Brain Stimulation Methods to Treat Tobacco Addiction

Brain Stimulation 6 (2013) 221e230

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Review Articles

Brain Stimulation Methods to Treat Tobacco Addiction Victoria C. Wing a, b, d, *, Mera S. Barr b, c, d, Caroline E. Wass a, b, d, Nir Lipsman e, Andres M. Lozano e, Zafiris J. Daskalakis b, c, d, Tony P. George a, b, d a

Biobehavioural Addictions and Concurrent Disorders Research Laboratory (BACDRL), Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada Schizophrenia Program, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada Brain Stimulation Clinic, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada d Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada e Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 February 2012 Received in revised form 8 June 2012 Accepted 30 June 2012 Available online 17 July 2012

Background: Tobacco smoking is the leading cause of preventable deaths worldwide, but many smokers are simply unable to quit. Psychosocial and pharmaceutical treatments have shown modest results on smoking cessation rates, but there is an urgent need to develop treatments with greater efficacy. Brain stimulation methods are gaining increasing interest as possible addiction therapeutics. Objectives: The purpose of this paper is to review the studies that have evaluated brain stimulation techniques on tobacco addiction, and discuss future directions for research in this novel area of addiction interventions. Methods: Electronic and manual literature searches identified fifteen studies that administered repetitive transcranial magnetic stimulation (rTMS), cranial electrostimulation (CES), transcranial direct current stimulation (tDCS) or deep brain stimulation (DBS). Results: rTMS was found to be the most well studied method with respect to tobacco addiction. Results indicate that rTMS and tDCS targeted to the dorsolateral prefrontal cortex (DLPFC) were the most efficacious in reducing tobacco cravings, an effect that may be mediated through the brain reward system involved in tobacco addiction. While rTMS was shown to reduce consumption of cigarettes, as yet no brain stimulation technique has been shown to significantly increase abstinence rates. It is possible that the therapeutic effects of rTMS and tDCS may be improved by optimization of stimulation parameters and increasing the duration of treatment. Conclusion: Although further studies are needed to confirm the ability of brain stimulation methods to treat tobacco addiction, this review indicates that rTMS and tDCS both represent potentially novel treatment modalities. Ó 2013 Elsevier Inc. All rights reserved.

Keywords: Repetitive transcranial magnetic stimulation (rTMS) Transcranial direct current stimulation (tDCS) Deep brain stimulation (DBS) Cranial electrostimulation (CES) Nicotine Cigarette smoking

Introduction This work was supported by grant an Idea Grant (#19588) from Canadian Tobacco Control Research Initiative to T.P.G, the Canadian Institute for Health Research Operating Grant (MOP#115145) to T.P.G, V.C.W and Z.J.D, the Chair in Addiction Psychiatry (to T.P.G.) and the Chair in Neuroscience (to A.M.L.) from the University of Toronto. V.C.W. and C.E.W were supported by Postdoctoral Fellowship Awards from the Centre for Addiction and Mental Health. M.S.B was supported by the Ontario Mental Health Foundation studentship award. Drs. Wing, Barr, Wass and Lipsman have no conflicts to report. Dr. Lozano is a consultant for Medtronic, Boston Scientific and St. Jude. Dr. George reports that he has received grant support from Pfizer, Inc., and has received consulting fees from Pfizer, Evotec, Eli Lilly, Janssen-Ortho, Astra-Zeneca and Novartis in the past two years. Dr. Daskalakis reports that he has received grant support from Brainsway, Inc., travel support through Pfizer, Inc. and Merck, Inc., and has received speaking honoraria through Pfizer, Inc. and Lundbeck, Inc. * Corresponding author. Centre for Addiction and Mental Health, 33 Russell Street, Room 1910A, Toronto, Ontario, Canada M5S 2S1. Tel.: þ(416) 535 8501 x 4882; fax: þ(416) 979 4676. E-mail address: [email protected] (V.C. Wing). 1935-861X/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2012.06.008

Although tobacco smoking rates have decreased in Western nations over the past decade [1], tobacco is still the leading cause of mortality in the USA [2] and third most frequent cause of preventable mortality in industrialized countries [3]. Various treatments have been shown to increase the odds for successfully quitting (up to 2e3 times compared to placebo), including counseling [4e6] and pharmaceutical aids such as nicotine replacement therapy (e.g., nicotine patch, gum and inhaler), bupropion (ZybanÒ) and varenicline (ChantixÒ) [7e12]. Nevertheless, the majority of those attempting to quit will relapse [13e17]. Nicotine is the main psychoactive ingredient in tobacco smoke and is believed to result in its addictive properties. Nicotine binds to ubiquitously distributed nicotinic acetylcholine receptors (nAChRs) [18] to influence the release of neurotransmitters including

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dopamine (DA), noradrenaline, serotonin, endogenous opioids, gaminobutyric acid (GABA) and glutamate [19]. Nicotine’s ability to induce the release of DA in the nucleus accumbens (NAc) underlies its reinforcing effects, which are thought to initiate the process of addiction [20]. Neuroadaptations following chronic nicotine exposure are thought to underlie the compulsive drug seeking, tolerance, withdrawal and craving seen in tobacco addiction [21,22]. In the past decade, progress has been made in developing neurobiologically-based interventions for smoking. The interest in brain stimulation as a potential treatment rests on its ability to induce changes in brain function. The purpose of this article is to review the literature on brain stimulation as a treatment for tobacco dependence, and provide a discussion on future directions for research in this novel area of addiction interventions. All relevant studies were identified through NCBI Pubmed (http://www.ncbi.nlm.nih.gov) and manual searches. Search terms included ‘repetitive transcranial magnetic stimulation,’ ‘rTMS,’ ‘transcranial direct current stimulation,’ ‘tDCS,’ ‘deep brain stimulation,’ ‘DBS,’ with adjoining terms, ‘tobacco,’ ‘nicotine,’ ‘smoking,’ and ‘addiction.’ Due to the paucity of literature in this area, N ¼ 15 studies were identified and included in this review (n ¼ 12 journal articles; n ¼ 3 conference abstracts). Repetitive transcranial magnetic stimulation (rTMS) rTMS is a non-invasive brain stimulation technique that has shown positive results in the treatment of depression [23,24], schizophrenia [25], and more recently addiction [26e32] (for further reviews see [33,34]). rTMS uses alternating magnetic fields to induce electric currents in the cortical tissue [35]. Low-frequency (LF; 1 Hz) rTMS is believed to inhibit neuronal firing in a localized area and is used to induce virtual brain lesions. High-frequency (HF; >3 Hz) rTMS is believed to be excitatory in nature and can result in neuronal depolarization under the stimulating coil [36]. However, the effects of rTMS are not limited to the site of stimulation and can induce changes in distant interconnected sites of the brain, and consequently may influence subcortical regions [35,37e40]. In rodents, rTMS has been shown to increase DA in the dorsal hippocampus [41] and NAc [41,42], and modulate GABA synthesis [43]. In humans, rTMS can induce changes in cortical inhibition. HF frequency rTMS (up to 25 Hz) applied to the motor cortex has been shown to both enhance [44] and reduce [45] neurophysiological indices of GABAB receptor-mediated inhibitory neurotransmission in different studies. HF rTMS also affects indexes of GABAA receptormediated inhibitory neurotransmission [46,47]. Positron Emission Tomography (PET) studies have demonstrated that 10 Hz rTMS over the dorsolateral prefrontal cortex (DLPFC) increases extracellular levels of DA in cortical and subcortical brain regions [48,49]. Regional cerebral blood flow (rCBF) studies have shown that HF and LF rTMS to the left DLPFC are respectively associated with increases and decreases in rCBF across a range of cortical and subcortical regions in depressed patients [50]. In contrast, LF rTMS to the right DLPFC in control subjects has been shown to be associated with increased rCBF at the stimulation site and in the ventrolateral prefrontal cortex [51]. These studies demonstrate that rTMS has the potential to treat tobacco addiction by altering cortical excitability through the modulation of neurotransmitters (e.g., DA and GABA). Ultimately, the effects of rTMS on cortical excitability will be influenced by the basic excitability niveau of the person being treated, which may explain why similar stimulation conditions have sometimes led to different neurobiological effects. Treatment of tobacco addiction with rTMS Our search identified 6 randomized double-blind shamcontrolled studies on rTMS and tobacco addiction (Table 1). Five

studies applied HF rTMS to the DLPFC [26,27,52e54]. In a crossover study, Johann et al. (2003) administered one active and sham session of 20 Hz rTMS delivered to left DLPFC to treatmentseeking smokers under 12 h abstinent conditions [26]. rTMS significantly reduced the level of craving reported after treatment. The same research group investigated the effects of two sessions of active and sham rTMS at the same parameters [27]. Cravings were not significantly reduced, but the number of cigarettes smoked in the 6 h following treatment was. Recently, Amiaz et al. (2009) assessed the effects of 10 days of treatment with either active or sham 10 Hz rTMS treatment applied to the left DLPFC. To test whether induction of tobacco craving before treatment would result in a more specific disruption of circuitries associated with craving, subjects were presented with either smoking or neutral cues immediately before rTMS treatment. rTMS, independent of exposure to smoking pictures, reduced subjective and objective measures of cigarette consumption and nicotine dependence [28]. It also reduced cue-induced craving and blocked the development of general craving induced by repeated presentation of smoking-related pictures. Interestingly, there was a trend for lower cigarette consumption in the active rTMS-smoking picture group at 6 month follow-up. Our research group has recently completed a preliminary parallel-groups sham-controlled trial of rTMS in combination with the nicotine patch to treat tobacco addiction in heavily-dependent patients with schizophrenia [52]. rTMS did not increase abstinence rates, but did significantly reduce tobacco cravings induced by shortterm (30e60 min) abstinence which was assessed before application of the nicotine patch. Together, these studies indicated that rTMS of the DLPFC has the potential to reduce tobacco cravings and cigarette consumption in smokers, including those with schizophrenia. Rose et al. (2011) implemented a within-subject design to examine the effects of rTMS to the Superior Frontal Gyrus (SFG). Compared to 1 Hz rTMS to the SFG or motor cortex, 10 Hz to the SFG resulted in increased cue-induced craving but lower craving during presentation of neutral cues [53]. These findings highlight the excitatory and inhibitory influence of SFG on tobacco cravings but do not provide evidence for the utility of rTMS of the SFG for the treatment of tobacco addiction. In addition to studies focusing on treatment-related outcomes, researchers have begun to examine the mechanisms underlying rTMS’s effects. The effects of 1 Hz rTMS applied to the left DLPFC on neural responses to smoking cues were reported in an abstract. Connectivity analysis revealed that the stimulated region became less responsive to input from the contralateral DLPFC and medial temporal regions which may have resulted in the trend for reduced craving following active rTMS [54]. It is clear that further studies are needed to fully understand the complex effects of rTMS on tobacco addiction.

Cranial electrostimulation (CES) Similar to rTMS, CES (also known as transcranial electrostimulation therapy or neuroelectric therapy) uses a low intensity alternating current commonly applied through two electrodes attached to the earlobes or mastoid [55,56]. CES was originally developed in the 1950s for anxiety and depression treatment, and was later used to treat pain [57]. The evaluation of CES to treat addictive disorders began in the 1980s with some positive findings [58]. However, optimal frequency and duration of stimulation parameters still need to be determined. The exact mechanism of CES is still largely unknown but the modulation via direct action upon the hypothalamus, limbic system and/or the reticular

Table 1 Review of studies evaluating the ability of brain stimulation to treat tobacco addiction. 1st Author

Year

Design

N (active, sham)

Participant characteristics

Cranial electrostimulation (CES) Patterson 1984 Open-labeld 186 (26 daily 61% M, substance users with co-morbid smokers) tobacco use

Jasinskia

1992 B/W

48, 52

1997 B/W

51, 50

Georgiou

1998 B/W

108, 108

Scheuera

2005 B/W

33, 33

Deep brain stimulation (DBS) Kuhn 2009 Case studyd

9

2011 Case studyd

1

Mantione

No of sessions

MP

10 days: 6 days continuous, Asymmetric rectangular pulse, reduced to 6 h/day 0.22 ms, 1e2000 Hz (narcotics lower, stimulants higher); 1.5e3 mA through 1 cm diameter electrodes 5 Not available

MP MP

2007 W/I

Amiaz

2009 B/W

22, 26

Wing

2010 B/W

6, 9

Rose

2011 W/I

15

10

CR

DE

CON

WT

Yf

/g

/g

Y

dh

/g

dh

g

h

Y days 2 &5 /g

30 mA, 2 ms, 10 Hz pulsed signal, positive electrode dominant side, 60min. 0.15 ms biphasic pulse, 0.5/0.8 mA in 1 KU load; either continuous 10 Hz or modulated 7e14 Hz current 10 mA, 35 V, active at 300 Hz, sham at 700 Hz

Y days 1e2

/

dh

/g

Y n.s.

dh

/g

/g

Y n.s.

Y

d

43 yo, 40% M, moderate nicotine-dependence, MP or back 24 cpd, treatment-seeking

7 days as needed

Treatment-seeking

MP

1 (96 h)

44 yo, 70%M, low nicotine-dependence, co-morbid psychiatric disorder (Tourette’s syndrome, OCD or anxiety), treatment-seeking for the co-morbid disorder 47 yo female, heavy nicotine-dependence, 35 cpd, co-morbid OCD, treatment-seeking for the co-morbid disorder

Uni- or bi-NAc

10 active, 5 sham

Quadripolar electrode tips in NAc; parameters varied to alleviate disorder

/g

Y 30% Y 30%c /g

Bi-NAc

5 months

Monopolar stimulation with contacts 0,1 negative (cathode); pulse width 90 ms; 185 Hz; 3.5 V; 3 weeks after, contacts 2, 3 used.

Y

/g

Yc

Y

1 active, 1 sham

Not available

Y

/g

/g

/g

2 active, 2 sham

20 Hz; 20 trains of 50 pulses/train (i.e., 1000 pulses); 42.5 s ITI; 90% RMT 1 Hz; 1800 pulses; 59% RMT

dh

/g

Y

/g

Y

/g

/g

/g

10 Hz; 20 trains of 50 pulses/train (i.e., 1000 pulses); 15 s ITI, 100% RMT 20 Hz; 25 trains of30 pulses/train bilaterally (i.e., 1500 pulses); ITI 30 s; 90% RMT 1 or 10 Hz for 2.5 mins (therefore more pulses in 10 Hz than 1 Hz condition); 90% RMT

Y

Y

Y

/g

Y

dh

dh

dh

/g

/g

/g

Repetitive transcranial magnetic stimulation (rTMS) 2003 W/I 11 Nicotine-dependence, treatment-seeking, L DLPFC Johannb 12-hr abstinent Eichhammer 2003 W/I 14 35 yo, 14% M, moderate nicotine-dependence, L DLPFC 17 cpd, treatment-seeking, 12-hr abstinent Hayashia

5

Stimulation parameters

19 cpd

L DLPFC

41 yo, moderate nicotine-dependence, 20 cpd, L DLPFC treatment-seeking

2 active, 2 sham [(un)expectant] 10

43 yo, 67% M, heavy nicotine-dependence, Bilateral DLPFC 20 28 cpd, treatment-seeking, co-morbid schizophrenia or schizoaffective 41 yo, 53% M, moderate nicotine-dependence, SFG 1 active (1 Hz), 16 cpd 1 active (10 Hz), 1 MOC (1 Hz)

Ye

V.C. Wing et al. / Brain Stimulation 6 (2013) 221e230

Pickworth

M & F, heavy nicotine-dependence, quit day before treatment 45 yo, 48% M, heavy nicotineedependence, 31 cpd, treatment-seeking

Site

(10 Hz)

(continued on next page) 223

5 27 yo, 56% M, moderate nicotine dependence, L DLPFC 15 cpd 13, 14 2009 B/W Boggio

Unless otherwise stated, ‘treatment-seeking’ refers to treatment-seeking for nicotine dependence or willing to quit smoking. B/W ¼ Between-subject; Bi- ¼ bilateral; CON ¼ Consumption; cpd ¼ group average cigarettes per day; CR ¼ Craving; DE ¼ Dependence; DLPFC ¼ dorsolateral prefrontal cortex; F ¼ female; ITI ¼ Inter-train interval; L ¼ left; M ¼ male; MOC ¼ motor cortex; MP ¼ mastoid process; n.s. ¼ non-significant finding; N ¼ number of subjects; NAc ¼ nucleus accumbens; R ¼ right; RMT ¼ resting motor threshold; SFG ¼ superior frontal gyrus; Uni- ¼ unilateral; W/I ¼ Within-subject; WT ¼ Withdrawal; yo ¼ group average years old. a Conference abstract. b Full article not available in English language. c Self-reported consumption not biochemically verified by expired breath carbon monoxide or plasma/urine nicotine or cotinine level. d No sham control group. e Cue-induced craving increased but general craving decreased. f Craving for all substances including nicotine assessed together. g Not measured. h No change.

Y /g

/g

/g /g 1 active (L), 1 active (R), 1 sham Transcranial direct current stimulation (tDCS) Fregni 2008 W/I 24

45 yo, 54% M, moderate nicotine dependence, DLPFC 19 cpd

Y 2 mA for 20 min; L ¼ anodal F3 (35 cm3), cathodal F4 (100 cm3), R ¼ vice versa; 48 h intersession interval 2 mA for 20 min; anodal F3 Y (EEG 10/20), cathodal F4

CON DE CR Stimulation parameters No of sessions Site Participant characteristics N (active, sham) Design Year 1st Author

Table 1 (continued)

/g

V.C. Wing et al. / Brain Stimulation 6 (2013) 221e230

WT

224

activating system [56] resulting in neurotransmitter secretion and downstream hormone production [59] has been suggested. Treatment of tobacco addiction with CES Three papers and 2 abstracts report on CES applied over the mastoid bone as a treatment for tobacco addiction (Table 1). Patterson and colleagues administered 10 days of CES in an open-label manner to persons addicted to a range of substances who were enrolled in a detoxification program (primarily in an inpatient setting), a subset of which reported nicotine as their primary substance of use. Craving, anxiety and withdrawal was assessed in a non-substance dependent measure; overall abstinence symptoms, anxiety and craving were reduced in the majority of patients over the course of the treatment [60]. However, given the lack of control group the effects of CES cannot be disentangled from the other aspects of the treatment. CES was subsequently evaluated in heavily dependent cigarette smokers who were asked to quit smoking 24 h before treatment began. 5 days of CES were administered in a randomized, sham-controlled, double-blind trial, and was found to reduce symptoms of withdrawal. However this difference only reached statistical significance at days 2 and 5 and no effects on tobacco craving or consumption were found [61]. The third study was a parallel-design double-blind, sham-controlled study of 5 days of CES in smokers who wanted to quit [62]. Subjects in the active group reported lower levels of craving and anxiety in the first 2 days of treatment but by day 5 there were no differences in smoking-related measures compared to sham. An abstract reported on a study using a parallel-design to evaluate the effects of CES administered at home in moderate to heavy smokers. Although abstinence rates were higher in the active group, the effect did not reach statistical significance [63]. More recently, the effect of 96 h active and sham CES in treatment-seeking smokers were studied; CES increased abstinence rates but group differences were marginal [64]. Combined with the negative conclusion of a recent meta-analysis [65] and studies evaluating the effects of CES on dependence to other drugs such as opiates and cocaine [66,67], these findings suggest that it is unlikely that CES will be an effective treatment for tobacco dependence. Transcranial direct current stimulation (tDCS) tDCS is another non-invasive brain stimulation technique that has been employed as a treatment for psychiatric disorders. In contrast to rTMS and CES, tDCS applies a weak and direct current (usually 1e2 mA) that flows in one direction between two small electrodes placed on the scalp and is therefore polarity dependent. Animal and human studies have shown that tDCS can modulate cortical excitability [68e70]; anodal stimulation increases, while cathodal stimulation decreases excitability [70e72]. These effects occur during and following stimulation and are dependent on factors including duration, intensity, and baseline cortical excitability [70]. tDCS has been shown to directly change spontaneous neuronal firing; specifically, anodal stimulation induces neuronal depolarization, while cathodal stimulation induces hyperpolarization [73e75]. It has been suggested that the after effects of tDCS are mediated through the modulation of N-methyl-D-aspartic acid (NMDA) [76] and DA-D2 receptor activity [77]. That is, anodal stimulation has been proposed to increase, while cathodal stimulation decreases, synaptic strength [76]. Although the exact mechanisms of tDCS are unclear, its ability to differentially influence cortical excitability and spontaneous neuronal firing has made this technique an attractive tool for the treatment of psychiatric illnesses with known alterations in cortical excitability [34,78]. There have been some positive reports on its ability to treat

V.C. Wing et al. / Brain Stimulation 6 (2013) 221e230

depression [78] and Parkinson’s disease (PD) [79], and more recently addiction, particularly alcoholism [80]. tDCS has been found to reduce cue-induced craving for food and alcohol [80e83], as well as modulate behaviors relevant to addictive disorders such as risk-taking and impulsivity [84e87]. Treatment of tobacco addiction with tDCS Our search identified two studies which evaluated tDCS in tobacco smokers (Table 1). Fregni et al. [81] conducted a randomized, double-blind, sham-controlled crossover study of a single session of anodal tDCS applied to the left or right DLPFC on cueinduced craving. Participants were exposed to cigarette manipulation and a smoking video before and after active or sham tDCS and craving assessed. Active stimulation of both left and right DLPFC reduced general craving and cue-induced craving [81]. Using the same methodology, a follow-up parallel-design study was conducted to evaluate the effects of repeated sessions of anodal tDCS to the left DLPFC. Cue-induced craving was dose-dependently decreased (i.e., treatment effects increased over repeated sessions) and a significant reduction in cigarette consumption was found compared to sham [88]. These two studies indicate tDCS can reduce tobacco cravings induced by short periods of abstinence but it remains to be determined if tDCS is capable of reducing cravings after longer periods of abstinence or increasing quit rates. Deep brain stimulation (DBS) DBS is a neurosurgical procedure that involves the stereotactic placement of unilateral or bilateral electrodes connected to a permanently implanted programmable pulse generator allowing current to be delivered to specific targets. DBS is more focal and can target deeper brain areas than other forms of brain stimulation. In PD, DBS of the subthalamic nucleus (STN) has been shown to be effective in controlling disabling tremor and dyskinesias [89e91]. Positive results have also been reported in the DBS literature for psychiatric indications, such as depression and obsessivecompulsive disorder (OCD), where targets have included the subgenual cingulate gyrus [92,93], STN [94] and ventral striatum/NAc [95]. In these studies, patients who are selected have reached the limits of conventional therapy, and are deemed treatmentresistant. The precise mechanism of DBS remains elusive. It has been suggested that continuous HF stimulation (130e185 Hz) decreases neural transmission through the inactivation of voltagedependent ion channels [96]. Trials that have combined DBS therapy with functional neuroimaging have shown that DBS can drive the activity of underactive circuits, as well as attenuate activity in overactive ones [92,97]. Whether determined by the nature of the target in question (e.g. gray or white matter, cell body or axons), or the predominant neurotransmitter system involved (e.g. DAergic or GABAergic pathways), it appears that DBS can exert measurable up- and down-stream influences in participating motor and affective circuits. It also appears that DBS’ therapeutic effects can at least partially be attributed to its influence on the brain’s reward pathways [98,99]; thereby suggesting that DBS may be an effective treatment for addiction. There is an established neurosurgical literature on the management of refractory addiction [100e102], however, the majority of published reports involve the generation of irreversible lesions, in structures such as the cingulate. Such work is often hampered by inconsistencies in surgical indications, scientific rationale, patient follow-up, and variable regulatory and ethical oversight. Much of the evidence for DBS in addiction therefore comes from indirect observations. For example, two PD patients with a severe addiction to DA replacement therapy reported a complete abolishment of cravings to

225

the drug following DBS to the STN [99]. It is thought that STN DBS results in the inhibition of neuronal circuits which, in turn, influence the direct and ascending DAergic and serotonergic pathways to the limbic area that contribute to the positive reinforcing effects of drug misuse [103]. An additional case report of NAc DBS in a patient with severe depression, anxiety, and co-morbid alcoholism, found significant improvements in alcohol dependency, but no improvement in mood and anxiety [104]. These results have led to the development of dedicated DBS trials in alcoholism, with promising results [105,106]. Animal studies indicate that DBS can also attenuate cocaine, morphine and alcohol reinforcement [107e110]. It is likely that DBS will be effective in reducing nicotine consumption given the common DAergic reward pathway that underlies the reinforcing effects of all addictive drugs [111]. Treatment of tobacco addiction with DBS There have been several case reports of spontaneous smoking cessation following NAc DBS administered to treat another cooccurring disorder (Table 1). Kuhn et al. reported that 3 out of 10 smoking patients treated for another psychiatric disorder were able to quit smoking after DBS and remained abstinent at the 24e30 month follow-up assessments [112]. Similarly, Mantione et al. described an OCD patient who quit smoking and lost weight without any effort following DBS of the NAc. However, these changes emerged after disappearance of OCD symptoms, making it difficult to determine if they were a direct effect of DBS treatment or an indirect effect of successful OCD treatment [113]. Currently, studies of DBS for the treatment of tobacco addiction are severely limited by the small number of cases, open-label designs, lack of an appropriate control group, and in some cases the retrospective nature of the assessment of smoking behavior. Although it appears that further research is warranted, dedicated DBS trials for tobacco addiction should not be trivialized, as they involve an invasive surgical procedure with attendant risks. Nevertheless, DBS studies in animals as well as a close, prospective assessment of smoking behavior in patients undergoing DBS for other indications, could help shed light on the mechanisms underlying tobacco addiction. Discussion Four brain stimulation techniques evaluated as treatments for tobacco addiction are reviewed, of which rTMS has been the most well studied. Evidence suggests that brain stimulation is a possible avenue to treat tobacco addiction due to its effects on craving, withdrawal and consumption. The comparative safety and efficacy of brain stimulation techniques to treat tobacco addiction Brain stimulation techniques have been evaluated in a range of different paradigms (e.g., open label vs. placebo-controlled; within-subject vs. between-subject designs) and populations (e.g., [non]treatment-seeking smokers, co-morbid populations) and using varying outcome measures (e.g., subjective measures of craving and withdrawal; self-report and objective measures of consumption). For these reasons it is impossible to accurately compare their efficacy. One aspect that was relatively consistent between studies was the level of nicotine dependence of the participants. Given the existing state of the literature there is the most evidence to support rTMS’s potential to treat tobacco addiction. All of the published studies reported positive effects on one or more addiction-related outcome measure, with the most consistent finding being on craving. Somewhat disappointingly

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Mechanisms by which brain stimulation may act to reduce tobacco addiction The exact mechanism by which it may reduce tobacco addiction is not fully understood; potential mechanisms are discussed below (Fig. 1). Modulation of brain reward systems rTMS modulates both cortical and subcortical excitability and neurotransmission [44,45]. Given that tobacco addiction is associated with striatal and cortical DAergic dysfunction [117], the ability of rTMS to increase DAergic transmission in these areas [48,49] may underlie its capacity to treat addictive disorders. It is also noteworthy that case reports of NAc DBS found several cases of spontaneous quitters.

Figure 1. Diagram to illustrate the potential mechanisms of action of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on tobacco addiction. rTMS and tDCS targeted to the dorsolateral prefrontal cortex (DLPFC) result in neuronal changes which in turn result in the release of neurotransmitters such as dopamine (DA) and g-aminobutyric acid (GABA) in cortical and subcortical brain regions. These effects are thought to lead to the observed behavioral changes such as increased inhibitory control, improved decision-making and decreased craving, which ultimately may reduce consumption of tobacco products.

these effects on craving have not always translated into reductions in consumption and abstinence rates. However, in most cases the studies were not optimally designed to probe for such effects, and it is likely that optimization of the parameters and duration of treatment could enhance rTMS efficacy. tDCS also shows great promise; studies examining its effects on tobacco craving were positive and effects increased with longer durations of treatment. It remains to be tested if these early findings are reproducible and will translate into increased abstinence rates. Both rTMS and tDCS have preferable safety profiles, especially when safety guidelines are followed [114,115]. rTMS is associated with a relatively low risk of seizures and syncope episodes [116], while tDCS-associated risks have not yet been identified. The efficacy of DBS to treat tobacco addiction has yet to be established in a randomized double-blind sham-controlled trial and may never be, given the likely opposition to conducting an invasive surgical procedure to treat an addictive disorder for which approved pharmacotherapies are already available. However, given that tobacco-related illnesses are the leading cause of death in the developed world, it could be argued that DBS may be an option for smokers who have exhausted the currently available treatments. Either way, it is clear that extensive research would be needed to confirm that the efficacy of DBS is higher than the other available options and that the risks associated with the surgery are minimal. The brain stimulation technique for which there is the least supporting evidence in tobacco addiction therapy is CES. Although early reports were positive, the large-scale clinical trials which followed provided only weak evidence for its efficacy.

Reduction of tobacco cravings Prefrontal brain regions, particularly the DLPFC, are critically involved in drug craving [118,119]. Stimulation of the PFC by rTMS or tDCS can inhibit food craving [120] and cue-induced food [82] and alcohol [80] craving respectively. It was therefore hypothesized that these techniques may disrupt tobacco craving, and early evidence supports this. Several explanations have been put forward to explain these effects. Eichhammer et al. (2003) proposed that stimulation of the DLPFC by rTMS may mimic craving-related processes (via DAergic and associated neurotransmitter systems) and thus reduce the need to use the drug to achieve the same effect. Modulation of the DLPFC may also have downstream effects on other areas associated with craving, such as the orbitofrontal cortex (OFC) which has extensive connections to other areas such as the striatum. It has been suggested that anodal tDCS may increase activity in the DLPFC and therefore reinforce drug-avoiding behavior [81] or alternatively, brain stimulation may inhibit drug craving by disrupting local and/or interconnected neural networks [31,54]. It is noteworthy that some paradigms involved exposure to smoking-related cues immediately before treatment. The presumption for this approach is that concomitant activation of craving-related networks may potentiate the effects of brain stimulation. As such, Amiaz et al. (2009) proposed that rTMS may alter the neuroadaptations that occur in the reward system during the development of addiction by its effects on cortical excitability [121,122] which in turn activate synaptic plasticity mechanisms such as long-term potentiation [123,124]. Modulation of decision-making and impulsivity The risky decision-making and impulsivity which contribute to drug-taking behavior, including cigarette smoking, is controlled by prefrontal brain regions such as the DLPFC [125]. rTMS and tDCS to the PFC can disrupt decision-making [126] and impulsivity [84]. It has therefore been proposed that brain stimulation techniques may have the capacity to reduce risky decision-making and impulsivity which lead to continued tobacco use; however this remains to be empirically tested. Future directions Current research is limited by the paucity of studies, small sample sizes, variation in stimulation parameters, and in some cases the lack of sham-controlled designed (i.e., for DBS) and objective measures of tobacco smoking (e.g., carbon monoxide or cotinine levels). One of the first steps for the field is to conduct larger-scale randomized double-blind treatment trials to firmly establish the efficacy of brain stimulation to treat tobacco addiction using objective direct assessments of smoking behavior (rather than focusing on intermediate markers such as craving).

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Subsequently it will be necessary to compare the efficacy of brain stimulation techniques to approved tobacco addiction treatments. It would also be of great benefit to evaluate these techniques in laboratory paradigms, such as functional neuroimaging in humans or microdialysis in rodents and behavioral assessment of addictionrelated constructs (e.g., craving, withdrawal, reinforcement), to gain a better understanding of the mechanisms underlying their efficacy. Another key area of research is establishing the optimal parameters (e.g., stimulation site, frequency, intensity, and duration) for treatment. This will require the lengthy but necessary process of systematically examining the effects of these factors on safety and efficacy. rTMS and tDCS studies have mainly involved stimulation of the DLPFC. Although there is clearly significant rationale for this (i.e., role in craving and connections to cortical and subcortical structures relevant to addiction), it is important to investigate the utility of targeting other brain regions involved in addiction. Studies conducted with other addictive disorders may help guide our choice of future targets. For example, one case study in alcohol dependence reported that rTMS targeting the dorsal anterior cingulate cortex resulted in a substantial and longlasting reduction in craving and consumption [31]. In regards to DBS, the NAc is the only area studied in relation to tobacco. However, STN DBS has been shown to reduce desire for cocaine [127] and pathological gambling in PD [128]. One particularly exciting target for brain stimulation techniques capable of affecting deeper brain regions, such as DBS and deep rTMS [129], is the insula, which has recently been identified as having an important role in the maintenance of smoking behavior [130e132]. Moreover, an anatomic target that is in a position to modulate activity within the insula, such as the NAc or cingulate, would be an attractive target for any neurostimulation approach to smoking addiction. Another factor to consider is which brain hemisphere to target. rTMS and tDCS have typically targeted the left DLPFC, although reductions in cravings have been reported following bilateral application to cigarette smokers and stimulation of the right hemisphere in alcoholics. One of the more consistent findings in the literature is the use of HF rTMS. That being said it is unclear what precise frequency produces optimal effects. The duration of brain stimulation treatment is also an important aspect to consider. Recent studies have suggested that increasing the ‘dose’ of brain stimulation can enhance its efficacy. Depression studies have shown that the therapeutic efficacy of rTMS may be enhanced by increasing the intensity of stimulation, number of pulses per day and number of days of treatment [24,133]. In addition, intensity of rTMS stimulation (i.e., % RMT) was correlated with rCBF [134] and recent work in our lab has shown that an increased number of pulses per session are more likely to lead to rTMSinduced lengthening in the cortical silent period (a measure of cortical inhibition related to GABAB neurotransmission) (unpublished findings). There has been less investigation of parameter modulation on the efficacy of tDCS but its effects on craving do appear to increase over sequential sessions [135]. It has been proposed that increasing the ‘dose’ of brain stimulation may help overcome (i.e., re-wire or perhaps un-wire) the neuroadaptations associated with chronic tobacco use [88]; and it may be the case that the brain stimulation parameters need to be personalized based upon the level of addiction, basal cortical excitability and the presence of co-morbid disorders. Given tDCS and rTMS’s effects on craving, it is possible that brain stimulation may be a useful adjunctive therapy and that neuromodulation could help reduce cravings at the pre-quit, initial abstinence stage and maintenance stage of the cessation process, while alternative therapies are used to target other aspects of tobacco addiction. Lastly, it is important to evaluate brain

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stimulation techniques in special populations, such as patients with co-morbid mental health and addictive disorders as these smokers are heavily dependent and less likely to quit with standard treatments [136]. As such, they are in the greatest need of novel and effective smoking cessation therapies. Our preliminary study conducted in smokers with schizophrenia indicated that rTMS exerts similar effects on tobacco cravings as seen in non-mentally ill smokers [52]. Optimization of the treatment parameters and duration or combination with other therapies may translate the effects found on cravings to abstinence. Conclusions Despite existing availability for tobacco addiction treatments, there are still smokers, particularly those with psychiatric disorders, who are unable to quit with standard pharmacological and behavioral therapies. Brain stimulation techniques represent novel and potentially useful treatment modalities for tobacco addiction. DBS requires further research to demonstrate its efficacy, while CES shows little promise. However, initial studies have demonstrated that rTMS and tDCS represent safe and possibly efficacious approaches for treating tobacco-dependence, alone or in combination with other therapies. Acknowledgments We thank Matthew Tracey for assistance in preparing this manuscript. References [1] CDC. Tobacco use among middle and high school students e United States, 2000e2009. Morbidity and Mortality Weekly Report 2010;59(33):1063e8. [2] CDC. Targeting tobacco use: the nation’s leading cause of death. Georgia: Department of Health and Human Services, Centers for Disease Control and Prevention; 2011. [3] Mackay J, Eriksen M. The tobacco atlas. Geneva: The World Health Organization; 2002. [4] Goldstein MG, Niaura RS, Willey C, Kazura A, Rakowski W, DePue J, et al. An academic detailing intervention to disseminate physician-delivered smoking cessation counseling: smoking cessation outcomes of the physicians counseling smokers project. Preventive Medicine 2003;36:185e96. [5] Maddison R, Roberts V, Bullen C, McRobbie H, Jiang Y, Prapavessis H, et al. Design and conduct of a pragmatic randomized controlled trial to enhance smoking-cessation outcomes with exercise: the Fit2Quit study. Mental Health and Physical Activity 2010;3:92e101. [6] Zhu SH, Stretch V, Balabanis M, Rosbrook B, Sadler G, Pierce JP. Telephone counseling for smoking cessation: effects of single-session and multiple-session interventions. Journal of Consulting & Clinical Psychology 1996;64(1):202e11. [7] Hurt RD, Sachs DPL, Glover ED, Offord KP, Johnston JA, Dale LC, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. New England Journal of Medicine 1997;337(17):1195e202. [8] Silagy C, Mant D, Fowler G, Lodge M. Meta-analysis on efficacy of nicotine replacement therapies in smoking cessation. The Lancet 1994;343(8890): 139e42. [9] Tønnesen P, Tonstad S, Hjalmarson A, Lebargy F, Van Spiegel PI, Hider A, et al. A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation. Journal of Internal Medicine 2003; 254(2):1365e2796. [10] Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. The Journal of the American Medical Association 2006;296(1):47e55. [11] Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, et al. Efficacy of varenicline, an a4b2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation. JAMA: The Journal of the American Medical Association 2006;296(1):56e63. [12] Oncken C, Gonzales D, Nides M, Rennard S, Watsky E, Billing CB, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Archieves of Internal Medicine 2006;166(15):1571e7. [13] Garvey AJ, Bliss RE, Hitchcock JL, Heinold JW, Rosner B. Predictors of smoking relapse among self-quitters: a report from the normative aging study. Addictive Behaviors 1992;17(4):367e77.

228

V.C. Wing et al. / Brain Stimulation 6 (2013) 221e230

[14] Kenford SL, Fiore MC, Jorenby DE, Smith SS, Wetter D, Baker TB. Predicting smoking cessation. Who will quit with and without the nicotine patch. Journal of the American Medical Association 1994;271(8):589e94. [15] Hughes JR, Keely J, Naud S. Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction 2004;99(1):29e38. [16] Piasecki TM. Relapse to smoking. Clinical Psychology Review 2006;26(2): 196e215. [17] Tonstadt S, Tonnesen P, Hajek P, Williams KE, Billing CB, Reeves KR. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. Journal of the American Medical Association 2006;296(1): 64e71. [18] Changeux JP, Bertrand D, Corringer PJ, Dehaene S, Edelstein S, Lena C, et al. Brain nicotinic receptors: structure and regulation, role in learning and reinforcement. Brain Research - Brain Research Reviews 1998;26(2e3): 198e216. [19] Wonnacott S, Irons J, Rapier C, Thorne B, Lunt GG. Presynaptic modulation of transmitter release by nicotinic receptors. Progress in Brain Research 1989; 79:157e63. [20] Di Chiara G. Role of dopamine in the behavioural actions of nicotine related to addiction. European Journal of Pharmacology 2000;393(1e3):295e314. [21] Volkow ND, Li TK. Drug addiction: the neurobiology of behaviour gone awry. Nature Reviews Neuroscience 2004;5(12):963e70. [22] Koob GF. The neurobiology of addiction: a neuroadaptational view relevant for diagnosis. Addiction 2006;101(Suppl. 1):23e30. [23] Bortolomasi M, Minelli A, Fuggetta G, Perini M, Comencini S, Fiaschi A, et al. Long-lasting effects of high frequency repetitive transcranial magnetic stimulation in major depressed patients. Psychiatry Research 2007;150(2): 181e6. [24] Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J. Transcranial magnetic stimulation in the treatment of depression: a doubleblind, placebo-controlled trial. Archives of General Psychiatry 2003;60(10): 1002e8. [25] Hoffman RE, Hawkins KA, Gueorguieva R, Boutros NN, Rachid F, Carroll K, et al. Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Archieve of General Psychiatry 2003;60(1):49e56. [26] Johann M, Wiegand R, Kharraz A, Bobbe G, Sommer G, Hajak G, et al. [Transcranial magnetic stimulation for nicotine dependence]. Psychiatrische Praxis 2003;30(Suppl. 2):S129e31. [27] Eichhammer P, Johann M, Kharraz A, Binder H, Pittrow D, Wodarz N, et al. High-frequency repetitive transcranial magnetic stimulation decreases cigarette smoking. Journal of Clinical Psychiatry 2003;64(8):951e3. [28] Amiaz R, Levy D, Vainiger D, Grunhaus L, Zangen A. Repeated high-frequency transcranial magnetic stimulation over the dorsolateral prefrontal cortex reduces cigarette craving and consumption. Addiction 2009;104(4):653e60. [29] Camprodon JA, Martinez-Raga J, Alonso-Alonso M, Shih MC, Pascual-Leone A. One session of high frequency repetitive transcranial magnetic stimulation (rTMS) to the right prefrontal cortex transiently reduces cocaine craving. Drug Alcohol Depend 2007;86(1):91e4. [30] Politi E, Fauci E, Santoro A, Smeraldi E. Daily sessions of transcranial magnetic stimulation to the left prefrontal cortex gradually reduce cocaine craving. American Journal on Addictions 2008;17(4):345e6. [31] De Ridder D, Vanneste S, Kovacs S, Sunaert S, Dom G. Transient alcohol craving suppression by rTMS of dorsal anterior cingulate: an fMRI and LORETA EEG study. Neuroscience Letters 2011;496(1):5e10. [32] Mishra BR, Nizamie SH, Das B, Praharaj SK. Efficacy of repetitive transcranial magnetic stimulation in alcohol dependence: a sham-controlled study. Addiction 2010;105(1):49e55. [33] Barr MS, Farzan F, Wing VC, George TP, Fitzgerald PB, Daskalakis ZJ. Repetitive transcranial magnetic stimulation and drug addiction. International Review of Psychiatry 2011;23(5):454e66. [34] Barr MS, Fitzgerald PB, Farzan F, George TP, Daskalakis ZJ. Transcranial magnetic stimulation to understand the pathophysiology and treatment of substance use disorders. Current Drug Abuse Reviews 2008;1(3):328e39. [35] Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. International Journal of Neuropsychopharmacolgy 2002;5(1):73e103. [36] Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G. Transcranial magnetic stimulation in the investigation and treatment of schizophrenia: a review. Schizophrenia Research 2004;71(1):1e16. [37] Post A, Keck ME. Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms? Journal of Psychiatry Research 2001;35(4):193e215. [38] Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. Transcranial magnetic stimulation induces alterations in brain monoamines. Journal of Neural Transmission 1997;104(2e3):191e7. [39] Conca A, Koppi S, Konig P, Swoboda E, Krecke N. Transcranial magnetic stimulation: a novel antidepressive strategy? Neuropsychobiology 1996; 34(4):204e7. [40] Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. American Journal of Psychiatry 2003;160(5): 835e45. [41] Keck ME, Welt T, Muller MB, Erhardt A, Ohl F, Toschi N, et al. Repetitive transcranial magnetic stimulation increases the release of dopamine in

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51] [52]

[53]

[54]

[55]

[56] [57] [58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

the mesolimbic and mesostriatal system. Neuropharmacology 2002;43(1): 101e9. Erhardt A, Sillaber I, Welt T, Muller MB, Singewald N, Keck ME. Repetitive transcranial magnetic stimulation increases the release of dopamine in the nucleus accumbens shell of morphine-sensitized rats during abstinence. Neuropsychopharmacology 2004;29(11):2074e80. Trippe J, Mix A, Aydin-Abidin S, Funke K, Benali A. Theta burst and conventional low-frequency rTMS differentially affect GABAergic neurotransmission in the rat cortex. Exp Brain Res 2009;199(3-4):411e21. Daskalakis ZJ, Moller B, Christensen BK, Fitzgerald PB, Gunraj C, Chen R. The effects of repetitive transcranial magnetic stimulation on cortical inhibition in healthy human subjects. Experimental Brain Research 2006;174(3): 403e12. Khedr EM, Rothwell JC, Ahmed MA, Shawky OA, Farouk M. Modulation of motor cortical excitability following rapid-rate transcranial magnetic stimulation. Clinical Neurophysiology 2007;118(1):140e5. Takano B, Drzezga A, Peller M, Sax I, Schwaiger M, Lee L, et al. Short-term modulation of regional excitability and blood flow in human motor cortex following rapid-rate transcranial magnetic stimulation. Neuroimage 2004; 23(3):849e59. Jung SH, Shin JE, Jeong YS, Shin HI. Changes in motor cortical excitability induced by high-frequency repetitive transcranial magnetic stimulation of different stimulation durations. Clinical Neurophysiology 2008;119(1):71e9. Strafella AP, Paus T, Barrett J, Dagher A. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. Journal of Neuroscience 2001;21(15):RC157. Cho SS, Strafella AP. rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex. PLoS One 2009;4(8):e6725. Speer AM, Kimbrell TA, Wassermann EM, Repella JD, Willis MW, Herscovitch P, et al. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biological Psychiatry 2000; 48(12):1133e41. Eisenegger C, Treyer V, Fehr E, Knoch D. Time-course of “off-line” prefrontal rTMS effectsea PET study. Neuroimage 2008;42(1):379e84. Wing VC, Bacher I, Wu B, Daskalakis ZJ, George TP. High frequency repetitive transcranial magnetic stimulation reduces tobacco craving in schizophrenia. Schizophrenia Research 2012;139:264e6. Rose JE, McClernon FJ, Froeliger B, Behm FM, Preud’homme X, Krystal AD. Repetitive transcranial magnetic stimulation of the superior frontal gyrus modulates craving for cigarettes. Biological Psychiatry 2011;70(8):794e9. Hayashi T, Ji HK, Strafella A, Pike B, Dagher A. A role of dorsolateral prefrontal cortex in drug-cue induced neural response. Journal of Cerebral Blood Flow 2007;27(1). BP17-04W. Fregni F, Freedman S, Pascual-Leone A. Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques. Lancet Neurology 2007;6(2):188e91. Gilula MF. Cranial electrotherapy stimulation and fibromyalgia. Expert Review of Medical Devices 2007;4(4):489e95. Kirsch DL, Smith RB. The use of cranial electrotherapy stimulation in the management of chronic pain: a review. NeuroRehabilitation 2000;14(2):85e94. Alling FA, Johnson BD, Elmoghazy E. Cranial electrostimulation (CES) use in the detoxification of opiate-dependent patients. Journal of Substance Abuse Treatment 1990;7(3):173e80. Gunther M, Phillips KD. Cranial electrotherapy stimulation for the treatment of depression. Journal of Psychosocial Nursing and Ment Health Services 2010;48(11):37e42. Patterson MA, Firth J, Gardiner R. Treatment of drug, alcohol and nicotine addiction by neuroelectric therapy: analysis of results over 7 years. Journal of Bioelectricity 1984;3(1&2):193e221. Jasinski DR, Sullivan JT, Testa M, Preston KL. Withdrawal symptoms by transcranial electrostimulation therapy (TCET). In: Harris L, editor. Problems of drug dependence 1991: Proceedings of the 53rd annual scientific meeting. Rockville, MD: The committee on problems of Drug Dependence Inc. Research Monograph 119; 1992. p. 329. Pickworth WB, Fant RV, Butschky MF, Goffman AL, Henningfield JE. Evaluation of cranial electrostimulation therapy on short-term smoking cessation. Biological Psychiatry 1997;42(2):116e21. Georgiou AJ, Spencer CP, Davies GK, Stamp J. Electrical stimulation therapy in the treatment of cigarette smoking. Journal of Substance Abuse 1998;10(3): 265e74. Scheuer E, editor. Effectiveness of neuroelectric therapy in inducing smoking cessation. Society for research on nicotine and tobacco, Europe. Tubingen, Germany: Taylor & Francis; 2004. White AR, Rampes H, Liu JP, Stead LF, Campbell J. Acupuncture and related interventions for smoking cessation. Cochrane Database of Systematic Reviews 2011;(1). CD000009. Gariti P, Auriacombe M, Incmikoski R, McLellan AT, Patterson L, Dhopesh V, et al. A randomized double-blind study of neuroelectric therapy in opiate and cocaine detoxification. Journal of Substance Abuse 1992;4(3): 299e308. Gossop M, Bradley B, Strang J, Connell P. The clinical effectiveness of electrostimulation vs oral methadone in managing opiate withdrawal. British Journal of Psychiatry 1984;144:203e8.

V.C. Wing et al. / Brain Stimulation 6 (2013) 221e230 [68] Bindman LJ, Lippold OC, Redfearn JW. Relation between the size and form of potentials evoked by sensory stimulation and the background electrical activity in the cerebral cortex of the rat. Journal of Physiology 1964;171: 1e25. [69] Bindman LJ, Lippold OC, Redfearn JW. The action of brief polarizing currents on the cerebral cortex of the rat (1) during current flow and (2) in the production of long-lasting after-effects. Journal of Physiology 1964;172: 369e82. [70] Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimul 2008;1(3):206e23. [71] Nitsche MA, Nitsche MS, Klein CC, Tergau F, Rothwell JC, Paulus W. Level of action of cathodal DC polarisation induced inhibition of the human motor cortex. Clinical Neurophysiology 2003;114(4):600e4. [72] Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. Journal of Physiology 2000;527(Pt 3):633e9. [73] Been G, Ngo TT, Miller SM, Fitzgerald PB. The use of tDCS and CVS as methods of non-invasive brain stimulation. Brain Research Reviews 2007;56(2): 346e61. [74] Fregni F, Boggio PS, Nitsche MA, Rigonatti SP, Pascual-Leone A. Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression. Depress Anxiety 2006;23(8):482e4. [75] Nitsche MA, Liebetanz D, Antal A, Lang N, Tergau F, Paulus W. Modulation of cortical excitability by weak direct current stimulationetechnical, safety and functional aspects. Supplements to Clinical Neurophysiology 2003;56: 255e76. [76] Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N, et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. Journal of Physiology 2003; 553(Pt 1):293e301. [77] Nitsche MA, Lampe C, Antal A, Liebetanz D, Lang N, Tergau F, et al. Dopaminergic modulation of long-lasting direct current-induced cortical excitability changes in the human motor cortex. European Journal of Neuroscience 2006;23(6):1651e7. [78] Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP, Pascual-Leone A. Treatment of major depression with transcranial direct current stimulation. Bipolar Disorders 2006;8(2):203e4. [79] Fregni F, Boggio PS, Santos MC, Lima M, Vieira AL, Rigonatti SP, et al. Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson’s disease. Movement Disorders 2006;21(10):1693e702. [80] Boggio PS, Sultani N, Fecteau S, Merabet L, Mecca T, Pascual-Leone A, et al. Prefrontal cortex modulation using transcranial DC stimulation reduces alcohol craving: a double-blind, sham-controlled study. Drug and Alcohol Dependence 2008;92(1e3):55e60. [81] Fregni F, Liguori P, Fecteau S, Nitsche MA, Pascual-Leone A, Boggio PS. Cortical stimulation of the prefrontal cortex with transcranial direct current stimulation reduces cue-provoked smoking craving: a randomized, shamcontrolled study. Journal of Clinical Psychiatry 2008;69(1):32e40. [82] Fregni F, Orsati F, Pedrosa W, Fecteau S, Tome FA, Nitsche MA, et al. Transcranial direct current stimulation of the prefrontal cortex modulates the desire for specific foods. Appetite 2008;51(1):34e41. [83] Goldman RL, Borckardt JJ, Frohman HA, O’Neil PM, Madan A, Campbell LK, et al. Prefrontal cortex transcranial direct current stimulation (tDCS) temporarily reduces food cravings and increases the self-reported ability to resist food in adults with frequent food craving. Appetite 2011;56(3):741e6. [84] Beeli G, Casutt G, Baumgartner T, Jancke L. Modulating presence and impulsiveness by external stimulation of the brain. Behavioral and Brain Function 2008;4:33. [85] Boggio PS, Zaghi S, Villani AB, Fecteau S, Pascual-Leone A, Fregni F. Modulation of risk-taking in marijuana users by transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). Drug and Alcohol Dependence 2010;112(3):220e5. [86] Fecteau S, Knoch D, Fregni F, Sultani N, Boggio P, Pascual-Leone A. Diminishing risk-taking behavior by modulating activity in the prefrontal cortex: a direct current stimulation study. Journal of Neuroscience 2007;27(46): 12500e5. [87] Fecteau S, Pascual-Leone A, Zald DH, Liguori P, Theoret H, Boggio PS, et al. Activation of prefrontal cortex by transcranial direct current stimulation reduces appetite for risk during ambiguous decision making. Journal of Neuroscience 2007;27(23):6212e8. [88] Boggio PS, Liguori P, Sultani N, Rezende L, Fecteau S, Fregni F. Cumulative priming effects of cortical stimulation on smoking cue-induced craving. Neuroscience Letters 2009;463(1):82e6. [89] Ostergaard K, Sunde N, Dupont E. Effects of bilateral stimulation of the subthalamic nucleus in patients with severe Parkinson’s disease and motor fluctuations. Movement Disorders 2002;17(4):693e700. [90] Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pollak P, Rehncrona S, et al. Bilateral deep brain stimulation in Parkinson’s disease: a multicentre study with 4 years follow-up. Brain 2005;128(Pt 10):2240e9. [91] Schupbach WM, Chastan N, Welter ML, Houeto JL, Mesnage V, Bonnet AM, et al. Stimulation of the subthalamic nucleus in Parkinson’s disease: a 5 year follow up. Journal of Neurology, Neurosurgery and Psychiatry 2005;76(12): 1640e4.

229

[92] Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45(5):651e60. [93] Kennedy SH, Giacobbe P, Rizvi SJ, Placenza FM, Nishikawa Y, Mayberg HS, et al. Deep brain stimulation for treatment-resistant depression: followup after 3 to 6 years. American Journal of Psychiatry 2011;168(5):502e10. [94] Mallet L, Polosan M, Jaafari N, Baup N, Welter ML, Fontaine D, et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. The New England Journal of Medicine 2008;359(20):2121e34. [95] Greenberg BD, Gabriels LA, Malone Jr DA, Rezai AR, Friehs GM, Okun MS, et al. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Molecular Psychiatry 2010;15(1):64e79. [96] Kilpatrick DG. The ethics of disaster research: a special section. Journal of Traumatic Stress 2004;17(5):361e2. [97] Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Annals of Neurology 2010;68(4):521e34. [98] Schlaepfer TE, Lieb K. Deep brain stimulation for treatment of refractory depression. Lancet 2005;366(9495):1420e2. [99] Witjas T, Baunez C, Henry JM, Delfini M, Regis J, Cherif AA, et al. Addiction in Parkinson’s disease: impact of subthalamic nucleus deep brain stimulation. Movement Disorders 2005;20(8):1052e5. [100] Gao G, Wang X, He S, Li W, Wang Q, Liang Q, et al. Clinical study for alleviating opiate drug psychological dependence by a method of ablating the nucleus accumbens with stereotactic surgery. Stereotact Funct Neurosurg 2003;81(1e4):96e104. [101] Stelten BM, Noblesse LH, Ackermans L, Temel Y, Visser-Vandewalle V. The neurosurgical treatment of addiction. Neurosurg Focus 2008;25(1):E5. [102] Dieckmann G, Schneider H. Influence of stereotactic hypothalamotomy on alcohol and drug addiction. Applied Neurophysiology 1978;41(1e4):93e8. [103] Lawrence AD, Evans AH, Lees AJ. Compulsive use of dopamine replacement therapy in Parkinson’s disease: reward systems gone awry? Lancet Neurology 2003;2(10):595e604. [104] Kuhn J, Lenartz D, Huff W, Lee S, Koulousakis A, Klosterkoetter J, et al. Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications? Journal of Neurology, Neurosurgery & Psychiatry 2007;78(10):1152e3. [105] Kuhn J, Grundler TO, Bauer R, Huff W, Fischer AG, Lenartz D, et al. Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring. Addiction Biology 2011;16(4):620e3. [106] Muller UJ, Sturm V, Voges J, Heinze HJ, Galazky I, Heldmann M, et al. Successful treatment of chronic resistant alcoholism by deep brain stimulation of nucleus accumbens: first experience with three cases. Pharmacopsychiatry 2009;42(6):288e91. [107] Henderson MB, Green AI, Bradford PS, Chau DT, Roberts DW, Leiter JC. Deep brain stimulation of the nucleus accumbens reduces alcohol intake in alcohol-preferring rats. Neurosurgical Focus 2010;29(2):E12. [108] Knapp CM, Tozier L, Pak A, Ciraulo DA, Kornetsky C. Deep brain stimulation of the nucleus accumbens reduces ethanol consumption in rats. Pharmacology Biochemistry and Behavior 2009;92(3):474e9. [109] Vassoler FM, Schmidt HD, Gerard ME, Famous KR, Ciraulo DA, Kornetsky C, et al. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats. Journal of Neuroscience 2008;28(35):8735e9. [110] Liu HY, Jin J, Tang JS, Sun WX, Jia H, Yang XP, et al. Chronic deep brain stimulation in the rat nucleus accumbens and its effect on morphine reinforcement. Addiction Biology 2008;13(1):40e6. [111] Wise RA. The role of reward pathways in the development of drug dependence. Pharmacology & Therapeutics 1987;35(1e2):227e63. [112] Kuhn J, Bauer R, Pohl S, Lenartz D, Huff W, Kim EH, et al. Observations on unaided smoking cessation after deep brain stimulation of the nucleus accumbens. European Addiction Research 2009;15(4):196e201. [113] Mantione M, van de Brink W, Schuurman PR, Denys D. Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report. Neurosurgery 2010;66(1):E218 [discussion E]. [114] Chen R, Gerloff C, Classen J, Wassermann EM, Hallett M, Cohen LG. Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters. Electroencephalography and Clinical Neurophysiology 1997;105(6):415e21. [115] Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W. Safety criteria for transcranial direct current stimulation (tDCS) in humans. Clinical Neurophysiology 2003;114(11):2220e2. author reply 2e3. [116] Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiology 2009;120(12): 2008e39. [117] De Biasi M, Dani JA. Reward, addiction, withdrawal to nicotine. Annual Review of Neuroscience 2011;34:105e30. [118] McBride D, Barrett SP, Kelly JT, Aw A, Dagher A. Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokers: an fMRI study. Neuropsychopharmacology 2006;31(12):2728e38.

230

V.C. Wing et al. / Brain Stimulation 6 (2013) 221e230

[119] Wilson SJ, Sayette MA, Fiez JA. Prefrontal responses to drug cues: a neurocognitive analysis. Nature Neuroscience 2004;7(3):211e4. [120] Uher R, Yoganathan D, Mogg A, Eranti SV, Treasure J, Campbell IC, et al. Effect of left prefrontal repetitive transcranial magnetic stimulation on food craving. Biological Psychiatry 2005;58(10):840e2. [121] Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 1994;117(Pt 4):847e58. [122] Berardelli A, Inghilleri M, Rothwell JC, Romeo S, Curra A, Gilio F, et al. Facilitation of muscle evoked responses after repetitive cortical stimulation in man. Experimental Brain Research 1998;122(1):79e84. [123] Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron 2005;45(2):201e6. [124] Cooke SF, Bliss TV. Plasticity in the human central nervous system. Brain 2006;129(Pt 7):1659e73. [125] Rorie AE, Newsome WT. A general mechanism for decision-making in the human brain? Trends in Cognitive Sciences 2005;9(2):41e3. [126] Knoch D, Gianotti LRR, Pascual-Leone A, Treyer V, Regard M, Hohmann M, et al. Disruption of right prefrontal cortex by low-frequency repetitive transcranial magnetic stimulation induces risk-taking behavior. Journal of Neuroscience 2006;26(24):6469e72. [127] Rouaud T, Lardeux S, Panayotis N, Paleressompoulle D, Cador M, Baunez C. Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation. Proceedings of the National Academy of Sciences of the United States of America 2010;107(3):1196e200. [128] Bandini F, Primavera A, Pizzorno M, Cocito L. Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson’s disease. Parkinsonism & Related Disorder 2007;13(6):369e71.

[129] Zangen A, Roth Y, Voller B, Hallett M. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil. Clinical Neurophysiology 2005;116(4):775e9. [130] Naqvi NH, Bechara A. The insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making. Brain Structure and Function 2010; 214(5e6):435e50. [131] Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science 2007;315(5811):531e4. [132] Forget B, Pushparaj A, Le Foll B. Granular insular cortex inactivation as a novel therapeutic strategy for nicotine addiction. Biological Psychiatry 2010;68(3):265e71. [133] Fitzgerald PB, Brown TL, Daskalakis ZJ. The application of transcranial magnetic stimulation in psychiatry and neurosciences research. Acta Psychiatrica Scandinavica 2002;105(5):324e40. [134] Speer AM, Willis MW, Herscovitch P, Daube-Witherspoon M, Shelton JR, Benson BE, et al. Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: II. Effects of prefrontal cortex rTMS. Biological Psychiatry 2003;54(8): 826e32. [135] Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, et al. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain 2006; 122(1e2):197e209. [136] Wing VC, Wass CE, Soh DW, George TP. A review of neurobiological vulnerability factors and treatment implications for comorbid tobacco dependence in schizophrenia. Annals of the New York Academy of Sciences 2012;248(1):89e106.