Neuropsychopharmacology (2016) 41, 2798–2809

© 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16

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Review
Brain Stimulation in Addiction



 Michael C Salling*,1 and Diana Martinez2,3


 1
Department of Anesthesiology, Columbia University, New York, NY, USA; 2Department of Psychiatry, Columbia University, New York, NY, USA;

 3
New York State Psychiatric Institute, New York, NY, USA







 Localized stimulation of the human brain to treat neuropsychiatric disorders has been in place for over 20 years. Although these methods

 have been used to a greater extent for mood and movement disorders, recent work has explored brain stimulation methods as potential

 treatments for addiction. The rationale behind stimulation therapy in addiction involves reestablishing normal brain function in target

 regions in an effort to dampen addictive behaviors. In this review, we present the rationale and studies investigating brain stimulation in


 addiction, including transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Overall, these

 studies indicate that brain stimulation has an acute effect on craving for drugs and alcohol, but few studies have investigated the effect of

 brain stimulation on actual drug and alcohol use or relapse. Stimulation therapies may achieve their effect through direct or indirect

 modulation of brain regions involved in addiction, either acutely or through plastic changes in neuronal transmission. Although these

 mechanisms are not well understood, further identification of the underlying neurobiology of addiction and rigorous evaluation of brain

 stimulation methods has the potential for unlocking an effective, long-term treatment of addiction.

 Neuropsychopharmacology (2016) 41, 2798–2809; doi:10.1038/npp.2016.80; published online 17 August 2016

INTRODUCTION of its safety and efficacy (see (Gorelick et al, 2014b; Hadar
and Zangen, 2015)).
There are four main procedures developed to stimulate
specific brain regions. These include: (i) transcranial
electrical stimulation; (ii) transcranial magnetic stimulation
(TMS); (iii) transcranial direct current stimulation (tDCS); TRANSCRANIAL MAGNETIC STIMULATION (TMS)
and (iv) deep brain stimulation (DBS). Transcranial electrical
stimulation delivers an electrical current to the brain across TMS uses electromagnetic induction to generate an electrical
electrodes, and it provided much of the early data on the current in the brain. The device consists of a conducting coil
neurophysiological effects of stimulating cortical regions and to produce the current, which induces a brief magnetic field
the propagation of the stimulus in the central nervous system orthogonal to the plane of the coil, which in turn generates
(Rossini et al, 2015). However, because transcranial electrical an electrical current in the brain. Early TMS coils were
stimulation requires a current of several hundred volts, circular, and the stimulation delivered was greatest around
transcranial electrical stimulation was largely replaced by the circle edge but low in the center. The figure 8 coil was
TMS, which uses magnetic pulse to induce an electrical designed to produce a field with the highest intensity at the
current in the brain. TDCS delivers a very low intensity juncture of the two circles (Rossini et al, 2015).
electrical current (1–2 mA), which is likely too low to initiate An issue with TMS is the limited depth of brain tissue that
action potentials in neurons, but may modulate firing rates can be reached (Figure 1b). The rapid attenuation of the
by changing the membrane potential of neurons. DBS is electrical field results in TMS being largely restricted to
currently the only method available to directly stimulate superficial cortical targets (Deng et al, 2014). As a result,
deeper brain regions, but a disadvantage of DBS is the need most TMS studies of psychiatric disorders, including
for surgery and the maintenance of implanted hardware. The addiction, have stimulated the dorsolateral prefrontal cortex
purpose of this review is to condense experimental findings (DLPFC). However, given the need to investigate the stimu-
from the large and growing literature of brain stimulation lation of deeper brain regions as therapeutic targets
and addiction, draw conclusions, and offer our perspective (Figure 1a), there is a demand to develop coils that can
on how to improve its evaluation. We refer the reader to reach these targets. Among these is the H coil, designed to
other recently published reviews for additional perspectives stimulate deeper brain structures using spatial summation to
reduce attenuation (Roth et al, 2002), although this comes at
*Correspondence: Dr MC Salling, Department of Anesthesiology, the cost of reduced focality (Zangen et al, 2005; Huang et al,
Columbia University, 630 West 168th Street, New York, NY 10032, 2009), so that larger brain regions are stimulated. There are
USA, Tel: +1 212 305 0944, E-mail: ms4431@columbia.edu a number of different types of H coils that target different
Received 18 November 2015; revised 13 May 2016; accepted 20 May brain regions, and these have been tested clinically in
2016; accepted article preview online 31 May 2016 psychiatric and neurologic disorders (Deng et al, 2014).
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Dorsolateral Prefrontal Cortex
Superior Prefrontal Cortex
Inferior Prefrontal Cortex
Orbitofrontal Cortex
Anterior Cingulate Cortex
Ventral Striatum
Amygdala
Ventral Tegmental Area
Skin + Skull + Dura

0 10 20 30 40 50 60 70
Depth from skin surface (mm)

Transcranial Magnetic Transcranial Direct Current Deep Brain

Stimulation (TMS) Stimulation (tDCS) Stimulation (DBS) Action Potential
Subthreshold
Depolarization

tDCS
Figure 8-coil TMS
H-coil TMS
DBS

0 10 20 30 40 50 60 70
Depth from skin surface (mm)

Figure 1 Overlap of brain regions to target in addiction with brain stimulation methods. (a) Human brain regions implicated in addiction. Top. Illustration of
the major areas of the brain implicated in addiction based on imaging studies. Perspectives are from (left to right) cortical surface, sagittal, coronal, and
horizontal perspectives (inset shows approximate view) Bottom. Approximate distances of implicated brain regions from skin surface above frontal and parietal
bones. (b) Methods of brain stimulation. Top. Illustrations depicting methods of brain stimulation used in human from left: repetitive transcranial magnetic
stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS) with theoretical range of depolarization and action
potential level of stimulation from current delivered. Bottom: Theoretical range of direct stimulation shown in distance from skin surface above frontal and
parietal bones. Both tDCS and rTMS can stimulate cortical regions, while can DBS reach deeper subcortical structures.

TMS applied to the motor cortex provides a method for increases cortical excitability, whereas LF stimulation reduces
investigating the neurophysiology of cortico-spinal connec- the measured MEP, although there are exceptions to this
tions, because changes in activation can be determined by observation (Gorelick et al, 2014a). An additional variation
measuring alterations in the motor evoked potential (MEP). in stimulation frequency, based on observations made using
In clinical studies, the intensity of the TMS stimulus is in vitro electrophysiology is called theta burst stimulation
determined by the minimum stimulation required to elicit a (TBS) where 3 pulses at 50 Hz is repeated at 5 Hz. When
reliable MEP in the targeted muscle group. This is assessed applied to the cortex, low amplitude continuous TBS (cTBS)
using the motor threshold (MT), identified as the intensity produces an inhibitory-like effect, similar to LF continuous
delivered to the MT that elicits the contraction of a muscle stimulation, whereas intermittent TBS (2 s TBS every 10 s)
(such as the hand or calf muscle). The MT is used to deter- produces a facilitatory effect similar to HF stimulation
mine the intensity of the TMS pulse that will be delivered to (Huang et al, 2005; Hanlon et al, 2015b).
the target brain region, such as the DLPFC. Repetitive TMS has been shown to cause lasting effects on
Generally, repetitive TMS (rTMS), in which a series of physiology and behavior. These actions are believed to follow
consecutive stimuli are delivered within a session, is used in or approximate traditional phenomena of Hebbian forms
clinical research. The frequency of the delivered stimuli can of synaptic plasticity including long-term potentiation and
be low frequency (LF, 1 Hz or below) or high frequency (HF, long-term depression (Hoogendam et al, 2010). For instance,
between 5 and 20 Hz), where LF stimulation is inhibitory and LF rTMS (~1 Hz) of the human motor cortex can decrease
HF stimulation increases cortical excitability (Gorelick et al, the MEP for over an hour following cessation (Chen
2014a). This theory is largely based on studies of cortico- et al, 1997; Iyer et al, 2003). HF stimulation with rTMS
spinal motor output, where HF TMS to the motor cortex (10 Hz) can increase the MEP for up to 2 h post cessation

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Table 1 Transcranial Magnetic Stimulation (TMS)
Drug Treatments n Target Stimulation Outcome measures Effect Citation

Nicotine 1 11 L DLPFC 10,20 Hz, 90,100% MT Craving ↓ Johann et al, 2003

1 16 L DLPFC 10 Hz, 100% MT Cue-induced craving ↓ Li et al, 2013a, b
2 14 L DLPFC 20 Hz, 90% MT Craving No effect Eichhammer et al, 2003
Ad libitum smoking ↓
1 14 L DLPFC 10 Hz, 90% MT Cue-induced craving ↓ Pripfl et al, 2014
EEG delta ↓
1 10 L DLPFC 1 Hz, 110% MT Cue-induced craving ↓ Hayashi et al, 2013
fMRI: ACC, OFC, VS ↓
1 15 SFG 1 Hz, 90% MT Cue-induced craving No effect Rose et al, 2011
SFG 10 Hz, 90% MT Cue-induced craving ↓
MOC 1, 10 Hz, 90% MT Cue-induced craving No effect
10 48 L DLPFC 10 Hz, 100% MT Cue-induced craving ↓ Amiaz et al, 2009
Cigarette consumption ↓
20, w therapy 15 L,R DLPFC 20 Hz, 90% MT Craving ↓ Wing et al, 2012
Smoking No effect
15 35 L DLPFC 10 Hz, 110% MT Smoking ↓ Prikryl et al, 2014
13, h-coil, w/cues 115 PFC, insula 1 Hz, 120% MT Cigarette consumption No effect Dinur-Klein et al, 2014
PFC, insula 10 Hz, 120% MT Cigarette consumption ↓

Alcohol 10 45 R DLPFC 10, Hz, 110% MT Craving ↓ Mishra et al, 2010

10 20 R and L DLPFC 10, Hz, 110% MT Craving ↓ Mishra et al, 2015
1 31 R DLPFC 20 Hz, 110% MT Craving (lab) No effect Herremans et al, 2012
Craving (home) No effect
1 29 R DLPFC 20 Hz, 110% MT Craving No effect Herremans et al, 2013
Response inhibition ↑
1 19 L DLPFC 20 Hz, 90% MT Craving No effect Hoppner et al, 2011
Depressive symptoms No effect
Alcohol cue attention ↓
20, h-coil 11 MPFC 20 Hz, 120% MT Craving ↓ Rapinesi et al, 2015
LPFC
10 18 MPFC 20 Hz, 120% MT Craving ↓ Ceccanti et al, 2015
Depressive symptoms ↓

Cocaine 1 6 R DLPFC 10 Hz, 90% MT Craving ↓ Camprodon et al, 2007

6 L DLPFC 10 Hz, 90% MT Craving No effect
10 36 L DLPFC 15 Hz, 100% MT Craving ↓ Politi et al, 2008
1 11 MPFC cTBS, 110% MT Craving ↓ Hanlon et al, 2015a, b

Methamph. 1 10 L DLPFC 1 Hz, 100% MT Craving ↑ Li et al, 2013a, b

Abbreviations: L, left; R, right; cTBS, theta burst simulation; DLPFC, dorsolateral prefrontal cortex; MOC, motor cortex; MT, motor threshold; MPFC, medial prefrontal
cortex; PFC, prefrontal cortex; SFG, superior frontal gyrus; VS, ventral striatum.

(Jung et al, 2008). Interestingly, the persistent effects of HF to investigate acute effects such as craving. Fewer studies
stimulation can be blocked by NMDA receptor antagonists used more sessions (10 or more), which are needed to assess
indicating that a glutamatergic mechanism similar to long- rTMS as a potential intervention for drug or alcohol
term potentiation is involved (Huang et al, 2008). Imaging consumption.
studies have supported these findings and demonstrate that
cortical stimulation can achieve lasting effects in brain
regions that receive efferent connections from the targeted Nicotine. Among the substance use disorders, nicotine
region including the anterior insula (Hanlon et al, 2015b) (tobacco) dependence has been the most studied with both
and the striatum (Cho et al, 2015; Hanlon et al, 2015b) when acute (1–2 sessions) and repeated (410 sessions) of rTMS.
the PFC is stimulated.
Acute effects of rTMS on craving. Six studies have
investigated the effect of 1–2 sessions of rTMS, and craving
rTMS Studies in Addiction
was the primary behavioral measure. Five of these targeted
There have been a series of studies investigating the effect of the left DLPFC, and one study stimulated the superior frontal
rTMS in addiction, and these are summarized in Table 1. gyrus (see Table 1). Of the studies targeting the left DLPFC,
Most studies used a limited number of sessions (usually 1–2), most (4/5) used HF rTMS at 90–110% of MT.

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The first study, by Johann et al (2003), compared HF Only one study has been published using an H coil to
rTMS with sham and showed a reduction in craving for stimulate the insula, ventrolateral prefrontal cortex and the
cigarettes. Similar results were reported by Li et al (2013a), DLPFC bilaterally (Dinur-Klein et al, 2014). This study was a
who compared a single session of HF rTMS with the left large randomized sham-controlled study (n = 115) that
DLPFC (vs sham) on cue-induced craving (smoking vs compared sham, high and LF stimulation administered for
neutral pictures) and showed that active rTMS reduced 10 days over 2 weeks followed by three non-consecutive
craving for cigarettes under both cue conditions. A third treatments for an additional week. The rTMS was delivered
study looked at both craving and cigarette smoking and in the context of smoking cues, and smoking was measured
showed that HF rTMS to the left DLPFC had no effect by urine cotinine levels and subjects’ self-report. The results
on craving, but did decrease smoking during an ad libitum showed that HF rTMS combined with exposure to smoking
smoking period following the delivery of rTMS cues led to a reduction in smoking of 44% at 3 months
(Eichhammer et al, 2003). (Dinur-Klein et al, 2014).
Two of the studies targeting the DLPFC investigated brain Overall, the studies of nicotine use disorders show that
function in addition to craving. Pripfl et al (2014) showed acute rTMS directed at the DLPFC reduces craving for
that HF rTMS reduced cigarette craving in nicotine-deprived nicotine. However, some of this work shows that there is a
smokers and reduced EEG delta power, a measure of mismatch between craving and actual smoking, indicating
wakefulness that has been implicated in nicotine dependence that studies investigating cigarette consumption are crucial.
(Pripfl et al, 2014). The second study delivered LF (1 Hz), in Of the studies investigating this, the largest (115 subjects)
contrast to the other studies, to inhibit the left DLPFC and showed that HF, but not LF, stimulation with the H coil
used fMRI to investigate changes in brain activation directed at the bilateral insula, ventrolateral prefrontal cortex,
(Hayashi et al, 2013). The results showed that one session and the DLPFC reduced smoking (Dinur-Klein et al, 2014).
of LF rTMS reduced craving for cigarettes and reduced the Similar results were shown in the study using the figure 8 coil
response to craving-related signals in the ventral striatum, delivering HF stimulation to the left DPLFC (Amiaz et al,
medial orbitofrontal cortex, and anterior cingulate (Hayashi 2009). Together, these studies indicate that HF rTMS,
et al, 2013). directed at the structures of the prefrontal cortex, may serve
Of the studies delivering short-term rTMS, one targeted as an effective intervention for nicotine use disorders.
the superior frontal gyrus, and compared high and LF
stimulation (Rose et al, 2011). The results showed that
craving, elicited by cigarette smoke, was increased following Alcohol. In alcohol use disorders, the majority of studies
10 Hz stimulation (compared with the 1 Hz), although have investigated craving only, with no randomized
cigarette craving was reduced following the neutral cues in controlled trials investigating alcohol intake. These studies
the 10 Hz condition (Rose et al, 2011). have used both the figure 8 coil to target the DLPFC and H
coil to stimulate broader regions of the prefrontal cortex.
Five studies targeted the DLPFC with HF rTMS, to investi-
Repeated sessions of rTMS. Four studies have investi- gate craving for alcohol. Mishra et al (2010) performed a
gated the effect of multiple sessions of rTMS as an single-blind, sham-controlled study of 10 sessions of HF
intervention for cigarette smoking. The first was a rando- rTMS to the right DLPFC in alcohol-dependent subjects who
mized, sham-controlled study (n = 48) performed with the were abstinent 410 days before starting rTMS. The results
figure 8 coil targeting the left DLPFC using 10 HF rTMS showed a greater reduction in craving for alcohol in the
sessions and a maintenance phase (Amiaz et al, 2009). active group over the sham condition. In a subsequent study,
Craving for cigarettes was elicited with smoking vs neutral this same group compared 10 sessions of HF rTMS with the
cues and cigarette consumption was measured by self-report right and left DLPFC and showed that both right and left
and urine cotinine levels. Both craving and cigarette smoking rTMS reduced craving for alcohol (Mishra et al, 2015).
were reduced in the active rTMS group, but there was However, other studies targeting the DLPFC have not
significant subject drop out and a dissipation of the effect shown that rTMS reduces craving in alcohol dependence.
during the maintenance phase, suggesting that longer Herremans et al (2012) investigated a single session of HF
stimulation may be needed. rTMS to the right DLPFC (vs sham), and did not report a
Studies in smokers with schizophrenia show split results. difference in craving, measured immediately after the session
A significant decrease in cigarette smoking was not seen in a nor in subjects’ regular home environment during the days
10-week, randomized, double-blind, sham-controlled trial of following rTMS (Herremans et al, 2012). In a second study
20 sessions of HF rTMS to the DLPFC (with the figure 8 coil) by this group, using similar methods, active rTMS was
in schizophrenic smokers (Wing et al, 2012). The rTMS was shown to improve cognitive performance on the Go-NoGo
delivered as an adjunctive treatment to transdermal nicotine task, indicating improved response inhibition, though again
and group therapy, and whereas the active rTMS group no change was seen in craving for alcohol (Herremans et al,
reported a decrease in craving compared with the sham 2013). Similarly, in alcohol-dependent women, one session of
group, no difference in smoking was seen between the two HF rTMS (20 Hz at 90% MT), vs sham, did not produce
groups. However, another study in smokers with schizo- changes in craving or depressed mood, although this group
phrenia showed that HF rTMS to the DLPFC (figure 8 coil) reported a decrease in attention to alcohol-related cues,
for 21 sessions reported a reduction in cigarette smoking. measured as attentional eye blink (Hoppner et al, 2011).
Craving was not assessed, and the amount of cigarettes Two studies have investigated the H coil, directed at
consumed was measured only by subjects’ self-report medial and lateral prefrontal cortex. Rapinesi et al (2015)
(Prikryl et al, 2014). performed a 6-month study in subjects with comorbid

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dysthymic disorder/alcohol use disorder using bilateral excitability can serve as surrogates for GABA and glutamate
rTMS to stimulate the medial and lateral prefrontal regions signaling, these studies provide some insight into potential
(including the orbitofrontal cortex), with a left preference alteration in these neurotransmitters (Bunse et al, 2014;
(Roth et al, 2007). The rTMS was used as an adjunctive Hanlon et al, 2015a).
treatment to pharmacotherapy. The results showed an
improvement in depressive symptoms and a reduction in Considerations. Overall, a number of studies indicate that
craving for alcohol. Similar results were reported in a pilot 1–2 sessions of HF rTMS may be effective in reducing
study using the H coil directed at the medial prefrontal craving in addiction compared with sham, and the strongest
cortex vs sham, where HF rTMS was shown to decrease evidence for this is in nicotine use disorders. However, most
craving for alcohol and reported alcohol intake (mean of the short-term rTMS studies in addiction included small
number of drinks per day and drinks on days of maximum numbers of subjects, and there is a degree of variability in the
alcohol intake) (Ceccanti et al, 2015). subjects’ clinical characteristics, brain regions targeted, and
Overall, the data in alcohol dependence are less cohesive methods for assessing and eliciting craving. In addition,
than that reported for nicotine use disorders, but there are some of these studies are inconsistent for drug or alcohol
fewer studies. In addition, most of the studies targeted the craving, indicating that studies investigating the effect of
right DLPFC, whereas the nicotine studies targeted the left rTMS on the consumption of substances are needed.
DLPFC. Nonetheless, the studies targeting the DLPFC and Randomized controlled studies on cigarette smoking
craving are more split than those investigating nicotine. have been performed in nicotine dependence. These
Small studies using the H coil, which stimulates broader studies indicate that HF rTMS reduces smoking, and there
prefrontal regions, show some promise for using rTMS in is evidence that pairing rTMS with smoking cues may
this disorder. Indicating that specific stimulation may not be increase the efficacy of rTMS. In addition, these studies indi-
necessary to achieve a therapeutic outcome. cate that multiple sessions are required, and that main-
tenance dosing may be needed to sustain the effect.
Cocaine and methamphetamine. Three studies have been
performed using TMS with the figure 8 coil in cocaine
dependence. The first study used two sessions of HF rTMS TRANSCRANIAL DIRECT CURRENT STIMULATION
and showed that craving for cocaine was reduced by rTMS (tDCS)
applied to the right, but not the left, DLPFC (Camprodon Transcranial direct current stimulation (tDCS) delivers a low
et al, 2007). In a second larger study, HF rTMS applied to the voltage, relatively weak current across an anode and cathode
left DLPFC did reduce cocaine craving in 10 daily sessions placed on the scalp. The electrical current penetrates the skull
(Politi et al, 2008). A sham-controlled, crossover study to a degree, and there are two mechanisms by which tDCS
investigated the effect of low amplitude TBS directed at the has been proposed to modulate brain activity: (i) by changing
mPFC on craving and brain activation using fMRI (Hanlon the resting membrane potential of the neurons, where the
et al, 2015b). The results showed that TBS to inhibit stimulus neurons proximal to the anode are depolarized and those at
evoked brain activity in the medial PFC reduced craving and the cathode are hyperpolarized; and (ii) by modulating
decreased activity in the striatum and anterior insula synaptic activity in a manner similar to long-term potentia-
(Hanlon et al, 2015b). tion (at the anode) and long-term depression (at the cathode)
Only one study has been performed in methamphetamine (Stagg and Nitsche, 2011). Thus, the modulatory effects are
dependence comparing a single session of LF (1 Hz) vs sham thought to be dependent on the intensity, duration, and
(Li et al, 2013b). rTMS was delivered to the DLPFC in the direction of the current, where excitability is increased with
presence of drug-related and neutral cues, and the results anodal tDCS and that cathodal tDCS contributes to
showed that the LF rTMS increased craving for metham- hyperpolarization and inhibition.
phetamine compared to sham.
tDCS Studies in Addiction
Cannabis. The only study we found investigating TMS in
cannabis abuse used single and paired pulse TMS to TDCS has been tested for the treatment for addictive
investigate differences in cortical excitability, and did not behaviors and the results of these studies are summarized
investigate craving or other measures of drug use (Fitzgerald in Table 2.
et al, 2009). Two groups of cannabis users, heavy and light,
were compared with controls and both groups showed short Nicotine. Studies investigating the effects of tDCS on
interval cortical inhibition, but no difference in other nicotine dependence have focused on craving and nicotine
measures of cortical inhibition or cortical excitability. cues, and the results suggest that tDCS may reduce craving
Other studies have investigated changes in cortical for nicotine, though they are not completely consistent.
inhibition and excitability in addiction, and these have been Fregni et al (2008) performed a randomized, crossover study
recently reviewed (Bunse et al, 2014). Overall, these findings of smokers using three conditions: sham, anodal tDCS to the
indicate that alcohol dependence is associated with altera- left DLPFC, and anodal tDCS to the right DLPFC. Both types
tions in cortical excitation and inhibition, depending on the of active tDCS reduced craving for nicotine, following cues,
duration of abstinence (Bunse et al, 2014). Cocaine abuse is compared with sham. A subsequent study by this same group
associated with a higher resting MTs and higher intracortical showed that repeated tDCS with the anode positioned at the
facilitation compared with controls (Bunse et al, 2014; left DLPFC resulted in a self-reported decrease in craving and
Hanlon et al, 2015a). Given that cortical inhibition and smoking, in the active group vs sham (Boggio et al, 2009). In

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Table 2 Transcranial Direct Current Stimulation (tDCS)
Drug Treatments n Target Stimulation Outcome measures Effect Citation

Nicotine 1, 20 min 24 R DLPFC Anodal. 2 mA Cue induced craving ↓ Fregni et al, 2008
L DLPFC Anodal, 2 mA Cue induced craving ↓
5, 20 min 23 L DLPFC Anodal, 2 mA Craving ↓ Boggio et al, 2009
Smoking, self-report ↓
5, 30 min 12 R DLPFC Anodal, 2 mA Craving, intent to smoke No effect Fecteau et al, 2014
Craving, desire to smoke ↓
Smoking, self-report ↓
Carbon monoxide monitor No effect
1, 20 min 24 L DLPFC Anodal, 2 mA Craving No effect Xu et al, 2013
Negative affect ↓

Alcohol 1, 20 min 13 R DLPFC Anodal, 2 mA Cue induced craving ↓ Boggio et al, 2008
L DLPFC Anodal, 2 mA Cue induced craving ↓
5, 26 min 33 R DLPFC Anodal, 2 mA Cue induced craving No effect Klauss et al, 2014
Anxiety/Depressive sympt No effect
Quality of life percept. ↑
5, repetitive 20 min 13 L DLPFC Anodal, 2 mA Cue induced craving ↓ da Silva et al, 2013
Anxiety/Depressive sympt ↓
Relapse ↑
1, 10 min. 41 L DLPFC Anodal, 1 mA Craving ↓ den Uyl et al, 2015
R IFG Anodal, 1 mA Craving No effect

Cocaine 1, 20 min 36 R DLPFC Anodal, 1.5 mA Risk taking ↓ Gorini et al, 2014
L DLPFC Anodal, 1.5 mA Risk taking ↑
5 13 R DLPFC Anodal, 2 mA Cortical excit. to drug cues ↓ Conti et al, 2014a
repetitive, 20 min R DLPFC Anodal, 2 mA
1, 20 min 13 R DLPFC Anodal, 2 mA Ant Cingulate excit ↓ Conti et al, 2014a
5, 20 min 36 R DLPFC Anodal, 2 mA Craving ↓ Batista et al, 2015

Cannabis 1, 15 min 25 R DLPFC Anodal, 2 mA Risk taking ↑ Boggio et al, 2010

L DLPFC Anodal, 2 mA Craving ↓
Risk taking ↑
Craving No effect

Abbreviations: L: left; R, Right; DLPFC, dorsolateral prefrontal cortex; IFG, inferior frontal gyrus.

a third study by this group, Fecteau et al (2014), investigated cathodal/right anodal over the DLPFC), in alcohol-
two tDCS conditions (active or sham), where the active dependent subjects showed no difference in alcohol craving
condition consisted of the anode at the right DLPFC and or depression/anxiety symptoms compared with sham
cathode at the left DLPFC. This group reported that active (Klauss et al, 2014).
tDCS reduced craving on the ‘desire to smoke’ scale but not In a third study, da Silva et al (2013) investigated active
on other measures. Cigarette smoking was decreased when tDCS (anode over the left DLPFC) vs sham in alcohol-
measured as subjects’ self-report in a smoking diary, but not dependent subjects receiving outpatient clinical treatment.
when using a carbon monoxide monitor (obtained before Measures of craving, depression/anxiety, and cue response
stimulation and at day 5 after stimulation). Only one other were also obtained. The results showed that active tDCS
group has performed a study of anodal stimulation over the was associated with a trend toward greater relapse, although
left DLPFC (Xu et al, 2013). The results showed improvement depressive symptoms, response to cues, and craving
in smoking-related negative affect compared with sham, but improved with tDCS vs sham.
no effect on cigarette craving. Finally, a study of tDCS to the DLPFC was compared
using tDCS directed at the right inferior frontal gyrus and
Alcohol. In alcohol dependence, tDCS shows a less sham in heavy drinkers that measured craving for alcohol
consistent effect on craving. Boggio et al (2008) performed and response bias toward alcohol (den Uyl et al, 2015). The
a sham-controlled study in alcohol-dependent subjects results showed that craving was reduced with tDCS to the
(abstinent 10 days) comparing three types of tDCS: (i) DLPFC, but not the inferior frontal gyrus, and that tDCS did
sham, (ii) anode at the left DLPFC/cathode right DLPFC, not have an effect on bias for alcohol, assessed with an
and (ii) anode at the right DLPFC/cathode left DLPFC. implicit association test.
Craving was elicited with alcohol-related cues, and the results
showed that both types of active tDCS reduced craving Cocaine. The tDCS studies in cocaine abuse have mostly
compared with sham. However, another study investigated focused on cognitive function. Gorini et al (2014) investi-
craving for alcohol using a similar type of tDCS (left gated the effect of tDCS in risky choices in cocaine abusers

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and controls under three conditions: (i) sham; (ii) left described above, many of the studies in addiction include
anodal/right cathodal stimulation of the DLPFC; (iii) a right small numbers of subjects, and use different methods with
anodal/left cathodal stimulation of the DLPFC. The results varying outcome measures. However, it should be noted that
showed that activation of the DLPFC (both conditions) this process is similar to that establishing rTMS as a
reduced risky choices on the balloon analog risk task. treatment for depression (George et al, 2009). The early
However, another measure of risk-taking, the game of dice studies in depression consisted of investigator-initiated
task, showed that right DLPFC anodal stimulation increased studies with small numbers of subjects and variations in
safe behavior, while risk-taking behavior increased after left methodology, which eventually led to a consensus on rTMS
DLPFC anodal stimulation in the cocaine abusers (Gorini and depression (George et al, 2009).
et al, 2014).
Conti et al (2014a) investigated the effect on tDCS on
cortical excitability using event-related potentials, under
neutral and drug cue exposure in cocaine abusers, using DEEP BRAIN STIMULATION (DBS)
bilateral (left cathodal/right anodal) tDCS to the DLPFC vs Deep brain stimulation (DBS) is a surgical procedure where
sham. The results showed that single session tDCS increased bipolar electrodes are placed into specific brain regions and
current density in response to cues the P3 segment, though stimulated through implanted pulse generators. Stimulation
the methods for obtaining current density were not explicit. parameters are programmable and depend on targeted brain
Craving was measured in this study, and no significant region, disorder, and patient response. Stimulation induces
change was seen following active tDCS. In a similar study, an electric field up to 1 cm depending on specific neural
Conti and Nakamura-Palacios (2014b) administered left tissue density (Hardesty and Sackeim, 2007). The mechanism
cathodal/right anodal or sham stimulation over the DLPFC of action is somewhat unclear as stimulation has variable
to cocaine abusers and recorded event-related potentials actions on cellular physiology; each neural process may be
during drug-related vs neutral cues. Active TDCS was found depolarized or hyperpolarized depending on distance from
to decrease activity in N2 EEG component in response to a the electrode (McIntyre et al, 2004). In addition, many
cocaine cue, whereas activity increased in the sham group. stimulation variables including brain region, frequency,
Most recently, a double-blind randomized clinical trial in intensity, and state of neuronal synchronization can
cocaine abusers was performed with five sessions of tDCS to influence the direction and duration of its effects on
the left cathodal/right anodal DLPFC vs sham (Batista et al, neuronal activity. Although the specific neuronal effect of
2015). The results showed that craving for cocaine was DBS remain largely debated, it is likely that DBS acts through
significantly reduced in the tDCS group after treatment when multiple concurrent mechanisms (reviewed by (Herrington
compared with sham. et al, 2016)). Macroscopic theories based on clinical data
posit that HF stimulation results in an ablative effect of
Cannabis. One study has looked at tDCS in chronic synchronized neural circuits, but a stimulatory effect in
marijuana smokers comparing: (i) sham; (ii) left anodal/ unsynchronized neural circuits (Murrow, 2014).
right cathodal tDCS of the DLPFC; and (iii) right anodal/left
cathodal tDCS of the DLPFC (Boggio et al, 2010). Craving
for marijuana was assessed in addition to risk taking with a DBS Studies in Addiction
task. The results showed that sham was associated with less
risky choices compared with the active tDCS but that craving DBS is currently in use in humans for some neurologic and
for marijuana was reduced after right anodal/left cathodal psychiatric disorders. DBS has not been used extensively in
DLPFC stimulation compared with sham stimulation. addiction, but there are some preliminary studies. In
humans, previous case studies in which patients received
DBS for other indications, such as anxiety or mood
Considerations. Taken together, the studies investigating disorders, have reported that stimulation to the ventral
the effect of tDCS on substance use disorders are unclear. striatum/nucleus accumbens reduced the consumption of
The studies using craving as an outcome measure are split, substances of abuse, such as alcohol, nicotine, and heroin
with some studies showing an effect while others do not. In (Kravitz et al, 2015). There have been some studies and case
addition, whereas tDCS at the anode is thought to increase reports evaluating DBS in addictive disorders (summarized
excitability, while the cathode is inhibitory, many of these in Table 3).
studies show the same effect with the anode and cathode
switched.
Only three studies measured actual drug or alcohol intake, Alcohol. Small studies have been conducted specifically
and these did not show a beneficial effect. One of these using DBS to treat refractory alcohol dependence. Five severe
investigated alcohol intake, and reported a trend toward alcohol dependent subjects have been reported in the
greater relapse in the active tDCS group. The other two literature, where bilateral DBS was performed to the ventral
studies investigated cigarette smoking, and found a decrease striatum (nucleus accumbens) (Muller et al, 2009; Heldmann
in smoking based on the subjects’ self-report (smoking et al, 2012; Voges et al, 2013). These studies showed that all
diary). However, when objective measures were used (one subjects experienced a reduction in craving and two achieved
study, breath carbon monoxide), no effect was seen from complete abstinent from alcohol. In another case report of
active tDCS over sham. one subject, similar results were reported where the subject
An issue with both tDCS and TMS in treating psychiatric improved error processing on cognitive testing and reduced
disorders is that of reliability and reproducibility. As addictive behaviors (Kuhn et al, 2011).

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Table 3 Deep Brain Stimulation (DBS)
Drug Treatments n Target Stimulation Outcome measures Effect Citation

Nicotine Chronic for other disorders 10 B VS Range: 130–145 Hz; Cessation 3/10 Kuhn et al, 2009
90–180 μs, 3–6.5 V

Alcohol Chronic 5 B VS 130 Hz; 90 μS, 4.5 V Craving ↓ Voges et al, 2013
Abstinence 2/5
Chronic 1 B VS 130 Hz; 120 μS, 5.5 V Alcohol consumption ↓ Kuhn et al, 2011
Cognitive control ↓

Heroin Chronic 2 B VS Range: 130–140 Hz; Drug use ↓ Kuhn et al, 2014
90, 120 μs; 0–5 V Anxiety/Depressive sympt ↓

Abbreviations: L, left; R, right; B, bilateral; VS, ventral striatum.

Heroin. A case report of two heroin-dependent subjects peutic effect. Finally, it is unclear whether focal stimulation
who received bilateral DBS to the ventral striatum reported as provided by DBS is more effective than widespread
that the subjects experienced an improvement in depressive stimulation by rTMS. In practice, these questions may be
symptoms and anxiety, and a reduction, though not answered on an individual basis where noninvasive stimula-
cessation, in their drug use (Kuhn et al, 2014). This group tion therapies like rTMS and tDCS would be initially
also reported that 3 of 10 nicotine-dependent subjects who attempted and that if there is no response, DBS could be a
had received DBS to the ventral striatum for the treatment of last resort step to treat addictive disorders in resistant
other disorders were able to quit smoking despite previous patients.
failed attempts (Kuhn et al, 2009).
Preclinical work has supported the use of DBS in addictive
behaviors. Studies in rodents have shown that brain TARGETING PLASTIC MECHANISMS IN ADDICTION
stimulation of the NAc reduces alcohol self-administration,
morphine seeking, and cocaine-seeking and relapse-like The progression to addiction is thought to be driven by
behavior (Liu et al, 2008; Vassoler et al, 2008; Knapp et al, maladaptive changes in the neural circuitry of reward learn-
2009; Henderson et al, 2010; Vassoler et al, 2013; Wilden ing and response inhibition (Kelley, 2004). Such changes
et al, 2014) (further reviewed in (Luigjes et al, 2012) and have been identified in animal models and occur as a result
summarized in Table 4). These studies have also shown of the repeated pharmacological effects of abused substances
effects on addictive behaviors when the prefrontal cortex, in the context of drug administration (Luscher, 2013). It is
lateral hypothalamus, subthalamic nucleus, and lateral believed that chronic, excessive drug use causes an over-
habenula have been targeted (Levy et al, 2007; Friedman learning of the environmental and internal cues associated
et al, 2010; Rouaud et al, 2010). A major limitation of these with drug use as compared with natural rewards (Di Chiara
studies are that the electrode and brain structures are difficult and Imperato, 1988; Hyman et al, 2006). Additional studies
to scale from human to rodent, which makes it surprising have shown that the cortical circuitry that regulates
that nonhuman primate studies have not been attempted. behavioral flexibility and the inhibition of drug-seeking
behavior can undergo adaptations as well (Kalivas et al, 2005;
Considerations. The data using DBS in addiction are Everitt, 2014). The motivation for drugs following extended
limited, and shows uneven results, with some subjects, but drug exposure is believed to driven by a shift from positive to
not the majority, reducing or stopping their addictive negative reinforcement (Koob and Le Moal, 1997) and as a
behaviors. However, these studies are small, and owing to result, drug-associated cues become increasingly salient and
invasive nature, the implantation of stimulation devices is can drive drug-seeking behaviors despite negative conse-
only performed in the most refractory of patients. Preclinical quences (Schultz, 2011). The potentiation of drug reward
work supports the use of DBS in modulating addictive systems and an attenuation of brain systems underlying
behaviors and provides a chance to better understand its response inhibition are thought to be mediated by long-term
therapeutic mechanisms. changes in synaptic plasticity and intrinsic excitability of
neurons (Kauer and Malenka, 2007; Stuber et al, 2010;
Kourrich et al, 2015).
Comparison of Stimulation Techniques
If addictive disorders are mediated by adaptations that are
Currently, there are no existing clinical or preclinical studies truly plastic, then it should be possible to reverse them if
that directly compare the effectiveness of brain stimulation affected circuits can be correctly identified and targeted.
methods; however, it is clear that each method has practical Evidence from animal models suggests this may be possible.
advantages and disadvantages. For instance, there are many Physiological measurements of synaptic strengthening in-
brain regions implicated in addiction such as the nucleus cluding long-term potentiation and its surrogate, an increase
accumbens and amygdala that are not accessible to direct in glutamate receptor AMPA/NMDA receptor ratio can be
stimulation from tDCS or rTMS (Figure 1). It is also induced in the rodent ventral tegmental area by acute
unknown whether continuous stimulation, not yet feasible exposures to many drugs of abuse including cocaine, alcohol,
with rTMS, would be required to achieve a long-term thera- nicotine, morphine, and benzodiazepines indicating

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Table 4 DBS in Animal Models
Drug Treatment Species n Target Stimulation Behavioral model Effect Citation

Alcohol DBS, during session LE Rat 4 NAc shell 160 Hz; 200 μS; 150 μA 2BC EtOH consumption (30 min.) ↓ Knapp et al, 2009
5 NAc core 2BC EtOH consumption (30 min.) ↓
DBS, 1 h during session P Rat 9 NAc shell 140–150 Hz; 60 μS; 200 μA 2BC EtOH consumption (1 h) No Effect Henderson et al, 2010
24 h doing session 6 NAc shell 2BC EtOH preference (1 h) ↓
2BC EtOH consumption (24 h) ↓
2BC EtOH preference (24 h) ↓
DBS, during session P Rat 4 NAc shell 150 Hz; 100 μS; 200 μA 2BC EtOH consumption (1 h.) ↓ Wilden et al, 2014

Cocaine DBS, during session SD Rat 14 LH 20–100 Hz; 100 μS; Seeking i.v. cocaine ↓ Levy et al, 2007
9 mPFC 200–400 μA PR i.v. cocaine No effect
7 Seeking, PR sucrose No effect
8 Seeking i.v. cocaine ↓
8 PR i.v. cocaine ↓
7 Seeking, PR sucrose No effect
DBS, during session SD Rat 7 NAc shell 160 Hz; 60 μS; 150 μA Priming induced reinstatement ↓ Vassoler et al, 2008
8 DS Priming induced reinstatement No effect
8 Food seeking No effect
DBS, during session LE Rat 9 STN 130 Hz; 60 μS; 50–130 μA SA, PR i.v. cocaine ↓ Rouaud et al, 2010
14 STN SA, PR food ↑
DBS, 15 min during session SD Rat 10 R LHb Low: 10 Hz;; 200 μA SA cocaine ↑ Friedman et al, 2010
12 High: 100 Hz; 200 μA SA cocaine No effect
30 Combined High and Low SA cocaine, Extinction, Reinstatement ↓
DBS, during session SD Rat 5 NAc shell 160 Hz; 60 μS; 150 μA Cocaine Reinstatement ↓ Vassoler et al, 2013
8 NAc core No effect
DBS, during session Mouse 7 NAc shell 130 Hz; 90 μS; 50 μA Locomotor sensitization ↓ Creed et al, 2015
DBS, 1, 7 days prior to session 7 NAc core 2–130 Hz; 90 μS; 50 μA Locomotor sensitization No effect
4–6 mPFC 2–130 Hz; 90 μS; 50 μA Locomotor sensitization No effect
8, 12 NAc shell 12 Hz; 90 μS; 50 μA Locomotor sensitization ↓
w/ D1 antagonist

Morphine DBS, intermittent SD Rat 10 L NAc core Range: 130 Hz; CPP ↓ Liu et al, 2008
210 μs; 200–500 μA

Abbreviations: L, Left, R, right, LE, Long–Evans; P, alcohol preferring; SD, Sprague-Dawley; LH, lateral hypothalamus; LHb, lateral habenula; NAc, nucleus accumbens;
mPFC, medial prefrontal cortex; STN, subthalamic nucleus; 2BC, 2-bottle choice; EtOH, ethanol; i.v., intravenous; i.p., intraperitoneal; PR, progressive ratio;
CPP, conditioned place preference.

common neural substrates (Ungless et al, 2001; Saal et al, demonstrated that the intrinsic excitability of the prefrontal
2003; Tan et al, 2010). Long-term glutamatergic adaptations cortex in compulsive drug-seeking animals is profoundly
can be observed in the NAc following chronic cocaine, reduced, and that this effect could be reversed with
alcohol, and nicotine exposure (Mameli et al, 2009; Gipson optogenetic stimulation of prelimbic neurons. Similarly,
et al, 2013; Wang et al, 2015). Behavioral data from drug- Pascoli et al showed that increased AMPA/NMDA ratio in
exposed mice has further supported a role of glutamate the NAc that underlies cocaine sensitization can be reversed
neurotransmission in the NAc in addictive behaviors. For by low-frequency optogenetic stimulation of corticostriatal
example, cue-induced seeking of nicotine, cocaine, and circuitry through a depotentiation of cortical inputs on
alcohol can be blocked by genetic and pharmacological NAc neurons (Pascoli et al, 2012; Pascoli et al, 2014).
inhibition of glutamate receptors in the NAc (Anderson et al, As optogenetics is not available for human use, recent work
2008; Conrad et al, 2008; Schroeder et al, 2008; Gipson et al, has focused on the use of DBS to mimic the effects
2013). Intriguingly, increased AMPA/NMDA ratio in VTA of optogenetic manipulation, and a recent study showed
and NAc neurons observed during withdrawal from cocaine that LF DBS, in the presence of a dopamine receptor 1 anta-
can be reversed through the induction of metabotropic gonist, reversed the cocaine-induced physiological changes
glutamate receptor-long-term depression which results in a in NAc neurons and blocked locomotor sensitization 1 week
redistribution of AMPAR subunits in the synapse (Mameli after treatment (Creed et al, 2015). These data highlight the
et al, 2007; Creed et al, 2015). The ability to block or reverse translatable potential of findings from emerging technologies
potentiated circuitry that regulates addictive behaviors like optogenetics into stimulation therapies as well as the
demonstrates the therapeutic potential of targeting plastic capability to combine pharmacological treatment with brain
mechanisms in addiction. stimulation to reverse drug-induced plasticity and addictive
In recent years, emerging strategies like optogenetics that behavior (Luscher et al, 2015).
can bi-directionally modulate specifically targeted neural In summary, brain stimulation modalities are being
circuits have advanced our understanding of the circuits explored as treatments for addiction as pharmacological
underlying addictive behaviors (Aston-Jones and Deisseroth, treatments have not been as successful as previously hoped.
2013). These techniques have also demonstrated the potential Whereas brain stimulation techniques have proven to be
to reverse drug-induced neuroadaptations and subsequent effective in treating a variety of neurological and psychiatric
drug-seeking behavior. For instance, Chen et al (2013) disorders, there are few randomized controlled clinical

Neuropsychopharmacology
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MC Salling and D Martinez
2807
trials in addiction. The studies described above indicate Cho SS, Koshimori Y, Aminian K, Obeso I, Rusjan P, Lang AE
that brain stimulation, may have an effect on craving, but et al (2015). Investing in the future: stimulation of the medial
more studies that measure drug or alcohol intake are prefrontal cortex reduces discounting of delayed rewards.
needed. Furthermore, optimization of stimulation strategies Neuropsychopharmacology 40: 546–553.
based on the known biology of the disorder will help Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y
et al (2008). Formation of accumbens GluR2-lacking AMPA
realize the potential of stimulation therapies for addictive
receptors mediates incubation of cocaine craving. Nature 454:
disorders. 118–121.
Conti CL, Moscon JA, Fregni F, Nitsche MA, Nakamura-Palacios
EM (2014a). Cognitive related electrophysiological changes
FUNDING AND DISCLOSURE induced by non-invasive cortical electrical stimulation in
The authors declare no conflict of interest. crack-cocaine addiction. Int J Neuropsychopharmacol 17:
1465–1475.
Conti CL, Nakamura-Palacios EM (2014b). Bilateral transcranial
direct current stimulation over dorsolateral prefrontal cortex
ACKNOWLEDGMENTS changes the drug-cued reactivity in the anterior cingulate cortex
FUNDING SOURCE: MCS is supported by AA023531. DM of crack-cocaine addicts. Brain Stimul 7: 130–132.
is supported by DA026525-05 and DA034433. Creed M, Pascoli VJ, Luscher C (2015). Addiction therapy. Refining
deep brain stimulation to emulate optogenetic treatment of
synaptic pathology. Science (New York, NY 347: 659–664.
da Silva MC, Conti CL, Klauss J, Alves LG, do Nascimento
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