. Benzodiazepines are thought to increase brain GABA levels via GABA A binding that are systemically decreased with chronic alcohol exposure (Sachdeva et al., 2015). All subclasses of benzodiazepines have shown to be effective in treating alcohol withdrawal syndrome, with the most commonly used being the longer-acting chlordiazepoxide and diazepam or the shorter- to intermediate-acting lorazepam and oxazepam. There are three pharmacotherapies FDA approved for the treatment of alcohol dependence. Disulfram has been used for relapse prevention for over 50 years and works by inhibiting the enzyme acetaldehyde dehydrogenase, resulting in unpleasant effects (headache, nausea, vomiting, chest pain, etc.) when combined with even a small amount of alcohol. This extinguishing effect of drinking behavior is effective, although patients are often not compliant. The FDA-approved opiate antagonist, naltrexone, has shown promise in relapse prevention, stemming the endorphin-mediated reinforcing effects of drinking alcohol. There is strong evidence that naltrexone significantly reduces alcohol relapse to heavy drinking, the frequency and quantity of alcohol in those who do drink, and alcohol craving. Naltrexone also comes in long-acting, one-time-per-month injectable form to help with compliance. Acamprosate is the third medication to receive FDA approval for post withdrawal maintenance of alcohol abstinence. It is thought to reduce craving for alcohol by modulating GABA and glutamate systems that are disrupted by chronic alcohol use.

2. Brain Stimulation Research

At the time of writing, there have been nine studies published on the use of rTMS for alcohol addiction (Table 2). Six of these studies targeted the DLPFC, with five delivering stimulation to the right side and one targeting the left. Two recent studies chose the MPFC as an alternative target. High-frequency stimulation (10 or 20 Hz) was used for all studies that targeted the DLPFC, and for one of the studies targeting the MPFC. The remaining MPFC study used cTBS. Most of these studies (n = 6) evaluated outcomes after 10 or more sessions. The optimal parameters, such as the number of sessions or target, are currently unknown. One difficulty is the large number of factors that may modulate TMS efficacy. For example, a study in 2016 used 20 Hz right DLPFC stimulation and found that the change in cue reactivity depended on the cue reactivity as measured before TMS was delivered (Herremans et al., 2016). These rate-dependent effects may represent a biomarker that can guide treatment targets or inform the interpretation of results. Another such biomarker can be derived from functional imaging of cue induction, which consistently highlights the role of the MPFC in cue reactivity (Schacht et al., 2013). By targeting this region with a single session of cTBS, Hanlon et al. (2017) found reductions in evoked responses in orbitofrontal and insular cortex relative to sham stimulation. (More studies will be needed to determine how these factors contribute to the effectiveness of rTMS.)

1. Brain Stimulation Research

To date, there have been seven published reports on the effects of rTMS for cocaine use disorder (Table 3). The majority of these studies have targeted the left DLPFC (n = 4), with one targeting the prefrontal cortex bilaterally. Two have chosen the MPFC as a target. Early studies evaluated the effects of just one session, whereas more recent work has explored outcomes after 8–12 sessions. All studies that stimulated the DLPFC, whether right, left, or both, have used high-frequency TMS (10 or 15 Hz). For studies that chose the MPFC as a target, cTBS was used. Although the exact parameters have yet to be determined, there are promising findings. For example, Terraneo et al. (2016) reported that left DLPFC stimulation alone led to a significantly greater number of cocaine-free urine tests compared with a control group that used pharmacotherapies. As in alcohol research, the MPFC is being explored as an alternative to the conventional DLPFC target. Hanlon et al. (2015b) reported that a single session of cTBS led to reduction in the stimulus evoke BOLD signal in the orbitofrontal cortex and striatum. Together these findings suggest that rTMS may be an alternative treatment or adjunct to a yet-to-be-discovered pharmacotherapy.

1. Approved Pharmacotherapy

There are three FDA-approved medications used for smoking cessation. Nicotine replacement therapies such as transdermal patches, gum, nasal spray, inhaler, and lozenges offer the patient a safer and therapeutically manageable form of nicotine to alleviate the symptoms of withdrawal and craving. One drawback with nicotine replacement therapies is the potential to become dependent on the replacement if the patient does not wean as directed. The antidepressant, bupropion, acts as a neuronal reuptake inhibitor of dopamine and noradrenalin and has been shown to be efficacious as a first-line treatment of nicotine dependence (Hurt et al., 1997). Varenicline is a partial agonist that has high and selective activity at α4-β2 receptor. It has been FDA approved due to its efficacy in reducing craving and withdrawal symptoms during abstinence and blocking the reinforcing effects of nicotine (Coe et al., 2005; Gonzales et al., 2006; Jorenby et al., 2006).

2. Brain Stimulation Research

Since 2003, there have been 10 studies on rTMS and cigarette smoking (Table 4). As with other drugs of abuse, the DLPFC is the primary target (six left, one right, one both). The insula and superior frontal gyrus have been targeted in one study each. Each left DLPFC study chose to use high-frequency stimulation (10–20 Hz). Half of these studies used more than one session. In the largest randomized controlled trial to date, Dinur-Klein et al. (2014) delivered 13 sessions of either high- or low-frequency rTMS bilaterally to the lateral prefrontal cortex and insulae, with and without cue exposure immediately before stimulation. High- but not low-frequency TMS was effective in reducing the number of cigarettes smoked. Individuals randomized to the high-frequency and cue-exposed condition showed the largest reduction in cigarettes smoked. These context-dependent effects may have large consequences on the efficacy of rTMS and should be considered as an additional parameter for optimization. Although cue induction is common in the addiction field, and can lead to reliable limbic system activation, there are a number of alternatives. One example is executive control circuitry, as engaging this before or during treatment may also be effective. Toward this end, Sheffer et al. (2018) delivered eight sessions of self-help therapy combined with active rTMS or sham TMS. Despite the use of therapy in both groups, active rTMS showed significantly greater abstinence groups relative to sham. These findings add to the number of parameters that must be explored when designing a TMS trial; however, they both suggest that there is an opportunity to improve TMS treatment outcomes.

1. Approved Pharmacotherapy

There are two general pharmacotherapy paths for opioid dependence, opioid maintenance treatment, or detoxification. Agonist and partial agonist medications are used for both maintenance and detoxification: α-2-adrenergic agonists used to enhance detoxification outcomes; antagonist medications used to accelerate the detoxification process. Methadone is a μ-opioid receptor agonist that is typically used as a replacement therapy for opioid dependence. Its long half-life (24–36 hours) allows it to be used as either a detoxification agent or for maintenance therapy (Ward et al., 1996). Buprenorphine is a partial agonist of μ-opioid receptors that has a slow onset and long duration, allowing for alternate day dosing for opioid maintenance treatment. As a partial agonist, it has a more reduced risk of unintentional overdose than methadone, but this may also reduce buprenorphine’s potential efficacy. A number of studies have shown the efficacy of buprenorphine over placebo for opioid maintenance. Mattick et al. (2004) showed that both methadone and buprenorphine are effective at decreased illicit opiate use and increased retention rates when higher doses of methadone (>60 mg) and buprenorphine (>8 mg) are used. The third FDA-approved pharmacotherapy for opioid dependence is the opioid antagonist naltrexone used for opioid maintenance. Naltrexone is safe, well tolerated, and effective at blocking the reinforcing properties of opiates. Unfortunately, in an analysis of 10 studies, Minozzi et al. (2011) showed weak support for the efficacy of naltrexone.

2. Brain Stimulation Research

In contrast to the variety of pharmacological treatments available for opiate dependence, there is a paucity of published reports on the effectiveness of rTMS. To the best of our knowledge, the only report of rTMS in opiate dependence is a short correspondence on 20 male heroin users. In this, Shen et al. (2016) reported a reduction in cue-induced craving after a single, 10-minute session of high-frequency stimulation to the left DLPFC, with further effects after an additional four treatments. Although the literature is currently limited, it is likely that this will soon change as a number of clinical trials are currently ongoing. Although present findings specific to opiate addiction are limited, there is a large body of evidence that rTMS is effective for reducing pain (for a review, see Galhardoni et al., 2015). Although many of these studies have focused on using the motor cortex as a target for stimulation, there is evidence that the DLPFC is also an effective target for pain reduction (Borckardt et al., 2007, 2008; Brighina et al., 2011; Taylor et al., 2013). This overlap represents a clinically meaningful and treatable target for both pain disorders and substance abuse. This is particularly important, considering opiate use disorders, which can be initiated or maintained by the presence of pain (Passik et al., 2006; Back et al., 2011; Barth et al., 2013; Lusted et al., 2013).

1. Dorsolateral Prefrontal Cortex

The importance of the DLPFC in conscious decision making, reasoning, working memory, inhibition, as well as outcome prediction (see Krawczyk, 2002), and its established reputation as a successful treatment target for TMS in patients with depression, all suggest that the DLPFC is most likely a very good candidate for TMS treatment development in substance use disorder. The DLPFC can be directly stimulated with traditional figure-of-eight TMS coils and circular TMS coils.

The majority of studies in TMS to date have focused on this brain region. The biggest trial to date was a cohort study of 115 treatment-seeking smokers randomized to receive 13 sessions of 10, 1 Hz, or sham TMS after viewing smoking cues. An H-coil (which induces a wider, deeper electromagnetic field in the brain than a figure-of-eight coil) focused on the left insula and lateral prefrontal cortex was used for this experiment. Ten hertz (LTP-like) rTMS decreased cigarette consumption and improved 6-month abstinence rates (Dinur-Klein et al., 2014). These data complement other evidence that the insula can be modulated by TMS (Gratton et al., 2013), and that functional connectivity (Moran-Santa Maria et al., 2015) and anatomic integrity (Naqvi et al., 2007) of the insula are critical for craving. A greater understanding of the neurobiological effects of these brain stimulation tools and protocols may allow us to more effectively translate preclinical knowledge into efficient, evidence-based treatments for patients.

2. Ventral Medial Prefrontal Cortex and Orbitofrontal Cortex

The MPFC extends throughout the medial section of the frontal cortex and into the OFC (BA 10). The ventral aspects of the MPFC typically are involved in mediating arousal, whereas the dorsal aspects of the MPFC play an important role in the cognitive decrements seen in individuals with substance use disorders (Bolla et al., 2003; Kaufman et al., 2003; Kubler et al., 2005). The OFC is located on the ventral section of the PFC and contributes to reinforcement of cocaine (e.g., with nucleus accumbens, thalamus, ventral striatum, and indirectly with amygdala, cingulate, hippocampus). Acute cocaine administration, for example, leads to elevated activity in the OFC, which may act as an information integrator, leading to reinforcement of drug taking (Volkow and Fowler, 2000). The OFC is involved in response inhibition and learning the association between a stimulus and outcome (Kringelbach and Rolls, 2004). Dysregulation of the OFC most likely perpetuates habitual drug use behavior as well as risky decision making, an inability to anticipate outcomes (see Krawczyk, 2002).

3. Relationship to Transcranial Magnetic Stimulation Treatment Development

The primary cortical inputs to the ventral striatum are the medial and orbital prefrontal cortices. Given that the ventral striatum is one of the primary brain regions involved in processing drug-associated reward, it seems that targeting the MPFC would be a more direct method to modulate ventral striatal activity than DLPFC stimulation. Specifically, a single pulse of TMS to the MPFC in healthy individuals leads to an increase in BOLD signal in the ventral striatum (Hanlon et al., 2013b). A recent study in cocaine users demonstrated that they have a hyperactive BOLD response in the dorsal and ventral striatum relative to controls (Hanlon et al., 2016). This elevated ventral striatal sensitivity following MPFC stimulation, a frontal–striatal circuit involved in the limbic aspects of craving, may be a prime circuit to attenuate to make these individuals less vulnerable to drug-related cues. Given that craving is associated with an increase in activity in the striatum (e.g., BOLD signal), LTD-like rTMS over the MPFC may attenuate activity in this neural circuit.

Our laboratory has spent the last 7 years systematically developing a TMS as an empirically derived treatment of cocaine use disorder and alcohol use disorder, wherein the ventral MPFC and OFC are the prime targets of interest. We have demonstrated that it is possible to differentially activate the vMPFC from the DLPFC using interleaved TMS/functional MRI (Hanlon et al., 2013b); shown that connectivity with the vMPFC was significantly different in the cocaine users relative to healthy controls and DLPFC connectivity was similar to controls (Hanlon et al., 2016); evaluated the feasibility of a vMPFC-focused treatment strategy for TMS (Hanlon et al., 2015b); and demonstrated that continuous TBS could dampen activity in the vMPFC, insula, and cingulate cortex (Hanlon et al., 2017). This attenuation was present in both the cocaine users (Fig. 4) and the alcohol users.

• Download figure
• Open in new tab
• Download powerpoint

Fig. 4.

The effect of frontal pole cTBS on brain reactivity in cocaine users and alcohol users (adapted from Hanlon et al., 2015, 2017). Interleaved TMS/BOLD imaging was used to measure TMS-evoked BOLD signal immediately before and after cocaine users (B) and heavy alcohol users (C) were given a dose of cTBS to the left frontal pole (A). The TMS coil was placed over FP1 (EEG:10-20 system) for both the interleaved TMS/BOLD scan (left and right panel) and the cTBS session (center panel). The red area represents the region of interest to which the coil is targeted (AAL: left superior and middle orbital prefrontal cortex inferior to the anterior commissure). Real cTBS (LTD-like) led to a significant decrease in BOLD signal in the left orbital/medial prefrontal cortex and ventral striatum (SPM 8, P < 0.05 family wise error correction, negative Z-scores shown). The cTBS protocol was two trains of 1800 pulses, 110% rMT, 60-second intertrain interval, intensity ramped from 80% to 110% over first 30-second L = left hemisphere. These data reveal that 3600 pulses of real cTBS to the left frontal pole decrease stimulus-evoked activity in the MPFC, cingulate, and striatum of cocaine users and MPFC and insula of alcohol users significantly more than sham cTBS.

4. Anterior Cingulate Cortex

The anterior cingulate cortex (ACC) is part of the limbic system and is involved in attention, emotion regulation, error monitoring, inhibitory control, and motivation (Bush et al., 2000). Relative to nondrug-using controls, cocaine users have lower rates of glucose usage in the ACC and OFC as measured with fluorodeoxyglucose and PET (Volkow et al., 1991, 1992, 2005; Goldstein and Volkow, 2002; Goldstein et al., 2004). These depressed rates of functional activity have been reported to persist for up to 3 (Volkow et al., 1993) to 5 months (Hanlon et al., 2013a) of abstinence. The ACC has increased activity during cocaine craving following administration (Breiter et al., 1997; Garavan et al., 2000; Maas et al., 1998; Risinger et al., 2005), and its activity is negatively correlated with reports of cocaine high. There is, however, a positive correlation with rush (Breiter et al., 1997). Cocaine users have decreased activity relative to controls in the ACC when completing a task requiring cognitive inhibition (Kaufman et al., 2003; Hester and Garavan, 2004) and visual attention (Kubler et al., 2005). From a structural perspective, cocaine users have decreased gray matter density in the ACC compared with controls (Matochik et al., 2003), and this reduction has been found to be greater for those with a longer history of abuse (Franklin et al., 2002; Ersche et al., 2011).

Additionally, activity in the ACC has been consistently linked to an enhanced attentional bias to smoking cues (Janes et al., 2009), alcohol cues (Vollstadt-Klein et al., 2012), and cocaine cues (Goldstein et al., 2009). Attentional bias is one of the most studied cognitive processes in addiction, as it is often linked to drug craving and relapse (Field and Cox, 2008). Several studies have, in fact, demonstrated that higher levels of ACC activity during an attentional bias task predict higher relapse probability in smokers (Janes et al., 2010) and cocaine users (Marhe et al., 2013).

5. Insula

The insula is a cortical structure located deep in the brain between the frontal and the temporal lobes, which has four subregions that are defined based on their cytoarchitecture: posterior/dorsal insula (granular), intermediate insula (dysgranular), anterior/ventral insula (agranular), and the fronto–insular cortex (agranular), which is only present in humans and great apes. Anatomical, visual, and functional imaging studies have shown that the fronto-insular and anterior subregions of the insula are extensively connected with the orbitofrontal cortex, anterior cingulate cortex, and the dorsal lateral prefrontal cortex (Bauernfeind et al., 2013). From a functional perspective, there appears to be laterality within the insula wherein the right anterior insula is elevated by negative emotional valence and sympathetic activation, whereas the left anterior insula is associated with positive affect and parasympathetic activation (Craig et al., 2000; Critchley et al., 2004).The insula has dense structural connectivity with the amygdala, basal ganglia, thalamus, OFC, and PFC, placing it as an important structural and functional hub involved in drug and alcohol use and relapse (see Singer et al., 2009). The insula has elevated activity, for example, in paradigms exploring cocaine craving as well as acute cocaine high (Kilts et al., 2001; Bonson et al., 2002; Risinger et al., 2005). The volume of the insula is also smaller and correlated with length of cocaine user among cocaine users compared with sibling controls (Ersche et al., 2011). Small insula volume is also associated with decrements in attentional control (Ersche et al., 2011; Hanlon et al., 2011). A large study by McHugh et al. (2013) demonstrated that cocaine users (n = 45) had lower connectivity between the insula and putamen than healthy controls (n = 22). They also showed increased impulsivity in cocaine-addicted individuals that was mediated by reduced insula–putamen connectivity.

6. Relationship to Transcranial Magnetic Stimulation Treatment Development—Anterior Cingulate Cortex and Insula

The ACC and the insula are nodes in the Salience network, a functional connectivity network in the brain which is involved in attentional bias and task switching. Given the importance of these processes to addiction, there is a lot of interest in directly modulating this network with rTMS. Whereas traditional figure-of-eight coils cannot directly reach the insular cortex or the ACC due to the magnetic field decay. It is possible to indirectly modulate the insula and ACC by stimulating the DLPFC (Nahas et al., 2001) or the frontal pole (Hanlon et al., 2017). This indirect modulation via both the dorsal lateral and ventral medial aspects of the cortex is due to the very high anatomic connectivity that exists between the anterior insula and these prefrontal regions. It is likely also possible to directly target the ACC and the anterior or posterior insula through novel TMS coil designs such as the H-coil design series. These coils have a unique geometry that enables their direct penetration depth to be as deep as 3–5 cm, which is most likely sufficient to engage the ACC and anterior insula (Deng et al., 2015). Hence, H-coils are actively being evaluated to addiction treatment development (Dinur-Klein et al., 2014). Targeting the insula via cTBS treatment of the MPFC may reduce the activation when experiencing cocaine craving and high shown by Bonson et al. (2002) and Kilts et al. (2001).

1. Task-Dependent Amplification of Transcranial Magnetic Stimulation Effects

One of the most interesting areas of recent methods development in neuromodulation involves choosing a task for the participants to perform (or a thought pattern to engage in) before or during the intervention. Translating established principles of task-dependent plasticity in animals to human clinical experiments, Dinur-Klein et al. (2014) were the first to demonstrate that it is possible to amplify the effects of TMS on smoking cessation by having individuals engage in a smoking cue-reactivity task immediately before the TMS session. In this large, double-blind, sham-controlled study of 115 cigarette smokers, individuals were randomized to receive 10 or 1 real or sham TMS for 13 sessions. Half of these participants were presented with visual cues of smoking for 20 minutes before the TMS session (Brainsway H-ADD coil; 120% resting motor threshold, left insula, and lateral prefrontal cortex). The group receiving 10 Hz TMS (but not 1 Hz) had significantly lower cigarette consumption and nicotine dependence than sham TMS. There was a significantly better outcome in the individuals that had been exposed to the smoking cues as measured by their change in the Fagerstrom test for nicotine dependence score and their abstinence rates (44% at the end of the trial; 33% 6 months later).

These results are comparable to treatment with varenicline, which has a 44% abstinence rate at the end of treatment (12 weeks) and 29.5% 6 months later. TMS treatment in this study appears to be better than treatment with bupropion hydrochloride (Wellbutrin Sustained Release), which has a 29.5% abstinence rate at the end of treatment (12 weeks) and 20.7% 6 months later (Gonzales et al., 2006).

Task-dependent amplification of TMS effects also applies to treating post-traumatic stress disorder (PTSD) (Isserles et al., 2013). In this study, 30 PTSD patients were randomized to one of three groups: sham rTMS, real rTMS following exposure to a 30-second patient-tailored trauma script, or real rTMS following exposure to a 30-second patient-tailored neutral script. The participants received 12 sessions of real or sham rTMS (three sessions/week, 4 weeks, Brainsway H-coil). The only group with a significant improvement in the clinician-administered PTSD scale was the group that received exposure to 30-second trauma scripts before their rTMS treatment. Although the mechanism through which cue exposure enhances the behavioral effects of rTMS is not clear, one possibility is that cue exposure reactivates latent memory traces (frequently referred to as the engram) (Josselyn et al., 2015), enabling them to be manipulated and reconsolidated (Dudai and Eisenberg, 2004; Dudai, 2006). To our knowledge, this has not been directly evaluated in patients with either substance dependence or PTSD.

Based on these empirical results from clinical studies and a strong preclinical foundation for task-dependent plasticity, all experiments in our brain stimulation laboratory now use a standardized behavioral prime, which is given before and during the brain stimulation intervention. For our present investigations using the vMPFC as a target, this behavioral prime includes a standardized drug-cue exposure paradigm based on standardized exposure therapy treatment questions (Concurrent Treatment of PTSD and Substance Use Disorder Using Prolonged Exposure Handbook). Specifically, participants are prompted to describe their most recent (index) drug use event (e.g., day of the week, time of the day, people they were with, and the sensory aspects of the experience). For some of our studies, individuals are then prompted: “During the stimulation, it is important for you to try to focus on (insert their drug of choice: cocaine, crack, alcohol, liquor, beer, wine, cigarettes, painkillers). This tablet will be displaying various pictures of (insert: cocaine/crack, alcohol drinking, cigarettes, painkillers). We would also like you to keep your eyes open, look at the screen, and think about your most recent experience with (insert: cocaine/crack, alcohol drinking, cigarettes, painkillers).” For other protocols, especially those in which we are using the DLPFC as our target (based on a conceptual framework of increasing cognitive control), they are prompted with statements that they are taught in cognitive behavioral therapy as they view the drug cues. Although the cues are routinely tailored to the patient group, and will change based on conceptual strategy for a specific TMS protocol, one thing that remains stable is the existence of a behavioral prime. Full details of the standard operating protocol and a description of the questions used to create these participant-tailored drug use scripts are included in prior work (Hanlon et al., 2017). In the future we anticipate that cutting-edge brain stimulation laboratories and clinics will capitalize on the increasingly widespread availability of virtual reality gaming environments that could be customized and adapted to treatment-seeking drug users and drug use treatment.